This approach consists of obtaining chest imaging studies, cardiac biomarkers (eg, B-type natriuretic peptide) and echocardiography to exclude cardiogenic pulmonary edema, and serologic and microbiologic studies of sputum, nasopharyngeal (NP) aspirates, blood, and urine to diagnose infection. In addition, newer molecular techniques are being implemented along with conventional methods in order to identify specific pathogens not only faster but more accurately without exposing patients to additional risks.
The most commonly performed noninvasive tests for diagnosing ARF are shown in Table 66–1.
Table 66–1Noninvasive tests for diagnosing acute respiratory failure. ||Download (.pdf) Table 66–1Noninvasive tests for diagnosing acute respiratory failure.
|Investigation ||Diagnosis/Specific Pathogen |
|Imaging (chest radiograph, high-resolution CT, chest ultrasound) ||Pattern of different radiologic findings may help in narrowing differential diagnosis |
|Transthoracic echocardiogram ||Congestive heart failure, cardiac tamponade, pulmonary embolism |
|Expectorated sputum ||Bacteria (S pneumoniae, Staphylococcus aureus, Hemophilus influenza, Enterobacteriaceae, Pseudomonas), Candida, other fungi (Histoplasma, Coccidioides) and M tuberculosis |
|Induced sputum (smear and cultures) ||P jiroveci, M tuberculosis |
|Nasopharyngeal aspirates ||Respiratory viruses, S pneumoniae |
|Blood cultures ||Various pulmonary infections |
|Polymerase chain reaction ||Herpes, Cytomegalovirus, P. jiroveci, M. tuberculosis |
|Circulating antigens ||Aspergillus, P. jirovecii |
|Serum immunoglobulins ||Chlamydia, Mycoplasma, Legionella |
|Urine antigens ||Legionella, S pneumoniae |
|Pleural fluid analysis (chemistry, microbiology, cytology and other ancillary tests) ||Malignancy, pulmonary embolism, collagen vascular disease, pancreatitis, uremia, yellow nail syndrome, sarcoidosis |
Important causes of ARF such as sepsis, aspiration pneumonia, diffuse alveolar hemorrhage, eosinophilic pneumonia, transfusion-related lung injuries and respiratory failure associated with cancer and other immunocompromised states are diagnosed clinically using a constellation of radiographic and other ancillary investigations.
The clinical presentation of suspected pulmonary infections is usually nonspecific. This is particularly important in immunocompromised patients who are prone to develop pulmonary infections with certain pathogens such as herpes simplex virus, Cytomegalovirus (CMV), Pneumocystis jirovecii (PCP), Mycobacterium tuberculosis, and Aspergillus species and hence require specific diagnosis and treatment as opposed to empiric therapy.
Gram stain of respiratory secretions, available within a few hours, may help in narrowing or broadening the antimicrobial spectrum but lacks sensitivity and specificity. Similarly, the yield of conventional stains for the diagnosis of other infections such yeast, other fungi, Aspergillus, M tuberculosis, and PCP pneumonia have been disappointing and slow which has led to a greater reliance on polymerase chain reaction (PCR)-based techniques. The latter has provided improved insight into the biology and genomic structure of the pathogens.
