Internal Medicine

APPROACH TO THE PATIENT

2009-04-11T07:34:00.000-07:00

PHYSICAL EXAMINATION
Examination of the patient with suspected pulmonary disease includes inspection, palpation, percussion, and auscultation of the chest. An efficient approach begins with observing the pattern of breathing, auscultation of the chest, and inspection for extrapulmonary signs of pulmonary disease. More detailed examination follows from initial findings.
The pattern of breathing refers to the respiratory rate and rhythm, the depth of breathing or tidal volume, and the relative amount of time spent in inspiration and expiration. Normal values are a rate of 12–14 breaths per minute, tidal volumes of 5 mL/kg, and a ratio of inspiratory to expiratory time of 2:3. Tachypnea is an increased rate of breathing and is commonly associated with a decrease in tidal volume. The rhythm is normally regular, with a sigh (1.5–2 times normal tidal volume) every 90 breaths or so to prevent collapse of alveoli and atelectasis. Alterations in the rhythm of breathing include rapid, shallow breathing, seen in restrictive lung disease and as a precursor to respiratory failure; Kussmaul breathing, rapid large-volume breathing indicating intense stimulation of the respiratory center, seen in metabolic acidosis; and Cheyne-Stokes respirations, a rhythmic waxing and waning of both rate and tidal volumes that includes regular periods of apnea. This pattern is seen in patients with end-stage left ventricular failure or neurologic disease and in many normal subjects at high altitude, especially during sleep.
During normal quiet breathing, the primary muscle of respiration is the diaphragm. Movement of the chest wall is minimal. The use of accessory muscles of respiration, the intercostal and sternocleidomastoid muscles, indicates high work of breathing. At rest, the use of accessory muscles is a sign of significant pulmonary impairment. As the diaphragm contracts, it pushes the abdominal contents down. Hence, the chest and abdominal wall normally expand simultaneously. Expansion of the chest but collapse of the abdomen on inspiration indicates weakness of the diaphragm. The chest normally expands symmetrically. Asymmetric expansion suggests unilateral volume loss, as in atelectasis or pleural effusion, unilateral airway obstruction, asymmetric pulmonary or pleural fibrosis, or splinting from chest pain.
The examiner may palpate as follows: the trachea at the suprasternal notch, to detect shifts in the mediastinum; on the posterior chest wall, to gauge fremitus and the transmission through the lungs of vibrations of spoken words; and on the anterior chest wall to assess the cardiac impulse. All these maneuvers are characterized by low interobserver agreement.
Chest percussion identifies dull areas that correspond to lung consolidation or pleural effusion or hyperresonant areas suggesting emphysema or pneumothorax. Percussion has a low sensitivity (10–20% in several studies) compared with chest radiographs to detect abnormalities. Specificity is high (85–99%). Since an insensitive test is a poor screening examination, percussion and palpation are not necessary in every patient. These techniques do serve as important confirmatory tests in specific patients when the prior probability of a finding is increased. For example, in a patient with a suspected tension pneumothorax, the finding of tracheal shift and hyperresonance can be lifesaving, permitting immediate decompression of the affected side.
Auscultation of the chest depends on a reliable and consistent classification of auditory findings. Normal lung sounds heard over the periphery of the lung are called vesicular. They have a gentle, rustling quality heard throughout inspiration that fades during expiration. Normal sounds heard over the suprasternal notch are called tracheal or bronchial lung sounds. They are louder, higher-pitched, and have a hollow quality that tends to be louder on expiration. Bronchial lung sounds heard over the periphery of the lung are abnormal and imply consolidation. Globally diminished lung sounds are an important finding predictive of significant airflow obstruction.
Abnormal lung sounds (“adventitious” breath sounds) may be continuous (> 80 ms in duration) or discontinuous (< 20 ms). Continuous lung sounds are divided into wheezes, which are high-pitched, musical, and have a distinct whistling quality; and rhonchi, which are lower-pitched, sonorous, and may have a gurgling quality. Wheezes occur in the setting of bronchospasm, mucosal edema, or excessive secretions. In each, the airway is narrowed to the point where adjacent airway walls flutter as airflow is limited. Rhonchi originate in the larger airways when excessive secretions and abnormal airway collapsibility cause repetitive rupture of fluid films. Rhonchi frequently clear after cough.
Discontinuous lung sounds are called crackles— brief, discrete, nonmusical sounds with a popping quality. Fine crackles are soft, high-pitched, and crisp (< 10 ms in duration). They are formed by the explosive opening of small airways previously held closed by surface forces and are heard in interstitial diseases or early pulmonary edema. Coarse crackles are louder, lower-pitched, and slightly longer in duration (< 20 ms) and probably result from gas bubbling through fluid. Coarse crackles are heard in pneumonia, obstructive lung disease, and late pulmonary edema.
Interobserver agreement regarding auscultatory findings is good. The clinical usefulness of these findings is also well established. The presence of wheezes on physical examination is a powerful predictor of obstructive lung disease. The absence of wheezes is not helpful since patients may have significant airflow limitation without wheezing. Such patients will have globally diminished lung sounds as the clinical clue to their obstructive lung disease. Normal lung sounds exclude significant airway obstruction. The timing and character of crackles can reliably distinguish different pulmonary disorders. Fine, late inspiratory crackles suggest pulmonary fibrosis, while early coarse crackles suggest pneumonia or heart failure.
Extrapulmonary signs of intrinsic pulmonary disease include digital clubbing, cyanosis, elevation of central venous pressures, and lower extremity edema.
Digital clubbing refers to structural changes at the base of the nails that include softening of the nail bed and loss of the normal 150-degree angle between the nail and the cuticle. The distal phalanx is convex and enlarged: its thickness is equal to or greater than the thickness of the distal interphalangeal joint. Symmetric clubbing may be a normal variant but more commonly is a sign of underlying disease. Clubbing is seen in patients with chronic infections of the lungs and pleura (lung abscess, empyema, bronchiectasis, cystic fibrosis), malignancies of the lungs and pleura, chronic interstitial lung disease (idiopathic pulmonary fibrosis), and arteriovenous malformations. It does not normally accompany asthma or COPD; when seen in the latter, one should suspect concomitant lung cancer. It is observed less often in small-cell cancer than in other histologic types. Clubbing is not specific to pulmonary disorders; it is also seen in cyanotic congenital heart disease, infective endocarditis, cirrhosis, and inflammatory bowel disease. Hypertrophic pulmonary osteoarthropathy is a syndrome of digital clubbing, chronic proliferative periostitis of the long bones, and synovitis. It is seen in the same conditions as digital clubbing but is particularly common in bronchogenic carcinoma. The cause of clubbing and hypertrophic osteoarthropathy is not known with certainty, but the disorder may reflect platelet clumping and local release of platelet-derived growth factor at the nail bed. Both clubbing and osteoarthropathy may resolve with appropriate treatment of the underlying disease.
Cyanosis is a blue or bluish-gray discoloration of the skin and mucous membranes caused by increased amounts (> 5 g/dL) of unsaturated hemoglobin in capillary blood. Since the oxygen saturation at which cyanosis becomes clinically apparent is a function of hemoglobin concentration, anemia may prevent cyanosis from appearing while polycythemia may lead to cyanosis in the setting of mild hypoxemia. Cyanosis is therefore not a reliable indicator of hypoxemia but should prompt direct measurement of arterial PO2 or oxyhemoglobin saturation.
Estimation of central venous pressure (CVP) and assessment of lower extremity edema are indirect measures of pulmonary hypertension, the major cardiovascular complication of chronic lung disease. Estimation of CVP can be done with precision. Elevated CVP is a pathologic finding associated with impaired ventricular function, pericardial effusion or restriction, valvular heart disease, and chronic obstructive or restrictive lung disease. Peripheral edema is a nonspecific finding that, in the setting of chronic lung disease, suggests right ventricular failure.

HEMOPTYSIS

2009-03-05T02:07:00.001-08:00

Hemoptysis is the expectoration of blood that originates below the vocal cords. It is commonly classified as trivial, mild, or massive, the last defined as more than 200–600 mL in 24 hours. The dividing lines are arbitrary, since the amount of blood is rarely quantified with precision. Massive hemoptysis can be usefully defined as any amount that is hemodynamically significant or threatens ventilation, in which case the initial management goal is not diagnostic but therapeutic.
The lungs are supplied with a dual circulation. The pulmonary arteries arise from the right ventricle to supply the pulmonary parenchyma in a low-pressure circuit. The bronchial arteries arise from the aorta or intercostal arteries and carry blood under systemic pressure to the airways, blood vessels, hila, and visceral pleura. The bronchial arterial circulation represents only 1–2% of total pulmonary blood flow but is frequently the source of hemoptysis: It is a high-pressure circuit; it provides the blood supply to the airways and lesions within those airways; and flow can increase dramatically under conditions of chronic inflammation—eg, chronic bronchiectasis.
The causes of hemoptysis can be classified anatomically. Blood may arise from the airways in chronic bronchitis, bronchiectasis, and bronchogenic carcinoma; from the pulmonary vasculature in left ventricular failure, mitral stenosis, pulmonary emboli, and arteriovenous malformations; or from the pulmonary parenchyma in pneumonia, inhalation of crack cocaine, or autoimmune diseases such as Goodpasture's disease or Wegener's granulomatosis. Iatrogenic hemorrhage may follow transbronchial lung biopsies, anticoagulation, or pulmonary artery rupture due to distal placement of a balloon-tipped catheter.

Clinical Findings
Blood-tinged sputum in the setting of acute bronchitis in an otherwise healthy nonsmoker does not warrant an extensive diagnostic evaluation if the hemoptysis subsides with resolution of the infection. However, hemoptysis is frequently a sign of serious disease, especially in patients with a high prior probability of underlying pulmonary pathology. The goal of the history is to identify patients at risk for one of the disorders listed above. Pertinent features are tobacco use, duration of symptoms, and the presence of respiratory infection. Nonpulmonary sources of hemorrhage—from the nose or the gastrointestinal tract—should be ruled out.
Laboratory evaluation should include a chest radiograph and complete blood count, including platelet count. Renal function tests, urinalysis, and coagulation studies are appropriate in specific circumstances. Flexible bronchoscopy reveals endobronchial cancer in 3–6% of patients with hemoptysis who have a normal (nonlateralizing) chest radiograph. Nearly all of these patients are smokers over the age of 40, and most will have had symptoms for more than a week. Bronchoscopy is indicated in such patients. High-resolution CT of the chest is complementary to bronchoscopy. It can diagnose unsuspected bronchiectasis and arteriovenous malformations and will show central endobronchial lesions in many cases. It is the test of choice for suspected small peripheral malignancies.

Treatment
The management of mild hemoptysis consists of identifying and treating the specific cause. Massive hemoptysis is life-threatening. The airway must be protected, ventilation ensured, and effective circulation maintained. If the location of the bleeding site is known, the patient should be placed in the decubitus position with the involved lung dependent. Uncontrollable hemorrhage warrants rigid bronchoscopy and surgical consultation. In stable patients, flexible bronchoscopy may localize the site of bleeding, and angiography can embolize the involved bronchial arteries. Embolization is effective initially in 85% of cases, though rebleeding may occur in up to 20% of patients over the following year. The anterior spinal artery arises from the bronchial artery in up to 5% of people, and paraplegia may result if it is inadvertently cannulated.

COUGH

2009-03-05T02:05:00.000-08:00

Cough is an important physiologic mechanism that defends against respiratory pathogens and helps to clear the tracheobronchial tree of mucus, foreign particles, and noxious aerosols. Excessive cough is one of the most common symptoms for which patients seek medical care and may represent up to one-third of a pulmonologist's outpatient practice referrals. Persistent severe cough, seen in interstitial lung disease or bronchiectasis, may impair respiration as well as disrupt sleep and social functioning. Bronchospasm (brought on by repetitive forced exhalation), syncope, rib fractures, and urinary incontinence are all potential complications. A reduced or absent cough, seen in some postoperative patients or those with neuromuscular disease, will reduce clearance of secretions and may impair oxygenation.
Cough may be voluntary or involuntary. Involuntary cough is stimulated by vagal afferent receptors in the trachea, especially at the carina, and the larynx but also from others throughout the head and neck. Stimulation of cough receptors may be mechanical, as in cases of aspiration, or irritative.

Clinical Findings
It is important to distinguish acute (< 3 weeks) from chronic cough. Acute cough most commonly follows viral or bacterial upper respiratory tract infection. Within 2 days after onset of the common cold, 85% of untreated patients cough; 26% are still coughing 14 days later; in a few, cough will persist for 6–8 weeks. Many patients with persistent cough following upper respiratory tract infection have underlying asthma. Other causes of acute cough include aspiration, pneumonia, pulmonary embolism, and pulmonary edema.
The most common cause of chronic cough is a low-grade chronic bronchitis secondary to exposure to tobacco smoke, though smokers do not commonly seek medical attention for this problem. Over 90% of nonsmokers presenting for evaluation of chronic cough suffer from postnasal drip, gastroesophageal reflux disease, or asthma (even without other symptoms). Angiotensin-converting enzyme (ACE) inhibitors have become another common cause. In primary care settings, single causes predominate.
The character and timing of chronic cough and the presence or absence of sputum production do not permit an etiologic diagnosis and should not be used as the sole basis for empirical therapy. The history and physical examination should attempt to identify anatomic locations of the afferent limb of the cough reflex in light of the common causes listed above. A nasal discharge, frequent need to clear the throat, and mucoid or mucopurulent secretions in the posterior pharynx suggest postnasal drip. Sinus radiographs may be diagnostic of acute or chronic sinusitis. Wheezing on chest auscultation or airflow obstruction on pulmonary function tests suggest asthma. In cough-variant asthma, methacholine bronchoprovocation testing may be positive in the absence of clinical findings of asthma. Gastroesophageal reflux disease is an important cause of chronic cough but is associated with the fewest clinical clues. Patients may complain of heartburn or regurgitation, but cough may be the only symptom. Barium swallow is specific but insensitive, and esophageal pH monitoring may be necessary. Chest radiographs are best reserved for cough in smokers and patients with hemoptysis or constitutional symptoms such as fever and weight loss.

Treatment
The first step is to eliminate irritant exposures such as tobacco smoke (primary or secondary) and occupational agents and to discontinue medications such as ACE inhibitors or beta-blockers, including eyedrops. Cough due to ACE inhibitors should subside within 1–4 days after discontinuing the medication, though it may take weeks to months. Postnasal drip syndrome due to allergic rhinitis that does not respond to antihistamines should be treated with intranasal steroids. Chronic sinusitis may require prolonged antibiotics directed against Haemophilus influenzae. Cough caused by asthma that does not respond after 2 weeks of bronchodilators and corticosteroids suggests another contributing condition. Cough due to gastroesophageal reflux disease is difficult to treat, since H2 blockers may not be adequate. Most practitioners now initiate antitussive therapy for gastroesophageal reflux disease with proton pump inhibitors. Patients whose cough began after an upper respiratory tract infection usually respond to treatment with an antihistamine-decongestant combination or treatment for asthma.

DYSPNEA

2009-03-05T02:02:00.000-08:00

Dyspnea is a common symptom. It is analogous to pain in that sensory input from multiple sites in the respiratory system is integrated in the cerebral cortex. In general, dyspnea increases with the level of functional impairment as measured by spirometry. However, there is only a weak correlation between airflow limitation or exercise tolerance and the severity of dyspnea.
Several pathophysiologic processes contribute to dyspnea. The most important is the increased respiratory effort that accompanies many different diseases: airflow obstruction (asthma; chronic obstructive pulmonary disease [COPD]), changes in pulmonary compliance (interstitial fibrosis, congestive heart failure) or chest wall compliance (obesity, pleural disease), intrinsic respiratory muscle weakness (inanition, neuromuscular disease, chronic respiratory failure), or the weakness conveyed by the mechanical disadvantage of hyperinflation (asthma or emphysema). Dyspnea is magnified by increased respiratory drive. Acute hypercapnia is therefore a potent stimulus to dyspnea, hypoxemia a weak one. In mechanically ventilated patients, failure to provide adequate inspiratory flow rates to patients with heightened respiratory drive commonly results in dyspnea that may present as agitation. Stimulation of irritant receptors in the airways intensifies dyspnea, while stimulation of pulmonary stretch receptors decreases it.

Clinical Findings
The history should focus on onset and timing of symptoms, the patient's position at onset of symptoms, the relationship of symptoms to activity, and any factors that may improve or exacerbate symptoms. The clinician can assess dyspnea and response to treatment with a ten-point numeric rating scale by asking the patient, “On a scale of zero to ten, with zero being no shortness of breath and ten being the worst shortness of breath you can imagine, how short of breath are you?” Exertional dyspnea should be quantified, but the absolute level of exertion that precipitates dyspnea is less important than acute changes in the threshold level of activity. A complete allergic, occupational, and smoking history is essential.
Acute dyspnea has a short list of causes, most of which are readily identified: asthma, pulmonary infection, pulmonary edema, pneumothorax, pulmonary embolus, metabolic acidosis, or acute respiratory distress syndrome (ARDS). Panic attacks may present as a respiratory complaint. Orthopnea (dyspnea on recumbency) and nocturnal dyspnea suggest asthma, gastroesophageal reflux disease (GERD), left ventricular dysfunction, or obstructive sleep apnea. Rapid onset of severe dyspnea when supine suggests phrenic nerve impairment and diaphragmatic paralysis. Platypnea (dyspnea that worsens in the upright position) is a rare complaint associated with arteriovenous malformations at the lung bases, resulting in increased shunting and hypoxemia in the upright position (orthodeoxia).
Chronic dyspnea is invariably progressive. Symptoms often first appear during exertion; patients learn to limit their activity to accommodate their diminished pulmonary reserve until dyspnea occurs with minimal activity or at rest. Episodic dyspnea suggests congestive heart failure, asthma, acute or chronic bronchitis, or recurrent pulmonary emboli. Constant dyspnea is most commonly due to COPD but may indicate interstitial lung disease (eg, pulmonary fibrosis), pulmonary vascular disease, or fixed airflow obstruction from severe asthma.
Dyspnea is increasingly being recognized as a major issue in the care of dying patients, and clinicians typically undertreat this symptom.
Evaluation should include a complete blood count, renal function tests, chest radiograph, spirometry, and noninvasive oximetry. Patients over 40 years of age or with a family history of early coronary disease should have an electrocardiogram. Arterial blood gases, measurement of lung volumes, ventilation/perfusion scanning, echocardiography, and cardiopulmonary exercise testing are reserved for cases that elude diagnosis on initial evaluation.

Treatment
In patients with advanced lung disease, the responsible condition may be easily identified but treatment only partially effective. Oxygen improves survival in those who are hypoxemic and can improve the exercise tolerance of all patients. Its effect on dyspnea is variable. Anxiety can play an important role in the distress caused by dyspnea and may be relieved by judicious use of benzodiazepines such as lorazepam, 0.5–1 mg orally every 4–6 hours. Pulmonary rehabilitation can improve respiratory function and train patients in energy conservation and breathing techniques that help moderate their sense of respiratory effort. Opioids reduce respiratory drive and blunt dyspnea. They can be titrated safely even in patients with advanced lung disease. Finally, fresh air or a fan may offer additional relief. Smokers with progressive exertional dyspnea should know that they can limit future loss of function through smoking cessation.

Reliability of Compendia Methods for Off-Label Oncology Indications

2009-02-19T21:43:00.000-08:00

Background:
The Centers for Medicare & Medicaid Services limit coverage of cancer drugs for off-label indications to indications listed in specified compendia.

Purpose:
To assess whether compendia provide comprehensive, research-based, and timely information for off-label prescribing in oncology.

Data Sources:
6 drug compendia, English-language literature searches of MEDLINE and the Cochrane Central Register of Controlled Trials from 2006 and 2008, and American Society of Clinical Oncology annual meeting abstracts from 2004 to 2007.

Data Assessment:
The compendia's stated methods, literature related to off-label indications of 14 cancer drugs in 2006, updated literature related to 1 off-label indication between 2006 and 2008, and completeness of compendia content and citations were assessed.

Data Synthesis:
The compendia's stated methods varied greatly from their actual practices. Compendia cited little of the available evidence, often neither the most recent nor that of highest methodological quality. Compendia differed in evidence cited, terminology, detail, presentation, and referencing. For the 14 off-label indications studied, the compendia differed in the indications included and whether and how they recommended particular agents for particular types of cancer. Update schedules varied, and documentation practices made it difficult to determine whether and when content was updated. For 1 indication, compendia citations did not increase between 2006 and 2008 despite accumulation of published evidence.

Limitations:
The 2006 analysis was limited to 14 off-label indications; the 2008 update examined 1 indication. Only off-label indications for cancer drugs were included, and results cannot be generalized to noncancer drugs or indications.

Conclusion:
Oncologists rely on compendia for up-to-date access to evidence and reimbursement information for off-label indications. Current compendia lack transparency and do not seem to follow systematic methods to review or update evidence.

The U.S. Food and Drug Administration (FDA) approves drugs for specific uses, yet physicians routinely prescribe FDA-approved drugs for uses other than those for which they received approval , known as off-label indications. Off-label prescribing is common across medical disciplines; however, it is critical in oncology, in which effective treatment options are often limited, prognoses are grim, and submission of FDA applications for every combination of agent and cancer is impractical. In 1991, a U.S. General Accounting Office study reported that up to 33% of all anticancer drug prescriptions were written for off-label indications. By 2005, the National Comprehensive Cancer Network estimated that 50% to 75% of all uses of cancer therapy were off-label . The Social Security Act, section 1861(t)(2)(B)(ii)(I) and (II), within the Omnibus Budget Reconciliation Act of 1993 , stipulates the Medicare insurability of anticancer drugs and biologics for off-label uses. This statute recognizes certain compendia as authoritative sources for determining a "medically accepted indication" of drugs and biological agents, unless the Secretary of Health and Human Services determines otherwise.

The statute originally designated 3 compendia: American Medical Association Drug Evaluations, American Hospital Formulary Service Drug Information , and United States Pharmacopeia Drug Information for the Health Professional . Although the statute pertained specifically to Centers for Medicare & Medicaid Services (CMS), most other payers and state legislatures have followed suit . The list of approved compendia has shifted over the past 15 years. American Medical Association Drug Evaluations is no longer published; United States Pharmacopeia Drug Information for the Health Professional was discontinued subsumed its contents. United States Pharmacopeia Drug Information for the Health Professional was discontinued in 2007 and its contents were rolled into a successor, DrugPoints. In 2008, (CMS) added Clinical Pharmacology, DRUGDEX, and National Comprehensive Cancer Network Drugs and Biologics Compendium to its list of approved compendia, bringing the total to 5 . In response to concerns about the influence of compendia, CMS proposed various changes, including review of currently approved compendia, additional compendia approval, and an annual review process. To inform policy discussions, they commissioned the Agency for Healthcare Research and Quality to sponsor our project, to explore the extent to which compendia provide comprehensive, evidence-based, and timely information for guiding off-label prescribing of cancer drugs.

Methods
Our study comprised 4 components: comparative description of each compendium's stated methods for including new, off-label indications of FDA-approved drugs; systematic literature review for 14 selected off-label indications in 2006; an updated comparison for 1 indication in 2008; and analysis of each compendium's content and citations against their stated methods and the evidence identified in our systematic reviews.

Comparative Description of Methods Used by Compendia
To better understand how compendia develop their content, we compared 6 compendia that we chose through discussions with 10 oncology pharmacists and oncologists at Duke and Tufts Medical Centers. We confirmed the list through discussions with the Agency for Healthcare Research and Quality, CMS, and financial officers at Duke University Medical Center. Our final compendia list included American Hospital Formulary Service Drug Information , United States Pharmacopeia Drug Information for the Health Professional , DRUGDEX Information System (United States Pharmacopeia Drug Information and DRUGDEX, both available through Thomson Reuters) , Drug Facts and Comparisons , National Comprehensive Cancer Network Drugs and Biologics Compendium , and Clinical Pharmacology . This list includes the compendia approved by CMS as well as 2 nonapproved compendia. These compendia list more than 40 000 drugs, and their editors are generally pharmacologists with training in research and evidence synthesis. In 2006, we gathered information on each compendium's methods by abstracting descriptive information from publicly available sources, conducting a 1-hour telephone interview with a senior editor from each compendium, and allowing the editors to respond to a methods table that summarized the information collected in the interview. We developed a list of evaluation criteria which we used to compare published methods and guide interviews. We then compared each compendium's methods with evaluation criteria and summarized the results. In 2008, we repeated the data abstraction to determine whether the compendia had updated their publicized methods. We did not include DrugPoints in the 2008 review because it differed structurally from the other compendia and could not be directly compared.

Literature Review of Evidence for 14 Off-Label Indications
We selected off-label indications for 14 agent and cancer combinations that included both newer and older agents, common and rare types of cancer, and biologics and drugs. In 2006, we systematically searched MEDLINE, the Cochrane Central Registry of Controlled Trials, and American Society of Clinical Oncology annual meeting abstracts (2004 and 2005) to identify, English-language studies in humans. We included prospective clinical trials (Phases I to III), case reports, and retrospective case series that reported tumor response, survival, quality of life, symptoms, and adverse effects. We excluded narrative reviews and studies that described only predictors of response, pharmacokinetics, or nonhuman results. For eligible studies, 1 reviewer abstracted data into evidence tables and a second reviewer verified the completed tables. For each agent and cancer combination, we created a summary table that listed the number of articles identified by study design and key outcomes. We scored identified studies by design (for example, Phase I to III), size, and outcomes reported (for example, tumor response, survival, quality of life, or adverse effects). Our intention was not to expose the compendia—which perform a vital function in oncology—but rather to examine their methods and the resulting comprehensiveness of their contents. We therefore did not score the evidence included in the compendia according to classic quality criteria. Instead, we adopted a conservative approach to content evaluation that entailed a simple count of independent studies, presentations of data, and other metrics but did not include evaluation of the quality and validity of the studies themselves. We used study design as a proxy for quality and validity, with Phase III studies considered generally more valid than Phase I or II studies.

Update of 1 Agent and Cancer Combination
In 2008, we repeated the systematic review for a single agent and cancer combination (gemcitabine for bladder cancer) by using the same methods, except we sought 2006 and 2007 conference abstracts. We chose the gemcitabine for bladder cancer indication because gemcitabine has been FDA-approved for longer than the other reviewed agents; gemcitabine has been widely studied (with the largest number of citations in our 2006 review); and, of the 3 gemcitabine combinations included, gemcitabine for bladder cancer had the fastest-evolving evidence base. This combination thus afforded compendia the most opportunity to demonstrate improvement.

Analysis of Compendium Content Against Evaluation Criteria
In 2006, we abstracted data for each of the 14 agent and cancer combinations from each of the 6 compendia. We evaluated all available versions (print and electronic) of the 6 compendia in 2006 but recorded data from the most current and complete version; in all cases, this was an electronic version. Data included whether the indication was explicitly stated; how the indication was graded; and comments on further refinement regarding the stage of cancer, treatment timing, route of administration, and use of monotherapy or combination therapy. We recorded outcomes mentioned specifically for the off-label use; toxicity data; presence of citations to evidence specifically regarding the off-label indication; number, identity, and years of citations; and time since any updates to the monograph or entry. We stratified publications cited in the compendia by study design, noting abstracts separately, and tabulated whether each compendium cited each publication; we compared the results with those of our systematic review. We updated this process in 2008 for the gemcitabine for bladder cancer indication.

Role of the Funding Source
The CMS funded the initial 2006 report through the Agency for Healthcare Research and Quality's Evidence-Based Practice Center program. These agencies participated in formulating questions, reviewing the list of agent and cancer combinations, and commenting on report findings. The 2008 update of the report was unfunded. The agencies had no role in the writing or approval of the manuscript.

Results
Comparison of Stated Methods Used by Compendia
All compendia described their scope and editorial policies, which did not change between the 2006 and 2008 reviews . Because United States Pharmacopeia Drug Information for the Health Professional was discontinued in 2007, our results do not include that compendium even though it was part of the 2006 review. Here, we focus our evaluation on frequency of updates, use of available evidence, and transparency of decision-making processes. Compendia had different update cycles for electronic versions, which varied from daily to quarterly . Several compendia published multiple electronic editions; these differed in content and update schedules. Compendia did not always provide revision dates for drug monographs, and when provided, they did not clearly indicate which content was revised. All compendia included off-label indications . Use of evidence to evaluate off-label indications also differed across compendia . In evaluating the quality of evidence, each compendium stated that they considered validity assessment to be a component of its editorial process. However, these practices were generally not provided in published material. Not all compendia explicitly linked recommendations to supporting evidence through specific citations. Methods for citing and updating evidence varied across compendia. In interviews, each of the editors noted that they either had made, or planned to make, changes in editorial policies to become more transparent with regard to the use of evidence in their evaluations; these changes were not evident in our 2008 review of the electronic compendia. Compendia policies with respect to inclusion of off-label indications varied in consistency and transparency. According to the compendia editors, the decision to recommend a non-FDA approved indication required a judgment by editorial staff regarding the quality and quantity of evidence and the magnitude of benefit versus harm. Several editors mentioned that a high degree of interest or evidence of clinical use would also be considered when deciding whether to include an off-label listing. Editorial discretion was used particularly in the case of equivocal indications; in general, editors reported favoring remaining silent rather than listing an equivocal indication.

Literature Review of Evidence for 14 Off-Label Indications
We retrieved citations in 2006 from a literature search for the off-label use of the following agent and cancer combinations: bevacizumab for breast and lung cancer (subsequently FDA-approved for breast cancer in February 2008); oxaliplatin for breast and lung cancer; irinotecan for breast cancer; docetaxel for esophageal, gastric, and ovarian cancer; gemcitabine for biliary tract, bladder, and ovarian cancer; rituximab for chronic lymphocytic leukemia; and erlotinib for head, neck, and pancreatic cancer. Our search identified 1314 citations for all 14 combinations. We identified an additional 18 unique citations from the Cochrane Central Register of Controlled Trials and 179 abstracts from the American Society of Clinical Oncology Web site. We sorted the studies that met our systematic review criteria by study design and report type: prospective published report (Phase I to II, II, or III), retrospective series, case report, and abstract. Our original report lists the complete search results. The systematic review that we conducted in 2006 on gemcitabine for bladder cancer identified 1 Phase III studies (2 publications, 28 Phase II studies, 14 Phase I to II studies, and 3 case report or retrospective series published from 1994 to 2005 and 15 conference abstracts presented at the 2004 or 2005 American Society of Clinical Oncology annual meetings.

Update of 1 Agent and Cancer Combination
In 2008, we repeated the systematic review on gemcitabine for bladder cancer. Published Phase I to III studies increased by 25, from 43 in the 2006 review to 68 in 2008 (22 additional Phase II studies and 3 Phase I to II studies), and 4 case reports or retrospective studies were found. Three conference abstracts were presented at the 2006 and 2007 American Society of Clinical Oncology annual meetings. The Phase III study we identified in our original systematic review had a new published report to update findings .

