Evaluation of pulmonary symptoms in persons with HIV

INTRODUCTION — The acquired immunodeficiency syndrome (AIDS) epidemic remains one of the most important global health problems of the 21st century [1-4]. Although the incidence of AIDS-related opportunistic infections declined dramatically in the United States and Europe following the introduction of potent antiretroviral therapy (ART), pulmonary disease remains a significant cause of morbidity and mortality [5-8].

This topic will focus on the evaluation of persons with HIV who present with pulmonary symptoms; specific conditions and their management are discussed separately. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV" and "Epidemiology of tuberculosis" and "Toxoplasma pneumonia and other parasitic pulmonary infections in patients with HIV" and "Diagnosis of pulmonary tuberculosis in adults".)

CAUSES OF PULMONARY DISEASE IN PERSONS WITH HIV — There are a variety of infectious and noninfectious pulmonary diseases that are more likely to be seen in persons with HIV. The immune reconstitution syndrome can also affect the lung and mimic other conditions, such as various infections and even lung cancer [9]. (See "Immune reconstitution inflammatory syndrome".)

Infections — The spectrum of pulmonary disease in individuals with HIV has changed over the past decades [5-7,10]. Although Pneumocystis pneumonia (PCP) remains the most common AIDS-defining opportunistic infection in the United States, its incidence has decreased with improved prophylactic and antiretroviral therapy (ART). (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV".)

Persons with HIV are at risk for a number of other pulmonary infections in addition to PCP. Bacterial pneumonia remains a common complication in patients with HIV and has increased as a proportion of diagnosed pulmonary infections despite an overall decrease in the number of cases [11,12]. A detailed discussion of bacterial pulmonary infections in patients with HIV is presented elsewhere. (See "Bacterial pulmonary infections in patients with HIV".)

In addition to bacterial pneumonia, many people with HIV have coinfection with tuberculosis (TB), especially in resource-limited countries. In Africa, TB is the most common pulmonary complication of HIV, and at least one-third of all cases occur in patients with HIV [13]. In addition, infection caused by endemic fungi and parasites contributes substantially to the morbidity and mortality of this population worldwide. (See "Epidemiology of tuberculosis" and "Toxoplasma pneumonia and other parasitic pulmonary infections in patients with HIV" and "Diagnosis of pulmonary tuberculosis in adults".)

Viral pathogens also contribute to the burden of pulmonary disease in patients with HIV. In one report of persons with HIV from Africa, where the seroprevalence of cytomegalovirus (CMV) is high, retinitis, pneumonia, and colitis were the most commonly reported manifestations of CMV [14]. CMV coinfection in these individuals was associated with more HIV transmission and increased mortality. The clinical significance, however, of isolating CMV from respiratory secretions remains controversial. (See "Approach to the diagnosis of cytomegalovirus infection".)

Non-PCP fungal pneumonia (eg, coccidioidomycosis, histoplasmosis, cryptococcus) has become less common following improvements in antiretroviral treatment, but its true incidence remains unknown. (See "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Patients with HIV' and "Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV" and "Cryptococcus neoformans infection outside the central nervous system".)

Noninfectious pulmonary diseases — The use of potent ART has been associated with a reduction in certain noninfectious pulmonary complications. As an example, the incidence of Kaposi sarcoma has declined, most likely as a result of immune reconstitution, although it still remains one of the most common neoplasms in patients with HIV [15]. In addition, the use of ART has contributed to a decrease in the incidence of non-Hodgkin lymphoma and also in the overall incidence of AIDS-related lymphoma [16,17]. (See "HIV infection and malignancy: Epidemiology and pathogenesis".)

Despite these improvements associated with ART, some noninfectious pulmonary diseases, such as lung cancer, Hodgkin lymphoma, constrictive bronchiolitis, and bronchiectasis, are on the rise [18,19]. HIV is also cited as a risk factor for the development of emphysema, independent of cigarette smoking. Among other factors, HIV infection may affect cytotoxic lymphocyte activation and capillary endothelial cell injury and apoptosis, leading to destruction of lung parenchyma [20].

