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Pathophysiology

Pathophysiology

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Pathophysiology

Six mechanisms have been identified in the pathogenesis of pneumonia in immunocompetent adults. Inhalation of infectious particles is probably the most important pathogenetic mechanism in the development of community-acquired pneumonia, with particular importance of pneumonia caused by Legionella species and M. tuberculosis.
Table 2: Pathogenetic Mechanisms in Pneumonia

Mechanism Inhalation of infectious particles Aspiration of oropharyngeal or gastric contents Hematogenous deposition Invasion from infection in contiguous structures Direct inoculation Reactivation © 2002 The Cleveland Clinic Foundation.

Frequency Common Common Uncommon Rare Less common More common in immunocompromised hosts

The aspiration of oropharyngeal or gastric contents is the most prevalent pathogenetic mechanism in nosocomial pneumonia, with several contributing factors. Swallowing and epiglottic closure may be impaired by neuromuscular disease, stroke, states of altered consciousness, or seizures. Endotracheal and nasogastric tubes interfere with these anatomic defenses and provide a direct route of entry for pathogens. Impaired lower esophageal sphincter function and nasogastric and gastrostomy tubes increase the risk of aspiration of gastric contents. Fortunately, aspiration rarely leads to overt bacterial pneumonia. Direct inoculation rarely occurs as a result of surgery or bronchoscopy but may play a role in the development of pneumonia in patients supported with mechanical ventilation. Hematogenous deposition of bacteria in the lungs is also uncommon but is responsible for some cases of pneumonia caused by S. aureus, Pseudomonas aeruginosa, and Escherichia coli. The direct extension of infection to the lung from contiguous areas, such as the pleural or subdiaphragmatic spaces, is rare. Reactivation of pathogens can take place in the setting of deficits of cell-mediated immunity. Pathogens such as Pneumocystis jiroveci, Mycobacterium tuberculosis, and cytomegalovirus can remain latent for many years after exposure, with flares of active disease occurring in the presence of immune compromise. Reactivation tuberculosis occasionally occurs in immunocompetent hosts. Once bacteria reach the tracheobronchial tree, defects in local pulmonary defenses can make infection more likely. The cough reflex can be impaired by stroke, neuromuscular disease, sedatives, or poor nutrition. Mucociliary transport is depressed with the aging process, tobacco smoking, dehydration, morphine, atropine, prior infection with influenza virus, and chronic bronchitis. Anatomic changes such as emphysema, bronchiectasis, and obstructive mass lesions prevent the clearance of microbes. Inflammatory cells drawn to

infected areas of the pulmonary tree release proteolytic enzymes, altering the bronchial epithelium and ciliary clearance mechanisms and stimulating the production of excess mucus. Community-acquired MRSA strains contain Panton-Valentine leukocidin, a toxin that creates holes in neutrophil cell membranes, releasing chemotactic and inflammatory factors.7 A blunted cellular and humoral immune response can also increase the risk of pneumonia. For example, granulocyte chemotaxis is reduced with aging, diabetes mellitus, malnutrition, hypothermia, hypophosphatemia, and corticosteroids. Granulocytopenia may be caused by cytotoxic chemotherapy. Alveolar macrophages are rendered dysfunctional by corticosteroids, cytokines, viral illnesses, and malnutrition. Diminished antibody production or function can accompany hematologic malignancies such as multiple myeloma or chronic lymphocytic leukemia. PATHOPHYSIOLOGY
Six mechanisms have been identified in the pathogenesis of pneumonia in immunocompetent adults. Inhalation of infectious particles is probably the most important pathogenetic mechanism in the development of community-acquired pneumonia, with particular importance in pneumonia due to Legionella species and Mycobacterium tuberculosis. Aspiration of oropharyngeal or gastric contents is by far the most prevalent pathogenetic mechanism in nosocomial pneumonia, with several factors contributing. Swallowing and epiglottic closure may be impaired by neuromuscular disease, stroke, states of altered consciousness, or seizures. Endotracheal and nasogastric tubes interfere with these anatomic defenses and provide a direct route of entry for pathogens. Finally, impaired lower esophageal sphincter function and nasogastric and gastrostomy tubes increase the risk of aspiration of gastric contents. Fortunately, aspiration rarely leads to overt bacterial pneumonia. Direct inoculation rarely occurs as a result of surgery or bronchoscopy but may play a role in the development of pneumonia in patients supported with mechanical ventilation. Hematogenous deposition of bacteria in the lung is also uncommon but is responsible for some cases of pneumonia due to Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. The direct extension of infection to the lung from contiguous areas such as the pleural or subdiaphragmatic spaces is rare. Reactivation of pathogens can take place in the setting of deficits of cell-mediated immunity. Pathogens such as Pneumocystis carinii, Mycobacterium tuberculosis, and cytomegalovirus may remain latent for many years after exposure, with flares of active disease in the face of immune compromise. Reactivation tuberculosis occasionally occurs in immunocompetent hosts. Once bacteria reach the tracheobronchial tree, defects in local pulmonary defenses may make infection more likely. The cough reflex can be impaired by stroke, neuromuscular disease, sedatives, or poor nutrition. Mucociliary transport is depressed with the aging process, tobacco smoking, dehydration, morphine, atropine, prior infection with influenza virus, and chronic bronchitis. Anatomic changes such as emphysema, bronchiectasis, and obstructive mass lesions prevent clearance of microbes. Inflammatory cells drawn to infected areas of the pulmonary tree release proteolytic enzymes, altering the bronchial epithelium and ciliary clearance mechanisms, and stimulating the production of excess mucus. A blunted cellular and humoral immune response may also increase the risk of pneumonia. For example, granulocyte chemotaxis is reduced with aging, diabetes mellitus, malnutrition, hypothermia, hypophosphatemia, and corticosteroids. Granulocytopenia may be caused by cytotoxic chemotherapy. Alveolar macrophages are rendered dysfunctional by corticosteroids, cytokines, viral illnesses, and malnutrition. Diminished antibody production or function can accompany hematologic malignancies such as multiple myeloma or chronic lymphocytic leukemia.