Analysis of Compendium Content Against Stated Methods and Available Evidence
The compendia varied substantially in whether they listed any given agent and cancer combination . For example, of the 14 off-label indications, only 1 compendium included all 14 combinations (DRUGDEX), whereas the others included 2 to 9. The only 2 indications discussed by all compendia were gemcitabine for bladder cancer and gemcitabine for ovarian cancer. When we repeated this tabulation in 2008, we found 1 change in the listing of off-label indications since the 2006 evaluation: Clinical Pharmacology added bevacizumab for breast cancer (which is now an FDA-approved indication). The compendia also varied in how they addressed aspects of prescribing and assessment of outcomes, including stage of cancer during which the agent should be prescribed, treatment order (first line or other), uses of the agent (monotherapy or combination), comparator discussed (placebo, standard therapy, or other), toxicity, outcomes, and method of administration. Moreover, the wording used by the compendia to provide recommendations varied, and several compendia used different terminology or approaches internally for different agent and cancer combinations. For example, the National Comprehensive Cancer Network Drugs and Biologics Compendium recommended gemcitabine plus cisplatin as a standard neoadjuvant, adjuvant, and metastatic treatment for bladder cancer but did not recommend gemcitabine monotherapy, whereas other compendia indicated gemcitabine as monotherapy or combined with other agents for metastatic bladder cancer. presents a comparative description of compendia monographs of gemcitabine for bladder cancer; we generated compendia comparisons for each of the 14 agent and cancer combinations in 2006, with similar results. The compendia referenced different literature for the same indications, and within each compendium, the cited literature diverged from the literature retrieved through our systematic review. The example of gemcitabine for bladder cancer illustrates this discrepancy. In 2006, our review identified 43 published Phase I to III studies and 15 conference abstracts; compendia varied in their use of these citations, referencing between 0 and 7. In 2008, our review identified an additional 25 reports published between 2006 and 2007. In this period, 1 compendium (DRUGDEX) increased from 3 to 11 citations, whereas the others had little or no change. All references cited by compendia that met our systematic review eligibility criteria were also identified by our systematic review. Compendia did not necessarily cite the most up-to-date evidence to support recommendations. Despite documentation indicating that the compendia were last updated in 2008, they all cited literature from 2001 or earlier, except DRUGDEX, which included citations through 2007. Two compendia included conference abstracts from 1995 and 1996; only 1 (DRUGDEX) updated its monograph with the citation of the published report. The best evidence for efficacy identified in the 2006 review resided in a single Phase III trial, which was cited by all compendia except Drug Facts and Comparisons. No compendium had cited the long-term follow-up report of the Phase III trial published in 2005 at the time of our 2006 review. Our 2008 systematic review update yielded an additional follow-up report for this trial ; only DRUGDEX had incorporated either of these follow-up reports into its monograph. Personal comments and narrative reviews were cited as supporting evidence by 1 compendium (American Hospital Formulary Service Drug Information). Drug Facts and Comparisons did not have any references.

Discussion
Compendia play an integral role in oncology practice. They serve as a mechanism for ensuring that patients have access to the newest, most effective registered drugs when evidence becomes available to support specific off-label indications. For off-label prescribing in oncology, legislation dating to 1993 has conferred disproportionate weight to the recommendations provided in a few specified compendia. These compendia have essentially functioned as gatekeepers; it is critical to examine their processes for evidence review, the reliability of the evidence they include, their decision-making pathways for adding new drugs, and their practices with regard to timely updating. Our review establishes a baseline against which to compare the performance of included and additional compendia in the future. According to their stated methods, compendia use evidence as a critical gauge for including and recommending off-label anticancer indications. We found little agreement between the results of systematic reviews of 14 off-label indications of cancer drugs and the evidence cited for those indications in these commonly used compendia. Cited evidence was scanty and inconsistent across compendia, which raises questions about the processes by which evidence is identified and selected to generate recommendations, the potential biases or conflicts of interest that affect decisions of whether to include an indication or how to present the evidence, and the comprehensiveness and quality of the evidence that the compendia include. The evidence included in the compendia we evaluated did not seem to be updated in a timely, regular, and explicit manner. We confirmed this observation with the 2008 update of 1 agent and cancer combination, which provided a case-in-point demonstration that the compendia did not follow their stated policies with regard to update cycles. This finding casts doubt on the compendia's adherence to other stated policies. Whether updated information would have changed recommendations is outside the scope of this review but is an important area for future consideration. The compendia varied in numerous ways, including which off-label indications they included, what they considered evidence, the level of detail each provided regarding use of the agent, and how the evidence was linked to the recommendation and referenced. The primary area of general uniformity across compendia was in discussions about adverse effects. In addition to the limited number of research studies cited, the cited literature was often neither the most recent nor derived from the highest available level of evidence. All compendia lacked explicit, systematic procedures for determining inclusion of off-label indications, and stated conditions for including non-FDA indications did not match actual practices of inclusion. A lack of transparency regarding inclusion policies obscured whether missing indications had been identified but excluded or were never identified. If indications were excluded, the rationale for exclusion was rarely provided, which again raises the possibility of potential bias or conflict of interest. A current study is exploring the potential for conflict of interest in editorial policies, expert panels, and evidence review at 4 compendia. The handling of equivocal information was particularly divergent across compendia. Editors mentioned in interviews that they exercised discretion in decisions regarding equivocal evidence. In many cases, the editorial decision would be to remain silent rather than to list an indication that would be qualified as equivocal. Here, expert evaluation of the existing evidence takes on critical importance. As with any decision to include or omit an off-label indication, silence constitutes a powerful decision in itself but is difficult to interpret; it may mean that the evidence was not deemed sufficiently strong to justify recommendation or that other considerations were involved. Because drugs for unlisted indications are unlikely to be prescribed, the absence of an indication from a compendium's listing may strongly influence clinical practice. Our study has limitations. We assessed a limited number of agent and cancer combinations—14 in 2006 and 1 in both 2006 and 2008. We included only off-label indications for cancer drugs and cannot claim generalizability to noncancer drugs or indications. We did not thoroughly evaluate identified studies in terms of magnitude of effects or methodological quality. Similarly, we did not consider the accuracy of compendia conclusions. We could not ascertain whether the relatively small number of studies referenced by the compendia accurately reflected the evidence on which they based their recommendations. We evaluated only current listings at 2 time points (2006 and 2008). Our methods did not permit us to ascertain whether silence about certain indications reflected a withdrawn off-label indication listing, indicating updated review, or one that had never been listed—and we could not determine the reason for silence about an indication. Generalizability of findings is a valid concern. We selected 14 combinations that reflected newer and older drugs, on and off patent, that treat a range of tumor types, but all are being used in areas with frequent requests to CMS for reimbursement of off-label indications. Although we cannot determine the generalizability of our findings to other agent and disease combinations or to other disease areas, one might expect the compendia's performance to be highest in oncology, given the importance of compendia in cancer drug reimbursement. We believe it would be useful for future studies to evaluate changes in inclusion of these same agent and disease combinations over time, to assess for improvement in compendia content. Although our study was not intended to develop recommendations, it does raise certain pivotal questions: In their current state, can we rely on the compendia as authoritative, comprehensive, and timely sources of information on off-label indications in oncology? If we improve the transparency and rigor of compendia processes, such as through more explicit practices and timely updates, can we expect an improvement in the quality and completeness of compendia content? In other words, is this a good and serviceable system which, although imperfectly implemented, could be improved? Alternatively, is the challenge of near-continuous systematic review of large numbers of indications a colossal task that would be unmanageable for any compendium publisher? With at least 6 compendia attending to off-label oncology indications, is there unnecessary duplication and waste of scarce systematic review capabilities when all compendia are expected to fully review all topics? If we accept this task as unrealistic for all compendia to achieve simultaneously, might another party—perhaps a government agency—have the capacity to manage it? No such government agency currently exists. The FDA is neither equipped nor authorized to provide the up-to-date, rigorous, and comprehensive review that is being expected of the compendia. Of note, the compendia's role in listing off-label indications largely came about because of lags in the FDA review and approval process. All discussions of process improvement or alternate scenarios must retain a focus on the goal: to ensure that patients have access to the most recent, evidence-based, effective, and safe treatments. Although important in any medical context, the timeliness of access to the latest evidence is most critical in oncology, in which dire prognoses, short windows in which to treat, the high expense of many drugs, and corollary acute emotional distress make medical decision making highly charged. Compendia are, in many ways, like clinical practice guidelines in that they examine the benefits and harms of pharmaceutical agents and present clinical conclusions based on an assessment of net benefit. Our review establishes a baseline for the methods and content of the compendia used in oncology. With this baseline, we can evaluate compendia in the future by comparing the proportion of qualifying evidence cited in included compendia in 2006 with that proportion at future time points, thereby benchmarking improvement. In the context of an annual review of the approved compendia, newly announced by CMS, this sort of tracking of compendia improvement could inform discussions regarding which compendia to retain in, or add to, the list of approved sources for coverage decisions. Evaluation of compendia should consider not only the volume of available evidence that they encompass but also their consistency, quality, transparency, and timeliness.

ACUTE & CHRONIC SINUSITIS

2008-08-16T05:05:00.000-07:00

Essentials of Diagnosis

• Fever, facial pain or pressure, headache, purulent nasal or postnasal discharge (PND), cough.

• Tenderness over the sinuses, PND, other signs of complications may be seen such as meningismus or periorbital cellulitis.

• Leukocytosis in some cases, sinus or blood cultures may be positive for S pneumoniae, H influenzae, or other bacteria.

• CT scan is a very sensitive method of detecting sinusitis.

General Considerations

Inflammation of the pseudostratified epithelium of the sinuses may occur as a result of an infection, allergy, toxin, or an autoimmune disorder. The paranasal sinuses (maxillary, ethmoid, frontal, and sphenoid) are sterile under normal conditions. Any one or all of them may become infected resulting in inflammation and edema of the pseudostratified epithelium that leads to an increase in tenacious secretions and the symptoms of acute sinusitis. The maxillary sinus is most commonly involved because its ostium is located at the highest part of the medial wall of the sinus. This leads to inadequate drainage and pooling of excess secretions, increased tenacity of secretions, and a drop in oxygen tension creating a more favorable environment for bacterial growth. Acute sinusitis occurs in all ages.

Infectious sinusitis may be bacterial, fungal, or viral. A large percent of acute sinusitis results from viral infection of the sinuses with or without bacterial superinfection. The latter is more symptomatic and patients are more likely to present to the physician. Episodes of sinusitis that occur all year round may be associated with allergies, polyps, or swimming.

The microbiology of acute bacterial sinusitis is similar to that of otitis media (Box 9-14). S pneumoniae and H influenzae account for > 50% of the sinusitis cases. Other pathogenic bacteria include M catarrhalis, a- and ß-hemolytic streptococci, S aureus, C pneumoniae, anaerobic bacteria, and occasionally gram-negative bacteria such as the Enterobacteriaceae or P aeruginosa. The ß-lactamase-producing H influenzae and M catarrhalis and intermediate or PRSP have proportionally increased in the microbiology of sinusitis and have important implications for management of sinusitis. Anaerobic bacteria, such as Peptostreptococcus, Fusobacterium, or Prevotella species, are implicated in ~ 8-10% of cases of acute sinusitis. These are usually polymicrobial and result from contiguous spread from the roots of the teeth.

Patients with craniofacial fractures have a higher incidence of sinusitis. P aeruginosa is a frequent cause of sinusitis in HIV-positive and in cystic fibrosis patients and must be considered in a patient who fails empirical antibiotic therapy that does not include antipseudomonal activity. S aureus is slightly more common in frontal or sphenoidal sinusitis. Fungi such as Aspergillus spp., Zygomycetes (Mucor spp.), and Pseudallescheria spp., among others, can occur in normal hosts or in immunocompromised hosts. Aspergillus sinusitis may occur in normal hosts or present as an allergic syndrome. Zygomycetes infection is more common in people with diabetes (particularly during acidosis), neutropenic patients, and patients on deferoxamine treatment. Viruses such as rhinovirus, influenza virus, adenovirus, coronavirus, and occasionally CMV, among others, account for sinusitis that presents with the primary rhinitis or upper respiratory tract infection syndrome. Coinfections of viruses and bacteria have a higher rate of prolonged duration of symptoms. Recurrent sinusitis may occur as a result of allergies, enlarged adenoids (especially in children), anatomic obstruction such as septal deviation, polyps, tumors, or craniofacial abnormalities, congenital primary or acquired immunodeficiency syndromes, or coexisting disease such as cystic fibrosis, asthma, or gastroesophageal reflux disease.

Chronic sinusitis, infection of the paranasal sinuses for 3 mo or more, may occur in patients with persistently impaired sinus drainage, immunodeficiency, or inadequately treated previous sinusitis episodes. The microbiology of chronic sinusitis is difficult to interpret with previous antibiotic use. However, chronic sinusitis is more often polymicrobial in etiology. There is a higher incidence of S aureus; anaerobes such as Peptostreptococcus, Fusobacterium, or Prevotella species (25-80%); gram-negative bacilli, such as P aeruginosa; and fungi in chronic sinusitis as compared with acute bacterial sinusitis.

Clinical Findings

A. Signs and Symptoms. The symptoms may vary with the severity, cause of the infection and presence of complications. Acute uncomplicated bacterial sinusitis presents with high fever, facial pain, headache, and nasal discharge predominantly. Nasal discharge or PND is purulent and may have a foul smell. Cough secondary to the PND may be present. A more common presentation is sinusitis associated with a viral upper respiratory tract infection. The course is usually milder and presents with "flulike" symptoms such as myalgias, rhinorrhea, and sore throat.

The symptoms of sinusitis may last longer than a viral syndrome and ~ 60% of these patients will have positive sinus cultures. Headache is common and may be frontal, temporal, vertex, or retro-orbital depending on the sinus involved. Sphenoidal sinusitis predominantly causes a vertex headache. Eustachian tube blockage caused by local edema and nasopharyngeal secretions may cause the sensation of "blocked ears." Patients may give a history of a predisposing condition such as sneezing or nasal itching with allergies. History of recurrent sinusitis or sinopulmonary disease, arthritis, and other organ disorders is important to identify immunodeficiencies and noninfectious etiologic diagnosis. Chronic sinusitis symptoms are occasional headaches, fatigue, irritability, low-grade temperature, facial pressure, and PND.

In acute uncomplicated bacterial sinusitis, there is severe tenderness overlying the affected sinuses. There may be swelling, erythema, and induration of the overlying area. Cloudy, yellow-to-green purulent drainage is noted. Intranasal examination should be conducted to attempt identifying the site of purulent discharge. Percussion examination of teeth should be done in patients with unilateral sinusitis or with a history of dental pain. Patients may have signs resulting from complications of sinusitis such as erythema, edema, and proptosis in orbital cellulitis. Purulent discharge and elevated temperature may be the only signs of acute sinusitis. Transillumination of the maxillary sinuses may demonstrate the presence of fluid.

B. Laboratory Findings. Acute sinusitis is usually associated with leukocytosis of > 10,000 cells/mm3. The sedimentation rate may be elevated. Cultures obtained by sinus puncture are regarded as the standard for an accurate microbiologic diagnosis and yield bacteria in ~ 60% of cases. Bacterial growth of > 105 colony-forming units (CFU)/mL suggests an etiologic role of those specific bacteria whereas growth of < 105 CFU/mL may represent contamination. Sinus puncture is recommended in patients who are severely ill; have intracranial or orbital complications, compromised immune systems, nosocomial sinusitis; or are not responding to standard empirical therapy. Newer endoscopic methods of collection of secretions are technically more difficult than puncture, especially from the maxillary antrum because of the location of its ostium. Endoscopic cultures obtained from the middle meatus may be contaminated with nasal secretions. In comparison with sinus puncture cultures, endoscopic cultures have a sensitivity of 65% and specificity of 40%, but this increases when evaluated specifically for S pneumoniae, H influenzae, and M catarrhalis.

C. Imaging. Standard radiography is useful for evaluating frontal and maxillary sinusitis with an anterior-posterior and Waters' view. Ethmoid sinuses are poorly seen on plain x-rays and difficult to interpret. Although standard radiography is less sensitive than CT, it may still be helpful in acute disease or determining bony erosion. The presence of air-fluid levels, opacification, and mucosal thickening is suggestive of acute disease. The coronal CT scan is a very sensitive imaging technique for sinus disease and is the imaging method of choice for accurate assessment. Findings on CT scan may include typical air-fluid levels that have a good correlation with acute bacterial sinusitis. Other findings such as membrane thickening, presence of polyps, and anatomic variations predisposing to or complicating sinusitis may help in defining the disease. Magnetic resonance imaging of the sinuses is also very sensitive in identifying mucosal disease. Both CT and magnetic resonance imaging are sensitive in detecting a fungus ball in the sinuses. Intracranial complications will require evaluation of the head with CT, especially if there are focal neurologic findings, or lumbar puncture for cell count, chemistry, and culture, and susceptibilities in a patient presenting with meningitis.

Differential Diagnosis

Patients with noninfectious sinusitis such as that related to Wegener's granulomatosis, tumors, or allergic rhinitis may present with signs and symptoms similar to those of infectious sinusitis.

Complications

The proximity of the orbits to the sinuses accounts for orbital complications. Orbital complications include periocular edema, orbital cellulitis, abscess, and further extension into the cavernous sinus leading to cavernous sinus thrombosis. Infection of the bone by direct spread or septic thrombophlebitis may occur. Frontal bone osteomyelitis and subperiosteal abscess cause a swelling and doughy feeling of the frontal bone called Pott's puffy tumor. Intracranial extension results in meningitis or epidural, subdural, or brain abscess. The incidence of these complications has declined, but they present as medical emergencies and require immediate attention. Cough or bronchitis from aspiration of postnasal drainage into the respiratory tract may also occur.

Treatment

Therapy of acute bacterial sinusitis includes symptomatic care along with an appropriate antibiotic regimen (Box 9-15). It may be helpful to stratify patients by the severity of symptoms. Patients who present with complicated sinusitis with evidence of intracranial or orbital extension should be hospitalized, undergo immediate appropriate diagnostic tests, and start on a parenteral empirical antibiotic regimen. Therapy should be guided by diagnostic sinus fluid aspiration. The recommended empirical antibiotic regimen in complicated sinusitis should include vancomycin, which is active against intermediate and highly PRSP, and a high-dose, third-generation cephalosporin (ie, cefotaxime or ceftriaxone) with activity against other usual pathogens. Empirical therapy should continue until culture and susceptibility results from sinus aspiration are available. Surgical consultations should be sought for possible drainage procedures. The increasing incidence of intermediate and highly PRSP and ß-lactamase-producing organisms has led to a decrease in the efficacy of amoxicillin for sinusitis.

Current recommendations for empirical antimicrobial therapy for acute uncomplicated bacterial sinusitis include amoxicillin/clavulanate or oral cephalosporins such as cefuroxime for 10 d. Other efficacious antibiotics include cefprozil, cefaclor, loracarbef, or cefpodoxime. TMP-SMX achieved 95% cure rates in older sinusitis studies; however, it is less effective against GAS and S pneumoniae.

Alternative antibiotics include macrolides such as clarithromycin (15 mg/kg/d for children, 500 mg every 12 h in adults) or azithromycin. Erythromycin has poor activity against H influenzae and is not recommended. Newer fluoroquinolones, such as levofloxacin or gatifloxacin (not approved for use in children and adolescents < 18 y old), have good activity against PRSP and are approved for use in adults with upper respiratory tract infections. TMP-SMX, cephalosporins or macrolides could be used for penicillin allergic patients. Odontogenic sinusitis treatment should include anaerobic coverage with either a ß-lactam/ß-lactamase inhibitor combination or the alternative regimen should include clindamycin or metronidazole. Fungal sinusitis requires aggressive surgical debridement along with parenteral or oral antifungal therapy.

Supportive measures for symptomatic relief may be considered. Decongestants provide symptomatic improvement by decreasing the nasal edema and obstruction. Oral decongestants are preferred over topical ones to avoid rebound vasodilatation. Steroid inhalers are not recommended unless the patient has significant allergy history and symptoms. Most symptoms will resolve in 7-10 d. Indiscriminate use of antibiotics is strongly discouraged to prevent the emergence of resistant strains of bacteria, particularly if the symptoms are consistent with a viral upper respiratory tract infection.

Persistent symptoms after an appropriate course of treatment may result from retained secretions, resistant or unusual organisms, presence of allergies, or possible immunodeficiency. Recurrent bacterial sinusitis should prompt further evaluation of the paranasal anatomy; immunoglobulin levels; neutrophil function analysis; HIV serology; sinus aspiration; and cultures for aerobic and anaerobic bacteria, fungi, and mycobacteria. Sinus aspiration and lavage or other drainage procedures may be more efficacious in relieving symptoms in these patients. Sinus aspirate should be sent for aerobic and anaerobic bacterial, mycobacterial and fungal culture, and susceptibilities. Patients with chronic sinusitis may require retreatment with a second course of broad-spectrum antibiotics to include antimicrobial activity against S aureus and anaerobes. This could be achieved with amoxicillin/clavulanate or combination therapy of a cephalosporin with clindamycin or metronidazole given for 4-6 wk. Occasionally antipseudomonal therapy may need to be added particularly in patients with cystic fibrosis, patients who are hospitalized, or patients who are HIV positive. Acute or chronic sinusitis exacerbations should be treated similarly to acute sinusitis.

Prognosis

Most community-acquired bacterial sinusitis episodes respond well to antimicrobial therapy. Complicated sinusitis or sinusitis in an immunocompromised host may require aggressive treatment including surgery. Such patients may continue to have recurrences and the attendant morbidity. Mortality in sinusitis is related mostly to complications such as meningitis.

Prevention & Control

Proper hygiene measures such as handwashing can reduce the incidence of acute sinusitis by decreasing transmission of infectious particles between persons (Box 9-16). Simple actions like covering the mouth with a handkerchief or tissue when sneezing or coughing can prevent aerosol or droplet transmission. Active immunization with pneumococcal polysaccharide vaccine or influenza vaccine may further decrease the incidence of these infections.

OTITIS EXTERNA

2008-08-16T05:03:00.000-07:00

Essentials of Diagnosis

• Infection and inflammation of the external auditory canal causing pain and itching, similar to infections of the skin and soft tissue.

• S aureus or group A Streptococcus often causes acute localized otitis externa, similar to furunculosis.

• Main symptoms are localized pain and itching.

• "Swimmer's ear" or acute diffuse otitis externa is often caused by P aeruginosa or by Aspergillus spp.

• Chronic otitis externa results from persistent drainage caused by chronic suppurative otitis media. This may present as chronic itching.

• "Malignant" otitis externa is a severe necrotizing P aeruginosa infection of the external auditory canal and adjacent tissues. Severe pain, tenderness, and other signs of complications may be present.

General Considerations

Inflammation of the EAC is particularly symptomatic because of the limited space for expansion of edematous tissue in the narrow external auditory canal.

Clinical Findings

A. Signs and Symptoms. Infection of the EAC is divided into four different categories (Box 9-12):

1. Acute localized otitis externa is the most common form of otitis externa. It is similar to staphylococcal infections of the skin and hair follicles. Because of limited area for expansion, inflammation and edema of the EAC wall cause intense pain and tenderness. The canal has local erythema, heat, and tenderness over the tragus. There may be associated preauricular lymphadenopathy.

2. Acute diffuse otitis externa or "swimmer's ear" is caused mainly by gram-negative organisms, particularly P aeruginosa. It occurs in hot, humid climates or may be associated with contaminated hot-tub baths. Fungal organisms such as Aspergillus spp. may also cause symptoms of pain and itching in the ear. The canal is erythematous, edematous, and, in some severe cases, hemorrhagic.

3. Chronic otitis externa is a complication of persistent chronic otitis media and resultant drainage into the EAC leading to chronic irritation. Itching of the EAC is the main symptom.

4. "Malignant" or invasive otitis externa is a severe, necrotizing infection of the EAC with invasion into the surrounding tissues including blood vessels, cartilage, and bone. P aeruginosa is the most frequently isolated organism. Immunocompromised hosts, elderly, and particularly diabetics are predisposed to this disease

B. Laboratory Findings. Laboratory findings are not helpful in the diagnosis and management of otitis externa. The white blood cell count and sedimentation rate may be elevated in malignant otitis externa. Cultures from the EAC or involved tissue in malignant otitis externa are frequently positive for P aeruginosa or other bacteria.

C. Imaging. Imaging is not required for otitis externa but CT or magnetic resonance imaging of the head delineates the extent of damage in malignant otitis externa and its complications. This could potentially aid in the further management of this condition.

Complications

Complications develop by local invasion such as temporal bone osteomyelitis, septic thrombophlebitis of the sigmoid or lateral sinus or jugular bulb, cranial nerve palsies, meningitis, or brain abscess.

Treatment

Gentle cleaning is recommended for most otitis externa. Local heat, topical antibiotic solutions such as neomycin, polymyxin, or ofloxacin, or systemic antibiotics, or some combination of these are effective in the treatment of acute otitis externa (Box 9-13). Irrigation with hypertonic (3%) saline and cleansing with alcohol and acetic acid mixed 1:1 are recommended for acute diffuse otitis externa, whether it is bacterial or fungal. Fungal otitis externa may also be amenable to treatment with m-cresyl acetate. Topical antibiotics combined with steroids are sometimes used for 1-2 d to decrease edema. Severe infections may require systemic antibiotics with activity against P aeruginosa. Malignant otitis externa may be treated with parenteral antipseudomonal antibiotics such as ceftazidime or penicillins with antipseudomonal activity such as piperacillin with aminoglycoside or oral antipseudomonal antibiotics such as the fluoroquinolones. Topical antipseudomonal antibiotics, such as neomycin, polymyxin, or ofloxacin, are used for 4-6 wk.

OTITIS MEDIA

2008-08-16T05:02:00.000-07:00

Essentials of Diagnosis

• Commonest cause of office visits in children between 6 mo and 2 y.

• Irritability, fever, earache, discharge from the ear, occasional vertigo.

• On otoscopic examination, the tympanic membrane is erythematous and has decreased mobility on pneumatic otoscopy, which demonstrates the presence of middle ear fluid.

• There may be diminished hearing.

• Laboratory values may show leukocytosis. Cultures of the ear are not routinely recommended.

General Considerations

Acute otitis media (AOM) is the middle ear inflammation that results in collection of fluid in the middle ear and associated local and systemic symptoms.

AOM is the most common reason for physician office visits for children under age 15 y. Children <> 6 children per room) centers, a sibling with AOM, parental smoking, and drinking from a bottle while lying flat on the back. Boys, Native Americans, and Alaskans have a higher incidence of AOM. A small percentage of children have an identifiable risk factor for recurrences such as congenital orofacial deformities and congenital or acquired immunodeficiencies such as HIV/AIDS. Recurrences occur in normal children with no apparent anatomic defects. A large percentage of AOM is viral, which may explain recurrences.

The most common bacterial organism responsible for otitis media is Streptococcus pneumoniae, which accounts for ~ 30-40% (Box 9-10) of cases. Cultures from the middle ear in various studies have demonstrated S pneumoniae, nontypable strains of H influenzae (21%), M catarrhalis (12%), S aureus, GAS (2-6%), and other less common gram-negative organisms including Pseudomonas aeruginosa. Penicillin-resistant S pneumoniae (PRSP) is increasing in the community and contributes to recalcitrant cases of AOM. PRSP is common in children < 6 y old, children who have received recent antibiotics, children with previous AOM, and children attending group daycare. Gram-negative organisms should be considered in neonates with AOM. Rare causes include M pneumoniae, which has a classic bullous lesion on the tympanic membrane, and Chlamydia trachomatis may be seen in very young infants. Occasionally mycobacterial or diphtheria middle-ear infections can occur.

Clinical Findings

A. Signs and Symptoms. Young infants or children may present with crying, irritability, anorexia, lethargy, or a history of pulling at the affected ear. Earache with or without associated drainage from the ear is the most common symptom in older children and adults. They may be febrile and occasionally present with vertigo, tinnitus, or decreased hearing.

Otoscopic examination reveals an erythematous tympanic membrane. The tympanic membrane may be bulging, retracted, or perforated and occasionally exuding purulent drainage from the perforation. Fluid in the middle ear is demonstrated by air-fluid levels, bulging, and decreased mobility of the tympanic membrane demonstrated by pneumatic otoscopy. Pneumatic otoscopy should be attempted in all children unless it is too painful. Other otologic techniques such as tympanometry and acoustic reflectometry can help assess the amount of fluid in the middle ear. Audiologic evaluation is necessary in children with hearing loss.

B. Laboratory Findings. Laboratory values are not helpful in the management of AOM. There may be polymorphonuclear leukocytosis. Routine middle ear cultures via tympanocentesis are not recommended unless the patient is toxic, has recurrent infections, or is not responding to empirical therapy. Swab cultures from the external auditory canal (EAC) do not accurately reflect the organism causing AOM because the EAC cannot be adequately decontaminated. Nasopharyngeal cultures are not specific in identifying the causative bacteria in AOM.

C. Imaging. Imaging is not of considerable help in otitis media. CT scans of the head should be done if mastoiditis or other complications are suspected.

Differential Diagnosis

Noninfectious causes of AOM, such as Wegener's granulomatosis, must be considered in a patient with recurrent and nonresponding disease. A foreign body in the EAC can present with earache and minimal erythema of the tympanic membrane. History and otoscopic visualization should identify a foreign body. A viral infection, fever, or crying or earwax removal can also cause a red tympanic membrane.

Complications

Chronic otitis media, effusion, mastoiditis, and intracranial extension may result from recurrent otitis media and persistent middle ear effusion. In the preantibiotic era, mastoiditis and intracranial extension occurred in ~ 20% and 2.5%, respectively, of AOM patients. Now that the use of antibiotics is common, these rates have decreased to 2.8% and 0.13%, respectively. Contiguous spread to the cranial fossae, temporal or petrous bone, or sigmoid or lateral sinuses results in suppurative complications. Conductive hearing loss because of chronic otitis media and effusion can potentially impair language development and academic functioning of the child.

Treatment

A large number of AOM cases are viral in nature with or without bacterial superinfection. Approximately 30% of AOM cases are bacterial. Studies have also demonstrated spontaneous resolution in 16% of S pneumoniae infections, 50% of H influenzae infections, and ~ 80% of M catarrhalis AOM, particularly in children older than 2 y. Because of concerns regarding suppurative complications, parental expectation, and perhaps convenience, antibiotic therapy has become the norm for most AOM treatment (Box 9-11). Numerous studies have now demonstrated that antibiotics benefit defervescence and otalgia, decrease suppurative complications, and improve tympanic membrane healing, but they have no significant benefit in long-term outcomes such as recurrence rates or chronic middle ear effusion. These studies and the recent increase in multi-drug-resistant organisms that have no or minimally efficacious treatment have brought this practice of judicious antibiotics use for AOM into question.

The approach to patients with AOM should be individualized. A delayed antibiotic approach can be considered in children older than 2 y with no immunodeficiency, no craniofacial anatomic abnormalities, intact tympanic membrane, and no previous AOM. The child should be scheduled for a follow-up visit. If a follow-up visit is not possible, an antibiotic can be started at the initial evaluation. The initial empirical antibiotic regimen should be active against the common organisms. Despite the emergence of resistance in these bacteria, amoxicillin is still the preferred and effective initial antibiotic of choice. In children with a history of antibiotic use in the preceding month, the initial antibiotic is still amoxicillin but given at a higher dose.

Antibiotics effective in the treatment of AOM include amoxicillin/clavulanate, cephalosporins such as cefaclor, cefixime, cefprozil, cefuroxime, cefpodoxime, loracarbef, or macrolides such as erythromycin, azithromycin, or clarithromycin, TMP-SMX, and erythromycin/sulfisoxazole (Pediazole). The newer expensive antibiotics do not have a significant benefit as first-line agents when compared with their cheaper counterparts (eg, amoxicillin and TMP-SMX). In patients with penicillin allergy, cephalosporins, macrolides, or TMP-SMX can be prescribed. Cephalosporins should be avoided in patients with histories of anaphylactic reaction to penicillin. Studies report mean clinical cure rates of 85-94% with amoxicillin.