Organizing pneumonia, sarcoidosis, drug hypersensitivity, primary effusion lymphoma, foreign body granulomatosis, and other forms of lung disease can occasionally develop in patients with HIV [21-30]. Lymphocytic interstitial pneumonitis, a rare interstitial lung disease in the general population, has declined with increased access to ART. (See "Primary effusion lymphoma" and "Lymphoid interstitial pneumonia".)

CLINICAL ASSESSMENT

History — When evaluating a patient with HIV and pulmonary symptoms it is important to obtain a careful history of their immune status (eg, CD4 count, history of opportunistic infections), when their current symptoms began, the nature of the symptoms, and associated findings. As an example, patients with Pneumocystis pneumonia (PCP) typically have a subacute onset of dyspnea and cough, whereas patients with bacterial pneumonia often have an acute onset of fever and cough. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Clinical Features of Pulmonary disease' and "Bacterial pulmonary infections in patients with HIV", section on 'Clinical manifestations'.)

Epidemiologic and environmental considerations are also important. As examples:

●A detailed assessment of any possible exposure to active tuberculosis (TB) is an important part of the medical history. Some cases of TB in patients with HIV represent newly acquired infection rather than reactivation of old disease. Risk factors for TB may include recent or remote travel to an endemic country. In addition, health care facilities, prisons, and homeless shelters are potential sources for transmission of TB. (See "Epidemiology of tuberculosis" and "Diagnosis of pulmonary tuberculosis in adults".)

●There is an increased incidence of pulmonary histoplasmosis and coccidioidomycosis in patients who live or travel in endemic areas (the Mississippi River Valley/parts of the Caribbean and the Southwest United States, respectively). Reactivation can occur especially in histoplasmosis; thus, patients who resided or spent time in endemic areas earlier in their lives are at risk for overt disease as they become more immunosuppressed. (See "Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV" and "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients", section on 'Patients with HIV'.)

●In addition to infection caused by endemic fungi, parasitic disease results in substantial morbidity and mortality among this population worldwide. Responsible organisms that cause pulmonary disease include Toxoplasma gondii and Strongyloides stercoralis. (See "Toxoplasmosis in patients with HIV" and "Toxoplasma pneumonia and other parasitic pulmonary infections in patients with HIV".)

Physical examination — Certain diagnostic clues on physical examination are often unrelated to examination of the chest but may suggest a pulmonary diagnosis.

●The skin can show manifestations of pulmonary-associated bacterial, fungal, viral, or neoplastic disorders. As an example, umbilicated lesions seen in association with headache and fever should prompt a search for cryptococcosis [31]. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV".)

●Examination of the fundus and optic disc may suggest the presence of viral, fungal, or mycobacterial infection. (See "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis" and "Tuberculosis and the eye".)

●Lymph nodes can be enlarged due to TB, fungal disease, or lymphoma. (See "Evaluation of peripheral lymphadenopathy in adults" and "Clinical manifestations and complications of pulmonary tuberculosis", section on 'Patients with HIV infection' and "HIV-related lymphomas: Clinical manifestations and diagnosis".)

HIV status

CD4 count — In patients with HIV, the risk of developing certain infections correlates with the degree of impairment of host defenses. As a result, the CD4 count can provide important information about a patient's susceptibility to specific types of pulmonary disease [32]. As examples:

●Sinusitis and bronchitis can occur at any CD4 count.

●Bacterial pneumonia and TB can occur at any CD4 cell count and before AIDS-defining opportunistic infections or neoplasms occur. However, both occur more frequently as immune function declines. (See "Bacterial pulmonary infections in patients with HIV" and "Epidemiology of tuberculosis", section on 'HIV infection'.)

●PCP usually occurs below 200 cells/microL. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV".)

●Disseminated histoplasmosis usually occurs below 150 cells/microL. (See "Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV".)

More detailed information on the relationship of the CD4 count with the risk of specific infections is presented in separate topic reviews. (See "The natural history and clinical features of HIV infection in adults and adolescents", section on 'Overview of stages of HIV infection' and "Overview of prevention of opportunistic infections in patients with HIV" and "Techniques and interpretation of measurement of the CD4 cell count in people with HIV".)

Antiretroviral therapy history — Patients who are not receiving antiretroviral therapy (ART) may be at increased risk for opportunistic infections, particularly those with a low CD4 count. (See 'CD4 count' above.)