Azoulay et al3 performed a multicenter randomized controlled trial (RCT) comparing noninvasive testing (of sputum, induced sputum, NP aspirates, serum and urine as well as chest imaging and echocardiography) with an invasive strategy involving fiberoptic bronchoscopy with bronchoalveolar lavage (FOB-BAL) in 219 hematology and oncology patients with ARF. Bacterial infection was the primary etiology of ARF followed by infections with viruses, yeasts and molds, or Pneumocystis. Noninvasive testing provided the diagnosis in 71% of cases and resulted in a change in management in 44% of patients compared to only 34% in those who underwent FOB-BAL. In 20% of cases, no diagnosis was made with either strategy. Additionally, the time to diagnosis of bacterial, non-Aspergillus, and viral infection was shorter and available quicker with noninvasive testing as compared to invasive testing. However, the diagnosis of PCP took longer in the noninvasive group (3 [-7] days vs 1 [0-1] day). In both groups, a specific diagnosis was established in 80% of cases. These diagnostic rates were significantly higher than those reported in the earlier observational study conducted by the same authors suggesting the improved utility and advances in noninvasive testing in recent years.4
The sensitivity of nasal swab and NP aspirate is comparable for all respiratory viruses except for the detection of respiratory syncytial virus due to the inherent lability and relatively lower viral load present in the nasopharynx.5 Although serologic testing for CMV IgM and IgG may be used to screen for primary CMV infection or exposure, this is not used for the diagnosis of active CMV infection. Viral load testing in serum, tissue specimens, or BAL fluid using both quantitative nucleic acid amplification testing (QNAT) and antigenemia testing are currently the cornerstone for diagnosis and monitoring for CMV infection and disease.6 Real-time QNAT testing for CMV is now the standard of care given its better precision, broader linear range, faster turnaround time, higher throughput, and less risk of contamination compared with conventional PCR tests. In contrast, the antigenemia test is labor intensive, lacks a standardized cutoff value, and the assay performance diminishes when the absolute neutrophil count is less than 1000/mm3.6
Streptococcus pneumoniae urinary antigen has sensitivity of up to 78% in nonbacteremic patients and 80% in bacteremic cases and a specificity of more than 90% in adults. However, there have been false-positive reports of pneumococcal infection rates ranging from 21% to 54% in children with NP carriage and no evidence of disease.7 This limitation may be overcome with quantitative real-time PCR testing of NP swab samples to estimate NP colonization density and using cutoff values more than or equal to 8000 copies/mL, which improved the sensitivity to 82% and specificity to 92% for distinguishing pneumococcal pneumonia from asymptomatic colonization.8 Similarly, detection of Legionella pneumophila antigen in urine is rapidly available and requires no specialized laboratory equipment. Sensitivity rates of 73% and 77%, respectively, were reported for the new Meridian TRU Legionella assay and BINAX urinary antigen test. Additionally, the sensitivity of the Meridian TRU Legionella test increased to 81% after 60 minutes of incubation.9
PCP cannot be cultured and hence diagnosis relies on visualization of the fungus on microscopic examination of respiratory specimens. The sensitivity of microscopy varies according to the staining technique and type of respiratory sample used. In one study, the sensitivity and specificity of Grocott–Gomori methenamine silver stain for PCP were 79.4% and 99.2%, respectively.10 A serum assay for beta glucan, a cell wall component of most pathogenic fungi, is currently being used for PCP diagnosis with sensitivity and specificity rates of 100% and 96.4%, respectively, using a cut off value of 100 pg/mL.11 In a select group of patients the yield of induced sputum-PCR assay for detection of PCP has been shown to be excellent with sensitivity of 100% and specificity of 90% which would make FOB-BAL or lung biopsy practically unnecessary.12 Of note, respiratory specimens should be collected before or immediately after initiation of therapy because the sputum-PCR assay for detection of PCP may turn negative quickly. A negative PCR may allow for the discontinuation of anti-PCP therapy.12
Both direct microscopy and cultures are insensitive methods to diagnose aspergillosis. Galactomannan is an Aspergillus-specific polysaccharide which is released during Aspergillus growth at the site of infection. This antigen can be detected by quantitative serum galactomannan index and is used as a biomarker of the disease. In addition, galactomannan antigen has a strong correlation with clinical outcome; thus the test is currently repeated frequently during the course of treatment. In contrast, the presence and magnitude of the galactomannan index in BAL fluid does not have any mortality implication.13 In a study of 500 patients, the diagnostic yield of acid-fast bacilli (AFB) smear, cultures and PCR of induced sputum for M. tuberculosis was increased consistently with repeated induction from 64%, 70%, and 89% for AFB smear, and from cultures and PCR, respectively, to 98%, 100%, and 100% on fourth induction.14 Current amplification techniques can detect M. tuberculosis and rifampin resistance directly from clinical specimens in approximately 2 hours with high sensitivity compared to the standard method.15
Early molecular detection methods are currently under development. With regards to bacterial pathogens, multiplex amplification assays might include frequently involved microorganisms. Despite the obvious advantages of PCR-based methods (rapidity, sensitivity, convenience), several limitations including the need of cut-off levels to distinguish between colonization and infection, the inability to detect living viruses from prolonged harmless shedding, lack of information about the antibiotic susceptibility and the high cost of these tests still limits their widespread use in clinical decision making. Moreover, studies measuring clinical outcomes and mortality benefits are lacking at this time. These limitations in diagnostic testing with noninvasive strategies have led to the development of antimicrobial guidelines for empiric treatment.16 At this time, PCR-based testing can supplement rather than replace culture-based methods for pathogens where antibiotic resistance is a concern.