Most patients start responding in 48-72 h. Causes for slower response or recurrence with lower-dose amoxicillin therapy include resistant organisms such as intermediate- or high-grade PRSP or ß-lactamase-producing H influenzae or M catarrhalis, suppurative complications, or noncompliance. Treatment failure is defined as lack of improvement in fever, ear pain, and persistent tympanic congestion, bulging, or otorrhea. It is important not to mistake a persistent middle ear effusion without signs of active infection as treatment failure. Treatment failure may be early (3 d) or late (10-25 d). If a child requires further treatment, high-dose (80 mg/kg/d) amoxicillin, a cephalosporin, amoxicillin/clavulanate, or a macrolide (either azithromycin or clarithromycin) may be prescribed. The choice of retreatment antibiotic depends on the risk of PRSP in the patient. Higher-dose amoxicillin or amoxicillin/clavulanate is still efficacious against intermediate-penicillin-susceptible S pneumoniae. Cefaclor and cefprozil are not good alternatives as second-line therapy because of their lower efficacy against nonsusceptible S pneumoniae and H influenzae. Because of the lack of activity against PRSP, clarithromycin, azithromycin, TMP/SMX, cefixime, ceftibuten, and loracarbef are recommended only as second-line antibiotics for patients at low risk for PRSP AOM.

Patients suspected of having PRSP AOM who fail high-dose amoxicillin should be considered for tympanocentesis for culture and susceptibilities. If empiric therapy is decided, the antimicrobial therapy should be effective against the ß-lactamase-producing H influenza and M catarrhalis in addition to being active against PRSP. Options include oral cefuroxime axetil, cefpodoxime or clindamycin, or parenteral cefotaxime, ceftriaxone or vancomycin. In children receiving clindamycin for PRSP, the addition of a ß-lactamase-stable cephalosporin may be required to cover for ß-lactamase-producing H influenzae. One parenteral dose of ceftriaxone 50 mg/kg/d is approved for AOM caused by susceptible S pneumoniae. However, ceftriaxone given daily for 3 d is likely to be more efficacious for AOM failing the first-line antimicrobial-agent therapy. Parenteral therapy is usually needed only for patients with severe AOM or those failing their second regimen. Middle ear aspirates should be sent for culture and susceptibilities to guide therapy in children failing second-line therapy. These patients should be reevaluated in 2 wk to ascertain that no suppurative complications have developed. A severely ill child failing initial therapy should be considered for admission and treatment with parenteral vancomycin and a third-generation cephalosporin, such as cefotaxime or ceftriaxone. A thorough evaluation for complications should also be conducted.

Symptomatic treatment is primarily pain control with analgesics such as acetaminophen or nonsteroidal anti-inflammatory drugs. On occasion, myringotomy (incision of the tympanic membrane) may be required to relieve the middle ear pressure. In most studies, myringotomy did not improve outcome even when combined with antibiotics. Antihistaminics and decongestants have equal efficacy as a placebo in AOM, and they are not recommended.

Treatment of recurrent otitis media includes prevention of recurrent attacks, a second course of antibiotics with broader antibacterial spectrum as mentioned above or specific treatment depending on middle ear cultures. Secondary antibiotic prophylaxis, surgical drainage or adenoidectomy, and active immunization are some of the measures used to prevent AOM. Children with three new episodes in 6 mo or four episodes in 1 y should be considered for antibiotic prophylaxis with amoxicillin or erythromycin/sulfisoxazole. Antibiotic prophylaxis decreases recurrences = 44%. The patient should be regularly evaluated for middle ear effusion. Middle ear effusion is seen in ~ 50% of children with AOM and usually resolves in 3 mo in the majority of patients. Persistent middle ear effusion or otitis media with effusion (OME) beyond 3-4 mo requires further management. Children with OME should have an audiologic test to detect any hearing loss. Patients with OME with normal hearing should be retreated with a 2- to 3-wk course of an antibiotic. If the effusion resolves, then a prophylactic antibiotic course of 3 mo may be of benefit to prevent recurrences. Children with OME and conductive hearing loss should be evaluated by an otorhinolaryngologist for surgical drainage procedures such as myringotomy and tympanostomy tubes (tubes placed in the tympanic membrane for permanent drainage).

Prognosis

Recurrent AOM or OME may impair hearing, language development, and learning capabilities of the patient. The prognosis is worsened in patients with intracranial extension of infection. Uncomplicated AOM resolves without significant sequelae.

Prevention & Control

Currently available 23 polyvalent pneumococcal polysaccharide vaccine produces poor immunologic responses in children <> 2 y . The Advisory Committee on Immunization Practices advises that this vaccine be given to children with higher likelihoods of pneumococcal infections such as HIV-positive, asplenic, or sickle cell anemia patients. Conjugated pneumococcal vaccine is available and is more efficacious in children < 2 y old and may contribute to lowering the incidence of pneumococcal otitis media.

ACUTE EPIGLOTTITIS

2008-08-16T05:00:00.000-07:00

Essentials of Diagnosis

• Occurs in children between 2 and 6 y , can occur in adults although it presents with less severity.

• Irritable, febrile, sore throat; odynophagia, dysphonia, and dyspnea.

• Sits forward drooling, toxic appearing, tachypneic

• Examination of the larynx should not be attempted. Direct examination should be performed only by a trained person and in a unit where immediate intubation or tracheotomy can be performed.

• Direct laryngoscopic examination reveals a "cherry red" edematous epiglottis.

• Polymorphonuclear leukocytosis is common. Blood and epiglottis cultures are often positive for Haemophilus influenzae type b, Staphylococcus aureus, or other bacteria.

General Considerations

Acute epiglottitis is a true respiratory emergency. An epiglottic infection leads to acute inflammation and edema of the epiglottis and can cause upper airway obstruction. Acute epiglottitis can occur at any age, however it is more common in children between 2-6 y and most often occurs in the winter and spring. Unlike croup, which is predominantly a viral disease, acute epiglottitis is a bacterial disease caused mainly by H influenzae type b, S aureus, or streptococcal species (Box 9-7). H influenzae type b was the most common organism isolated from children with acute epiglottitis, but widespread use of the H influenzae type b vaccine has dramatically decreased the incidence of H influenzae type b acute epiglottitis.

Clinical Findings

A. Signs and Symptoms. The child presents with a short (6- to 12-h) rapidly progressive febrile illness, sore throat, pain on swallowing, and shortness of breath. There is usually no antecedent history of a viral infection. Adults have a similar clinical presentation with sore throat being a predominant symptom.

The patient looks anxious, appears toxic, and assumes a forward-leaning, neck-extended posture. Drooling of oral secretions and muffled voice are the sine qua non. The child has marked tachypnea and may have an inspiratory stridor from the supraglottic mucosa prolapsing into the glottis. Lung auscultation may reveal crepitations or bronchial breath sounds if there is associated pneumonia.

B. Laboratory Findings. The white blood cell count is elevated with a polymorphonuclear reaction. The blood and epiglottis cultures are frequently positive. Bacteremia occurs in almost all of the children with H influenzae type b acute epiglottitis. Serum latex agglutination tests against H influenzae type b may be helpful in making a rapid microbiologic diagnosis in patients from whom cultures were not obtained before starting antibiotics.

C. Imaging. Caution must be exercised in sending these patients for tests or x-rays without adequate supervision and to avoid a delay in intubation. Radiographs of the neck show an enlarged edematous epiglottis with a normal subglottic space. Some x-rays may be negative or show subglottic obstruction, and the diagnosis may be obscured. (Figure 9-3). Chest x-rays may show evidence of pneumonia. Laryngoscopic evaluation should be carried out by trained personnel in a controlled setting such as an operating room or unit equipped for immediate intubation.

Differential Diagnosis

Croup or acute LTB presents with a clinical picture similar to that of acute epiglottitis. Croup has slower-onset, viral prodromal symptoms, a nontoxic appearing child, and absence of drooling. Anterior-posterior x-rays of the neck confirm the diagnosis. Other conditions that have a similar presentation include angioedema, foreign-body aspiration, and retropharyngeal or peritonsillar abscesses. Angioedema and foreign-body aspiration are suspected based on history and imaging or endoscopic evaluation. Radiographs or laryngoscopic evaluation identifies retropharyngeal or peritonsillar abscesses.

Complications

Mortality associated with untreated obstructive acute epiglottitis is ~80%. Respiratory failure from upper-airway obstruction is the most common complication. Occasionally patients will develop pulmonary edema along with the respiratory distress.

Treatment

Acute epiglottitis is a medical emergency. Once acute epiglottitis is suspected, the child should be kept in an upright position and be accompanied at all times by personnel trained in advanced cardiopulmonary life support. Diagnosis should be expeditiously established clinically or radiographically. Laryngoscopic examination should be attempted only in a unit equipped for immediate intubation and only by experienced personnel. Maintenance of a patent airway is of foremost importance in the care of a patient with acute epiglottitis. Patients with impending respiratory failure who cannot be intubated may require an emergency subglottic tracheotomy. All pediatric patients with acute epiglottitis should be intubated preferably via a nasotracheal or an uncuffed endotracheal tube. Observation alone is not recommended in pediatric patients because of high associated mortality. Management of adult patients depends on the severity of clinical symptoms and signs of upper-airway obstruction.

Blood and epiglottic cultures should be obtained once the airway is secured. Patients should be started on parenteral antibiotics that are active against H influenzae type b, S aureus, and streptococci (Box 9-8). Because of the high degree of ß-lactamase-mediated resistance in H influenzae type b, third-generation cephalosporins such as ceftriaxone or cefotaxime or a ß-lactam/ß-lactamase inhibitor combination antibiotic such as ampicillin/sulbactam should be started. Patients with acute epiglottitis usually improve within 12-48 h with appropriate antibiotics, and these should be continued orally or parenterally for 7-10 d. The average period of intubation is ~ 2 d, and direct visualization is the most effective way to determine time of extubation.

Prognosis

Expeditious diagnosis, immediate management of upper-airway obstruction, and institution of antibiotics decreases morbidity and mortality related to acute epiglottitis. Full recovery without sequelae is expected in such patients.

Prevention & Control

H influenzae type b polysaccharide vaccination can further decrease the incidence of acute epiglottitis (Box 9-9). However, patients can still be susceptible to non-type-b H influenzae and other bacterial etiologies of epiglottitis.

The secondary attack rate of H influenzae type b among all household contacts, especially in children < 4 y old, can be decreased by a prophylactic 4-d course of rifampin (20 mg/kg/d in a single daily dose). Rifampin prophylaxis should be given to the patient and all household contacts regardless of previous immunization status, to prevent carriage state.

ACUTE LARYNGOTRACHEOBRONCHITIS (CROUP)

2008-08-16T04:59:00.000-07:00

Essentials of Diagnosis

• Most often in children ages 6 mo to 6 y, peak is at 2 y.

• Fever, hoarseness of voice followed by paroxysms of nonproductive, brassy cough that ends with a characteristic inspiratory stridor.

• The child appears anxious and has tachypnea, inspiratory stridor, retraction of intercostal muscles, and associated rhonchi or wheezing.

• Anterior-posterior x-ray view of the neck shows the subglottic obstruction.

• Microbiologic diagnosis can be established by serology, viral or bacterial cultures from the pharynx, or rapid antigen detection enzyme immunosorbent assays such as for RSV or influenza type A.

General Considerations

Acute laryngotracheobronchitis (LTB) or croup is subglottic inflammation and edema caused by a viral or bacterial infection of the larynx, trachea, and bronchi (Box 9-5). Croup is the most common cause of upper respiratory tract obstruction in children between the ages of 6 mo and 6 y, with the peak occurrence at 2 y old. It is caused mostly by viruses, primarily parainfluenza virus types I and II, although others, such as influenza type A or B, RSV, and adenovirus are also implicated. Occasionally M pneumoniae can cause LTB.

Clinical Findings

A. Signs and Symptoms. Most children have hoarseness of voice and a brassy cough with an associated inspiratory or even an expiratory stridor. Fever, rhinorrhea, sore throat, and cough usually precede this. Symptoms may vary in intensity and last ~ 3-4 d if mild. Patients appear apprehensive and tend to lean forward. The child may have tachypnea and might be using accessory respiratory muscles. Inspiratory or expiratory stridor is prominent. Pulmonary examination may reveal rhonchi, crepitations, or wheezing. Breath sounds may be diminished if upper airway obstruction is severe and air entry is greatly decreased.

B. Laboratory Findings. The white blood cell count may be normal or mildly elevated. Noninvasive pulse oximetry to monitor the oxygen saturation is recommended. Arterial blood gas assessment shows hypoxemia and/or hypercapnia, depending on the severity of the disease.

C. Imaging. Lateral neck x-rays show overdistended hypopharynx, subglottic narrowing that is wider on expiration than inspiration, thickened vocal cords, and a normal epiglottis. Anterior-posterior views of the neck show edematous subglottic walls converging to create a characteristic "steeple sign" (Figure 9-1). There may also be diffuse narrowing of the trachea and bronchi (Figure 9-2).

Differential Diagnosis

Acute epiglottitis is a major differential diagnosis to be considered when a child presents with these symptoms. Radiographs of the neck can easily help differentiate the two conditions. Other causes of similar symptoms include foreign-body aspiration, which can be determined by history, x-rays, or endoscopic evaluation. Membranous croup or bacterial tracheitis should also be considered if the child presents with a clinical picture similar to croup but appears more toxic and has subglottic narrowing on radiographs of the neck.

Complications

Severe croup, as may occur with influenza type A, may require tracheotomy or intubation in = 13% of patients and have an associated mortality of 0-2.7%. A small percentage of children with prolonged intubation or severe disease may develop subglottic stenosis. A few follow-up studies have shown an increase in hyperactive airways in children with a history of croup.

Treatment

Antibiotics are not routinely recommended for the treatment of croup unless the patient has symptoms or cultures suggestive of bacterial etiology (Box 9-6). Cool air humidification and supportive care are essential to keep the child calm, to prevent further tachypnea and distress. Respiratory rate is the best predictor of hypoxemia. Noninvasive pulse oximetry or arterial blood gas testing for PaO2 or PaCO2 should aid in assessment of the patient's condition and response to therapy. Noninvasive monitoring is preferred to prevent further anxiety in the child.

Nebulized racemic epinephrine is important in the therapy for croup because the a and ß agonists decrease edema and relieve obstruction by vasoconstriction. Racemic epinephrine nebulization is well tolerated, even by the younger children, and may decrease the need for intubation. Children receiving racemic epinephrine should be observed for relapse because epinephrine has a short half-life and rebound vasodilatation and edema can occur. Racemic epinephrine nebulization should be used cautiously in children with left ventricular outflow tract obstruction such as tetralogy of Fallot or idiopathic hypertrophic subaortic stenosis. In severe croup, corticosteroids (eg, dexamethasone) decrease subglottic edema, the number of racemic epinephrine treatments, and intubations.

Some children will fail medical management and require intubation. Intubation should be done in fully equipped units and preferably via the nasotracheal route. Extubation is usually attempted in ~ 5-7 d if extubation criteria are met. Extubation criteria include decreased secretions, decreased leakage around the endotracheal tube (which indicates decreased edema), and an alert child. Failure to extubate should prompt further endoscopic evaluation.

Prognosis

Croup is mostly a self-limited disease with complete uncomplicated resolution. As mentioned above, some children may develop hyperactive airways or become predisposed to recurrent croup. A few may develop subglottic stenosis caused by severe disease or prolonged intubation.

Prevention & Control

Good handwashing and cleanliness can help decrease transmission from an infected patient, particularly at daycare centers or even in the home environment.

ACUTE LARYNGITIS

2008-08-16T04:57:00.000-07:00

Essentials of Diagnosis

• Hoarseness or loss of voice (aphonia).

• Associated symptoms of rhinitis, pharyngitis, or cough.

• Children tend to develop airway obstruction.

• On direct examination, the larynx is hyperemic and edematous, with or without ulcerations.

• Mostly viral, occasionally bacterial.

• Persistent hoarseness lasting > 10 d should prompt laryngoscopy to exclude other etiologies.

General Considerations

Laryngitis is the infection of the larynx that results in an inflammatory reaction and consequential symptoms and signs. Common cold viruses such as rhinovirus, influenza virus, adenoviruses, RSV, or parainfluenza viruses may cause acute laryngitis. It usually presents in winter as part of an upper respiratory tract infectious syndrome. Bacterial laryngitis is less common and is caused mainly by S pyogenes or Moraxella catarrhalis. Rarely laryngitis may be caused by Mycobacterium tuberculosis, syphilis, or fungi such as Histoplasma capsulatum, Blastomyces dermatiditis, or Candida albicans.

Clinical Findings

A. Signs and Symptoms. Hoarseness, aphonia, and symptoms of associated upper respiratory tract infection such as rhinitis or pharyngitis may accompany acute laryngitis. Respiratory obstruction may occur particularly in children. Direct examination when done shows the larynx to be hyperemic and edematous, with or without ulcerations. An exudate or membrane may be seen in diphtheria, streptococcal, or EBV laryngitis.

B. Imaging. Lateral x-ray of the neck may be helpful to exclude acute bacterial epiglottitis or bacterial tracheitis. If symptoms of hoarseness persist beyond 2 wk, patients should be evaluated by direct visualization of the larynx by laryngoscopy.

Differential Diagnosis

Voice abuse is the most frequent noninfectious cause of hoarseness. Differential diagnosis includes tumors, paralysis of the vocal cords, chemical irritants, or gastroesophageal reflux. Patients with laryngitis must also be differentiated from those with acute epiglottitis or bacterial tracheitis, which usually present with more systemic symptoms.

Complications

Respiratory obstruction in children is the most serious complication.

Treatment

Because the majority of laryngeal infections are viral, therapy is mostly supportive with voice rest, warm saline gargles, and increased humidity. If specific microbiologic diagnosis is made with positive microbiologic cultures, then therapy should be directed at the organism isolated.

Prognosis

Long-term prognosis is excellent with no residual symptoms.

Prevention & Control

Preventive measures for laryngitis are similar to those for common cold and pharyngitis.

PHARYNGITIS

2008-08-16T04:55:00.000-07:00

Essentials of Diagnosis

• Pharyngeal discomfort or pain, pain on swallowing (odynophagia).

• Associated symptoms such as myalgia, fever, rhinorrhea, and lymphadenopathy depend on the etiologic agent.

• Pharyngeal erythema with or without exudate or lymphadenopathy.

• Leukocytosis, GAS RADT, and bacterial culture or other serologies may provide the definitive microbiologic diagnosis.

General Considerations

Pharyngitis is an acute infection of the pharyngeal mucosa caused by a variety of pathogenic microorganisms, the majority of which are viral (Box 9-2). A minority of pharyngitis episodes are bacterial and, of those, group A streptococcus is the most common cause. Viral pharyngitis is caused by respiratory viruses such as rhinoviruses, coronaviruses, adenoviruses, influenza, and EBV. Bacteria causing pharyngitis include group A and non-group A streptococci, Corynebacterium diphtheria, Corynebacterium pseudodiphtherium, Neisseria gonorrhoeae, Yersinia enterocolitica, Arcanobacterium hemolyticum, and anaerobic bacterial species. Persons infected with the human immunodeficiency virus (HIV) may present with an HIV-induced exudative pharyngitis during the acute retroviral syndrome or with Candida-induced pharyngitis. The etiology of pharyngitis remains obscure in 40% of cases. Most pharyngitis occurs as result of respiratory or contact transmission; few cases are foodborne. Outbreaks are common in winter or in crowded living situations, especially in families with children who serve as reservoirs by acquiring infections in daycare centers or school.

Clinical Findings

A. Signs and Symptoms. The severity of the pharyngitis may vary from mild to life threatening depending on the etiologic agent. Symptoms of mild pharyngitis are irritation or sore throat. With increasing severity there may be severe pain that increases on swallowing or talking, plus cervical lymphadenopathy with or without fever. Pharyngitis can be life threatening with inflammatory edema of pharyngeal walls and extension to the larynx leading to respiratory distress.

An erythematous pharynx with or without exudates or cervical lymphadenopathy is the common finding on examination. Because it impacts therapeutic decision-making, it is important to attempt clinical differentiation between viral and bacterial pharyngitis. However, this may be difficult. Associated clinical signs and symptoms provide diagnostic clues to formulate a differential diagnosis. Mild pharyngeal symptoms with rhinorrhea usually suggest a viral etiology. Pharyngeal exudates suggest streptococcal pharyngitis, HIV, or EBV. Presence of vesicles and ulcers is seen with herpes simplex and coxsackievirus. Coxsackievirus-related vesicles often occur on the hard palate. Adenoviral pharyngitis is associated with conjunctival congestion. EBV, HIV, A hemolyticum, and streptococcal toxic shock can present with pharyngitis and a generalized rash. Pharyngitis with elevated transaminases, splenomegaly, and atypical lymphocytosis is the typical manifestation of EBV-induced infectious mononucleosis. Aseptic meningitis along with pharyngitis should suggest an acute HIV or enteroviral syndrome. Systemic viral infections with CMV, measles, and rubella, among others, can present with acute pharyngitis.

Sore throat with cough and signs of pneumonia may suggest influenza, Chlamydia pneumoniae or Mycoplasma pneumoniae. Diphtherial pharyngitis is associated with a grayish pseudomembrane.

GAS (Streptococcus pyogenes) pharyngitis frequently presents with fever of > 38.3 oC, chills, sudden-onset sore throat, painful and difficult swallowing, and tender cervical lymph nodes. Lymphadenopathy is more likely to be anterior and tender in GAS pharyngitis, unlike viral pharyngitis, which is more likely to be generalized and nontender. Exudate with intense pharyngeal and tonsillar pillars erythema is seen. Occasionally patients, especially children, present with systemic symptoms of nausea, vomiting, and headache. Symptoms of non-group A, such as group C or G, streptococcal pharyngitis are very similar to GAS and clinically indistinguishable. These symptoms and signs are nonspecific for GAS pharyngitis. However, absence of fever or presence of other symptoms such as rhinorrhea, cough, oral ulcers, and viral exanthema strongly suggests a viral rather than a GAS pharyngitis.

B. Laboratory Findings. Laboratory values may not be of considerable help. Testing for GAS should be done in all patients in whom GAS pharyngitis cannot be confidently excluded on clinical grounds. Diagnosis of GAS pharyngitis can be made by RADT, which has a sensitivity of 80-95% and specificity of 95%. Use of RADT significantly increases the number of patients receiving appropriate antibiotic treatment. Because of its relatively lower sensitivity, a negative test should be confirmed with a throat culture. Throat cultures taken from the tonsillar fossae and posterior pharyngeal wall are 90-95% sensitive for the diagnosis of GAS pharyngitis. Follow-up cultures are not generally recommended except in patients with histories of acute rheumatic fever or poststreptococcal glomerulonephritis or in outbreaks. Asymptomatic contacts of the patient do not need to be screened unless there is an outbreak or the patient has a history of acute rheumatic fever.

Special culture media for N gonorrhoeae or C diphtheria should be specifically requested when these bacteria are suspected. Serologic testing can establish the diagnosis of EBV, HIV, CMV, influenza, M pneumoniae, and C pneumoniae. During acute HIV retroviral syndrome, HIV RNA polymerase chain reaction, or HIV culture can help make a diagnosis because HIV serology may be negative.

C. Imaging. A lateral neck x-ray should be done if the patient has associated symptoms of stridor or respiratory compromise, to rule out laryngeal obstruction.

Differential Diagnosis

In children, Kawasaki's syndrome can present with a clinical picture similar to an infectious pharyngitis. Noninfectious causes of pharyngitis include chemotherapy-induced mucositis, drug reactions, agranulocytosis, or connective-tissue disorders.

Complications

Local complications of bacterial pharyngitis include peritonsillar or retropharyngeal abscesses or Fusobacterium necrophorum jugular vein thrombophlebitis and its embolic complications (Lemeire's syndrome). In the United States, appropriate and timely antibiotics have decreased nonsuppurative complications of S pyogenes such as rheumatic heart disease or poststreptococcal glomerulonephritis. C diphtheria pharyngitis may become complicated by acute upper-airway obstruction, myocarditis, or neuritis. Viral pharyngitis may be complicated by secondary bacterial infection of the sinuses or lower respiratory tract.

Treatment

In patients with a clinical picture consistent with GAS pharyngitis, empirical therapy should be started to prevent suppurative and nonsuppurative complications, to decrease infectivity and transmissibility, and to induce clinical improvement of symptoms (Box 9-3). Patients with a high index of suspicion for GAS pharyngitis but negative or pending RADT/culture results can be given empirical antibiotics until the results are available. An alternative approach is to withhold antibiotics until the culture is positive for S pyogenes. Delaying therapy against GAS does not increase the incidence of rheumatic heart disease or recurrences with the same strain of S pyogenes. Following the latter course will decrease inappropriate antibiotic use and control the increase in antibiotic resistance.

Antibiotic selection is based on efficacy, ease of administration, cost, compliance, and spectrum of the antibiotic. The treatment of choice is penicillin V or amoxicillin for 10 d to treat and eradicate carriage. Intramuscular benzathine penicillin G may be given in patients unlikely to complete a 10-d course. Shorter courses are not recommended until more definitive studies are available. Erythromycin or other macrolides (such as clarithromycin or azithromycin), or oral cephalosporins are the recommended alternatives for bacterial pharyngitis in patients who are allergic to penicillin. Absence of penicillin-resistant GAS and limited (5%) resistance to erythromycin make it imperative to choose a cheaper alternative to the newer more expensive antibiotics. In some patients with recurrent GAS pharyngitis, penicillin is unable to eradicate nasopharyngeal carriage. In such patients, rifampin, clindamycin, or amoxicillin/clavulanate use may decrease colonization. Patients with negative throat RADT/cultures should have antibiotics discontinued.

Pharyngitis caused by anaerobic bacteria may respond to penicillins, amoxicillin/clavulanate, or clindamycin. A hemolyticum is susceptible to erythromycin. Yersinia pharyngitis requires treatment with a third-generation cephalosporin, an aminoglycoside or trimethoprim-sulfamethoxazole (TMP-SMX). Effective therapies for gonococcal pharyngitis include ceftriaxone, cefixime, or fluoroquinolones such as norfloxacin, ofloxacin, or ciprofloxacin. Treatment of choice for Mycoplasma pharyngitis is either doxycycline or macrolides. Doxycycline is contraindicated in children < 8 y old because it causes discoloration of teeth.

Symptomatic oropharyngeal herpes simplex ulcers, particularly in an immunocompromised host, should be treated with acyclovir for 7-10 d. Influenza type A pharyngitis can be treated with amantadine or rimantadine or the neuraminidase inhibitors if the patient presents within 48-72 h of onset of symptoms. HIV acute retroviral syndrome should be considered for treatment with combination antiretroviral therapy.

General measures for symptomatic relief include fluids, warm saline gargles, and nonsteroidal anti-inflammatory drugs. Aspirin should be avoided in children with viral infections, particularly varicella-zoster virus infection, to prevent Reye's syndrome. Patients that appear toxic or patients with suppurative complications should be hospitalized for parenteral or surgical management.

Prognosis

Uncomplicated pharyngitis results in no sequelae. Prognosis of GAS pharyngitis complicated by rheumatic heart disease or poststreptococcal glomerulonephritis is good with penicillin prophylaxis in rheumatic heart disease and spontaneous remission in poststreptococcal glomerulonephritis. Suppurative complications have minimal long-term adverse effects.

Prevention & Control

Active immunization plays a role in prevention with regard to diphtheria and influenza types A and B (Box 9-4). Tonsillectomy is recommended in selected patients. Penicillin prophylaxis is required in patients at risk for recurrent rheumatic fever.

THE COMMON COLD

2008-08-16T04:51:00.000-07:00

Essentials of Diagnosis

• Acute rhinorrhea, sneezing, sore throat, burning eyes, cough, malaise, headache, anosmia.

• Usually there is no or low-grade fever in adults, higher fever in infants and children.

• Examination may demonstrate serous nasal discharge, conjunctival and/or pharyngeal congestion, and rhonchi.

• Diagnosis is made clinically, can be confirmed by serology or nasopharyngeal viral cultures in selected cases.

• Imaging is helpful if bacterial superinfective complications suspected (ie, sinusitis).

General Considerations

A "cold" is a self-limited viral infection of the upper respiratory tract presenting with a coryzal syndrome. It is the most common cause for physician visits and absenteeism in school and industry. Infection rates increase sharply during the fall through spring months with peak activity being in the winter. During these months, adults and children have an average of 2-4 and 6-8 colds per year, respectively.

Rhinoviruses are the most common cause of colds, accounting for one third of all colds (Box 9-1). Parainfluenza 1-4 viruses, coronaviruses, influenza types A and B, adenovirus, respiratory syncytial virus (RSV), and their numerous serotypes also are predominant viruses that induce colds. These viruses share a common property of frequent antigenic variation and evasion from the host humoral defense mechanisms, thereby permitting their persistent survival in the community. Other viruses can present with coldlike symptoms during the prodromal period, but their primary syndrome may be localized to another organ system(s).

Transmission is via aerosol, droplet, or direct contact with infected saliva or fomite from an infected person. The rate of infection increases in families with school-age children and in overcrowded and poorly ventilated living spaces. Cigarette smokers are more likely to develop severe disease as compared with nonsmokers.

Once the virus enters the cell, replication and subsequent shedding of the virus occur. The cytopathic effect of the virus on the epithelium varies depending on the virus, being relatively mild in rhinovirus and more marked with influenza virus infection. There is an acute inflammatory response, increased vascular permeability, tissue edema, mucus production, and serum transudation, resulting in the typical cold symptoms of rhinorrhea, nasal obstruction, and cough. After the initial neutrophilic response, there is immunoglobulin M (IgM), IgG antibody, and cytokine production such as interferon, tumor necrosis factor-a, interleukin 8, interleukin 6, and others. Cytolytic T-cell response is more marked and significant in the immune response against influenza viruses than rhinoviruses. Antibody neutralization is the predominant immune mechanism for the latter. Production of antibodies coincides with the cessation of viral replication and waning of the inflammatory response and symptoms. This period may vary depending on the infecting virus. Viral shedding may occur for a few days to weeks.

Clinical Findings

A. Signs and Symptoms. Onset of symptoms is between 24 and 72 h after the infectious contact. Symptoms include malaise, rapid progression to serous nasal discharge and obstruction, sneezing, throat irritation, and cough. There may be nasal intonation of voice with nasal obstruction or hoarseness with laryngeal involvement, or both. Patients may complain of burning of the eyes. Fever usually is low-grade or absent in adults but can be much higher in infants and children. Loss of smell and taste occurs as a result of nasal mucosal edema and obstruction. Overall, the symptoms can last for 1-2 wk.

Associated clinical findings can suggest a specific viral diagnosis; for example, the presence of conjunctivitis suggests an adenoviral upper respiratory infection; myalgias and lower respiratory symptoms such as pneumonia or bronchiolitis may suggest an influenza or RSV infection. Mild disease suggests rhinovirus or coronaviruses. Symptoms of complications such as sinusitis, otitis media, or lower respiratory tract infection may be present. Patients with previous hyperactive airways or asthma can develop exacerbations.

The patient usually appears tired, with thin serous nasal discharge, mild tenderness over the sinuses, and mildly suffused conjunctiva without frank conjunctivitis, and the skin over the nostrils may be red from recurrent blowing of the nose. Pharyngeal erythema without any exudates or lymphadenopathy may be present. Lung examination may reveal evidence of bronchitis or bronchiolitis.