By contrast, effective ART results in sustained suppression of HIV RNA, improved cellular immunity (ie, CD4 count), and reduced HIV-immune activation (eg, proinflammatory cytokines, chronic inflammation, and T cell activation), which can otherwise lead to end-organ damage (eg, coronary artery disease, liver and kidney disease, neurologic disease, malignancy). ART also results in both a decreased incidence of HIV-related comorbid conditions and an improvement in outcomes among those who develop a comorbid disease. (See "The natural history and clinical features of HIV infection in adults and adolescents".)

In patients presenting with pulmonary disease, it is important to assess when ART was initiated. Patients recently started on ART may develop an immune reconstitution inflammatory syndrome to pathogens or recrudescence of diseases that have been dormant. As an example, patients with latent mycobacterial disease may develop fever, lymphadenopathy, and pulmonary opacities following immune restoration [21]. Immune reconstitution inflammatory syndromes can also occur with other infections, malignancies, or inflammatory syndromes, including PCP, Kaposi sarcoma, and sarcoidosis. (See "Immune reconstitution inflammatory syndrome".)

IMAGING STUDIES — Plain chest radiographs, computed tomographic (CT) scans, and (on occasion) nuclear imaging scans all may play a role in the diagnostic evaluation of a patient with HIV and pulmonary symptoms.

Chest radiography — Plain chest radiography is an appropriate initial imaging study for patients with HIV who present with unexplained pulmonary or constitutional symptoms. Any new abnormalities, including focal or diffuse opacities, nodules with or without cavitation, pleural effusions, and/or intrathoracic adenopathy, should be pursued for a definitive diagnosis.

Certain specific radiographic patterns may assist in this process (table 1). Disease specific considerations include:

●Pneumocystis pneumonia – Typical radiographic findings in patients with Pneumocystis pneumonia (PCP) include bilateral airspace infiltrates, often characterized as having a finely granular, reticular, or "ground glass" appearance [33]. However, nodular densities, lobar consolidation, cystic lesions, upper lobe opacities, and pneumothoraces can all be seen. Aerosolized pentamidine prophylaxis appears to increase the probability of an atypical radiographic presentation of PCP infection with cavitation or pneumatocele formation in the upper lobes or periphery due to inadequate deposition of pentamidine into those areas [33,34]. Approximately 10 percent of patients with HIV and PCP have normal chest x-rays. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV".)

●Mycobacterial disease – Patients with HIV and pulmonary tuberculosis (TB) can present with atypical radiographs. In early studies, postprimary ("typical") patterns, with upper lobe opacification and/or cavitation, were seen in only 20 to 30 percent of patients with pulmonary TB [35,36]. Findings compatible with primary infection, including intrathoracic adenopathy, lower lobe opacities, and/or pleural effusions, were present in up to 35 percent of these patients [35,36]. A subsequent study, comparing the radiographic presentation of HIV-associated TB in the era prior to and after the introduction of potent antiretroviral therapy (ART), found that the incidence of "typical" postprimary chest radiographic changes increased from 25 to 45 percent, respectively [37]. The chest radiograph tends to correlate with the CD4 count; patients with CD4 counts above 200 cells/microL more commonly have a postprimary ("typical") pattern, while patients with CD4 counts below 200 cells/microL tend to have radiographs that are normal or compatible with primary TB infection [38]. (See "Clinical manifestations and complications of pulmonary tuberculosis".)

One study found that persons with HIV who had abnormal chest radiographs (including nodules/masses, opacities, cavities, lymphadenopathy, and effusions) and absence of pulmonary symptoms had a high incidence of infectious disorders, especially typical and atypical mycobacterial diseases [39]. (See "Mycobacterium avium complex (MAC) infections in persons with HIV".)

●Bacterial pneumonia – Opacities localized to a segment or lobe, particularly if they contain air bronchograms, are suggestive of bacterial pneumonia. The probability is even greater when observed in patients with CD4 lymphocyte counts >200 cells/microL. A majority (60 to 90 percent) of patients with HIV who have bacterial pneumonia will have localized opacities. Diffuse opacities have been described, particularly in patients with pneumonia caused by Haemophilus influenzae [40-42].