HISTORY AND PHYSICAL EXAMINATION

Because the clinical syndromes characterizing pneumonic infections caused by various agents frequently overlap with each other and interobserver variability regarding physical findings of pneumonia is high, the diagnosis of pneumonia can be challenging. A diligent history and physical examination can help narrow the differential diagnosis. In general, typical bacterial pathogens such as S pneumoniae, H influenzae, and the enteric gram-negative organisms usually present acutely with high fever, chills, tachypnea, tachycardia, and productive cough. Examination findings are localized to a specific lung zone and may include rales, rhonchi, bronchial breath sounds, dullness, increased fremitus, and egophony. In contrast, atypical pathogens such as Mycoplasma, Chlamydophilia, and viruses can present in a subacute fashion with fever, nonproductive cough, constitutional symptoms, and absent or diffuse findings on lung examination. Rapid progression of disease to respiratory failure can be seen in severe pneumococcal or Legionella pneumonia. Influenza may be complicated by bacterial pneumonia with S. aureus or S. pneumoniae. SARS presents with high fever and myalgia for 3-7 days followed by non-productive cough and progressive hypoxemia with progression to mechanical ventilation in 20%. This can be distinguished from other viral infections by the higher fever and lack of conjunctivitis, sneezing, rhinorrhea, and pharyngitis. Inhalation anthrax can present with "flu-like" symptoms of myalgia, fatigue, and fever before rapidly progressing to respiratory distress, mediastinitis, meningitis, sepsis, and death. The age of the patient can play an important role in disease presentation. Older patients often have humoral and cellular immunodeficiency as a result of underlying diseases, immunosuppressive medications, and aging. They are more frequently institutionalized with anatomic problems that inhibit pulmonary clearance of pathogens. The presentation is often more subtle than in younger adults, with more advanced disease and sepsis despite minimal fever and sputum production. Extrapulmonary physical findings can provide clues to the diagnosis. Poor dentition and foulsmelling sputum may indicate the presence of a lung abscess with an anaerobic component. Bullous myringitis can accompany infection with M pneumoniae. An absent gag reflex or altered sensorium raises the question of aspiration. Encephalitis can complicate pneumonia with M pneumoniaeor Legionella pneumophila. Cutaneous manifestations of infection can include erythema multiforme (M pneumoniae), erythema nodosum (C pneumoniae and M tuberculosis), or ecthyma gangrenosum (P aeruginosa).

DIAGNOSIS AND TREATMENT SETTING
The composition of the diagnostic workup for pneumonia is the subject of some disagreement between experts (see "National Guidelines"), but a well-chosen evaluation can both support a diagnosis of pneumonia and identify a pathogen. Radiography A cornerstone of diagnosis is the chest x-ray, which usually reveals an Pulmonary infiltrate in infiltrate (Figure 1) at presentation. However, this finding may be absent Legionella pneumonia. in the dehydrated patient. Also, the radiographic manifestations of Source: CDC/Dr. William B. Baine chronic diseases such as congestive heart failure, chronic obstructive pulmonary disease (COPD), and malignancy may obscure the infiltrate of Figure 1 pneumonia. Although radiographic patterns are usually nonspecific, they can suggest a microbiologic differential diagnosis(Table 4). Initial Management Risk Stratification and Treatment Setting When community-acquired pneumonia is strongly suspected on the basis of history, physical examination, and chest radiography, the next critical management decision is whether the patient will require hospital admission. Health care budgetary constraints have given rise to a number of studies addressing the need for hospitalization in community-acquired pneumonia. A recent study