B. Laboratory Findings. Most colds are diagnosed clinically and do not need any further investigations. Mild leukocytosis or leukopenia with or without thrombocytopenia may be noted. Serologies and viral cultures can make a specific viral diagnosis; however, this should be attempted only in selected cases. Rapid RSV or influenza type A antigen detection enzyme immunoassays are very sensitive for nasopharyngeal specimens. Influenza, parainfluenza, adenovirus, cytomegalovirus (CMV), and other viruses can be isolated on cell line cultures. Serologies are available for influenza, parainfluenza, RSV, adenovirus, CMV, and Epstein-Barr virus (EBV). The serologic test is considered positive for active infection if an IgM is present during acute infection or a fourfold rise in IgG in paired sera is detected. Patients with equivocal histories for colds versus group A streptococcal (GAS) pharyngitis should have a rapid antigen detection test (RADT) and bacterial cultures for group A streptococcus.

C. Imaging. No imaging is recommended for uncomplicated colds. However if bacterial or viral complications such as sinusitis or pneumonia are suspected, then appropriate radiographs should be done. A computed-tomography (CT) scan study in patients with a common cold shows frequent involvement of the sinuses.

Differential Diagnosis

A common dilemma is clinically differentiating the common cold from GAS pharyngitis and prodromal symptoms related to systemic syndromes caused by other viruses such as measles, chickenpox, EBV, or CMV. The presence of high fever, chills, severe pharyngeal congestion with exudate, and tender lymphadenopathy is more likely to suggest GAS pharyngitis. An RADT and bacterial culture may be able to confirm this. An exposure history to chickenpox or other viral disease may be a helpful clue to the correct diagnosis. A diagnosis of allergies is evident with rapid resolution and no recurrences in the absence of exposure.

Complications

A complication of the common cold is viral or bacterial sinusitis. A common cold CT scan study by Gwaltney et al (1994) showed that sinus involvement occurs in > 60% of patients with a cold, with 79% of these resolving spontaneously in 2 wk without antibiotics. However, bacterial superinfections of the sinuses, middle ear, or both are potential complications. Viral pneumonia or worsening of bronchospastic airway disease is seen, particularly in children or immunocompromised hosts.

Treatment

The old idiom of "prevention is better than cure" is certainly true for the treatment of the common cold. Multiple different viruses, their many serotypes, and rapid mutations pose a considerable challenge in the development of one vaccine or drug for cold prevention or treatment. Symptomatic support is the only therapy because no effective antiviral therapy is available.

Treatment is directed to rhinorrhea, nasal obstruction, sore throat, and cough. Sneezing, rhinorrhea, and nasal blockage improve markedly with topical or systemic decongestants that decrease edema by vasoconstriction. Topical decongestants such as phenylephrine (0.5% or 0.25%) or ephedrine (1%) nasal spray or drops should be used for a short period. Rebound congestion particularly with use of decongestant sprays beyond 3-4 d can occur. Systemic decongestants include pseudoephedrine hydrochloride, ephedrine, phenylephrine hydrochloride, propylhexedrine hydrochloride, phenylpropanolamine hydrochloride, xylometazoline hydrochloride, oxymetazoline hydrochloride, naphazoline hydrochloride, and tramazoline hydrochloride. Decongestant side effects include tachycardia, elevated blood pressure, fatigue, and dizziness. These should be used cautiously in patients with hypertension and dysrhythmias.

Nasal anticholinergics are effective in inhibiting the parasympathetic activation that contributes to rhinorrhea. Ipratropium bromide nasal spray reduces rhinorrhea and sneezing in the first 3 d of the cold.

Antitussives such as codeine, dextromethorphan, hydrocodone bitartrate, and diphenhydramine hydrochloride suppress the cough reflex in the medullary cough center. Analgesics can be used to improve the myalgias, headache, and sore throat that accompany the common cold. Antihistaminics have no role in the treatment of common cold. The majority of the above mentioned drugs are available over the counter in combination with antihistaminics, analgesics, or antitussives.

Nonspecific measures such as warm saline gargles are encouraged. The role of vitamin C in the common cold is controversial. Studies with dosages of 1-30 g/d demonstrate a 5-29% decrease in severity and duration of symptoms. However, these studies had significant variations for conclusive evidence. Similarly, despite numerous studies of the role of zinc in the management of cold, zinc's role is still controversial and needs further confirmation. Antibiotics have no role in colds unless patients have evidence of bacterial superinfection of the upper respiratory tract.

Prevention & Control

Handwashing is key in the prevention of common colds. Minimizing aerosol or droplet transmission with tissues or covering the mouth should be taught to children and adults. Experimental therapies with interferon-a2 and leukocyte A interferon show some role in the prevention of cold. Producing vaccines for these viruses is difficult because of their numerous serotypes. However, active vaccination can be used for influenza types A and B along with the prophylactic use of amantadine or rimantadine.

INFECTIOUS DISORDERS WITH DYSPHAGIA & DYSARTHRIA AS DOMINANT FEATURES

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Introduction

Involvement of cranial nerves nine through twelve is less frequent in meningeal infections, perhaps because their dysfunctions are less obvious, and they are less carefully examined. Involvement of their nuclei in the brainstem is, however, common in polio, leading to severe dysphagia, dysarthria, and respiratory difficulties. Thus, polio must be considered in unvaccinated individuals who have traveled abroad.

Botulism & Pseudobotulism

Although botulism is a disorder of the neuromuscular junction rather than peripheral nerves, patients with botulism commonly present with dry mouth, dysarthria, dysphagia, diplopia, and impaired ocular accommodation. Rapid recognition of this disease is important. Prompt administration of antitoxin along with ventilatory support is essential in the management of botulism. In addition, recognition of the disease should prompt an intensive search for contaminated foodstuffs, which are most often the cause of the condition in adults. Victims who have only early symptoms may be recognized only because they were identified as sharing certain foodstuffs with individuals who have clear-cut disease.

A cluster of signs and symptoms similar to those in botulism may occur after ingestion of any part of the plant, Jimson weed (Datura stramonium); the syndrome may mimic botulism in patients who present with dysphagia; dilated, fixed pupils; and dry mouth (pseudobotulism), which is often accompanied by visual or auditory hallucinations. The Datura plant contains the anticholinergics atropine and scopolamine, which are highly concentrated in the seeds and can cause serious illness or death. Teenagers seeking mind-altering experiences sometimes experiment with Datura, only to die, probably from the cardiotoxic principle in the plant. They usually present with the pseudobotulism syndrome (fixed, dilated pupils and dry mouth), which is distinguishable from true botulism primarily by the history of contact with the Datura plant or its seeds and by the hallucinations, which are not a feature of true botulism. If the cardiovascular system is stable, the patients usually improve over time without therapy, other than emptying the stomach, using activated charcoal, or both; however, if the patients manifest profound toxicity, including bradycardia or tachycardia, the use of the antidote physostigmine should be considered.

Datura poisoning might also suggest rabies to the initial observer, if the hallucinations are mistaken for encephalopathy and if the dysphagia is mistaken for hydrophobia.

Rabies

Rabies should also be considered in the differential diagnosis of patients presenting with dysphagia and dysarthria, with or without hydrophobia and laryngeal spasms. Rabies must be considered in any patient who has traveled to third-world countries and who has had any contact with potentially infected animals. Skunks, raccoons, and bats are the main animal reservoirs of rabies in the United States.

Treatment with human immune globulin and diploid cell-derived vaccine is very effective for individuals exposed to or bitten by rabid animals, but it is ineffective once neurological symptoms have developed. It is important for persons in close contact with the victims, whose body fluids may be infectious or for others who have had contact with the same or other infected animals to receive postexposure prophylaxis. A detailed review of the indications and procedures for postexposure prophylaxis has been provided by the Centers for Disease Control and Prevention (CDC/MMWR, 1999).

INFECTIOUS DISORDERS INVOLVING CRANIAL NERVES

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Essentials of Diagnosis

• History: antecedent meningeal infection; infections of paranasal sinuses or skull base.

• Signs: cranial nerve deficits, especially nerves two, four, five, six, and seven.

• Laboratory: evidence of meningeal infection in CSF studies; MRI imaging of skull base and paranasal sinuses showing signs of an inflammatory process.

Involvement of the cranial nerves by infectious processes is usually the result of infection in the subarachnoid space at the base of the brain or in structures at the base near or through which cranial nerves course (eg, the cavernous sinus, as discussed previously). In the differential diagnosis, one must be aware that cranial nerves are also commonly involved by neoplastic processes, by inflammatory processes of other types (eg, sarcoidosis), or by vasculitic diseases, especially those affecting medium and small size vessels (eg, giant cell arteritis, polyarteritis nodosa, and diabetes mellitus).

Involvement of cranial nerves three, four, and six and the first division of five can be seen together because they traverse the cavernous sinus. Thus infections or infective thrombosis in the cavernous sinus can involve these nerves together.

Any meningeal infection, particularly if prolonged, can involve the cranial nerves at the base of the brain, so that palsies, particularly of the third, sixth, seventh, and eighth cranial nerves, can be seen in the course of pyogenic meningitis of any type or in more slowly evolving meningitides caused by tuberculosis, fungal infections, syphilis, or Lyme disease. Lyme disease seems to have a particular affinity for the seventh nerve; unilateral or bilateral facial paralysis is commonly seen. Involvement of the fifth nerve can be seen from reactivation of varicella-zoster virus in the trigeminal ganglion producing the well-known shingles eruption in one or more divisions of the nerve. Involvement of the intracranial portion of the carotid artery may occur in the course of ophthalmic zoster with thrombosis of the vessel and a middle cerebral distribution stroke. In contrast, reactivation of HSV in the same ganglion usually results only in the production of fever blisters on the lip.

The common Bell's palsy involving the facial nerve is tenuously associated with herpes simplex infections, prompting some authorities to recommend treatment of such cases with acyclovir. Involvement of the facial nerve by varicella results in the Ramsey-Hunt syndrome, with the appearance of vesicles in the ear. The facial nerve is susceptible to a variety of infections; in addition to those mentioned above, it is vulnerable to bacterial infections in the petrous apex. It, along with the eighth nerve, can be involved in Pseudomonas infections of the ear in diabetics (malignant external otitis).

INFECTIOUS DISORDERS WITH FOCAL DISTURBANCES AS A DOMINANT FEATURE

2008-08-16T04:46:00.000-07:00

Essentials of Diagnosis

• History: fever, headache, chills, sweats, malaise; focal neurological deficits—acute or subacute; infections in paranasal sinuses, mastoid, or elsewhere; intravenous drug use.

• Signs: Fever, leukocytosis; heart murmur; focal neurological deficits.

• Laboratory studies: MRI imaging; lumbar puncture, if not contraindicated by papilledema or presence of a mass lesion on MRI scanning; blood cultures, where appropriate.

The presence of fever, headache, focal neurological deficits, alterations of mental status, seizures, or some combination of these features suggests both focal disturbance of brain parenchyma and meningeal irritation. The range of conditions that can produce these disorders is large. Among the noninfectious causes, one must consider cerebrovascular disorders and primary or metastatic cancer as leading possibilities. In approaching such problems, it is important to try to determine the precise tempo of progression of the problem (ie, did the symptoms appear and become maximal in seconds to minutes, over a few hours, or over days?). Apoplectic onset or a seizure suggests an embolic process, whereas the development of a deficit over minutes to hours is more consistent with thrombosis or hemorrhage. Slower developing deficits suggest the growth of a mass lesion or sequential vascular insults which become additive.

Bacterial Endocarditis

The neurological complications of bacterial endocarditis are multiple, but the most frequent are those due to multiple emboli with infarction of the brain. Although larger emboli can cause obvious strokelike syndromes (most often in middle cerebral artery distribution), multiple smaller emboli may produce complex confusion states admixed with lesser degrees of focal disturbance. Brain abscesses, although infrequent in endocarditis, are usually associated with S aureus endocarditis and, if present in endocarditis, are usually small. They usually resolve with antimicrobial therapy alone. The formation of mycotic aneurysms at the site of embolism is not uncommon and may occur late in the course of the condition. As noted above, rupture of such aneurysms may be fatal.

One must be alert to the possibility of bacterial endocarditis in any patient with known congenital or acquired alteration of the heart valves, particularly if there has been recent oral or urogenital surgery or intravenous drug use. The traditional signs and symptoms of subacute bacterial endocarditis include asthenia, arthralgias, myalgia, anorexia, heart murmurs, splenomegaly, Roth spots, clubbing, fever, and sweats. Most such cases were caused, in the preantibiotic days, by oral streptococci, which have intrinsically low virulence, infecting heart valves damaged by rheumatic fever and causing small vegetations. However, such cases are now less prevalent and, with increasing intravenous drug use, S aureus, which can infect normal heart valves, is an increasingly prevalent cause of endocarditis. S aureus causes "acute" endocarditis with large vegetations, which embolize to cause metastatic abscesses, Osler's nodes, and, a much more toxic appearance than is typical of subacute endocarditis. The metastatic abscesses in staphylococcal endocarditis often occur in the brain and other parts of the CNS, so that the first presentation of endocarditis is often (20-40%) with stroke or another neurologic problem. The signs of endocarditis may all be easily overlooked, and the cause of the neurologic dysfunction missed if attention is devoted exclusively to the neurological phenomena. Thus, fever in the patient with neurologic findings should prompt a search for signs and symptoms of endocarditis, outlined above. The diagnostic criteria have recently been codified by Durack et al (1994). Once endocarditis is suspected, the most sensitive and specific diagnostic study is the transesophageal echocardiogram (ECHO). Repeated blood cultures may be required to identify the causative organism, but identification of the infecting microorganism and quantitative determination of its susceptibility to antibiotics are of critical importance in determining the nature and duration of treatment with intravenous antibiotics.

Herpes Simplex Virus-Induced Encephalitis

Encephalitides caused by viral infection of the brain frequently result in acutely or subacutely developing syndromes that combine headache, fever, alterations of mental status, seizures, and focal deficits. The most frequent cause of sporadic viral encephalitis is herpes simplex virus (HSV). The process in neonates is most frequently due to HSV type 2 (HSV2) resulting from maternal genital infection that was present at the time of birth. In children or adults, the encephalitic process is almost always caused by type 1 HSV (HSV1). Whether the brain infection results from exogenously acquired virus or from virus resident in cranial sensory ganglia or in the brain has not been determined.

In children or adults, the process usually takes place over a few hours to days. Initially the patient may exhibit behavioral changes or loss of memory or occasionally may complain of unusual olfactory or gustatory sensations. If present, these are valuable hints that herpes encephalitis should be considered. These symptoms may be followed by the development of headache, fever, focal deficits (hemiparesis or aphasia), and progressive disturbance of consciousness. Signs of meningeal irritation (stiff neck or vomiting) are often lacking. The diagnosis is most easily established by an MRI scan combined with typical CSF changes. The MRI scan is more sensitive than a CT scan for detecting HSV1 encephalitis; CT scans often appear normal during the first several days of the illness (when therapy is likely to have the greatest impact). Abnormalities on an MRI scan typically consist of contrast-enhancing lesions (bright on T-2-weighted images) in the medial temporal lobe and inferior frontal lobe, often extending medially and upwards into the putamen. Occasionally a seemingly separate area of disease is present in the cingulate gyrus.

The lesions are often associated with cerebral edema, and they are often bilateral, though rarely symmetrical. In our experience the lesions of HSV may be mimicked by cerebrovascular lesions in the temporal lobe or by the lesions associated with mitochondrial encephalopathies. The CSF is abnormal with a lymphocytic pleocytosis and moderately elevated protein concentration. The presence or absence of erythrocytes in the CSF is not of diagnostic help. Use of the HSV1 PCR to detect the presence of HSV genomes in CSF is generally very sensitive and highly specific, and this method has generally supplanted brain biopsy for diagnosis. The test may be falsely negative on the first day or two of the illness and after the second week. Tests for HSV antibody in the CSF are rarely positive early in the disease; cultures for HSV are almost always negative. The electroencephalogram may point to the presence of a temporal lobe abnormality; however, it is not highly specific for HSV infection. Nonetheless, a normal electroencephalogram weighs against a diagnosis of HSV encephalitis.

Treatment with intravenous acyclovir should be instituted as soon as the diagnosis is suspected, because delay in treatment is associated with a poorer outcome. With early, specific therapy, the mortality and morbidity are substantially reduced, and there is little risk from the drug except in patients with renal failure.

Arbovirus-Induced Encephalitis

A variety of arthropod-borne viruses (togaviruses) cause encephalitis, often in localized outbreaks associated with summertime increases in mosquito populations. The treatment of these encephalitides requires excellent supportive care until the patients improve on their own; there are no currently available specific antiviral compounds that are effective against arboviruses.

Brain Abscesses

A variety of bacterial infections must be considered in producing the brain abscess symptom complex. Brain abscesses commonly cause seizures, focal deficits, and, as they enlarge, progressive obtundation. Although many patients with brain abscesses have no evident primary source of infection, it is imperative to search carefully for a primary focus in the paranasal or mastoid sinuses with contiguous spread to the brain. These sites may yield the organism(s) causing the brain abscess. Additionally, metastatic (or "hematogenous") abscesses, ones seeded via the bloodstream, can arise from infection in skin or lung, by IV drug use, in association with endocarditis, or in association with dental procedures.

Brain abscesses are usually recognized by contrast-enhanced CT or MRI scans. The importance of performing CT or MRI scans with contrast enhancement when testing for brain abscesses is demonstrated in Figure 7-1. Brain abscesses may be confused with brain tumors but are usually more spherical with thinner walls; gas, if present, is a valuable diagnostic feature indicating their bacterial etiology. Brain abscesses are often associated with marked degrees of cerebral edema.

Management of patients who have brain abscesses usually involves a combination of surgery for diagnosis and drainage or excision, antibiotic therapy, and treatment of cerebral edema. The bacterial flora causing brain abscesses are highly variable and are often composed of mixed aerobic and anaerobic bacteria. Staphylococci, anaerobic streptococci, and Bacteroides species predominate, but gram-negative bacilli may also be found in brain abscesses. Initial treatment should include a penicillinase-resistant penicillin such as nafcillin or oxacillin to treat a staphylococcal component, a third-generation cephalosporin for gram-negative organisms, and metronidazole for anaerobic streptococci and Bacteroides species. Some authors include an anti-Pseudomonas drug if the abscess complicates chronic otitis.

Stereotaxic surgical aspiration is advisable to establish bacteriologic diagnosis and is often useful to decompress large abscesses or abscesses that block or threaten to rupture into the ventricular system. Repeated aspirations may be necessary to control a mass effect. Abscesses tend to enlarge by extending toward the ventricular system, and they pose a risk for rupture into the ventricles with an often fatal outcome. Thus, drainage efforts must be especially vigorous with abscesses enlarging toward the ventricular surfaces. Extirpation of abscesses should be considered when they are solitary, well encapsulated, and surgically accessible. Surgical extirpation should be considered for posterior fossa abscesses because of their propensity to compress the brainstem and to obstruct the ventricular system.

Management of the cerebral edema that accompanies brain abscesses should include dexamethasone administered intravenously. Mannitol may be used, especially as a temporizing measure prior to surgical drainage. Note that the cessation of steroid therapy, used to diminish cerebral edema, may allow an increase in the inflammatory component of the abscess, with a resulting increase in the degree of enhancement of the abscess wall on contrast-enhanced CT scans. This phenomenon may unnecessarily raise alarm that the abscess is not yielding to therapy; but this conclusion may be erroneous in the face of steroid withdrawal.

Subdural Empyemas

Abscesses in the subdural space (subdural empyemas) are often associated with frontal, sphenoid, or ethmoid sinus infection. For reasons that are not understood, these empyemas are seen almost exclusively in males. Because the subdural space is continuous over the entire surface of the brain and between the hemispheres, large amounts of pus can be contained within it, causing widespread irritation and edema of the underlying brain. The organisms responsible are similar to those in brain abscesses, with aerobic streptococci, anaerobic streptococci, S aureus, and Bacteroides species predominating. In addition, S pneumoniae and H influenzae may cause these empyemas. Often there is associated meningitis if organisms and/or cells spread through the arachnoid into the subarachnoid space. In addition, involvement of cortical veins and venous sinuses in the inflammatory process and possibly with associated thrombosis can be seen.

Seizures are common. Because the CSF is usually abnormal and under raised pressure in these cases, the hazard of a spinal tap often outweighs the potential value of the information that can be gained. The diagnosis is most readily established by MRI or CT scan with contrast enhancement. The treatment consists of prompt surgical drainage through bilateral or multiple burr holes or by means of formal craniotomy. Provisional antibiotic choices can then be modified on the basis of Gram staining and culture of the aspirated pus.

Cerebral Venous Sinus Infections

Infections of the cerebral venous sinuses can be seen in association with any of the above purulent infections (meningitis, brain abscess, or subdural empyema) or as a consequence of mastoid or sinus infection. Usually the venous sinus involved is contiguous to an infected structure such as an infected sinus. The lateral venous sinuses thus may be involved when there is mastoid or ear infection, and cavernous sinus thrombosis may be associated with ethmoid or sphenoid sinus infection or with facial cellulitis. With extension of infective thrombus into cortical veins, seizures and cortical venous infarction are common. Infections of the cavernous sinus may produce proptosis and chemosis of the eye and palsies of the third, fourth, and sixth cranial nerves because these nerves traverse the cavernous sinus. This constellation of signs is also seen in diabetics with nasal or sinus infection caused by Mucor or Rhizopus fungal species. Involvement of the superior sagittal sinus frequently produces cortical vein thrombosis with seizures and may result in infection of the upper convexities of the brain with consequent leg paralysis.

The diagnosis of thrombosis of these venous structures is best made by MRI scanning, which can demonstrate the presence or absence of flow voids, clotted blood, engorgement of these structures, or some combination of these findings. The diagnostic certainty can be further enhanced by the use of magnetic resonance venography.

Treatment consists of antibiotics as for the treatment of brain abscesses or for other specific causative microorganisms that may be identified. Consideration should be given to administration of anticoagulants to inhibit the propagation of clots within the venous sinuses. However, the use of anticoagulants must be weighed against the possibility of worsening the process by hemorrhage, accompanying venous occlusion and infarction of brain.

Fungal Infections

Fungi may cause focal disease in the brain with a constellation of signs and symptoms similar to those considered above. Fungal infections are most often encountered in hosts with compromised cell-mediated and other types of immunity. They are thus seen more often in patients with AIDS, lymphoma, Hodgkin's disease, leukemia, or advanced diabetes or in patients receiving cytotoxic or immunosuppressive regimens. Cryptococcal infection usually presents as severe meningitis and should be considered in the differential of acute bacterial meningitides discussed earlier. Infection caused by Mucor or Rhizopus species occurs most frequently in diabetics with multiple episodes of acidosis. The infection may spread from the oropharynx or paranasal sinuses into the skull base, involving the orbit, cranial nerves two through six, and the cavernous sinus as well as the carotid artery. The clinical picture of a red or proptotic eye with third or sixth nerve paralysis in a diabetic should prompt aggressive biopsy and culture of affected tissues as well as culturing of the nasopharynx and sinuses for Mucor or Rhizopus species. Optimal management requires a combination of surgical debridement and therapy with high-dose amphotericin B or lipid-formulated amphotericin B.

The most frequent fungi associated with parenchymal infection of brain are Aspergillus and Candida species. These infections are seen most frequently in immunocompromised hosts, particularly in those with neutropenia. Aspergillus infections usually have their origins in pulmonary or sinus infections whereas Candida infections are often seen in patients with indwelling intravenous lines, in intravenous drug users, or in patients who have previously been treated with corticosteroids or broad-spectrum antibiotics.

These organisms, especially Aspergillus and Mucor or Rhizopus species, share a predilection for invading the walls of cerebral blood vessels with resulting thrombosis of the blood vessel. Thus, in addition to causing cerebral abscesses and meningitis, they often produce strokelike events as a result of thrombi forming in inflamed vessels. Treatment of these fungal infections is with high-dose amphotericin B or lipid-formulated amphotericin B. Therapy for Candida infection is amphotericin B or lipid-formulated amphotericin B with or without 5-fluorocytosine, depending on the patient's underlying disease and the species of the Candida strain (some strains of certain species of Candida, such as parapsilosis, are exquisitely susceptible to the synergism of amphotericin B with 5-fluorocytosine).

Toxoplasmosis

Toxoplasmosis in the CNS presents most commonly with multifocal lesions, causing focal deficits, seizures, and impairment of cognitive functions over a period of days to weeks. Before the advent of AIDS, CNS toxoplasmosis was encountered only rarely, and then usually in the setting of Hodgkin's disease, lymphoma, or other states of severe immunosuppression. It has become a frequent complication in AIDS patients and should be immediately considered in the AIDS patient who develops multifocal neurologic deficits over a period of a few days to weeks.

The disease is often easily visualized by contrast-enhanced CT or (preferably) MRI scans, most often appearing as multicentric solid or ringlike enhancing lesions in the brain; the appearances are often quite characteristic but can be mimicked by cerebral lymphoma, also an AIDS-associated condition. A negative immunoglobulin G antibody test for Toxoplasma gondii makes the diagnosis unlikely. If the immunoglobulin G antibody test is positive, some experts advocate a therapeutic trial of sulfadiazine pyrimethamine, and folinic acid, in association with monitoring the clinical course as well as the size of the cerebral lesions on MRI scan. If there is no response in 10-14 days or if there is deterioration, a brain biopsy to examine other diagnostic possibilities should be strongly considered.

INFECTIONS PRESENTING AS STROKE SYNDROMES

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Essentials of Diagnosis

• History: known or recently acquired valvular heart disease plus prior infectious processes (eg, staphylococcal sepsis), genitourinary or dental procedures, or intravenous drug use; presence of indwelling intravenous catheters; immunocompromised host predisposed to fungal infections.

• Antecedent signs of infection: fever and chills, heart murmurs.

• Signs of systemic embolism: ocular (Roth spots and other hemorrhages); skin or mucosal (petechiae, Osler's nodes); renal (hematuria); splenic (abdominal pain).

• Laboratory studies: imaging of brain, CSF analysis, cardiac echo studies, blood cultures.

Infections as a cause of stroke are uncommon but must be considered in young individuals, in patients with valvular or congenital cardiac disease, or in immunocompromised hosts. Stroke in young individuals is less often due to atherosclerosis or hypertension and more often related to thrombosis or endocarditis complicating congenital or acquired valvular heart disease as a result of intravenous drug use, right-to-left cardiac shunts, or combinations of the above.

Bacterial Endocarditis

Bacterial endocarditis must always be considered in at-risk individuals, particularly if there is intravenous drug use or if the patients have recently undergone oral or genitourinary surgery or have a prosthetic cardiac valve (see Chapter 11). Embolic infarctions of brain in these individuals, although dominantly in the middle cerebral distribution, can occur in any vascular distribution and are often multiple, frequently in the distal territories of the cerebral vessels, and most frequently encountered when the causative organism is S aureus. The formation of mycotic aneurysms at the site of embolism is not uncommon, and may occur late in the course of the condition. Rupture of the mycotic aneurysm with subarachnoid hemorrhage is uncommon, but, when it occurs, is frequently fatal. The management of these problems, if caused by infective endocarditis, requires prolonged intravenous optimal antibiotic therapy and often repair or replacement of damaged cardiac valves.

Clues to the presence of subacute bacterial endocarditis include known previous congenital or rheumatic heart disease or rheumatic fever and the development of anorexia, backaches, myalgia, or signs of emboli in the spleen, kidney, eyes, or skin. The foregoing signs may all be easily overlooked if attention is devoted exclusively to the neurological phenomena. Repeated blood cultures may be required to identify the causative organism; identification and determination of the organism's susceptibility to antibiotics is of critical importance in determining the nature and duration of treatment with intravenous antibiotics.

Fungal Infections

Immunocompromised hosts, particularly if neutropenic or diabetic, are susceptible to fungal diseases and, of these, Candida, Aspergillus, and Mucor species have a predilection for invading the walls of cerebral blood vessels, resulting in stroke syndromes. The source for Aspergillus infection of cerebral vessels is often in the respiratory tract (see Chapter 75). Candida infection with involvement of cerebral vessels is seen in association with prolonged use of intravenous lines and in intravenous drug users (see Chapter 73). Mucor infections are characteristically seen in diabetic patients with frequent episodes of acidosis (see Chapter 75). Branches of the internal carotid artery, cranial nerves III through VI, and orbital tissues are often involved.

Other Meningeal Infections

Stroke syndromes may be seen in a variety of meningeal infections as a result of the involvement in the inflammatory exudate of penetrating vessels at the base of the brain. Often such vascular involvement is seen relatively late in the course of a meningeal infection and is related perhaps to the duration and intensity of the inflammatory process. It is also seen in acute bacterial meningitides caused by pneumococci (see Chapter 47) or H influenzae (see Chapter 56), in subacute meningitides caused by tuberculosis or fungal infections, and in low-grade chronic meningeal infections such as those caused by syphilis (see Chapter 64). It is rarely observed in viral meningitides but can be seen in the aftermath of herpes zoster (see Chapter 33) when it affects the trigeminal nerves, presumably resulting from a zoster infection of adjacent cranial vessels.

INFECTIOUS DISORDERS WITH DEMENTIA AS A DOMINANT FEATURE

2008-08-16T04:42:00.000-07:00

Essentials of Diagnosis

• If caused by infection, the progression of dementia is over weeks to months rather than years.

• Frontal lobe abscesses may produce dementia without lateralizing or localizing signs.

• Creutzfeldt-Jakob disease should be considered in middle-aged patients with dementia that progresses over a few weeks.

Most dementing processes with infectious causes progress subacutely, that is, over weeks to months rather than over a course of years. A more slowly progressive course may be seen occasionally with communicating hydrocephalus, as a result of prior meningeal infection and interference with reabsorption of CSF. The dementia of tertiary syphilis may also progress over a very long time course.

Frontal Lobe Infections

Infections localized to the frontal lobes of the brain can present as dementias with few other manifestations. For example, a brain abscess in the frontal lobes may fail to produce lateralizing or localizing signs that would be obvious if the abscess were located elsewhere in the brain. Progressive multifocal leukoencephalopathy (PML) (see Chapter 45), even though a disease predominantly affecting the white matter can be present in the frontal lobes and produce dementia prior to the appearance of focal deficits. Although previously encountered as a rare complication of lymphoma or Hodgkin's disease, PML is now most often seen as a complication of AIDS. Dementia in AIDS is commonly seen in the late stages of the process, where it appears to be a direct result of the viral infection. The dementia is characterized by slowness of thought, apathy, and inability to perform consecutive tasks. Loss of motor functions with ataxia and spasticity are seen as the disease progresses. Dementia becomes increasingly frequent as AIDS progresses, with 50-75% of patients affected in the terminal course of the disease.

Creutzfeldt-Jakob Disease

In middle-aged patients with dementia progressing over a few weeks, one must consider the possibility of Creutzfeldt-Jakob disease, which appears to be a prion disease (Ferrer et al, 2000). The dementia in these patients often presents abruptly and worsens perceptibly every few days to weekly, evolving into a state of mutism within 2-5 months. Myoclonic jerking of limb and trunk muscles often accompanies the process, and the patients often startle easily. The electroencephalogram is always abnormal and sometimes may show a characteristic periodic burst-suppression pattern. The CSF is usually normal. An unusual protein has recently been described in the CSF of Creutzfeldt-Jakob patients, but its presence is not sufficiently specific to serve as a diagnostic test. Recently a few cases of Creutzfeldt-Jakob disease have been described in which MRI has demonstrated increased signal in the anterior striatum.

