When confronted with possible CAP, the physician must ask two questions: Is this pneumonia, and, if so, what is the likely pathogen? The former question is answered by clinical and radiographic methods, whereas the latter requires laboratory techniques.

Clinical Diagnosis The differential diagnosis includes infectious and noninfectious entities, including acute bronchitis, exacerbations of chronic bronchitis, heart failure, and pulmonary embolism. The importance of a careful history cannot be overemphasized. The diagnosis of CAP requires a compatible history, such as cough, sputum pro duction, fever and dyspnea, and a new infiltrate on chest radiography.

Unfortunately, the sensitivity and specificity of physical examination findings are only 58% and 67%, respectively. Chest radiography is often unable to differentiate CAP from other conditions. Radiographic findings may suggest increased severity (e.g., cavitation or multilobar involvement) and occasionally suggest an etiologic diagnosis, such as pneumatoceles in S. aureus infection or an upper-lobe cavitating lesion in tuberculosis. Computed tomography (CT) may be of value in suspected loculated effusion or cavitary cases or in postobstructive pneumonia caused by a tumor or foreign body. For outpatients, clinical and radiologic assessments are usually all that is required before treatment is started since most laboratory results are not available soon enough to influence initial management. In certain cases, the availability of rapid point-of-care outpatient tests can be important, such as for rapid diagnosis of influenza infection, and can prompt specific anti-influenza treatment and secondary prevention measures.

Etiologic Diagnosis The etiology of pneumonia usually cannot be determined solely on the basis of clinical or radiographic presentation. Data from >17,000 emergency department CAP cases showed an etiologic determination in only 7.6%. Except for CAP patients admitted to the ICU, no data exist showing that treatment directed at a specific pathogen is statistically superior to empirical therapy. The benefit of establishing a microbial etiology may be questioned, particularly in light of the cost of diagnostic testing. However, a number of reasons exist for attempting an etiologic diagnosis. Identification of a specific or unexpected pathogen allows focusing of the initial empirical regimen, with a consequent decrease in antibiotic selection pressure and the risk of resistance. Pathogens with important public safety implications, such as Mycobacterium tuberculosis, influenza, and SARS-CoV-2 viruses, may be found. Finally, without susceptibility data, trends in resistance cannot be followed accurately, and appropriate empirical therapeutic regimens are harder to devise.

GRAM STAIN AND CULTURE OF SPUTUM The main purpose of the sputum Gram stain is to ensure suitability of a specimen for culture. To be suitable, a sputum sample must have >25 neutrophils and < 10 squamous epithelial cells per low-power field. However, staining may also identify certain pathogens (e.g., S. pneumoniae, S. aureus, and gram-negative bacteria). The sensitivity and specificity of the sputum Gram stain and culture are highly variable. Even in cases of proven bacteremic pneumococcal pneumonia, the positive sputum cultures are ≤50%.

Many patients, particularly elderly individuals, may be unable to produce an appropriate sputum sample. Others may be taking antibiotics that interfere with culture results. Inability to produce sputum can be caused by dehydration, whose correction may result in increased sputum production and a more obvious infiltrate on chest radiography. For patients admitted to the ICU and intubated, a deep-suction aspirate or bronchoalveolar lavage sample has a high yield on culture when sent to the laboratory as soon as possible. Since pathogens in severe and mild CAP may differ (Table1), the greatest benefit of staining and culturing respiratory secretions is to alert the physician to unexpected and/or resistant pathogens and to permit appropriate modification of therapy. Other stains and cultures (e.g., for M. tuberculosis or fungi) may be useful as well. The sputum Gram stain and culture are recommended only for hospitalized CAP patients, particularly those with severe cases or those with risks of MRSA or P. aeruginosa infection.

Table1. Microbial Causes of Community-Acquired Pneumonia, by Site of Care

BLOOD CULTURES The yield from blood cultures, even when samples are collected before antibiotic therapy, is disappointingly low. Only 5–14% of cultures from hospitalized CAP patients are positive, and the most common pathogen is S. pneumoniae followed by S. aureus and P. aeruginosa. Since recommended empirical regimens all provide pneumococcal coverage, a blood culture positive for this pathogen has little, if any, effect on clinical outcome. However, susceptibility data may allow narrowing of antibiotic therapy in appropriate cases, and such data help to track microbial resistance patterns on a national basis. Because of the low yield and lack of significant impact on outcome, blood cultures are not considered de rigueur for all hospitalized CAP patients. Certain high-risk patients should have blood cultured, including those with neutropenia secondary to pneumonia, asplenia, complement deficiencies, chronic liver disease, or severe CAP and those at risk of MRSA or P. aeruginosa infection.

URINARY ANTIGEN TESTS Two commercially available tests detect pneumococcal and Legionella urinary antigens. The Legionella pneumophila test detects only serogroup 1, which accounts for most community-acquired cases of Legionnaires’ disease in the United States. Its sensitivity and specificity are 70% and 99%, respectively. The pneumococcal urine antigen test also is quite sensitive and specific (70% and >90%, respectively). Although false-positive results can be obtained for pneumococcus-colonized children, the test is generally reliable. Both tests can detect antigen even after initiation of appropriate antibiotic therapy. Testing for urinary pneumococcal antigen can be reserved for severe cases; Legionella antigen can be sought in severe cases and when relevant epidemiologic factors are present.

POLYMERASE CHAIN REACTION PCR tests amplify a microorganism’s DNA or RNA, and multiplex PCR panels test for a number of viral and bacterial pathogens. These tests dramatically improve response times, compared to standard cultures, but the contamination of respiratory specimens by upper-airway flora may make semiquantitative or quantitative assays necessary for best results. PCR of nasopharyngeal swabs has become the standard for diagnosis of respiratory viral infection, including influenza and coronaviruses. PCR can also detect the nucleic acid of Legionella species, M. pneumoniae, C. pneumoniae, and mycobacteria. The cost-effectiveness of PCR testing, however, has not been definitively established.

SEROLOGY A fourfold rise in specific IgM antibody titer between acute- and convalescent-phase serum samples is generally considered diagnostic of infection with a particular pathogen. Until recently, serologic tests were used to help identify atypical pathogens as well as selected unusual organisms such as Coxiella burnetii. However, these tests have fallen out of favor because of the delays in obtaining convalescent phase results and difficulties with interpretation.

BIOMARKERS Two of the most commonly used markers are C-reactive protein (CRP) and procalcitonin (PCT). Levels of these acute-phase reactants increase in the presence of an inflammatory response, particularly to bacterial pathogens. Nevertheless, PCT is insufficiently accurate for use in the diagnosis of bacterial CAP, and initial serum PCT levels should not be used as a basis for withholding initial anti biotic treatment. CRP is considered even less sensitive than PCT for detecting bacterial pathogens. These tests should not be used alone but, in conjunction with findings from the history, physical examination, radiography, and laboratory tests, may facilitate antibiotic stewardship and appropriate management of seriously ill CAP patients.

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progesterone receptor assay (PR assay, PRA, PgR)

progesterone assay

pregnancy-associated plasma protein-A (PAPP-A)

Laboratory Detection of Immunologic Responses

HPV DNA Detection

platelet volume, mean (Mean platelet volume [MPV])

platelet count (Thrombocyte count)

platelet antibody detection (Antiplatelet antibody detection)

Future Directions of Molecular Diagnostic Testing

Next Generation Sequencing Technology

Analysis of Amplification Products

platelet aggregation test (Ristocetin test)