by the Patient Outcome Research Team (PORT) investigators validated a risk scale for mortality in community-acquired pneumonia, assigning point values based on patient characteristics, comorbid illness, physical examination, and basic laboratory findings (Table 5).7 Patients less than 50 years of age without comorbid illness or significant vital sign abnormalities (risk class I) were found to have a low risk for mortality. The authors suggested that such patients might be eligible for outpatient antibiotic therapy without extensive laboratory evaluation. All others were evaluated with the laboratory testing listed in Table 5 and assigned to risk classes by point totals (Table 6). Classes I and II are considered excellent candidates for outpatient oral therapy, assuming no hemodynamic instability, no chronic oxygen dependence, immunocompetence, and ability to ingest, absorb, and adhere to an oral regimen. Patients in risk class III may be considered for either outpatient or brief inpatient therapy, depending on clinical judgment. Patients in risk categories IV and V are recommended for hospital admission. Ultimately, each decision to admit must be individualized. Diagnostic Testing When the patient with few risk factors falls into PORT class I, the guidelines of the Infectious Disease Society of America suggest empiric therapy without extensive lab evaluation (Table 7). For the patient falling outside of this group, basic labs and a chest radiograph should be used to stratify the patient into classes II through V. If the patient is hospitalized, further workup may help to identify a pathogen (Table 7). The value of such studies is not uniformly agreed upon (see "National Guidelines"). However, pathogen identification has important implications for breadth of therapeutic antibiotic spectrum, development of resistance, and epidemiology. A gram-stained sputum specimen can help focus empiric therapy. Unfortunately, sputum is frequently difficult to obtain from elderly patients because of a weak cough, obtundation, and dehydration. Nebulized saline treatments may help mobilize secretions. Nasotracheal suctioning can sample the lower respiratory tract directly but risks oropharyngeal contamination. A sputum specimen reflects lower respiratory secretions when more than 25 white blood cells (WBCs) and less than 10 epithelial cells are seen in a lowpowered microscopic field.8 Empiric therapy based on a predominant organism in such a specimen is likely to contain appropriate coverage.9 Other stains, such as the acid-fast stain for mycobacteria, modified acid-fast stain for Nocardia, or the toluidine blue and Gomori methenamine silver stains should be employed when directed by the history or clinical presentation. Direct fluorescent antibody (DFA) staining of sputum, bronchoalveolar lavage fluid, or pleural fluid may help identify Legionella species. In a like fashion, DFA testing of nasopharyngeal specimens provides rapid diagnosis of influenza A and B, as well as other common respiratory viruses such as respiratory syncytial virus, adenovirus, and parainfluenza virus. In an outbreak setting, DFA and other rapid techniques can assist in therapeutic and infection control decision-making. The sputum culture remains a controversial tool but is still recommended to help tailor therapy. Culture is particularly helpful in identifying organisms of epidemiologic significance, either for patterns of transmission or resistance. Expectorated morning sputum specimens should be sent for mycobacterial culture when the history is suggestive. Blood cultures may also shed light on a pathogen, and should be drawn in hospitalized patients (see "Outcomes"). Pleural or cerebrospinal fluid should be sampled when infections in these spaces are suspected. When these procedures fail to yield a microbiologic diagnosis and when the patient fails to respond to empiric antibiotic therapy, more invasive diagnostic techniques may be indicated. Fiberoptic bronchoscopy allows the use of several techniques in the diagnosis of pneumonia. Bronchoalveolar lavage with saline can obtain deep respiratory specimens for the gamut of stains and cultures mentioned above. Transbronchial biopsy of lung parenchyma can reveal alveolar or interstitial pneumonitis, viral inclusion bodies, and fungal or mycobacterial elements. The protected brush catheter is used to quantitatively distinguish between tracheobronchial colonizers and pneumonic pathogens. A more substantial amount of lung tissue may be obtained for culture and histologic examination by thoracoscopic or open-lung biopsy. Because these procedures can carry considerable

morbidity, they are usually reserved for the deteriorating patient with a pneumonia that defies diagnosis by less invasive techniques. Serologic Testing Often relegated to retrospective or epidemiologic interest because of delays in testing or reporting, serologic testing for such pathogens as Legionella species, Mycoplasma species, and C pneumoniae should include sera drawn in both the acute and convalescent phases for comparison. A fourfold increase in the immunoglobulin G (IgG) titer is suggestive of recent infection with these organisms. An IgM microimmunofluorescence titer of > 1:16 is considered diagnostic of C pneumoniae infection. Infection with SARS associated coronavirus is most often diagnosed by antibody testing and polymerase chain reaction testing. A sensitive enzyme immunoassay has been developed for the detection of L pneumophila type 1 antigen in urine. Because the antigen persists for up to a year after infection, it is difficult to differentiate between past and current infections when using this assay. A newer urinary assay for detection of S pneumoniae cell wall polysaccharide has recently been approved by the FDA. This assay may offer some advantage in the rapid diagnosis of pneumococcal pneumonia in culture proven or unknown cases, but assay specificity is an ongoing question. Molecular Techniques Powerful molecular techniques are now being applied to the early diagnosis of pneumonia. DNA probes have been used for the detection of Legionella species, M pneumoniae, and M tuberculosis in sputum. These probes have excellent sensitivity and specificity but can produce some false-positive results. The polymerase chain reaction has been shown to be a sensitive tool for the early detection of M tuberculosis in sputum specimens. Given the large percentage of pneumonia cases for which no microbial etiology is identified, it is likely that molecular tools will eventually be applied to identification and antimicrobial susceptibility testing of nearly all agents of pneumonia.

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