Although Creutzfeldt-Jakob disease, as it is seen sporadically, is not due to an infection, it is thought to result from a mutation in the prion protein gene with production of abnormal isoforms of normal prion proteins; these abnormal prion proteins, if transmitted into another human host, are infectious and, after prolonged incubation, cause the same disease in the recipient. Examples have been the occurrence of the disease in recipients of corneal transplants, dura mater grafts, and human-derived pituitary growth hormone after incubation periods of many months to many years. A variant form of the disease has recently appeared in Great Britain in young individuals, perhaps related to ingestion of beef from animals afflicted by "mad cow disease," another disorder related to infectious prions.

ASEPTIC MENINGITIS SYNDROME

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Essentials of Diagnosis

• Signs and symptoms suggestive of the aseptic meningitis syndrome include fever, headache, nausea, and vomiting.

• CSF pleocytosis is present.

• Gram's stains as well as routine bacterial and fungal cultures are negative.

Some patients who present with the signs and symptoms of meningitis have CSF pleocytosis, but they also have negative Gram stains and routine bacterial cultures of the CSF, and they have no other evidence (such as positive blood cultures) to indicate the etiology of the meningeal inflammation. In considering the management of such patients, it is helpful to designate them as having the aseptic meningitis syndrome rather than "viral meningitis" because some of these patients have proven to have infectious processes that require antimicrobial therapy (Table 7-7), which is not indicated for most cases of viral meningitis.

Diagnosis and management of the aseptic meningitis syndrome and optimal care of the patient is made more difficult if a patient with the aseptic meningitis syndrome is casually diagnosed as having viral meningitis, with a resulting cessation of attempts to make an etiologic diagnosis or to determine the cause of the meningeal inflammation.

General Considerations

Although viral infection is the most frequent cause of aseptic meningitis syndrome, there are many antimicrobial-requiring causes of the syndrome (see Table 7-7). Arthropod-borne viruses (arboviruses) cause disease more often in late summer and early fall; enterovirus disease follows a similar seasonal pattern, with echoviruses and coxsackieviruses predominating. Mumps virus meningitis occurs more often in late winter and early spring. Meningitis due to herpes simplex virus may occur at any time, often in association with a first episode of genital herpes infection.

Clinical Findings

In general, patients with aseptic meningitis syndrome are alert and complain of severe headache, primarily when they turn their eyes to one side or the other or flex their necks. They often seek a dark, quiet room. They rarely become confused or obtunded; so, if confusion or obtundation is evident, bacterial meningitis becomes much more likely. Nevertheless, patients in the early stages of bacterial meningitis can look exactly like those with the aseptic meningitis syndrome.

To determine the cause of the aseptic meningitis syndrome in a particular patient, it is helpful to consider three characteristics of the patient's illness: (1) the pace of development of the illness, (2) the presence or absence of focal or lateralizing neurologic findings, and (3) the presence or absence of confusion.

1. The Pace of Development of the Illness—Depending on the underlying disease and the specific causative microorganism, the development of signs and symptoms of meningeal inflammation may be relatively slow (taking weeks to months) or rather rapid (taking hours to days). Tuberculous and fungal meningitis, as well as syphilitic meningitis and meningeal inflammation caused by bacterial endocarditis, generally develop at a slower pace, whereas pyogenic bacterial meningitis and viral meningitis develop more rapidly (over hours to days). Tuberculous meningitis and fungal meningitis are most expeditiously diagnosed if consultation with a microbiology laboratory is sought, so that optimal media and genetic probing techniques can be used to test the CSF. Similarly, the most incisive serologic tests for syphilis should be used in consultation with an immunology laboratory if syphilis appears to be a likely etiologic agent. Syphilitic meningitis develops more often during the secondary or tertiary stages of the disease and presents with seizures in ~ 18% of patients. Thus, in patients with signs and symptoms suggestive of meningitis, especially seizures, syphilitic meningitis should be considered as part of the differential diagnosis, and appropriate serologic tests for syphilis should be performed on the serum and CSF.

2. The Presence or Absence of Focal or Lateralizing Neurologic and Other Findings—Whereas acute bacterial meningitis may cause cranial nerve abnormalities such as deafness or ophthalmoplegias, viral meningitis seldom causes such neurologic dysfunction. Similarly, brain abscesses, even if they have not ruptured into the subarachnoid space, may cause CSF pleocytosis in the absence of detectable bacteria in the CSF. Brain abscesses are more likely than bacterial or viral meningitis to cause focal neurological findings such as hemiparesis or aphasia. Spinal epidural abscesses, which may cause fever, CSF pleocytosis, and focal neurologic deficits, are usually accompanied by pain and percussion tenderness over the spine. With both brain abscesses and spinal epidural abscesses, CT scans with enhancement or MRI scans may be required to determine the cause of the culture-negative meningeal inflammation.

3. The Presence or Absence of Confusion—In general, patients with aseptic meningitis syndrome as a result of viral meningitis are alert; therefore, if confusion or obtundation is evident, a bacterial etiology or some other nonviral etiology of the meningeal inflammation is more likely.

A. Signs and Symptoms. Signs and symptoms suggestive of the aseptic meningitis syndrome depend on its underlying etiology, but often include fever, headache, nausea, vomiting, and neck stiffness.

B. Laboratory Findings. CSF pleocytosis is present. Gram stain and routine cultures are negative. The CSF glucose, protein, leukocyte count, and differential can be helpful in determining the cause of the syndrome (see Table 7-4).

C. Imaging. A number of the antimicrobial-requiring causes of aseptic meningitis syndrome require imaging studies to identify the lesion for diagnosis, optimal antimicrobial therapy, and, if indicated, surgical drainage. Whereas the CSF in true viral aseptic meningitis has a lymphocytic pleocytosis, abscesslike processes, including contiguous sinusitis, often have predominantly polymorphonuclear leukocyte pleocytosis of the CSF. Thus, the presence of the aseptic meningitis syndrome plus clinical signs suggesting the presence of a mass lesion, especially if there is polymorphonuclear pleocytosis of the CSF, should prompt imaging studies of the areas likely to be involved. A CT scan may suffice if acute intracranial hemorrhage is a possibility or if the patient cannot remain motionless in an MRI scanner; otherwise, MRI scans are the preferred imaging modality. Brain abscesses may not be visualized on CT scans unless contrast enhancement is used (Figure 7-1). Thus, contrast enhancement should be used with CT scans that are performed because a brain abscess is in the differential diagnosis. If a brain abscess is a possibility, a CT scan should not be considered to be completed unless it was done with contrast enhancement.

Differential Diagnosis

There are a substantial number of causes of aseptic meningitis syndrome, which can be life-threatening if not treated appropriately, sometimes with antimicrobial agents (see Table 7-7). The antimicrobial-requiring causes of aseptic meningitis syndrome should be excluded before embarking on an extensive workup of the non-antimicrobial-requiring causes (Table 7-8).

Some antibiotics and other pharmaceutical products can induce aseptic meningitis syndrome (Table 7-9). Whereas infectious causes of the meningitis should be excluded first, the drugs that cause meningitis are usually not critical, and substitutions of drugs that do not cause meningitis can easily be made. In a patient with meningitis who is having seizures, treatment with phenytoin usually suffices when intravenous administration is necessary; carbamazepine may be used when oral administration is possible, keeping in mind that it rarely may produce an aseptic meningitis syndrome.

To avoid inducing drug-related meningitis, avoid antimicrobial treatment of respiratory tract infections (eg, sinusitis and pneumonia) with oral antibiotics that do not have optimal activity against pneumococci and other streptococci. A substantial number of patients have acquired fatal pneumococcal sepsis and meningitis while taking such antibiotics. For instance, life-threatening pneumococcal and other streptococcal infections, including meningitis, have complicated therapy with the following oral antimicrobial agents: ciprofloxacin (Lee et al, 1991; Righter, 1990) and cefixime (Ottolini et al, 1991).

Complications

The complications of aseptic meningitis syndrome depend on its etiology. If caused by a pharmaceutical product such as ibuprofen, cessation of the inciting drug usually results in disappearance of the meningitis without complications. On the other hand, aseptic meningitis syndrome resulting from a brain abscess may be fatal if the brain abscess is not identified and treated properly, so that it is allowed to rupture into the CSF space.

Treatment

As with bacterial meningitis, the antimicrobial therapy should be specifically targeted toward the most likely organism to cause the aseptic meningitis syndrome. For instance, the most likely organism to cause an epidural abscess is S aureus, whereas multiple brain abscesses associated with endocarditis are likely to be caused by the same organism that is infecting the heart valves.

In some patients, the best therapy for aseptic meningitis syndrome may be stopping a drug that is causing the meningitis. For instance, in a patient with AIDS who develops aseptic meningitis syndrome while receiving sulfa-trimethoprim prophylaxis against Pneumocystis carinii infections, it would be reasonable, after excluding infectious causes of the aseptic meningitis syndrome, to change the prophylaxis from sulfa-trimethoprim, which can cause an aseptic meningitis syndrome (see Table 7-9), to pentamidine for Pneumocystis prophylaxis. Antiviral therapy is not indicated for most cases of viral meningitis.

Prognosis

The prognosis of aseptic meningitis syndrome is the same as that of its underlying cause. For instance, neoplastic meningitis as the cause of aseptic meningitis syndrome has a dire prognosis, whereas drug-induced aseptic meningitis syndrome and virus-caused aseptic meningitis syndrome have an excellent prognosis.

Prevention & Control

Aseptic meningitis syndrome has such diverse causes that there is no single means of prevention and control. For instance, syphilis-related aseptic meningitis syndrome might be prevented by the use of condoms, and Lyme disease-related aseptic meningitis syndrome might be prevented by using an insect repellent that protects against the Ixodes tick vector.

Infections of the Central Nervous System

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INTRODUCTION

*The author is grateful to J. Richard Baringer, MD, Professor of Neurology, University of Utah School of Medicine, for his careful review of this chapter, his constructive suggestions, and the several sections he wrote on subjects that represent special areas of his expertise.

The signs and symptoms of infections of the central nervous system (CNS) are not specific to each type of infection (eg, brain abscess or meningitis), but certain clusters of signs and symptoms can limit the range of CNS infectious diseases that must be considered. The following elements of a patient's history, signs, and symptoms may indicate or accompany meningeal or parenchymal CNS infections, especially if one or more occur in the same patient: fever; headache; nausea and vomiting; confusion, obtundation, or uncharacteristic behavior; stiff neck; or focal neurologic dysfunction.

When these signs and symptoms follow those of infection of the upper or lower respiratory tract, the cluster suggests the transition of the respiratory tract infection to bacteremia or viremia and then its progression to meningitis or another type of CNS infection.

ACUTE BACTERIAL MENINGITIS

General Considerations

More than most other infectious diseases, acute bacterial meningitis threatens the life, personality, and functional ability of a patient. The disease may be obvious or quite subtle in its initial presentation. Empiric therapy usually relies on a one-step (or monosynaptic) thought process (disease ? antimicrobial agent) that is not optimal for managing most infectious diseases. Optimal recognition and management of acute bacterial meningitis use a progressive, three-step (or polysynaptic) thought process that is also effective for managing most other infectious diseases (Table 7-1).

1. DISEASE (DIAGNOSIS)

The key findings in meningitis are the presence of fever, headache, stiff neck, nausea and vomiting, and, often, variable states of confusion. Note that neck stiffness, although usually present, is often overlooked. Although a stiff neck is not required to make the diagnosis of meningitis, its presence demands immediate pursuit of the diagnosis of meningitis.

Perhaps the most helpful indication that the diagnosis of meningitis should be considered seriously enough to warrant the performance of a spinal tap (if a thorough examination yields no signs of an intracranial mass or increased intracranial pressure) is the transition of a sore throat or other upper respiratory tract irritation to nausea and vomiting. Whereas most patients who actually have meningitis have fever and headache, the pattern of evolution of meningitis, especially meningococcal meningitis, is from sore throat to tachypnea (perhaps a sign of early meningococcemia with disseminated intravascular coagulation) and then to nausea and vomiting as the meningococcemia seeds the cerebrospinal fluid (CSF) space and establishes meningitis with cerebral edema.

The constellation of headache, fever, nausea, vomiting, or a combination of these symptoms should immediately prompt the consideration of meningitis, especially in the context of previous disease or irritation of the upper respiratory tract (eg, sinusitis, otitis media, or pharyngitis). Often patients with meningitis will complain of ocular pain or an increase in headache when turning their eyes from side to side. Although this sign is not specific for meningitis, its presence should prompt suspicion of the disease.

Although the accuracy of the clinical examination in the diagnosis of meningitis is limited by the paucity of prospective data, Attia et al (1999) have evaluated the clinical findings in meningitis and cite the 97% sensitivity and 60% specificity of the jolt test of Uchihara and Tsukagoshi (1991) in diagnosing meningitis. The jolt test, accentuation of headache by rapid movement of the head from side to side, appears to have potential usefulness, but more widespread systematic evaluation is needed before incorporation of the test into routine practice can be recommended.

In a febrile patient with a history of previous upper respiratory tract irritation, vomiting should elicit concern about meningitis rather than being considered a sign of gastroenteritis or "the flu."

Note that almost all patients with bacterial meningitis give a history of upper respiratory tract irritation that can be interpreted as pharyngitis. However, health care personnel should consider the context of such complaints, and, if there is fever > 101 °F, nausea or vomiting, headache, confusion, or any signs of neurologic irritation, meningitis should be strongly suspected. The author has seen patients who suffered permanent neurologic damage because their meningitis was not recognized and health care personnel, using an algorithm for pharyngitis, gave oral antimicrobial therapy, which is inappropriate for meningitis.

Although patients often do not complain spontaneously of neck stiffness, they frequently will admit to the symptom if questioned. Detecting neck stiffness is best done by cupping the patients occiput in the examiner's hands, gently turning the head from side to side, which usually causes little discomfort, and then gently flexing the neck while observing the patient's face for signs of pain and feeling for sudden resistance as the neck is flexed. Modest degrees of meningeal irritation are usually evident with this procedure. Whereas the traditional Kernig and Brudzinski signs may be present in acute meningitis, in the author's experience they are present much less often than is neck stiffness and are less sensitive in the detection of minor degrees of meningeal irritation than is testing for neck stiffness as described above.

Once the diagnosis of meningitis has been seriously considered and care has been taken to assure that there are no signs of an intracranial mass (eg, no papilledema or focal neurologic abnormalities), a lumbar puncture should be performed.

2. PREDICTION OF THE MOST LIKELY CAUSATIVE ORGANISM

Introduction

Acute meningitis is most often caused by bacteria that have capsules (eg, Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae). These organisms are passed from person to person by droplet spread or mucosa-to-mucosa spread during close contact. Although some yeasts (eg, Cryptococcus neoformans) cause acute meningitis in patients with ostensibly normal immunity, they cause meningitis more often in patients whose cell-mediated immunity is compromised (eg, by lymphoma, AIDS, steroids, or other forms of iatrogenic immunosuppression), and yeast infections must be sought in such patients.

Empiric therapy entailing the choice of broad-spectrum antibiotics instead of organism-specific therapy is suboptimal for acute meningitis, because such therapy is at danger of being less active and less effective than therapy specifically targeted for the most likely organism. Therefore, optimal therapy entails predicting the most likely organism to be causing the meningitis and then administering the therapy that is optimal for that organism. Usually one can correctly deduce the most likely organism to be causing the meningitis by considering four kinds of information regarding the patient: (1) personal risk factors, (2) community risk factors, (3) physical examination, and (4) laboratory and imaging studies (see Tables 7-1, 7-2, 7-3, and 7-4).

Personal Risk Factors

The bacterial pathogen most likely to cause meningitis varies with the site of acquisition and the age of the patient (Table 7-2). Patients who are asplenic or alcoholic or who have preexisting ear or paranasal sinus infections are at greater risk of having infections with S pneumoniae.

Among patients who have conditions that allow access of stool to CSF, for instance, a pilonidal sinus or Strongyloides stercoralis infestation, Escherichia coli is often the most likely organism to be causing their meningitis.

In some cases, the most likely organism may be predicted by the nature of prior antimicrobial therapy. Certain broad-spectrum, oral antimicrobial agents such as ciprofloxacin or cefixime may predispose a patient to bacterial meningitis, apparently by eradicating normal nasopharyngeal flora and allowing overgrowth of meningitis-causing bacteria, especially S pneumoniae, which is less susceptible to these antibiotics than are normal flora. A substantial number of patients have developed fatal pneumococcal sepsis and meningitis while being treated with such antibiotics (Lee et al, 1991; Ottolini et al, 1991). Ironically, most of the antibiotics were prescribed for upper respiratory tract infections, bronchitis, and otitis media, which may not benefit from antimicrobial therapy (Gonzales et al, 1997; Nyquist et al, 1998).

The microorganism causing the antecedent respiratory tract or other type of infection is the likely cause of meningitis in many patients. Patients with enteroviral meningitis have sometimes had recent contact with children or others with diarrhea. A recent episode of genital herpes should prompt consideration of a herpetic etiology of the meningitis.

Community Risk Factors

Cases of meningococcal disease may occur in epidemics or clusters, and state or local health departments may be helpful in predicting the most likely organism from such epidemiologic data.

Similarly, clusters of meningitis caused by Listeria monocytogenes have occurred in conjunction with the ingestion of raw and cooked meat, poultry, and, especially, unpasteurized dairy products such as cheese that have entered the commercial food supply contaminated with L monocytogenes.

Physical Examination

Several physical signs, considered in light of the patient's age, can be extremely helpful in correctly predicting the infecting organism (Table 7-3). If there are no physical signs suggesting the most likely organism, the organism can be predicted on the basis of the locale of acquisition of the meningitis and the patient's age as described above (see Table 7-2).

Laboratory/Imaging Studies

The laboratory findings in the CSF can also be helpful in either predicting or determining with certainty the most likely organism or type of organism to be causing the meningitis (Table 7-4).

Chest x-rays showing pneumonia in conjunction with meningitis suggest that the cause of the pneumonia may be the same as that of the meningitis; this association has been observed with N meningitidis and S pneumoniae infections. If the pneumonia in conjunction with meningitis is cavitary, organisms that cause cavitary pneumonia such as Staphylococcus aureus or Pseudomonas aeruginosa should be suspected.

3. DESIGN OF OPTIMAL THERAPY FOR THE PARTICULAR PATIENT

Introduction

It is important to initiate therapy as promptly as possible. In general, it is preferable to begin therapy after CSF and blood cultures have been obtained, but before the results of the laboratory examinations are available. Therefore, the hypothesis about the most likely organism should be used to initiate therapy, then the hypothesis should be tested by examining the CSF with nonspecific tests such as the leukocyte count and differential and CSF protein and glucose concentrations, all of which can be helpful in indicating groups of causative agents (see Table 7-4). A more sensitive and specific identification of the most likely organism often can then be obtained by performing a Gram stain on CSF subjected to cytospin slide centrifugation and culture and, if the Gram stain is negative, also testing the CSF for evidence of cryptococcal antigen and tuberculous infection, using polymerase chain reaction (PCR) or culture. Microscopic detection of the organism causing meningitis is more effective if the CSF is first subjected to cytospin slide centrifugation, which substantially increases the sensitivity of the Gram-staining endeavor (Shanholtzer et al, 1982). Rapid bacterial antigen tests were once used to attempt identification of the causative microorganism if prior antimicrobial therapy made it undetectable. However, bacterial antigen tests were found to be of "no detectable clinical benefit" in diagnostic and therapeutic decision-making (Perkins et al, 1995), and many laboratories no longer perform these tests.

If pneumococcal meningitis is likely (see Table 7-2), a premium should be put on culturing the organism from blood or CSF so that knowledge of its penicillin susceptibility can help facilitate design of an optimal treatment regimen. If specific tests such as PCR analysis of the CSF point to an organism different from the one originally hypothesized, the therapy can be changed to another specific therapy (such a change will seldom be necessary).

Whereas the foregoing considerations represent the optimal approach to acute bacterial meningitis, one must remember that tuberculous, cryptococcal, and occasionally coccidioidal meningitis also may have an acute onset and may produce clinical findings indistinguishable from those in acute bacterial meningitis.

Differential Diagnosis

Note that vomiting, although a common symptom of gastrointestinal disease, occurs frequently in meningitis. Meningitis is likely to be much more threatening to the life and function of the individual than is gastrointestinal disease, so one should not assume that vomiting in the febrile patient represents gastroenteritis.

A patient with meningococcal sepsis may have a normal or low total peripheral leukocyte count, but there is often an increased proportion of "bands" or immature polymorphonuclear leukocytes in the peripheral blood. In patients who have such laboratory findings in conjunction with other signs or symptoms of sepsis, strongly consider initiating parenteral therapy for sepsis, using antimicrobial agents appropriate for the most likely causative microorganism.

Syphilitic meningitis develops more often during the secondary or tertiary stages of the disease, generally at a slower pace than meningitis caused by other microorganisms, and presents with seizures in ~ 18% of patients with this disease. Thus, in patients with signs and symptoms suggestive of meningitis, especially seizures, syphilitic meningitis should be considered as part of the differential diagnosis, and appropriate serologic tests for syphilis should be performed on the serum and CSF.

Cautions Prior to Lumbar Puncture

It is very important to establish whether the patient with signs and symptoms of acute meningitis has papilledema, which is rare in acute meningitis without complications such as a mass lesion. A thorough examination should also be performed to detect any lateralizing findings (eg, hemiparesis or hemianopic field defect) or localizing findings (eg, aphasia), which might suggest the presence of some other process such as a brain abscess, subdural empyema, or cerebral infarction with mass effect. The presence of papilledema, localizing signs, or lateralizing signs mandates an imaging study before the performance of a lumbar puncture. A lumbar puncture performed in the presence of a mass lesion, particularly one that displaces intracranial structures, can result in a herniation syndrome and possibly death. However, antimicrobial therapy for the meningitis should be initiated before the patient is sent for the imaging study, as noted below.

In many emergency rooms, it is common practice to obtain a computed tomography (CT) scan for patients who have signs and symptoms suggestive of meningitis, before a diagnostic lumbar puncture is performed or antimicrobial therapy is instituted. Most authorities agree that any delay involved in obtaining such imaging studies could result in a significant hazard to the patient with meningitis if antibiotic treatment has not already been instituted. Bacteria multiply rapidly in the sheltered environment of the subarachnoid space, and the delays that are commonly encountered in obtaining imaging studies create a significant additional hazard to the patient. Therefore, if imaging studies are indicated (see previous paragraph), the patient should be stabilized, and optimal parenteral antibiotic therapy should be begun before such imaging studies are obtained. However, Baker et al (1994), after a systematic study of the efficacy of routine head CT scans prior to lumbar puncture in the emergency department concluded, "Routine use of CT scans in the absence of localizing signs prior to lumbar puncture in the emergency department is not indicated."

In some instances it may be necessary to perform a lumbar puncture without CT or magnetic resonance imaging (MRI) to establish the diagnosis of meningitis in order to permit initiation of prompt, optimal, specific antibiotic treatment. For instance, if a patient with signs of meningitis (but with no suggestion of papilledema or lateralizing or focal neurological deficits) is cared for in a setting where imaging studies are not available, eg, a rural office or clinic, it may be necessary to perform a lumbar puncture to establish the diagnosis of meningitis and institute optimal parenteral therapy. In such a situation, if the patient is to be transferred to a tertiary facility, the parenteral antimicrobial therapy should be continued and part of the CSF, as well as blood cultures obtained before therapy, should be transported with the patient. In addition, in the midst of a community-wide epidemic of meningococcal meningitis or when the patient has signs of meningococcal sepsis (eg, petechiae or purpura fulminans) with meningitis, it is probably safe to do a lumbar puncture without antecedent CT or MRI imaging if there are no signs of an intracranial mass.

Once treatment of meningitis has commenced and the patient has been stabilized, it is the practice of some experts to image the brain at some time during the course of therapy because of the frequency of associated pathologic processes. These associated processes include paranasal or mastoid sinusitis, subdural empyemas or effusions, basilar skull fractures, intracerebral abscesses or infarctions, and hydrocephalus, many of which may require neurosurgical intervention. Other experts reserve CT or MRI scans for patients with signs of a mass lesion, patients who remain febrile for > 5 days after initiation of optimal antimicrobial therapy, patients who have altered consciousness, or patients who were initially infected with bacteria such as S pneumoniae that are especially likely to cause sinusitis or loculated pus that requires drainage.

Optimally, for the diagnosis and therapy of most patients with known or suspected meningitis, the steps in Table 7-5 should be taken, but, if the presence of even questionable findings of papilledema, lateralizing signs, or localizing signs raises concerns over a possible mass lesion, or, if there is worsening headache or a diminishing level of consciousness, imaging studies should be considered as follows:

A. Immediately Available CT Scan. If a CT scan can immediately be performed, obtain a CT scan and proceed to a lumbar puncture if no mass lesion is present, and follow the remainder of the steps in Table 7-5.

B. CT Not Readily Available. If a CT scan is not readily available or a significant delay is anticipated, most experts recommend that blood cultures be obtained immediately and antibiotic treatment optimal for the most likely organism (see Tables 7-2 and 7-3) be instituted before the CT or other imaging study and before a lumbar puncture (see Treatment section below). The prior institution of antibiotic therapy will only minimally decrease the diagnostic sensitivity of CSF cultures and may still allow detection and identification of the causative microorganism by stains or PCR. The initial emergency therapy can be changed if findings of stains, cultures, or PCR on the CSF so indicate. A change in therapy will seldom be necessary. Especially in pneumococcal meningitis, with increasing resistance of pneumococci to beta-lactam antibiotics, it is helpful to culture the organism rather than simply detecting it with stains or PCR, because the viable organisms are necessary for determining the penicillin susceptibility of the infecting pneumococcus, which is information that may be important in designing an optimal antipneumococcal antimicrobial regimen.

Patients with known or suspected meningitis should not be sent out on oral antibiotics, but should be admitted to the hospital and treated with parenteral antimicrobial agents that are optimal for the most likely organism.

Treatment

To put the imperative for speed in initiating therapy into more concrete terms, some experts have suggested a goal of allowing no more than 30 min from the time of clinical diagnosis to starting an IV infusion of the best antibiotic for the most likely organism to be causing the meningitis. A suggested use of the 30 min appears in Table 7-5 and assumes that the above-mentioned precautions and procedures regarding signs of a mass lesion will be observed.

Intravenous antimicrobial agents are the optimal types of therapy for acute bacterial meningitis. Specific, optimal antimicrobial agents for the therapy of acute meningitis that is known or suspected to be caused by particular organisms are reviewed in Table 7-6. The antimicrobial agent chosen should meet a number of criteria, which are listed under "Best Antimicrobial" in Table 7-1. As noted, the antimicrobial agent chosen should avoid the patient's special vulnerabilities. For example, if possible, the patient should not be given an antibiotic to which he or she is allergic; patients with myasthenia gravis, which causes intrinsic neuromuscular blockade, should not be given aminoglycosides, which may induce further neuromuscular blockade; and, if possible, patients with hemolytic anemias such as sickle cell disease should not be given chloramphenicol, which diminishes erythrocyte production.

Complications

It may be difficult to separate the complications of the bacteremia and septicemia that are associated with the meningitis from the complications of the meningitis per se. The complications of the septicemia include coagulation disorders such as disseminated intravascular coagulation (manifested in meningococcemia as a petechial rash and "purpura fulminans" or in some cases as hemorrhagic adrenal necrosis—"Waterhouse-Friderichsen syndrome"), myocarditis with congestive heart failure, shock, and prolonged fever. The more frequent complications of the meningitis per se result from the inflammatory reaction, including tumor necrosis factor-alpha (TNF-a) induction, which may cause damage to cranial nerves with resulting ophthalmoplegias, deafness, and blindness. Seizures or hydrocephalus may occur as early or late complications. In meningitis caused by H influenzae in children, some of these complications appear to occur less frequently if dexamethasone is administered in conjunction with antimicrobial agents to diminish the production of TNF-a (see Table 7-6). No comparable information is available for meningitis in adults or for meningitis caused by other bacteria.

Prognosis

Although the mortality rate for bacterial meningitis varies with the specific etiologic agent and the clinical circumstances, especially the age of the host, with early diagnosis and prompt, targeted (not broad-spectrum) antimicrobial therapy, the mortality rates for meningococcal and H influenzae meningitis are generally < 10% and 5%, respectively. Pneumococcal meningitis has a worse prognosis, with mortality rates of ~ 20%; in addition, neurologic complications, such as hydrocephalus, subdural empyema, seizures, and cranial nerve palsies, occur more frequently in meningitis caused by S pneumoniae.

Prevention & Control

A first line of defense against meningitis is the induction of anticapsular antibodies by means of vaccines or natural exposure. Timely administration of H influenzae type b (Hib) conjugate vaccine has dramatically reduced the frequency of H influenzae meningitis in the United States; however, in some states, less than half of the eligible children have been immunized.

By reducing pneumococcal bacteremia, a pneumococcal vaccine theoretically should decrease the frequency of pneumococcal meningitis, and the limited immunogenicity of some of the pneumococcal serotype polysaccharides in children < 2 years old has recently been circumvented by conjugating the polysaccharides to a diphtheria protein. The resulting, currently available, 7-valent pneumococcal vaccine has been shown to prevent pneumococcal carriage and invasive pneumococcal infections, including meningitis, in children < 2 years old.

A 23-valent pneumococcal vaccine is recommended for all patients aged = 65 and for nursing home residents, as well as for immunocompromised and other high-risk patients. Anatomic or functional asplenia is an absolute indication for the vaccine, and the vaccine should be given, if possible, at least 2 weeks before splenectomy. The vaccine is also recommended 2 weeks before beginning any immunosuppressive treatment.

The conjugate pneumococcal vaccine is indicated for the active immunization of infants and toddlers against invasive disease caused by pneumococci of the capsular types represented in the vaccine. The routine schedule is vaccination at 2, 4, 6, and 12-15 months of age. This vaccine is not for use in adults.

A quadrivalent meningococcal vaccine (including groups A, C, Y, and W135) is available. If there is an epidemic or cluster of cases in a closed population, such as that of a college campus or group home, or for individuals traveling to countries where meningococcal disease is epidemic, the use of the meningococcal vaccine should be considered. The quadrivalent vaccine is recommended for use in epidemics of meningococcal disease caused by strains of any group whose capsular type is represented in the vaccine. Help in determining the need for a vaccine administration program and in planning such a program should be sought from the appropriate state health department or from the Centers for Disease Control [telephone (404) 639-2215].

Protection of Contacts in Cases of Meningitis

A. Meningococcal Meningitis. Individuals who have had prolonged close contact with a meningococcal meningitis patient, especially those who have had mucosa-to-mucosa contact with such a patient, are at risk of becoming newly colonized with meningococci either from the patient or from the same source as the patient. It is newly colonized individuals, lacking serum anti-meningococcal antibodies, that are at greatest risk of developing meningococcemia or meningitis. The purpose of chemoprophylaxis is to eradicate the newly acquired meningococci and their progeny before they cross the nasopharyngeal epithelium and enter the bloodstream.

The physician managing a patient with meningococcal meningitis should notify local public health authorities about the case and work out a strategy for announcing promptly and proactively who does need and who does not need chemoprophylaxis.

Meningococcal vaccine should not be used instead of rifampin chemoprophylaxis for individuals at risk, because the response to meningococcal vaccine is not rapid enough to meet the immediate need of protecting the contacts of patients with meningococcal meningitis. Such at-risk individuals should be given chemoprophylaxis with rifampin.

Chemoprophylaxis should be given to close contacts of the patient (eg, family members, girlfriends or boyfriends, or others who may have had direct contact with the index patient's oral secretions). Chemoprophylaxis is not recommended for casual contacts, such as individuals with no history of direct exposure to the index patient's oral secretions (eg, school- or workmates). Those medical personnel who have had mucosa-to-mucosa contact with victims of meningococcal disease (eg, through mouth-to-mouth resuscitation, intubation, or suctioning before antibiotic therapy is begun) appear to be at risk and should receive chemoprophylaxis. Other medical personnel appear to be at minimal risk, but most experts would offer them chemoprophylaxis if they were exposed to a case.

The chemoprophylaxis regimens for protecting individuals exposed to a case of invasive disease caused by N meningitidis or Hib are the same as those used to eradicate the carrier state of the index patient prior to discharge from the hospital (see boldfaced text under the respective organisms in Table 7-6). The rifampin powder in the proper dosage can be made into a liquid formulation or incorporated into other vehicles such as applesauce for young children.

B. H influenzae Meningitis. The recommendation for chemoprophylaxis for contacts of cases of Hib meningitis is as follows: "In those households with at least one contact younger than 48 months whose immunization status against Hib is incomplete, rifampin prophylaxis is recommended for all household contacts, irrespective of age" (1997 Red Book, p. 223). See Table 7-6 for the recommended rifampin prophylaxis for protection of individuals exposed to a case of invasive Hib disease.

Because penicillins and some cephalosporins—antimicrobial agents often used to treat meningococcal or H influenzae meningitis—do not penetrate human cells well, meningococci and H influenzae organisms may remain safely inside cells of the nasopharyngeal mucosa of a patient cured of meningitis and emerge later to cause meningitis in the patient's siblings. Therefore, depending on the type of therapy of a patient with meningitis, the patient may need to be given chemoprophylaxis-like antimicrobial therapy to eradicate his or her carrier state before discharge. Such predischarge therapy is recommended for patients with either meningococcal or H influenzae meningitis and, for children older than 1 month, should consist of rifampin given essentially as indicated for chemoprophylaxis of contacts and detailed in Table 7-6. Some experts do not give such therapy if the cephalosporin used for treatment of the meningitis was cefotaxime or ceftriaxone, either of which appears to eradicate nasopharyngeal foci.

Diagnosis of Viral Infections

2008-08-16T04:29:00.000-07:00

INTRODUCTION

It is becoming increasingly important for the practitioner to perform viral diagnostic studies because prognostic, epidemiologic, and therapeutic considerations may be greatly influenced by knowledge of the specific virus causing a given illness. Even if no therapy is available, the establishment of a definite diagnosis of viral infection is often beneficial in (1) epidemiologic monitoring, (2) educating physicians and patients, (3) defining the disease process, and (4) evaluating therapeutic implications, both positive and negative. Moreover, identification of a virus as the cause of a patient's illness may be cost effective, because expensive diagnostic procedures and antibiotic therapy may be avoided or discontinued.

The virology laboratory can confirm the suspected diagnosis by cytologic examination of clinical specimens; attempting to isolate the virus; detecting the presence of viral antigens, or nucleic acids or evaluating the patient's immune response to the virus (serology).

CYTOLOGY

The simplest technique for viral diagnosis is cytologic examination of specimens for the presence of characteristic viral inclusions, but this approach is insensitive and applicable to only a few viruses, especially herpes viruses. These intracellular structures may represent aggregates of virus within an infected cell or may be abnormal accumulations of cellular material resulting from the virus-induced metabolic disruption. Papanicolaou (Pap) smears may show these inclusions in single cells or in large syncytia (aggregates of cells containing more than one nucleus), as in a patient with herpes simplex infection of the cervix. Cytology can be used to detect infections with herpes simplex virus, varicella-zoster virus, cytomegalovirus, human papillomavirus, and adenoviruses. Rabies infection may also be detected by finding Negri bodies (rabies virus inclusions) in brain tissue.

CULTURE-BASED METHODS

Introduction

The historical "gold standard" of viral diagnosis is recovery of the agent in tissue culture, embryonated eggs, or experimental animals. Embryonated eggs are still used for the growth of virus for some vaccines but have been replaced by cell cultures for routine virus isolation in clinical laboratories. Likewise, the use of experimental animals rarely occurs in most clinical laboratories. Just as multiple media are used in bacteriology, several different types of tissue culture cells (eg, monkey kidney, human fetal lung, human amnion, or human cancer cells) are inoculated with each viral specimen.

Most clinically significant viruses can be recovered in at least one of these cell cultures, but several clinically important viruses are not isolated in these cells. For example, specimens submitted for the identification of viruses such as human immunodeficiency virus, coxsackie A virus, and rubella virus require, respectively, cocultivation with normal human peripheral blood mononuclear cells, inoculation of suckling mice, and the use of specialized cell cultures, which are not generally available. Therefore infections caused by these and several other viruses are most frequently diagnosed serologically or by detection of virus-specific antigens or nucleic acids.

Detection of the growth of a virus is by observation of changes in the cell culture monolayer [cytopathic effect (CPE)]. Characteristic CPEs include changes in cell morphology, cell lysis, vacuolation, syncytia formation, and presence of inclusion bodies. Inclusion bodies are histologic changes in cells caused by the presence of viral components or changes in cell structures. With experience a technologist can distinguish CPE characteristics of the major virus groups. The observation of which cell culture exhibits CPEs and the rapidity of viral growth can be used for the presumptive identification of many clinically important viruses. This approach for identifying viruses is similar to bacterial identification based on growth and morphology of colonies on selective, differential media. Some viruses do not readily cause CPEs in cell lines typically used in clinical virology laboratories. However, some of these can be detected by other techniques, such as (1) erythrocyte hemadsorption onto cells infected with paramyxoviruses or mumps virus or (2) interference with the replication of other viruses (eg, picornaviruses cannot replicate in cells previously infected with rubella virus; this is known as heterologous interference).

In contrast with the intrinsic delay of antibody studies, the results of viral culture can be surprisingly rapid. Almost 50% of all viral isolates can be reported within 3 to 4 days of culture, with herpes simplex virus and influenza A virus usually detected within 1 to 3 days (Table 6-6).

The selection of the appropriate specimen for viral culture is complicated because several different viruses may cause the same clinical disease (Table 6-7). For example, several types of specimens should be submitted from patients with viral meningitis to enhance the recovery of the possible etiologic agents: CSF (enteroviruses, mumps virus, and herpes simplex virus), throat swabs and washings (enteroviruses), and stool or rectal swabs (enteroviruses). Also, serum should be collected as an acute-phase specimen in case subsequent serologic tests are indicated (eg, acute and convalescent sera for mumps virus or arbovirus infections). Many considerations, however, allow the physician to select the most appropriate specimens (Table 6-8). For example, during the summer, when enteroviral meningitis is prevalent, CSF, throat, and stool specimens should be submitted. On the other hand, the development of encephalitis in children after being bitten by mosquitos in wooded areas endemic for California encephalitis virus suggests that a serum specimen for antibody testing would be preferred. Central nervous system disease after parotitis would suggest collection of CSF and urine for the isolation of mumps virus. The specimens that should be collected for other viruses are summarized in Table 6-7.

Timing of Specimen Collection

Proper timing of specimen collection is essential for adequate recovery of viruses. Specimens should be collected early in the acute phase of infection. Studies with respiratory viruses indicate that the mean duration of viral shedding may be only 3-7 days. Also, herpes simplex virus and varicella-zoster virus may not be recovered from lesions beyond 5 days after onset. Isolation of an enterovirus from the CSF may be possible for only 2-3 days after onset of the central nervous system manifestations.

Transport to Laboratory

The shorter the interval between collection of a specimen and its delivery to the laboratory, the greater is the potential for isolating an agent. When feasible, all specimens other than blood, feces, urine, and tissue, which need special processing, should be inoculated directly onto cell cultures at the patient's bedside (Table 6-9). These should then be transported to the laboratory promptly.

For specimens that cannot be inoculated onto cell cultures immediately, several types of transport media have been used. It is generally believed that protein (serum, albumin, or gelatin) incorporated into a transport medium enhances survival of viruses.

Improper storage of specimens before processing can also adversely affect viral recovery. Significant losses in infective titer occur with enveloped viruses (eg, herpes simplex virus, varicella-zoster virus, or influenza virus) after specimens have been frozen and then thawed. This is not observed with nonenveloped viruses (eg, adenoviruses or enteroviruses). Therefore, when it is impossible to process a specimen immediately, it should be refrigerated but not frozen and packed in shaved ice for delivery to the laboratory if delays in transit are anticipated. Storage of specimens for the recovery of viruses at 4oC is far superior to storage at ambient temperature.

Interpretation of Culture Results

In general the detection of any virus in host tissues, CSF, blood, or vesicular fluid can be considered highly significant. Recovery of viruses other than cytomegalovirus in urine may be diagnostic of significant infection. For example, both mumps virus and adenovirus type 11 (associated with acute hemorrhagic cystitis) may be recovered in urine and indicate acute infection. However, the presence of cytomegalovirus in urine is difficult to interpret because this may reflect asymptomatic virus replication long after infection or indicate a significant active infection in the patient. In the newborn, viruria (isolation of virus in urine) in the first 3 weeks of life establishes a diagnosis of congenital cytomegalovirus infection, whereas the onset of viral excretion after 3-4 weeks of life reflects intrapartum or postpartum infection. Diagnosis of acquired cytomegalovirus in older patients usually requires a combination of findings, including positive cultures, illness compatible with cytomegalovirus disease, reasonable exclusion of other potential etiologic agents, and support by specific serologic or histologic data.

The significance of viruses isolated in upper respiratory tract, vaginal, or fecal specimens varies greatly. At one extreme, isolates such as measles, mumps, influenza, parainfluenza, and respiratory syncytial virus are significant because asymptomatic carriage and prolonged shedding of these viruses are unusual. Conversely, other viruses can be shed continually or intermittently without symptoms for periods ranging from several weeks (enteroviruses in feces) to many months or years (herpes simplex virus or cytomegalovirus in the oropharynx and genital tract; adenoviruses in the oropharynx and intestinal tract). Herpes simplex virus, cytomegalovirus, varicella zoster virus, and Epstein-Barr virus may remain latent for long periods and then become reactivated in response to a variety of stressful stimuli, including other infectious agents. In this setting their detection may not be significant, may merely represent a secondary problem complicating the primary infection (eg, herpes simplex virus "cold sores" in patients with bacterial sepsis), or may be associated with significant disease, especially in the immunocompromised patient.

Based on the epidemiology of adenovirus infections and observed serologic responses, the simultaneous isolation of these viruses from throat and feces is significantly associated with febrile respiratory disease. Isolation of viruses from the throat alone is less frequently associated with disease, and isolates from feces alone are probably nondiagnostic in a patient with respiratory disease.

Enteroviruses are generally found in infants and children, particularly during the late summer and early autumn. A knowledge of the relative frequency of virus shedding among various age groups in a particular locale is extremely helpful in assessing the significance of results of throat or stool cultures. For example, the peak prevalence of enteroviruses in the stools of toddlers during the late summer may range from 5% in temperate zones to > 20% in subtropical climates. Even in temperate areas, rates may approach 30% in infants during periods of enterovirus activity. Shedding of enterovirus in the throat usually occurs for 1-2 weeks, whereas fecal shedding may last 4-16 weeks. Thus, in a clinically compatible illness, isolation of an enterovirus from the throat supports a stronger temporal relationship to the disease than does an isolate from only the feces.

Herpes simplex virus is unusual in a fecal culture. In such cases it usually represents either severe disseminated infection or local infection of the perianal areas. Detection of herpes simplex virus in the upper respiratory tract may mean nothing other than nonspecific reactivation of virus caused by fever unless typical vesicles or ulcers are also present. Because of the fever-related phenomenon, isolation of herpes simplex virus in the throat or mucocutaneous lesions of patients with encephalitis cannot be interpreted as causing the central nervous system disease. Currently the definitive way to establish a diagnosis of herpes simplex encephalitis is by direct demonstration of the virus in a brain biopsy or by polymerase chain reaction (PCR) on CSF. In neonates, however, isolation of the virus from any site should raise the possibility of severe infection.

Isolation of adenoviruses, herpes simplex virus, varicella-zoster virus, and some enteroviruses from the cornea and conjunctiva in patients with inflammatory disease at these sites usually establishes the etiology of the infection.

DETECTION OF VIRAL ANTIGENS

Antibodies can be used as sensitive tools to detect, identify, and quantitate the presence of viral antigen in clinical specimens or cell culture. Monoclonal or polyclonal antibodies prepared in animals may be used. Viral antigens on the cell surface, within the cell, or released from infected cells can be detected by IF, EIA, RIA, and latex agglutination (LA). IF detects and locates cell-associated antigens, whereas RIA or different variations of enzyme-linked immunosorbent assay (ELISA) are used to detect and quantitate soluble antigens. LA is a rapid, easy assay for antigen; viruses or viral antigens in a sample cause the clumping of latex particles coated with specific antibody.

Virus-infected tissue or cell cultures can be detected by IF or EIA. By attaching a fluorescent signal to an antiviral antibody, and reacting it with the sample, viral antigen can be detected; this is called direct IF. A modification of this technique is the use of unlabeled antiviral antibodies and then a second antibody with a fluorescent label that will bind to IgM or IgG antibodies. EIA uses a second antibody conjugated to an enzyme, such as horseradish peroxidase or alkaline phosphatase, which releases a chromophore to mark the presence of antigen.

Direct IF assay is especially useful for (1) respiratory viruses (eg, respiratory syncytial virus or influenza A), (2) varicella-zoster virus and herpes simplex virus antigen in lung and visceral biopsies, and (3) cytomegalovirus in leukocytes from blood or CSF.

Soluble antigen can be quantitated by ELISA, RIA, and LA. The basis for these procedures is the separation and quantitation of antibody-bound and free antigen. Many of the ELISA and RIA techniques use an antibody immobilized to a solid support to capture soluble antigen and a labeled antibody to detect captured antigen.

Influenza, parainfluenza, and togaviruses produce a glycoprotein that binds erythrocytes. This property allows detection of free virus produced in cell culture by agglutination of erythrocytes, a process termed hemagglutination. The infected cells also adsorb erythrocytes to the surface by a process referred to as hemadsorption.

Detection and assay of characteristic enzymes can identify and quantitate specific viruses. For example, reverse transcriptase in cell culture is used as an indicator of infection by retroviruses.

SEROLOGIC TEST METHODS

Introduction

Serology can be used to determine whether an infection is primary or a reinfection and if acute or chronic. The first antibodies to be produced by the immune system are directed against antigens on the virion or infected cell surfaces and are best detected by, eg, IF. Later in the infection, when cells have been lysed by the infecting virus or the cellular immune response, antibodies are directed against the cytoplasmic viral proteins and enzymes and can be detected by, eg, complement fixation. Seroconversion is characterized by a change from negative to positive antibody between serum taken during the acute phase of disease and that taken = 2-3 weeks later; it is the best serologic marker of recent infection. A fourfold or greater rise in antibody titer in paired sera may also be significant but fluctuations in antibody titer do occur naturally. Detection of virus-specific IgM is theoretically associated with recent infection, but technical difficulty in measuring specific IgM responses may lead to false-positive and false-negative results.

For many viruses, culture or antigen detection is the best diagnostic test. However, certain viruses (eg, HIV, hepatitis A and B viruses, rubella virus, Epstein-Barr virus, measles virus, coronaviruses, and togaviruses) are difficult to isolate in cell culture, and infections are diagnosed most easily by serologic techniques. When a virologic workup is planned for a patient, it is generally useful to obtain = 2-3 ml of serum during the acute phase of disease and store it at -20oC. This may become valuable, particularly if virus detection subsequently fails or if the significance of an isolate is uncertain. In these instances a convalescent-phase serum specimen may be requested 2-3 weeks later, and both the acute and convalescent sera may then be tested against appropriate viral antigens. In general, if a virus is isolated, the antibody titers need not be measured to confirm infection; for example, if a patient has aseptic meningitis and an enterovirus is recovered from the throat, that agent is probably responsible for the illness. Similarly, if influenza virus is recovered from the throat of a patient who has clinical influenza, no serologic confirmation of the etiology is necessary.

Complement fixation is a standard but technically difficult serologic test. The serum is first reacted with the suspected viral antigen and complement, and the residual complement is assayed by lysis of indicator antibody-coated erythrocytes. If the complement is used in the first reaction and is therefore not available for the second reaction, it indicates the presence of antibody to the suspected virus. Antibodies measured by this system generally develop slightly later in the course of an illness than those measured by other techniques. This delayed response is useful for documenting seroconversion when the initial serum specimen is collected late in the clinical course. Members of some virus groups (eg, enteroviruses) do not possess group-specific antigen and must be tested individually.

The neutralization test is essentially a protection test. When a virus is incubated with homologous type-specific antibody, the virus is rendered incapable of producing infection in an indicator cell culture system. A neutralization antibody response is virus type specific, with titers rising rapidly and persisting for long periods.

The hemagglutination inhibition test can be performed with a variety of viruses that can selectively agglutinate erythrocytes of various animal species (eg, chicken, guinea pig, or human). The hemagglutination capacity of a virus is inhibited by specific immune or convalescent sera. Hemagglutination-inhibiting antibody develops rapidly after the onset of symptoms, plateaus, declines slowly, and may last indefinitely at low levels. This test is useful for both the detection of acute viral infection and the determination of immunity.

For the indirect fluorescent antibody test, virus-infected cells are placed in prepared wells on microscope slides and then fixed in cold acetone and dried. Patient serum is applied and, after incubation, anti-human globulin conjugated with fluorescein is added. If fluorescence is observed, it indicates the presence of specific antiviral antibody.

Interpretation of Serologic Results

Virus-specific IgM antibody usually rises during the first 2-3 weeks of infection and persists for several weeks to months. Thus an elevated titer of specific IgM antibody suggests a recent primary infection, which may be further supported by demonstrating a fall in IgM antibody in subsequent sera. Detection of specific IgM has been used with success in the diagnosis of infections caused by cytomegalovirus and rubella virus and is currently the procedure of choice to establish a recent or acute infection from hepatitis A or B.

Several limitations of interpretation must be remembered. It is now recognized that IgM-specific antibody responses are not always restricted to primary infections. Reactivation or reinfection may result in IgM responses, particularly in herpes virus infection. In addition, patients may continue to produce IgM-specific antibody to rubella virus or cytomegalovirus for many months after a primary infection. Heterotypic IgM responses may also occur. For example, antibody responses to cytomegalovirus may develop in Epstein-Barr virus infections and vice versa. Other pitfalls include falsely low or negative IgM titers caused by competition from high-titer IgG antibody for antigen-binding sites and false-positive reactions resulting from rheumatoid factor. Both types of errors appear to occur most frequently in solid-phase assays with IF.

The serologic diagnosis of most viral infections is based on demonstration of a seroconversion or a rise (fourfold or greater) of IgG antibody. However, significant antibody titer rises may result from cross-reactions to related antigens; for example, an antibody rise to parainfluenza virus may actually result from infection with mumps virus. Furthermore, seroconversions may not be seen with some patient populations (eg, infants and immunocompromised patients) or when the initial serum is collected late in the course of disease.

A serum specimen can also be used for screening an infant's blood for certain antibodies of the IgG class. Antibodies to Toxoplasma spp., rubella virus, cytomegalovirus, and herpes simplex virus (known as the "TORCH" screen) may be measured to determine possible congenital infection with these agents. However, the value of these tests must be understood. They are useful in excluding a possible infection but not in proving an etiology. For example, if rubella antibody is absent, an infant almost certainly does not have congenital rubella infection. To diagnose active rubella infection in such a baby, viral cultures are required. Screening of blood supplies for cytomegalovirus antibody is used to eliminate transmission of antibody-positive blood to seronegative babies and other immunocompromised patients.

Serologic Panels

Selection of several antigens for testing with paired sera in cases in which a virus is suspected can usually be made based on clinical syndrome, the known local epidemiology of particular viruses, and the patient's age. This has led to the concept of serologic batteries of panels. Some examples of possible panels are included in Table 6-10.

Antigens from mumps, western equine encephalitis, eastern equine encephalitis, St. Louis encephalitis, and California encephalitis viruses—and perhaps lymphocytic choriomeningitis virus, Epstein-Barr virus, and HIV—may be included in a panel of tests for central nervous system diseases. Although herpes simplex antigen is sometimes included in such a panel, a rise in antibody titer is not sufficient to diagnose herpes encephalitis. Many viral central nervous system illnesses, especially aseptic meningitis, are caused by the enteroviruses; however, the many serotypes and the cumbersome serologic methods necessary for their diagnosis usually make it impractical to include them in a panel. When one or two enteroviruses have been shown to be epidemic in an area in one summer, one can pick up some additional cases by performing neutralization tests on paired sera by using only those specific enteroviruses that are endemic in the community.

The viral antigen panel for testing respiratory syndromes might include influenza A and B; respiratory syncytial virus; parainfluenza types 1, 2, and 3; and adenoviruses.

To test for viral causes of exanthems, the panel would include measles and rubella. If the disease is vesicular, herpes simplex virus and varicella-zoster virus should be included, although the herpes viruses are best diagnosed by culture or antigen detection.

Antigens from group B coxsackie virus types 1-5 and perhaps influenza A and B viruses could make up the panel for myocarditis and pericarditis. Although numerous viruses have been implicated in inflammatory diseases of the heart and its covering membranes, the group B coxsackieviruses are believed to account for almost one half of the cases. Unfortunately, much of the clinical illness is expressed late in the infection, at the time when standard methods of virus detection are likely to fail and it is too late to demonstrate seroconversion or significant antibody titer rises.

MOLECULAR TEST METHODS

In recent years a variety of assays have been developed to detect viral nucleic acid—either DNA or RNA. The best known of these is PCR, an amplification technique that allows the detection and selective replication of a targeted portion of the genome. The technique uses special DNA polymerases that initiate replication in either the 3' or 5' direction. The specificity is provided by primers that recognize a pair of unique sites on the genome so that the DNA between them can be replicated by repetitive cycling of the test conditions. Because each newly synthesized fragment can serve as the template for its own replication, the amount of DNA doubles with each cycle. The amplification power of PCR offers a solution for the sensitivity problems inherent in the direct application of probes. Although the nucleic acid segment amplified by PCR can be seen directly on a gel, the greatest sensitivity and specificity are achieved when probe hybridization is carried out after PCR. A probe is a fragment of DNA that has been cloned or otherwise recovered from a genomic or plasmid source. In some cases the probe is synthesized as a single chain of nucleotides (oligonucleotide probe) from known sequence data. The probes are labeled with a radioisotope or other marker and used in hybridization reactions either to detect the homologous sequences in unknown specimens or in gel electrophoresis.

The diagnostic use of DNA probes is to detect or identify microorganisms by hybridization of the probe to homologous sequences in DNA extracted from the entire organism. A number of probes have been developed that will quickly and reliably identify organisms that have already been isolated in culture. The application of probes for detection of infectious agents directly in clinical specimens such as blood, urine and sputum is more difficult.

Recently, the branched DNA (bDNA) a rapid assay for direct quantification of viral nucleic acid has been developed for hepatitis B, hepatitis C, and HIV infections. Because the bDNA assay measures viral nucleic acids at physiological levels by boosting the reporter signal, rather than by amplifying target sequences, it is not subject to the errors inherent in the amplification steps of PCR-based methods. Inherently quantitative and amenable to routine use in a clinical setting, the bDNA assay may be useful in the management of patients with chronic viral diseases. Recent studies have illustrated the potential clinical utility of the bDNA assay in determining the prognosis and in therapeutic monitoring of infection. Additional nucleic acid tests include hybrid capture and nucleic acid sequence-based amplification.

Diagnosis of Bacterial, Fungal, & Parasitic Infections

2008-08-16T04:24:00.000-07:00

INTRODUCTION

Tables 6-1, 6-2, and 6-3 summarize currently available recommended test methods for the detection of bacterial, fungal, and parasitic pathogens from human specimens. Methods for detection of viral pathogens are discussed later in this chapter. For completeness, the tables include pathogens common to both normal and immunocompromised hosts. Selected specimen collection procedures are shown in Table 6-4. However, this important step in the diagnostic-testing process cannot be overstated. An adequate amount of specimen (using sterile techniques when appropriate) should be placed in the appropriate transport device, and the specimen should be transported to the laboratory under appropriate environmental conditions and within a reasonable period. Because a large number of transport devices are available, consultation with the laboratory personnel is important, especially when unusual bacteria are considered. Comprehensive reviews of the specifics of specimen collection, transport, and storage are described elsewhere. As a general point, specimens requiring strictly anaerobic conditions for viability must be sent in appropriate anaerobic transport devices. Depending on the volume, most other specimens can be sent in either a swab transport device (the swab is immersed in nutrient broth) or a sterile container. Some studies have demonstrated the utility of blood culture bottles for transporting as well as culturing sterile body fluids, especially peritoneal fluid.

RAPID, DIRECT TEST METHODS & CULTURE-BASED METHODS

Introduction

Direct, rapid diagnostic-test methods if available should be used in addition to conventional culturing techniques for diagnosing bacterial or fungal infections in critically ill patients. Most parasitic infections can be diagnosed by direct staining methods, and these tests should be performed emergently, especially if life-threatening infections like malaria are suspected. Rapid diagnostic tests are provided in Table 6-1, and culture-based diagnostic tests, which require longer time periods to complete, are presented in Table 6-2.

Blood

Both direct and culture-based techniques may be useful for identifying common and uncommon bacterial, fungal, and parasitic pathogens in blood. Some of the specialized testing methods shown in Tables 6-1 and 6-2 are generally available only at reference laboratories. If the clinician feels strongly that one of these tests is useful, an aliquot of the specimen should be sent to a reference laboratory. Direct test methods for the detection of bacterial or fungal pathogens in blood are limited in the number of different bacteria that they can detect and are less sensitive than culture methods. Bacterial-antigen tests for commonly encountered encapsulated organisms (Haemophilus influenzae type b, Neisseria meningitidis, or Streptococcus pneumoniae) are easy to perform and available in most laboratories. A latex agglutination procedure can be used to detect the yeast Cryptococcus neoformans.

Blood cultures should be obtained from all patients in whom sepsis is considered. The standard blood culture set for adults consists of 20-30 ml of blood equally distributed between two or among three culture receptacles. Blood volume for pediatric patients is less and is dependent on patient weight. When 20 ml of blood is drawn, the standard practice is to culture 10 ml in an aerobic atmosphere and 10 ml in an anaerobic atmosphere. If 30 ml of blood is drawn, the same practice is followed except that the additional 10 ml is cultured under aerobic conditions. In patients with suspected endocarditis or endovascular infections, conditions in which bacteremia is continuous, two or three separate blood cultures collected at various intervals over a 24-h period are sufficient. For other types of bacteremia, 99% will be detected by three separate blood cultures collected at various intervals over a 24-h period. Most conventional broth-based blood culture systems also have the ability to detect candidemias. Specialized broth or procedures (see lysis centrifugation below) may be required to detect fastidious bacteria and dimorphic fungi, especially Histoplasma capsulatum.

Recently some authorities have questioned whether anaerobic blood cultures should be performed routinely in all patients, especially those in whom anaerobic bacteremia is unlikely. However, it has recently been demonstrated that anaerobic blood cultures may recover some facultatively anaerobic bacteria (eg, Enterococcus spp. and viridans streptococci) more efficiently than aerobic blood cultures. The lysis centrifugation method is a specialized blood culture method which is useful for recovering common as well as many unusual bacterial pathogens and fungi. In this system, blood is inoculated into a test tube containing saponin, a chemical that lyses erythrocytes and leukocytes, thereby releasing intracellular bacteria. The tube is centrifuged, and the sediment is inoculated onto solid agar plates or into broth. Mycobacterium spp., especially Mycobacterium avium-intracellulare, occasionally produce bacteremias in severely immunocompromised patients. The inoculation of the sediment from a lysis centrifugation blood culture tube onto specialized mycobacteria agar or into BACTEC 13A broth bottles is useful for recovering mycobacteria. Controversy exists as to whether blood cultures can be obtained from intravascular lines. Several investigators have shown that such a practice results in the isolation of more contaminating microorganisms than if blood is obtained from peripheral veins. Whenever possible, blood for culturing should be obtained from peripheral veins; however, this recommendation must be considered in the context of the clinical situation of the patients. For example, phlebotomy via peripheral veins may be risky in severely thrombocytopenic bone marrow transplant patients.

Parasitemias caused by malarial or filarial organisms are diagnosed with thick and thin blood smears. Thick smears permit screening for malaria parasites, and speciation is possible by careful evaluation of thin smears. When parasitemias are suspected, the laboratory director should be notified so that proper processing and careful evaluation of blood specimens are undertaken. In some cases, referral of specimens to reference laboratories may be beneficial.

Other Sterile Body Fluids or Tissues

Direct antigen testing for H influenzae type b, N meningitidis, S pneumoniae, group B streptococci, E coli, and C neoformans can be performed on cerebrospinal fluid (CSF) or urine. Direct antigen testing for Legionella pneumophila and H capsulatum can be performed on urine. For staining and culturing methods, CSF or joint, peritoneal, or pleural fluids should be concentrated by filtering or centrifugation. In contrast, Gram stains of urine should be performed on unconcentrated specimens. The presence of =2 bacteria per oil immersion field (×1000) in a Gram-stained smear of a drop of unconcentrated urine should represent ~ 105 colony forming units of bacteria/ml of urine. Other rapid screening tests for bacteruria are commercially available. These tests, which detect either bacteria or leukocytes by direct or indirect methods, are generally no more accurate than the Gram stain method and may be more costly.

Cultures of bone marrow specimens may be particularly valuable for diagnosing Salmonella typhi (the agent of typhoid fever), Brucella spp., disseminated mycobacteria infections (M avium-intracellulare) or H capsulatum and can be processed by using the lysis centrifugation method. Granulomas surrounding small vessels in a bone marrow biopsy (ring granulomas) are associated with Coxiella burnetti (agent of Q fever) infection. Bone marrow specimens may be positive by staining methods in patients with disseminated infection caused by a variety of organisms, including H capsulatum, M avium-intracellulare, Trypanosoma spp. or Leishmania spp.

Respiratory Tract Specimens

All spontaneously produced sputa that are submitted for general bacteria culture should be screened for the presence of squamous epithelial cells. It has been demonstrated that expectorated sputum samples having > 25 squamous epithelial cells per low-power microscopic field are unacceptable for bacterial culture, because these samples likely are contaminated by oropharyngeal secretions. Common community-acquired respiratory bacterial pathogens include S pneumoniae, Streptococcus pyogenes (Lancefield group A ß-hemolytic streptococci), Klebsiella pneumoniae, S aureus, Legionella spp., Chlamydia pneumoniae, and Mycoplasma pneumoniae. Gram-negative bacilli, especially Enterobacteriaceae and Pseudomonas spp., and VRE and staphylococci may cause nosocomial respiratory infection. Pseudomonas aeruginosa and B cepacia are frequently associated with pulmonary infection in patients with cystic fibrosis. All of the above bacteria, with the exception of C pneumoniae and M pneumoniae, are easily diagnosed by culture-based methods. Indirect serologic methods are the best methods for diagnosing the latter two pathogens.

Although Legionella spp., Mycobacteria spp., and Nocardia spp. can cause pulmonary disease in normal hosts, they may be a more frequent cause of pulmonary disease in immunocompromised hosts. Legionella spp. can be diagnosed by direct examination of pulmonary secretions or alveolar tissue, with a fluorescent antibody technique. Alternatively, acute infection with the most frequently encountered Legionella spp., L pneumophila, can be diagnosed by screening for antigen in the urine. Legionella antigenuria can persist for months after acute infection, a factor that may limit the usefulness of this direct test for diagnosing subsequent L pneumophila infections. Microorganisms that stain poorly by the Gram stain method and that appear to branch or are beaded in appearance should be suspect for Nocardia spp. These organisms frequently stain acid-fast by a modified acid-fast staining method. This method uses less intense decolorizing agents than those used for conventional acid-fast staining of mycobacteria. Nocardia spp. grow more slowly than other bacteria, but can be recovered on standard bacteriologic media. Nocardia spp. also grow well on media used for isolating fungi and mycobacteria and on media used to isolate Legionella spp. (buffered charcoal yeast extract). A recently described opportunist gram-positive bacillus, Rhodococcus equi, also may cause pulmonary infection in immunocompromised patients and, like Nocardia spp., may branch and stain acid-fast by a modified acid-fast staining method.

The dimorphic fungal pathogens (yeast and hyphal forms) H capsulatum, Blastomyces dermatitidis, Coccidioides immitis and Paracoccidioides brasiliensis and the monomorphic fungus (yeast form only) C neoformans may cause pulmonary or disseminated disease in both normal and immunocompromised hosts. The dimorphic fungal pathogen Sporothrix schenckii rarely produces respiratory disease and more frequently presents as cutaneous disease in normal hosts. Monomorphic fungi (hyphal form only) such as Aspergillus spp. generally cause respiratory or disseminated infection in immunocompromised hosts. Pneumocystis carinii has recently been reclassified as a fungus. It is an opportunistic fungal pathogen that causes disease only in immunocompromised hosts, especially patients coinfected with human immunodeficiency virus (HIV). All fungal pathogens, with the exception of P carinii, can be cultured from pulmomary secretions. Diagnosis of P carinii requires direct examination of pulmonary secretions or tissue. Some fungal infections can also be diagnosed by indirect serologic methods; additionally, H capsulatum antigen and C neoformans antigen can be detected in urine and in the serum in disseminated disease.

In certain areas of the world where helminths (Ascaris lumbricoides, Strongyloides stercoralis, Paragonimus westermani, and Echinococcus granulosa) are endemic, pulmonary infection with these parasites may occur. Disseminated infection with S stercoralis, including respiratory infection, may occur in immunocompromised hosts. Toxoplasma gondii may cause pulmonary disease in immunocompromised hosts. Direct examination of wet preps of pulmonary secretions may be useful to identify helminths; direct examination of tissue, culture, and indirect serologic methods are useful for diagnosing T gondii.

Feces

Enteric infections caused by Salmonella spp., Shigella spp., Yersinia enterocolitica, pathogenic E coli, and Campylobacter spp. are increasing in frequency in the United States. These infections are diagnosed by culture of feces, although direct detection of antigens by enzyme-linked immunoassays are sometimes useful for Salmonella spp. and E coli O157:H7. At present, Whipple's disease caused by the bacterium Tropheryma whippelii can be definitively diagnosed by evaluating small-bowel tissue for the presence of nucleic acid that is unique to this organism. Traditionally, periodic acid Schiff staining has been used to demonstrate the organism in tissue (see subsequent discussion).

Occasionally, in severely immunocompromised patients, acid-fast staining and culture may be useful for diagnosing enteric infection caused by Mycobacterium tuberculosis or M avium-intracellulare. However, cultures for mycobacteria should be performed only on stools with positive acid-fast stains. If mycobacteria are recovered from feces, disseminated disease is frequently present.

Enteric parasitic infections are diagnosed by direct examination of fresh or preserved stools; however, direct immunoassays may be useful for some parasitic organisms (Giardia lamblia and Cryptosporidium parvum). Extraintestinal parasitic infections may require other methods, including culture for diagnosis. Not shown in Table 6-2 are culture methods for Trypanosoma spp., Leishmania spp., T gondii, and Entamoeba histolytica. These specialized tests are available only at a few reference laboratories in North America. Culture methods for Acanthamoeba spp. and Naegleria spp. are included in Table 6-1. These methods are easy to perform and especially useful for diagnosing these parasitic infections in patients with corneal infections, which can occur with contact lens use.

Considerable attention has focused recently on newly discovered parasites that are opportunists in immunocompromised patients. These include species of four genera of coccidia (Isospora, Sarcocystis, Cryptosporidium, and Cyclospora) and species of five genera of microsporidia (Enterocytozoon, Septata, Nosema, Encephalitozoon, and Pleistophora). Infections caused by the coccidia or microsporidia have been reported in immunosuppressed patients, notably those patients coinfected with human immunodeficiency virus. Intestinal disease has been demonstrated to occur with all coccidia genera, Enterocytozoon spp., and Septata spp. Extraintestinal disease has been reported with Sarcocystis spp., Cryptosporidium spp., Septata spp., Encephalitozoon spp., Nosema spp., and Pleistophora spp. As previously mentioned, T gondii and the helminth S stercoralis can cause severe disseminated disease in immunocompromised hosts.

Intravascular Catheters

Patients who have indwelling central intravascular catheters for prolonged periods are susceptible to infection. If other sources for infection are ruled out, then infection related to the intravascular catheter must be considered. Diagnosing intravascular-catheter-associated infection can be challenging for the clinician, considering that a definitive diagnosis cannot be achieved unless the catheter is removed and a culture of the tip yields potentially pathogenic bacterium in sufficient quantity (ie, >15 colony forming units of bacteria). If there is evidence for a catheter tunnel infection (subcutaneous infection around the catheter), swabs of the affected area or pus if present should be stained and cultured for bacteria, mycobacteria, and fungi. Occasionally, the fungus Malassezia furfur can infect intravascular catheters and the blood in patients receiving intralipid infusions. Special culture techniques are required to isolate this organism (see Table 6-2).

Surveillance Cultures

In certain instances, surveillance cultures for bacteria and fungi may be useful. Patients who are immunocompromised, receiving broad-spectrum antimicrobial agents, or both may be surveyed for drug resistant bacteria or fungi. As part of infection control programs, institutionalized patients may be surveyed for VRE or methicillin-resistant S aureus carriage. In both of these examples, cultures of the upper airway, feces, or both may be useful to screen for carriage of these potential pathogens.

SEROLOGIC TEST METHODS

Indirect serologic methods may be useful for diagnosing infections caused by certain bacteria, fungi, and parasites and in some cases may be the only means by which a diagnosis is achieved. To diagnose infections by Rickettsia spp., for which alternative diagnostic test methods are limited (attempts at culturing these organisms should be avoided owing to their high infectivity), these tests may be the only means by which a diagnosis is established. Table 6-3 shows the serologic test methods currently available at most reference laboratories. Of note, these methods detect immunoglobulin G (IgG) antibody, IgM antibody, or both to specific bacteria pathogens and for the most part require that the infection has existed in a patient for a finite period so that detectable levels of antibody exist. For IgG analyses, a fourfold increase between baseline and convalescent antibody titers may be required to confirm infection. Because the demonstration of a fourfold rise in antibodies may require > 4 weeks, the diagnostic utility of IgG analyses may be limited, especially in the acute disease phase. However, in some situations, baseline IgG antibody levels may exceed a critical threshold, which is considered diagnostic for infection. Except for the last example, indirect serological methods cannot be considered as rapid diagnostic tests and therefore may be of limited utility. These tests may also be of limited value in patients who lack a humoral response, especially bone marrow transplant recipients.

MOLECULAR TEST METHODS

Molecular test methods, including nucleic acid-probing and -sequencing techniques, allow for the detection of pathogens directly from human specimens. Molecular test methods and nucleic acid amplification techniques, which are frequently available at most reference laboratories are shown in Table 6-5. These methods are potentially useful for fastidious or slowly growing organisms like Legionella spp., Bartonella spp., Mycobacterium spp., Borrelia burgdorferi, and dimorphic fungi. The bacterial agent of Whipple's disease, T whippelii, has never been recovered on culture and presently can be diagnosed only by nucleic acid testing methods. Quantities of parasites in blood or tissue might be sufficiently low (eg, T gondii or Babesia microtii) that direct examination does not provide a diagnosis. In these cases, molecular diagnostic tests may also be useful. It must be emphasized that some studies, particularly those that have evaluated molecular identification methods for group A streptococci and mycobacteria, have demonstrated that these methods, including those that use nucleic acid amplification techniques, are less sensitive than culture. Therefore, if the results for molecular test methods such as these are negative, other diagnostic test methods including culture techniques should be considered.

SUSCEPTIBILITY TESTING OF BACTERIAL & FUNGAL ISOLATES TO ANTIMICROBIAL AGENTS

The National Committee for Clinical Laboratory Standards (NCCLS) provides published guidelines for conventional susceptibility test methods for commonly encountered bacterial organisms that grow aerobically or anaerobically and for yeasts. For bacteria that are not easily cultured (eg, Bartonella spp., Ehrlichia spp., or T whippelii), antimicrobial susceptibility testing is currently not possible. Tentative NCCLS guidelines exist for mycobacteria. No standards exist for parasites. Antimicrobial susceptibility methods include disk diffusion, broth dilution, and agar dilution. For disk diffusion, the inhibition of growth of an organism on solid media is assessed around a paper disk from which an antimicrobial agent diffuses. The greater the zone of inhibition of bacterial growth, the more effective the antimicrobial agent. In the broth dilution procedure, the effect of a known concentration of antimicrobial agent dispersed along with the organism in liquid media is assessed. No growth of the organism (the broth remains clear) indicates that the organism is inhibited at the concentration of antimicrobial agent tested. For agar dilution, a known amount of antimicrobial agent is dispersed in solid medium, and its effect on growth of organisms that are spot inoculated onto the surface of the medium is assessed. No visible growth of the organism means that it is inhibited by the specific concentration of antimicrobial agent that is present in the solid medium.

Interpretation of the results for each of these methods may differ with the antimicrobial agent and organism tested, and guidelines for such are provided by the NCCLS. These interpretations are provided as the following categories: resistant, susceptible, or intermediately susceptible. If an organism is identified as resistant to a particular antimicrobial agent, that agent should not be used in the clinical setting.

Basic Principles of Host Defense

2008-08-16T03:34:00.000-07:00

INTRODUCTION

Higher animals have evolved many host defense mechanisms that ensure the relatively long-term survival of individuals despite their coexistence with countless microorganisms. Healthy people are at equilibrium with the microbial world; their internal soma, rich in nutrients, remains free of replicating microorganisms. Disease can be viewed as progression away from this equilibrium, in which microorganisms invade the body from the environment and replicate, causing inflammation and destruction of the tissues, as well as depletion of the host's nutrients. Unchecked, the rapid expansion of the microbial population leads to the death of the host.

A similar but distinct scenario is that the internal environment contains a variety of viruses, bacteria, fungi, protozoa, and microscopic metazoa, which are acquired throughout life. Again, these organisms achieve equilibrium with the mammalian host. Under these conditions they do not replicate, nor do they produce toxins. Instead, they exist in a dormant or latent state, which is infection without disease. Disease is a progression away from the equilibrium. When the balance is disturbed, microbial replication begins; host nutrients are then consumed by the proliferating population of microorganisms. This process leads to disease and ultimately death unless microbial replication is blocked.

To maintain equilibrium with the microbial world—that is, to maintain a state of health—host-protective mechanisms must fulfill distinct functions. In a broad sense, the functions come in two forms.

The first form includes the antimicrobial defense mechanisms that have evolved throughout the vertebrate species. Specifically, this first form is composed of a variety of mechanisms to prevent invasion of sterile tissues from contiguous body sites that are teeming with microbial flora. These mechanisms involve the actions of specialized cells—phagocytes and lymphocytes. For example, the upper respiratory tract is colonized with large numbers of bacteria, yet further down into the respiratory tract, below the vocal cords and into the lungs, few or no bacteria are found. Those bacteria that do gain access to the lung are rapidly destroyed. In another example, microbes may gain entrance to sterile body sites when an open injury introduces bacteria into the skin, subcutaneous tissue, muscle, or bone. This is countered by mechanisms in which the injured tissue is walled off to prevent spread and is invaded by phagocytic cells that envelop and kill bacteria. This is bactericidal activity. Yet another example involves specialized microorganisms that have evolved into successful parasites and that gain ready access to sterile sites in the host. They may be highly resistant to host-killing mechanisms. Under these conditions, equilibrium between parasite and host is reached by establishing microbiostasis in the tissues. In this way, living microbes may remain dormant or latent within host tissues for years, or even decades. This scenario implies microbiostatic host-defense mechanisms. For example, the human tubercle bacillus (Mycobacterium tuberculosis) is inhaled into the lung. In the immunocompetent host, immunity is acquired, microbial replication ceases, and the mycobacteria become dormant, especially (but not exclusively) in the lung apices.

A second way to thwart infectious disease is through a set of uniquely human prevention schemes that have resulted from brain development and intelligence. Our understanding of infectious disease transmission has led to effective prevention methods, such as the addition of chlorine to the water supply and modern sewage treatment. Knowledge of immunology has led to vaccine strategies that have achieved results such as the elimination of smallpox from the human population. Understanding microbial physiology and metabolism led to the discovery of antibiotics for treating heretofore lethal infections.

This chapter deals exclusively with the first category of anti-infection mechanisms. These mechanisms can be subdivided into two broad categories: (1) innate or natural host defenses and (2) adaptive immune responses. There are distinct mechanisms characteristic of each of these two, but there is overlap as well. Some innate responses use mechanisms that, when analyzed at the cellular and molecular levels, were previously thought to reside exclusively as part of the adaptive immune response. Conversely, acquired immunity may lead to microbicidal mechanisms, which are not immunologically (antigen) specific and probably exist as an evolutionary blend of the innate and adaptive host defenses.

INNATE HOST DEFENSES

DEFENSE MECHANISMS AT THE PHYSIOLOGIC LEVEL

Introduction

Numerous physiologic factors influence susceptibility to infection. Prime examples of these factors are discussed in the sections that follow.

Normal Microbial Flora

Body surfaces in continuity with the environment typically support a complex but characteristic set of numerous microbial species (Table 2-1). This group of microorganisms is called the normal flora and includes microorganisms that inhabit the integument, upper respiratory tract, gastrointestinal tract, and urogenital tract. More than 200 different bacterial species occupy the human colon as normal flora. The normal flora fill these body sites to the exclusion of other species. Thus, the presence of the normal flora provides a protective function. A relatively virulent species such as the fungus Candida albicans cannot occupy the vagina unless the normal flora are eliminated, for example, by use of broad-spectrum antibacterial agents used to treat urinary tract infections. Sometimes virulent microorganisms colonize a body site and coexist along with the normal flora. For example, Streptococcus pneumoniae is often found in the oropharynx of healthy individuals. Colonization is a critical requirement for the pathogenesis of bacterial pneumonia caused by this pathogen. At some point microaspiration events introduce S pneumoniae into the lower respiratory tract. Then virulence mechanisms prevent the killing of these microorganisms by innate host defense mechanisms. This leads to microbial replication in a nutrient-rich environment that is devoid of competing microbial species, and bacterial pneumonia results.

What determines which species predominate as the normal flora at a particular site? Although this is a complex process, the phenomenon of attachment to host cells is an important requisite. Particular microbial species express structures on their surface that bind to receptors on host epithelial cells. For example, strains of viridans streptococci adhere (by special attachments) to pharyngeal epithelial cells and are able to flourish and exist as the predominant species in the oropharynx.

Anatomic & Physiologic Factors

The normal human anatomy provides numerous examples of anatomic barriers that prevent microbial replication and invasion. This is best illustrated when a breach in these barriers occurs and infection follows. The skin is a highly efficient barrier that prevents bacteria and fungi from entering into the subcutaneous tissue. In burn victims this barrier is lost. Without aggressive countermeasures, individuals with extensive burns succumb to overwhelming bacteremia because enormous numbers of bacteria invade the damaged tissue and thereby gain access to the circulatory system.

Physiologic mechanisms provide similar functions that prevent microbial invasion. Secretions contain antimicrobial molecules. For example, lysozyme in tears dissolves the cell walls of particular gram-positive bacteria. Salivary secretions contain bactericidal proteins. Smooth muscle peristaltic movements prevent the overgrowth of bacteria in the small intestine by creating a continuous flow, which has a cleansing effect; hydrochloric acid in the stomach kills numerous bacterial cells that enter upon swallowing. The respiratory tract contains a mucociliary carpet that is under constant motion outward, which helps remove inhaled bacteria from the respiratory epithelium.

Similar to a breach in an anatomical barrier, when physiologic processes malfunction, disease is usually the result. For example, autoimmune diseases that destroy the salivary glands lead to severe problems with dental caries and gingivitis, which are caused by overgrowth of oral bacteria. Periodontal disease and loss of permanent teeth follow. This is in part because the saliva normally contains antibacterial and antifungal compounds.

Host Nutritional Status

The nutritional status of the host ranks as a critical factor for both innate and acquired resistance to infection. Protein-calorie malnutrition in children is associated with severe measles (rubeola virus). Historical observations point to reactivation of dormant tubercle bacilli during acute food shortage in populations with a high prevalence of this pathogen. Pyogenic bacterial infections and periodontal disease are additional examples. The original description of Pneumocystis carinii as a human pathogen was based on observations of pulmonary disease in starving European infants during and after World War II. Experimental research shows that starvation impairs phagocytes and cell-mediated immunity (CMI) before its effects on antibody production are observed.

Hormonal Influences

Glucocorticoids exert profound effects on host resistance to infection. In severe bacteremia, physiologic cortisol secretion improves chances of survival. Yet it is well known that pharmacologic dosages of glucocorticoids depress the inflammatory response and increase susceptibility to primary infection as well as reactivation of latent infection. Pregnancy, as it progresses into the third trimester, results in immunosuppression, primarily of CMI. This leads to increased susceptibility to certain infections such as the food-borne infection listeriosis.

Aging

Aging affects many aspects of innate defenses. Consequently, pneumonia, urinary tract infections, cholecystitis, diverticulitis, and bacteremia caused by pyogenic bacteria are increased. The aged are more likely to reactivate latent organisms such as Herpes zoster virus and Mycobacterium tuberculosis, which suggests decreased CMI. Aged individuals have reduced ability to mount immunoglobulin (Ig) synthesis against polysaccharide antigens.

The Acute-Phase Response

The acute-phase response is a phylogenetically primitive, pleiotropic collection of responses designed by evolution to inhibit microbial replication and enhance acquired immune responses. The acute-phase response is triggered by invasion of microorganisms. Its complex, multiorgan involvement is fundamental for the inflammatory response characterized by swelling, pain, redness, heat, and loss of function. With the evolution of specific adaptive immune responses in vertebrates, the acute-phase response was preserved and is used as an activator of T and B lymphocytes.

Signal molecules that emanate from bacteria and other microorganisms (eg, endotoxin, muramyl dipeptide from the peptidoglycan of cell walls, glucans, mannans, and microbial toxins) bind to receptors on mononuclear phagocytes (MNPs) and endothelial cells [the reticuloendothelial system (RES)]. Secretion of a major proinflammatory cytokine, interleukin-1 (IL-1), and possibly others induces a pleiotropic response that involves a variety of different organs and functions (Table 2-2). The acute-phase response also leads to induction of specific immune responses, namely antibody synthesis by B cells and CMI, which are controlled by T cells. In a practical sense, measurements of the acute-phase response in blood samples are used in diagnosis of infections and other inflammatory diseases. Phenomena affected by IL-1, namely fever, increased erythrocyte sedimentation rate, high white blood cell count, and muscle wasting are important clues to the presence of infection, autoimmune inflammatory diseases, and neoplastic diseases that involve lymphoreticular cells.

INNATE DEFENSE MECHANISMS AT THE CELLULAR LEVEL

Introduction

Ever-present cells and molecules (constitutive mechanisms) form an on-the-spot defensive line against microbial invasion. Compromise of this innate multifaceted system results in predictable serious infections, usually with invading species of the microflora. Thus, the importance of constitutive nonspecific defense mechanisms is revealed. Phagocytes and natural killer (NK) cells are discussed as examples of innate cellular defenses.

Phagocytes

Two types of cells can be considered "professional phagocytes" or cells that consume microbes. These are the polymorphonuclear leukocytes (called neutrophils, or granulocytes) and the MNPs (monocytes and macrophages). These cells emanate from bone marrow precursors and enter the circulation to perform their antimicrobial functions. Lack of either of these cell lineages is incompatible with life.

Neutrophils live for 1-4 days after entering the circulation. Continued neutrophil production is essential for survival. Neutrophils are an important regulator of homeostasis between the body, which harbors sterile enclaves, and the microbial world. Neutrophils deal with pyogenic bacteria and fungi. Neutrophils possess tightly regulated microbicidal systems that are activated within seconds after encountering microorganisms. In healthy individuals, neutrophils are constantly at work destroying small numbers of microbes that enter the body by various routes. Severe neutropenia (< 500 cells/uL of blood) leads to overwhelming bacteremia from enteric bacilli. Neutrophils are constitutively bactericidal to a high degree for gram-positive and gram-negative cocci and enteric bacilli. To maintain this constitutive defense, neutrophils have special functional properties, to be discussed below. A defect in any one of these important functions invariably leads to a life-threatening infection. However, neutrophils have less or little activity against facultative or obligate intracellular pathogens such as mycobacteria, dimorphic fungi, and protozoans. The human immune system has evolved other mechanisms for dealing with these pathogens.

MNPs leave the bone marrow as blood monocytes. They mature into macrophages in the periphery. Stationed throughout all organs of the body, they compose the RES. The RES of the sinusoids of the liver and spleen provides an important clearance mechanism to remove a variety of microbes from the circulation. Thus, the spleen serves as a highly efficient, specialized RES site for removal of virulent bacteria. These bacteria avoid clearance in other RES sites, such as the lung or liver, because they possess virulence factors that have extraordinary antiphagocytic properties, such as particular serotypes of exopolysaccharide capsules. Individuals with no spleen may succumb to high-grade infection caused by bacteria that possess antiphagocytic capsules. The alveolar spaces of the lung are inhabited by macrophages, which form a first-line defense of the lung. These cells phagocytize and kill inhaled viruses, bacteria, and fungi. Macrophages and macrophage-like cells (eg, dendritic cells) contribute to the adaptive immune response. Macrophages, which function in concert with T lymphocytes, are responsible for CMI defense against intracellular pathogens. Macrophages process and present antigen to lymphocytes and receive "activating" signals during the immune response. These signals enable the macrophages to control the replication of intracellular microorganisms; they are also capable of killing these microorganisms (see below). Some of the functions listed in Table 2-3 for neutrophils are also relevant for MNPs.

To kill bacteria and fungi, phagocytes must make physical contact with them. This involves a coordinated sequence of regulated events: (1) production, (2) release into the circulation, (3) attraction to a site of infection, (4) adherence onto and translocation through (diapedesis) adjacent capillary walls, (5) chemotaxis, (6) attachment to and phagocytosis of the microbe, (7) activation of killing mechanisms, and (8) digestion of dead microorganisms (see Table 2-3). These events are depicted in Figure 2-1. Genetic or acquired conditions that interfere with one or more of these steps are associated with increased propensity to develop pyogenic infections caused by microorganisms which are usually constituents of the normal flora.

A. Phagocyte Production (Stage 1). Phagocytes are produced in the bone marrow (see Figure 2-1A). Neutrophils are produced in bone marrow from precursor stem cells under the mitotic and differentiation influence of several low-molecular-weight proteins called colony-stimulating factors (CSF). CSF for granulocytes (neutrophils) (granulocyte CSF), monocytes/macrophages (macrophage CSF), phagocytes (granulocyte-macrophage CSF), and multiple cell types (IL-3) are secreted by endothelial cells, fibroblasts, and cells of the immune system. A large number of granulocytes are produced each day (~ 1011 cells). Granulocytes are short-lived cells; once they enter the tissues their half-life is only 6-8 h. There may be as many as 1010-1011 granulocytes/ml of abscess fluid. Thus, the turnover of these cells is high, and, when production is inhibited, by anticancer drugs, for example, neutropenia may become severe and lead to invasive bacterial and fungal infections.

B. Phagocyte Release (Stage 2). Phagocytes are released into the circulation (see Figure 2-1B). IL-1, a cytokine product from macrophages, signals release of neutrophils from the marrow. The circulating neutrophil population increases the peripheral white blood cell count, a hallmark of acute infection. Neutrophils that normally adhere to the vascular endothelium form the marginated pool. Certain chronic stimuli (eg, drugs, hypoxia, stress, and exercise) cause demargination with increased white blood cell counts.

C. Chemokinesis (Stage 3). Phagocytes are guided to sites of infection by chemical signals called chemokines. Sentinel tissue macrophages and migrating immune cells, in response to invading microbes, secrete proteins called chemokines. Numerous distinct molecules have been identified—some are the ligands for specific receptors on different leukocytes, and some control the types of leukocytes that infiltrate inflammatory foci. The chemokines exert their effect by facilitating adherence of particular cell types to endothelium adjacent to an inflammatory site.

D. Margination, Spreading, and Diapedesis (Stage 4). For phagocytes to enter foci of infection, they must adhere to adjacent capillaries and migrate out of the bloodstream into the tissues. This is a multistep, tightly regulated process. The initial adherence step is mediated by surface molecules called selectins that bind neutrophil (L-selectin) to the endothelial cell (E-selectin) as well as to platelets (P-selectin). At this stage leukocytes roll along the endothelium in the direction of blood flow (Figure 2-1C). Tight adherence with leukocyte flattening is mediated by receptors (ß-integrins) that bind to intercellular adhesion molecules called ICAMs that are expressed on endothelial cells. This interaction is controlled by regulation of these surface molecules through inflammatory mediators that diffuse from an infected site. Cytokines and arachidonic acid metabolites up-regulate ß-integrin (on neutrophils) and ICAM-1 (on endothelial cells) expression. Specialized adhesion molecules localized at endothelial cell junctions (platelet/ endothelial cell adhesion molecules) guide neutrophil motility between endothelial cells into infected tissue by a process called diapedesis (Figure 2-1D).

E. Chemotaxis (Stage 5). Phagocytes seek pathogens by attraction to gradients of microbial products and signals generated by the host inflammatory response. Motility of neutrophils increases in response to environmental signals called chemotaxins, which include cytokines [IL-6, IL-8, granulocyte macrophage CSF, tumor necrosis factor a (TNFa), interferon-? (IFN-?)], leukotrienes, and chemical products from microorganisms themselves (eg, microbial oligopeptides such as formylmethionine-leucine-phenylalanine). When no concentration gradient is present, increased motility is random [chemokinesis (Figure 2-1E)]; however, in the presence of even weak gradients, neutrophil motility becomes directed toward an increased concentration of stimulus [chemotaxis (Figure 2-1F)]. The interaction between chemotaxins, their high-affinity receptors on the neutrophil surface, and cytoplasmic cytoskeletal events, which propel the cell forward, are not entirely worked out. However, it is important that phagocyte motility depends on a substrate upon which the phagocytes crawl. These cells cannot swim. Thus it becomes clear that whenever bacteria gain access to nutrient-rich fluid-filled spaces (eg, cerebrospinal, pleural, peritoneal, pericardial, or synovial fluid), phagocyte defenses are put at considerable disadvantage. Neutrophils must make physical contact with the bacteria they kill. In a fluid-filled space (eg, massive ascites), this contact depends on random collisions between bacterial and phagocytic cells. Indeed, in the preantibiotic era, pyogenic infections of fluid-filled spaces were frequently fatal. Because bacteremia is often a precursor to meningitis, pericarditis, peritonitis, or septic arthritis, one major function of the RES is to clear bacteria from the bloodstream, which thereby prevents seeding of fluid-filled spaces. Bacteria that most often cause these infections are notoriously difficult to clear from the bloodstream because they possess antiphagocytic factors, most often capsules (S pneumoniae, Streptococcus pyogenes, Neisseria meningitidis, and Haemophilus influenzae).

F. Phagocytosis (Stage 6). Phagocytosis is required to kill invading microorganisms. Phagocytosis is a two-step process: (1) attachment of the particle to the phagocyte occurs and (2) the phagocyte extends lamellipodia circumferentially around the particle to enclose it within a phagocytic vacuole called the phagosome (Figure 2-1G). As noted above, opsonic proteins (Igs and complement proteins) coat microorganisms and, by engaging their receptors on the surface of phagocytes, they mediate attachment. These receptor-ligand interactions also induce intracellular events, which activate the engulfment process. Engulfment itself is a highly energy-dependent process and is powered by an ATP-dependent cytoskeletal polymerization-depolymerization of actin microfilaments. Nonopsonic phagocytosis may occur for some microorganisms. Molecules on the surfaces of both target and phagocyte interact with oligosaccharide moieties, which mediate attachment and activate the engulfment "motor" of the phagocyte.

Another aspect of phagocytosis involves interaction between the phagocyte and the surrounding tissue substrate (ie, the surface on which the phagocyte is crawling). This involves specialized serum molecules (extracellular matrix proteins) such as fibronectin, laminin, and vitronectin. These proteins do not interact with microorganisms directly. However, facilitation of interaction between phagocyte and substrate by these molecules leads to substantial enhancement of phagocytosis.

G. Microbicidal Activity (Stage 7). There are numerous phagocyte microbicidal mechanisms (Figure 2-1H). As microorganisms are internalized within phagosomes, microbicidal functions are initiated. Two general categories of killing mechanisms are recognized. These are the oxygen-dependent and -independent mechanisms. Oxygen-dependent killing is by the oxidative burst, sometimes called the respiratory burst. There are multiple oxygen-independent mechanisms that are mediated by microbicidal proteins that are delivered into the phagosome by degranulation. Degranulation occurs when specific cytoplasmic granules in the neutrophil fuse with the phagocytic vacuole and discharge their contents on particles sequestered therein. A phagosome that has undergone this process is called a phagolysosome. The phagolysosomal membrane contains a proton pump that acidifies the compartment. The low pH (~ pH 4.5) is an ideal environment for many enzymes, acid proteases, defensins, cationic proteins, and other proteins (bactericidal permeability-increasing protein, azuricidin, indolicin, and bactenectins) that kill and digest (stage 8; see Figure 2-1H) bacteria.

The oxidative burst is based on a unique enzyme system, which in the resting cell is inactive. This enzyme is the NADPH/oxygen oxidoreductase of neutrophils and MNPs. The NADPH oxidase is activated upon stimulation induced by phagocytosis of a microorganism. Oxygen is reduced to superoxide with NADPH serving as the electron donor. There is abrupt, large-scale oxygen consumption by the enzymatic reaction—the respiratory or oxidative burst. Of the numerous biochemical events that ensue, the most important is the generation of several microbicidal products. All are formed ultimately from superoxide itself, the proximal enzymatic product. Hydrogen peroxide, singlet oxygen, and hydroxyl radical—all highly efficient microbicidal agents—are generated from superoxide. Hydrogen peroxide and chloride form hypochlorite and, ultimately, chloramines, through catalysis by myeloperoxidase. Thus the neutrophil relies on an arsenal of chemical weaponry to kill microorganisms. In the test tube, several million neutrophils undergoing the respiratory burst kill 10 million Escherichia coli within minutes; the same process occurs in the body, but only if neutrophils can phagocytose their targets and if substrates for the respiratory burst are available. It is evident that these highly reactive and toxic oxygen reduction products may destroy host cells along with invading microbes. Consequently, systems have evolved in mammals for protection of the surrounding host tissues at sites of inflammation. Catalase, superoxide dismutase, and glutathione peroxidase/glutathione reductase are detoxifying enzymes whose mechanisms scavenge oxygen intermediates. Other small organic molecules function as nonenzymatic scavengers. Neutrophil oxidative metabolism is extremely important for the maintenance of homeostasis in humans. Rare mutations that ablate NADPH oxidase activity lead to serious, frequent and invariably fatal pyogenic infections in children. Recent advancements have led to strategies that can augment other defenses and thereby prevent serious infections in these children.

Oxygen-independent microbicidal mechanisms compose a heterogeneous group. The most important are the microbicidal peptides and proteins that are released after bacteria are ingested during phagolysosomal fusion. An extensively studied example is the defensin family of molecules. By assembling into hydrophobic structures, which form pores through which bacterial components are lost, defensins lead to perturbation of bacterial membranes. This culminates in death of the bacterial cell.

Natural Killer Cells

NK cells are non-B, non-T lymphocytes that circulate in blood and function in constitutive host defense by identifying and destroying cells infected with viruses. Equipped with specialized proteins and enzymes packaged within intracellular granules, NK cells lyse virus-infected host cells and thereby interfere with viral replication. NK cells can bind yeast cells and destroy them. NK cells are an important source of cytokines, chemical messenger molecules that regulate the immune response. In rapidly developing infections, NK cell-derived IFN-? (one of the most important cytokines) activates macrophages to a microbicidal state.

DEFENSE MECHANISMS AT THE LEVEL OF PROTEIN MOLECULES

The complement proteins, designated collectively as C´, constitute a complex system of plasma zymogens that operate as part of innate host-defenses (the alternate pathway) and with antibodies, in adaptive immunity (the classical pathway). Although composed of different proteins, the complement system bears a striking analogy to the blood clotting system.

Complement proteins are produced primarily in the liver by hepatocytes. MNPs also synthesize and secrete all of the complement proteins, but the bulk of production depends on the liver.

The initial step of the alternative pathway is always active, but it occurs at a very low level. When bound to a microbial surface product, such as the lipopolysaccharide polymer from the cell wall of gram-negative bacteria, limited proteolysis proceeds stepwise until C3 is cleaved to C3b and C3a. C3b is a short-lived protein. It forms a covalent thioester bond near its formation site, namely on the surface of a bacterial cell. MNPs and polymorphonuclear phagocytes express a family of distinct C3 receptors. Ligand-receptor binding anchors the bacterial cell to the phagocyte. This attachment event initiates phagocytosis. In animal models, depletion of C´ proteins with cobra venom factor renders the host highly susceptible to infection with encapsulated bacteria such as S pneumoniae. Thus, the main function of the complement system is to generate opsonins, primarily C3b, molecules that increase the efficiency of phagocytosis.

Further in the complement cascade, C5 is cleaved into large C5b and small C5a proteolytic fragments. C5a diffuses from the site of inflammation, which sets up a concentration gradient that directs phagocyte emigration by chemotaxis.

Still later in the cascade a complex forms composed of C7, C8, and C9—the membrane attack complex (MAC). The MAC inserts itself into the outer lipid bilayers of gram-negative bacteria-forming pores visible by electron microscopy; this drastic perturbation leads to bacteriolysis. Bacteriolysis effected by the MAC is thus a mechanism for killing bacteria by fluid phase components—a phagocyte is not directly involved. However, bacteriolysis has limitations. First, gram-negative bacteria spawn mutants that are resistant to the lysing capability of the MAC. Second, gram-positive bacteria, mycobacteria, and fungi are naturally resistant to the MAC. Although protozoa may be killed by the MAC, CMI is the main defense mechanism against these pathogens.

The complement system performs three important host-defense functions: (1) it generates C3b, a major opsonic component that promotes phagocytosis; (2) it generates C5a, a chemotaxin that directs phagocyte motility toward an inflammatory stimulus; and (3) it kills some gram-negative bacteria through the MAC.

Humans with complement deficiencies, although uncommon, have been identified. These individuals exhibit characteristic susceptibilities to infection, such as disseminated infection with Neisseria meningitidis and N gonorrhoeae.

ADAPTIVE IMMUNE RESPONSES

INTRODUCTION

There are two general categories of adaptive immune responses. The first comprises the synthesis of specific Ig proteins (antibodies) by specialized lymphocytes called plasma cells. This is called humoral immunity. The second type of response, CMI, involves direct or indirect attack on microorganisms mediated by lymphocytes and other accessory cells (eg, macrophages). Both humoral immunity and CMI are characterized by two important features. First, the responses are directed toward specific biochemical moieties on microorganisms, called antigens. Second, the responses impart a "memory" in the host. This means that subsequent exposures to specific antigens are met with a much enhanced immune response.

HUMORAL IMMUNITY

Production of Antibodies

Antibodies are complex glycoproteins called Igs, which bind specifically to moieties called antigens. After an antigen is bound by an antibody, a variety of cellular and molecular mechanisms come into play. These mechanisms, which function to protect the host from microbial invaders, are discussed in the sections that follow. In conjunction with the complement system, antibodies are the main effector molecules of humoral immunity. Antibodies are used to inhibit or destroy foreign cells. In the circulation and on mucosal surfaces, antibodies help define acquired resistance to particular pathogens. The mechanistic bases for antibody-mediated resistance are varied and complex. It is necessary for the antibody alone to bind the antigen. Even this is not sufficient in all cases because additional mechanisms may be required to kill microorganisms (eg, participation by a phagocyte). Examples of antibody effector mechanisms include the following: (1) complement activation that leads to bacteriolysis; (2) opsonophagocytic function, in which antibodies attach microorganisms to phagocytes, which then kill the microorganisms; (3) antibody-dependent cellular cytotoxicity (ADCC), an antibody bridge between an effector cell (eg, lymphocyte or monocyte) and target cell (eg, virus-infected somatic cell) that activates a killing mechanism, whereby the target cell is destroyed; and (4) neutralization, whereby the antibody binds to a microbial toxin or virus, which renders it unable to bind to its receptor through stearic hindrance.

Two critical functions are encoded in the structure of the antibody molecule. The N-terminal end (variable or V region) of the molecule defines the antigen recognition site. There are many possible different amino acid sequences that lead to different antigen-binding specificities. The carboxy-terminal portion determines one of nine classes and subclasses of Ig isotypes. Each isotype carries a distinct functional attribute suited for various biologic tasks, such as complement fixation, opsonization, or distribution into certain body sites and surfaces. B lymphocytes produce antibodies that express surface-bound Igs of a single specificity. When these antigen receptors are engaged by specific ligands, B cells proliferate and differentiate into plasma cells. These cells then begin to secrete Ig molecules that are specific for the target antigen.

Immunoglobulin Structure

All Igs share the same basic molecular structure. This structure consists of two identical peptide heterodimers linked by disulfide bridges. Each heterodimer consists of a heavy chain (CH) and a light chain (CL) (Figure 2-2).

The antigen-binding site is in the Fab portion. Three hypervariable regions containing 10-12 amino acids with markedly viable sequences occupy the VK and VH domains. The quaternary structure of the CL and CH in this region determines antigen specificity. Because each Ig molecule has two heavy and two light chains, antibodies are bivalent for antigen binding. The portion of the antigen recognized is called the epitope. The complementary Fab-binding site is called the paratope.

A constant region of the CH is the product of distinct genes. This region defines the "class" of Igs. A hinge region determines flexibility of the molecule related to biological function. The Fc portion is critical for biological function, such as complement activation, the ability to bind to phagocyte receptors, and the ability to cross anatomic barriers such as placental membranes.

Immunoglobulins in Humans

Five Ig classes defined by their CH type are present in humans (Table 2-4). There are four IgG and two IgA subclasses. There are two classes of CLs (? and ?). Each B lymphocyte produces only one class of CL.

A. Immunoglobulin M. During the primary immune response, IgM antibodies are the first to be produced. The pentameric structure endows IgM with 10 antigen-binding sites. This assists in complement activation and aggregation of antigen and microbes. Antigen affinity for IgM is usually less than for IgG. Measurement of IgM antibody specificity and concentration is useful in diagnosis because its presence correlates with primary, active infection.

B. Immunoglobulin D. IgD is expressed on the surface of B cells and functions as antigen receptor. Membrane anchoring is a function of the extended hinge region of IgD molecules.

C. Immunoglobulin G. IgG is the most abundant Ig, making up ~ 75% of the total. It crosses the placenta and hence provides protection to the newborn during the first 6 months of life. It is present in the lower respiratory tract and in exudative secretions. There are four subclasses (IgG1, IgG2, IgG3, and IgG4), which are determined by the constant regions of their heavy chains. Each bears distinct biologic activities. IgG1 and IgG3 fix complement well. IgG3, but not IgG2 and IgG4, binds and activates leukocyte Fc receptors. IgG2 is produced against the polysaccharide determinants of bacterial capsules. IgG4 may compete with IgE for antigen and thereby alter immediate-type hypersensitivity reactions.

D. Immunoglobulin A. There are two subclasses of IgA—IgA1 and IgA2. IgA is produced in gut lymphoid tissue and is dimeric. It is transported from submucosa to the gut lumen. This is mediated by a special secretory component, expressed as an integral membrane protein on the basolateral surface of gastrointestinal epithelial cells. This secretory component is a receptor for dimeric IgA and initiates endocytosis, transcytoplasmic transport, and release of IgA dimers into the intestinal lumen. This process occurs at other mucosal sites in the respiratory and urogenital tracts, as well as in nasal secretions, tears, saliva, and colostrum. IgA interferes with attachment of microorganisms to mucosal surfaces. It neutralizes ingested toxins, and it may promote phagocytosis by leukocytes emigrating into mucosal epithelium.

E. Immunoglobulin E. Although only trace amounts are present in the circulation, IgE predominates on the surface of mast cells and basophils through noncovalent high-affinity receptor binding of its Fc portion. Immediate-type hypersensitivity or reaginic responses occur when antigen binds to cell surface IgE. Degranulation with release of histamine, eicosanoids, and peptide mediators of inflammation from mast cells may lead to urticaria, laryngeal and intestinal wall edema, and anaphylactic shock. The evolution of reaginic responses was driven by the necessity for a host-defense mechanism against invasion of tissues, especially epithelial surfaces, by helminths and ectoparasites. Monocytes, eosinophils, and platelets may cooperate with IgE in ADCC reactions against certain trematodes.

B Cells

Generation of an effective humoral immune response is vested in progenitor cells located in the bone marrow, which undergo differentiation to become mature B cells in the spleen and lymph nodes. Activation of mature B cells into antibody-producing plasma cells is a complex, highly regulated process. Regulation occurs through the expression of B-cell surface receptor molecules, which alter cell function upon binding ligand. Important B-cell receptors and their functions are shown in Table 2-5.

Antigen binding to its specific receptor on B cells leads to the formation of the B-cell receptor complex. When formed, the complex lowers the threshold for B-cell activation. Intracellular signal transduction through protein phosphorylation by Src kinases activates membrane phospholipase C?2. Inositol triphosphate and diacylglycerol are formed. Intracellular calcium is mobilized and protein kinase C is activated. Transcription of cellular genes is induced by regulating cell division, differentiation, and Ig synthesis. However, these events are usually not sufficient for high-level antibody production. T cells, which recognize processed antigen-derived peptide in association with complementary major histocompatibility complex (MHC) class-II determinants, physically aggregate with B cells and promote B-cell activation. This is called T-cell helper function. This is the main pathway for antibody production against protein antigens.

Certain polymeric antigens, especially bacterial polysaccharides bearing repetitive monosaccharide units, can activate B cells without T cells. This type of T-cell-independent antibody response may relate to cross-linking B-cell receptor complexes (and hence more efficient signal transduction) by long strands to linear polysaccharide antigen molecules. T-cell-independent antibody responses tend to produce low-affinity IgM and IgG2 isotypes in relatively low levels. Furthermore, memory B-cell formation is inefficient. Thus, bacterial polysaccharide vaccines may not be particularly immunogenic. By coupling a bacterial polysaccharide to a protein component (eg, tetanus toxoid) a T-cell-dependent B-cell response is induced, and memory cells become more abundant. Recently, lymphocytes not ordinarily classified as T or B cells, which bear the CD1 surface marker, were shown to help process polysaccharide antigens covalently attached to lipid moieties. This pathway of antigen presentation, which is not restricted by MHC, could prove useful for future development of polysaccharide vaccines.

Antibody Diversity

Antibody diversity is explained by rearrangements of DNA sequences within unique regions of Ig genes. Antibodies produced during a primary antibody response after an encounter with a new antigen are IgM in isotype. They appear 5-10 days after exposure to antigen, and their antigen affinity is relatively low. On reexposure to antigen, secondary antibody responses result in rapid production (1-3 days) of higher-affinity, higher-titer IgG, IgA, or IgE isotypes. Memory B cells formed during a primary response mediate the more efficient secondary response with the help of T cells. Switching of isotypes from IgM to IgG, for example, is controlled by T cells and the cytokines they secrete to communicate with B cells. Isotype switching and affinity maturation and epitope diversity of Igs are the result of four distinct molecular processes:

1. Multiple segments within the hypervariable region of the DNA encoding light and heavy chains (VL and VH; Figure 2-2) undergo recombination.

2. The segments are rejoined inexactly.

3. The quaternary association between VH and VL protein products leads to unique antigen-binding sites. These events lead to an enormous repertoire of B cells bearing different antigen receptor specificities. These specificities are directed against those portions of antigen molecules called epitopes.

4. A nonrecombinatorial mechanism involving somatic point mutations in the VH and VL regions leads to idiotype diversity. This mechanism is believed to account for maturation, when repeated administration of antigen results in antibody production with incrementally increased affinity for the eliciting epitope.

Immunoglobulin Fc Receptors

Antibodies function in host defense in conjunction with other proteins (eg, complement components) and cells (eg, phagocytes). Antigen bound to the Fab portions is connected to functional components by the Ig Fc portion. Thus, the specificity of Fc ligands interacting with Fc receptors on other immune cells determines the character of immune responses mediated by antibodies. Families of Fc receptors and their functional activities are shown in Table 2-6.

Function of Antibody-Mediated Host Defense

Through specific binding of antigen and Fc portion receptor-ligand interaction, antibodies facilitate destruction of microbes and neutralize toxins. They may act at a distance from their cell of origin, and their soluble properties allow for dispersion throughout the body in the circulation and lymph. The utility of Igs in host defense is multifactorial. However, the overriding feature is their functional capability for attaching microorganisms to phagocytes and lymphocytes bearing microbicidal mechanisms. The following sections summarize antibody-directed immune mechanisms.

A. Activation of Complement Proteins. The CH2 (IgG) and CH3 (IgM) domains (see Figure 2-2) of antibody Fc regions activate complement by binding to microbes and then interacting with multiple sites on C1q, the first component of the complement cascade (classical complement pathway). Activation of complement on microbial surfaces leads to bacteriolysis in some instances or, more commonly, to phagocytosis. Gram-negative bacteria are susceptible to bacteriolysis as are some protozoans. But gram-positive bacteria, fungi, and viruses cannot be lysed. Furthermore, gram-negative bacilli resistant to complement-mediated lysis (serum resistance) can be selected for during natural infection. Opsonophagocytic antibodies important for the resolution of infection have been identified during infection with S pyogenes, S pneumoniae, H influenzae, N meningitidis, and Staphylococcus aureus.

B. Promotion of Phagocytosis. The three classes of IgG Fc receptors mediate phagocytosis of IgG-coated particles. IgG2 and IgG3 subclasses are generally required. Mucosal phagocytes, namely macrophages and neutrophils, bearing IgA Fc receptors facilitate engulfment of microorganisms. Fc receptors alone are usually sufficient for phagocytosis of most bacteria and fungi; however, removal of encapsulated bacteria may require Fc and C3 receptors functioning in concert. In experimental S pneumoniae bacteremia caused by highly virulent strains, clearance of bacteria from the circulation failed when animals were depleted of complement proteins, even when anticapsular IgG antibody was present.

C. Antibody-Dependent Cellular Cytotoxicity. ADCC is a mechanism by which leukocytes destroy somatic cells infected with microorganisms. Antibody-coated microorganisms or parasitized host cells can be killed when Fc receptors on leukocytes are engaged. This reaction occurs without phagocytosis, but depends on contact between effector and target cells. Nonphagocytic immune cells (eg, NK cells) lyse antibody-coated virus-infected host cells through IgG RIII receptors. In this reaction, NK cells exocytose cytotoxin protein molecules called perforins onto target cells. Perforins assemble in the target cell membrane-forming pores similar to the MAC of complement. Rapid lysis ensues. Macrophages and neutrophils participate in ADCC reactions. IgE-coated metazoans such as parasitic helminths are destroyed by eosinophils bearing Fc receptor II molecules. Eosinophils exocytose a cytotoxic molecule, called major basic protein, onto the parasite surface on engagement and cross-linking of these Fc receptors.

D. Neutralization of Microbial Toxins. Microbial toxin neutralization is a striking example of protection mediated by antibodies. Lethal toxins produced by Clostridium spp. (eg, botulinum toxin and tetanus toxin) and by Corynebacterium diphtheriae (diphtheria toxin) are efficiently detoxified by specific IgG. Antibodies bind to toxin molecules and, through stearic hindrance, block their receptor-mediated uptake by susceptible cells. The antitoxin effect of antibodies is the basis for some of the most successful immunization practices in medicine.

Endotoxins are the lipopolysaccharide polymers that form part of the structure of the outer membrane of gram-negative bacteria. Their biologic effects are myriad, but they include the induction of lethal collapse of the circulatory system. Much effort has been made to produce protective antibodies against endotoxins for administration to patients in shock. Despite broad reactivity and monoclonal antibody technology, this strategy has not yet led to significant advances for the treatment of endotoxemia.

E. Neutralization of Viruses. IgM, IgG, and IgA antibodies bind to specific epitopes on virions and block virus access to host cells. The effective prevention of polio, smallpox, hepatitis A and B, and rabies by immunization is based on this principle. Other viruses, most notably herpes viruses and human immunodeficiency virus (HIV)-1, spread from cell to cell and hence evade neutralizing antibody. One exception may be the intracellular neutralization of viruses within mucosal epithelial cells as polymeric IgA is transported through these cells.

F. Blockage of Microbial Adhesion. Pathogenic microorganisms entering the body via mucosal surfaces first attach to epithelial cells by receptor-ligand binding. Specific IgA directed at these determinants may block adherence and hence abort microbial invasion.

G. Agglutination of Microorganisms into Large Aggregates. Polyvalent IgM, IgG, and IgA can cross-link microbes forming large aggregates. In the respiratory tract, the mucociliary clearance mechanism may then facilitate removal of these aggregates before invasion can occur.

CELL-MEDIATED IMMUNITY

Introduction

CMI refers to an immune response against organisms (usually facultative or obligate intracellular microorganisms) in which antibody has a subordinate or no role. CMI was first demonstrated experimentally as an immune response that occurred in passively immunized animals transfused with cells (lymphocytes) but not with specific Igs. Such strict division between cell-mediated and humoral immune responses is oversimplified because specific Igs and antigen-antibody complexes interact to both enhance and inhibit CMI reactions.

CMI involves signal transmission between cells participating in the response. Intercellular signaling is accomplished in two ways: (1) by cell-cell interaction involving surface molecules on the interacting cells and (2) via chemical messenger molecules called cytokines. These mechanisms operate both in innate immune responses and in antigen-specific CMI. Intercellular signaling mechanisms are then used to activate cytotoxic effector cells for microbiostatic and microbicidal functions. Cell signaling and activation are discussed individually in the next section.

Cell-Cell Interactions

A. Major Histocompatibility Complex Molecules. MHC molecules compose a group of polymorphic integral membrane proteins encoded by segments of clustered genetic loci. These molecules participate in binding antigenic peptides for T-cell recognition. Two structurally distinct types of MHC molecules exist. MHC class I molecules are involved in classic immune responses to virus-infected cells, foreign tissue grafts, and tumors. There are ~ 70 different alleles composing three separate subclasses of MHC class I genes. MHC class I molecules express peptides synthesized within the host cell (eg, a protein encoded by a viral gene) and transported from endoplasmic reticulum via the Golgi apparatus to the cell surface. ß2-Microglobulin and calnexin are required to stabilize MHC class I complexes. MHC class I antigens are presented as nonapeptides, and class I can be presented by all nucleated cells.

MHC class II molecules express antigens only on "professional" antigen-presenting cells (APCs), such as MNPs (macrophages) and related cells, dendritic cells throughout the body and Langerhans cells in the skin, and some B lymphocytes. MHC class II antigens are presented as 12- to 24-amino-acid peptides that are endocytosed from the environment and are expressed on the cell surface, having made their way through the endosomal/liposomal pathway.

B.T Lymphocytes. T cells interact directly with APCs. This cell-cell interaction drives specific immune responses by inducing clonal expansion of antigen-specific T cells. This expansion in turn results in secretion of signaling molecules, called cytokines. Cytokines direct the activities of additional immune response cells. Thus, the response to a specific antigen is vastly amplified. T cells bear receptors that bind to peptide antigen-MHC molecule complexes on antigen-presenting cells. Antigen-presenting cells bearing MHC class I antigens bind to T cells expressing the CD8+ T-cell receptor surface marker. MHC class II antigens bind to CD4+ T cells. This means that class I and II antigens stimulate separate populations of T cells. This separation directs the immune response toward different mechanisms adapted to deal with different antigenic challenges. CD4+ T cells function as cytokine secretors, and they help B cells produce Igs. CD8+ T cells become efficient cytotoxic cells, capable of lysing cells infected with viruses. Both CD4+ and CD8+ T cells bear the CD3 cell surface marker. The CD3 molecule transduces an up-regulating intracellular signal on binding to MHC class I or II antigens with CD8 or CD4 receptors, respectively. Mice with null mutations of the CD4 gene lack T-cell helper function; mice with null mutations of the CD8 gene lack cytotoxic T-cell function.

T-cell activation is maximized by coaggregation of the T-cell receptor with CD4 or CD8 bound to an MHC molecule-antigen complex on the APC. Other costimulatory molecules participate in T-cell activation, such as the CD28 T-cell marker bound to the B7/BB1 family of molecules on APCs. Upon aggregation and binding of these molecules between T cells and APCs, a complex cascade of intracellular events ensues. These events lead to T-cell differentiation and T-cell replication with clonal expansion. The latter is mediated by the T-cell growth factor, IL-2, which is secreted upon T-cell activation. The immunosuppressant antibiotic cyclosporin A inhibits IL-2 secretion by T cells by blocking the intracellular calcium-dependent functions in the complex cascade during T-cell activation.

Microbial superantigens activate T cells. Particular microbial toxins (ie, staphylococcal enterotoxin, toxic shock syndrome toxin, and streptococcal pyrogenic exotoxin A) are presented as MHC class II antigens, but they bind nonspecifically to the T-cell receptor. Up to 10% of T cells may be activated. This leads to widespread cytokine secretion and the systemic toxicity of a generalized cell-mediated immune response. Particular MHC class II genotypes and the T-cell receptor ß-chain genotypes are more prone to these reactions.

Memory T cells help mediate secondary cell-mediated immune responses. These T cells bear the CD29 surface marker. Memory T cells show enhanced secretion of particular cytokines, and they mediate rapidly developing cytotoxicity responses.

Lymphocyte adhesion molecules mediate trafficking and homing of T cells to particular body sites. Some T cells home to mucosal sites where they are strategically stationed to participate with APCs upon entry of foreign antigens into the tissues.

Cytokines

Cytokines function as chemical messengers, sending signals from one immune cell to another. Cytokines are glycoprotein molecules secreted by lymphocytes. These molecules were originally called lymphokines. As their identities and cells of origin were defined, the term lymphokine was replaced by cytokine to include signal molecules elaborated during CMI whose cells of origin included other cell types (eg, macrophages, endothelial cells, and fibroblasts). As cytokines became characterized molecularly through cloning, sequencing, and expression techniques, they were assigned numbers and designated as interleukins (Table 2-7). However, some cytokines retained their original names, based primarily on their immunologic activities (eg, IFNs, TNFs, and CSFs). During CMI, cytokines act locally, infiltrating tissue sites of inflammatory cells. However, they may exert systemic effects when released into the circulation. This occurs during widespread infection and certain toxemias (eg, in response to superantigens as noted above).

Cytokines act to amplify or attenuate the immune response coordinately. Their action is not antigen specific, but their secretion is often driven by antigen-specific reactions. Certain microbial products (eg, lipopolysaccharide of gram-negative bacilli) directly stimulate cytokine secretion (eg, TNF and IL-1). Cytokines regulate clonal expansion for both T and B lymphocytes. They mediate recruitment of immune cells to sites of inflammation. They activate effector cells (eg, macrophages) to microbicidal states. Some cytokines deactivate cells to prevent local tissue damage after the destruction of invading microbes. Cytokines interact with specific receptors on the cells they signal. The receptors act as transducers and relay signals into the cells, leading to additional secretions, replication, cell cycle arrest, and activation for microbicidal activities.

Cytokines secreted by MNPs are called monokines. Monokines help initiate CMI as macrophages phagocytose microbes and present their antigens to T cells. Two important cytokines come almost exclusively from T cells (hence they are lymphokines)—IL-2 and IFN-?. IL-2 leads to many effects including replication of T cells activated by specific antigen. IFN-? is the main lymphokine for activation of effector cells (macrophages) to destroy or inhibit pathogens. T cells respond with lymphokine secretion only if the T-cell receptor is engaged with specific antigen presented in context with MHC class I or class II molecules. An exception is the stimulation by superantigens. This is in contrast to monokine secretion, which occurs in response to a wide variety of stimuli. NK cells are also a source of IFN-? during primary infection, before T-cell activation.

CD4+ T cells change the profile of cytokines they secrete, and this directs the cell-mediated immune response toward activities suited best for defense against particular pathogenic agents. In the mouse during infection with intracellular pathogens, CD4+ T cells secrete IL-2 and IFN-?. This leads to macrophage activation and arrest of microbial intracellular replication by unknown mechanisms (TH1 response). The monokine, IL-12, directs CD4+ T cells into a TH1 phenotype. During systemic helminth infections CD4+ T cells secrete IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. This profile leads to expansion of B-cell clones for production of Igs, including IgE (so-called TH2 response). IgE participates in release of products from basophils, mast cells, and eosinophils that mediate cytotoxicity for multicellular animals that invade tissue usually via the intestinal tract. IL-10 directs CD4+ T cells into a TH2 phenotype.

Transforming growth factor-ß, IL-4, and IL-10 down-regulate CMI to intracellular pathogens. Mice lacking a functional transforming growth factor-ß gene die after birth with massive infiltration of lymphocytes and macrophages in their vital organs.

Other roles for cytokines include (1) control of hematopoiesis, (2) T-cell maturation and proliferation, (3) B-cell differentiation, and (4) T-cell suppressor function. Cytokines also regulate innate immune responses such as fever (IL-1) and the acute-phase response (IL-6, IL-1, and TNF). Cytokines released systemically cause shock (TNF) during septicemia.

Activation of Effector Cells

Effector cells of the cell-mediated immune response are microbiostatic and microbicidal for intracellular pathogens. These cells are cytotoxic T-cells, NK cells, and macrophages. Effector cells mediate and cytokines modulate antimicrobial activity during cell-mediated immune responses. Effector cells participating in CMI along with the functions they perform are listed in Table 2-8.

A. Cytotoxic T Cells. Cytotoxic T lymphocytes (CTLs) kill somatic cells that are infected with microbial pathogens. These T cells express CD8 and mediate antigen-specific, class I MHC-restricted cytolytic activity. Recall that class I recognition occurs for antigens synthesized within the host cell. This occurs during the replication cycle of viruses. CTLs are ideally suited for destroying virus-infected cells. Release of immature, unassembled virus components upon host-cell lysis blocks efficient viral replication. CTLs may lyse cells infected with bacteria. This thwarts the strategy of some facultative intracellular pathogens, whose survival in the host may depend on evasion of the immune system by sequestration within an intracellular niche. Differentiation of CTLs to the cytotoxic state is regulated by cytokines. Of those involved, IL-2 is most important. The biochemical mechanisms of cytolysis involve a Ca2+-dependent assembly of a protein present in CTL granules, called perforin. The protein is assembled into a cylinderlike structure that is inserted into the plasma membrane of the antigen-bearing target cell. Serine proteases within CTL granules, called granzymes, enter the target cell through perforin pores. The enzymes then become catalytically active and participate in target cell destruction.

B. Natural Killer Cells. NK cells participate in CMI by acting as effector cells and cytokine-secreting cells. NK cells are CD158+ lymphocytes that lack the T-cell receptor. They lyse certain neoplastic cells and virus-infected cells by a recognition mechanism that does not involve antigen-MHC restriction. These cells are active against virus-infected host cells, in particular the human herpes viruses. NK cells also function as an important source of IFN-? early during bacterial infections before CD4 cell activation. Their large granules contain granzymes and perforin monomeres, such as CTLs.

C. Mononuclear Phagocytes. MNPs include circulating monocytes and tissue macrophages. They play two key roles in the cell-mediated immune response, as APCs and as cytotoxic effector cells. Their latter role is discussed here. Activated MNPs are recruited from a pool of precursor cells in the bone marrow. These phagocytes are released into the circulation and adhere to capillaries adjacent to infected tissue by a process involving intracellular adhesion molecules. Chemokines specific for MNPs participate to attract these cells. MNPs migrate between capillary endothelial cells and crawl toward microorganisms by chemotaxis. Chemotactic molecules from the host and infecting microbes act as stimuli, setting up a concentration gradient sensed by MNPs.

In the inflammatory milieu, MNPs are exposed to activating cytokines, primarily IFN-? and TNF. Macrophages phagocytize microorganisms via a variety of receptor interactions involving IgG, IgA, and complement components, as well as via lipopolysaccharide and carbohydrate ligands present on bacteria, protozoa, fungi, and virus outer envelopes. Lysosomal granules within MNPs fuse with phagocytic vacuoles forming phagolysosomes. Granule components, including proteases, lysozyme, and microbicidal proteins, are released as the phagolysosome is acidified.

Activated MNPs inhibit and kill phagocytized microorganisms by a variety of mechanisms involving reactive-oxygen and reactive-nitrogen (from nitric oxide) intermediates, microbicidal proteins, liposomal proteases, and as-yet-unknown biochemical mechanisms. Activated MNPs play an important host defense role in combating a wide variety of bacteria, protozoans, fungi, and metazoans that have adapted virulence mechanisms for intracellular survival. Activated MNPs are critical for granuloma formation. They become epithelioid cells occupying the centers of granulomas. Granulomas are the histopathologic hallmark of the cell-mediated immune response against intracellular pathogens such as tubercle bacilli. TH1 response cytokines are required for granuloma formation. Activated MNPs may also mediate destruction of these same pathogens through a contact-dependent mechanism not requiring phagocytosis. Activated MNPs may also participate in cell-mediated immune responses through more efficient antigen presentation to T cells as well as through the production of cytokines that enhance T-cell-dependent killing mechanisms. Table 2-9 lists some examples of activated MNP-dependent host defenses against microbial pathogens.

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