●Other infections – Patients with advanced HIV are at increased risk of pulmonary and systemic infections, such as Rhodococcus equi, a Nocardia-like organism associated with cavitary pneumonia and pleuropericardial effusion [43-45]. (See "Clinical features, diagnosis, therapy, and prevention of Rhodococcus equi infections".)

Chest CT — Chest CT scans have become an important part of the diagnostic evaluation of persons with advanced HIV and pulmonary symptoms. Chest CTs are more sensitive than plain chest radiographs in the detection of early interstitial lung disease, lymphadenopathy, and nodules. In a study of patients with HIV who had evidence of pulmonary disease on chest CT, 17 percent had normal findings reported on plain chest radiograph [46]. (See "Principles of computed tomography of the chest" and "High resolution computed tomography of the lungs".)

Chest CT scans have a greater ability than chest radiographs to identify and characterize pulmonary nodules both in patients with and without HIV. Nodules (with or without cavitation) in patients with HIV can result from infection (especially bacterial pneumonia and mycobacterial disease) or malignancy (particularly lymphoma). A biopsy, usually CT-guided transthoracic needle aspirate, is often required to make a definitive diagnosis [47,48].

Chest CTs are also helpful in identifying adenopathy. In another study of 318 patients, 35 percent had evidence of lymphadenopathy on CT; typical and atypical mycobacterial disease, bacterial pneumonia, and lymphoma were the most common diagnoses [49].

Certain patterns noted on CT may also lead to a specific diagnosis. As an example, one prospective study evaluated the accuracy of high resolution CT scans (HRCT) in distinguishing between PCP and other causes of lung disease in 30 patients with CD4 counts <200/microL, pulmonary symptoms, and nondiagnostic chest radiographs [50]. The diagnosis "suggestive of PCP" was applied to cases showing a diffuse or ground-glass pattern predominately in the upper lobes with or without cystic changes. Other findings such as "tree in bud" appearance, consolidation, bronchiectasis, and lymphadenopathy were classified as "not suggestive of PCP." The sensitivity and specificity, as well as the positive and negative predictive values of the HRCT for the diagnosis for PCP were 100, 83.3, 90.5, and 100 percent, respectively. A more detailed discussion of HRCT for the diagnosis of PCP is presented elsewhere. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Evaluation and diagnosis'.)

Nuclear scanning — Various forms of nuclear scanning have been used to evaluate persons with HIV who have pulmonary symptoms:

●Although highly sensitive for detecting PCP, gallium citrate (67 gallium) lung scanning has limited utility in the diagnostic evaluation of patients with HIV and pulmonary symptoms since this study is nonspecific. Thus, this test is rarely performed.

●Kaposi sarcoma is positive on Thallium-201 (TI-201) scans but negative on Gallium citrate (67 gallium) scans. This type of imaging may be helpful in patients when there is no cutaneous disease and lung tissue sampling is not feasible [51].

●Positron emission tomography (PET) scanning has been used to evaluate opportunistic infections or malignancies; however, since false positive scans have been associated with high levels of HIV RNA, PET scanning may not offer significant advantages to other imaging modalities that are not affected by clinical status [52]. In addition, PET scanning cannot differentiate malignancy from infection.

OTHER TYPES OF TESTING

Physiologic studies — Physiologic studies, including measurements of pulmonary function and gas exchange, may be useful in the evaluation of patients with HIV and pulmonary symptoms. (See "Overview of pulmonary function testing in adults".)

Pulse oximetry or arterial blood gas analysis — The use of pulse oximetry or arterial blood gases performed before and after exercise can be helpful to identify pulmonary disease in patients with HIV who experience dyspnea or cough, especially when chest radiographs are normal. As an example, investigators found that desaturation below 90 percent (measured by oximetry) occurred in 74 percent of patients with Pneumocystis pneumonia (PCP) who rode a bicycle ergometer for 10 minutes [53]. In this study, the best independent predictors of PCP were exercise-induced desaturation (odds ratio [OR] 5.4, 95% CI 2.6-11.3) and infiltrates on chest radiograph (OR 4.9, 95% CI 2.2-10.9); resting arterial hypoxemia was much less predictable. In another report of patients with HIV and documented PCP, an abnormal exercise test showing a marked decrease in the alveolar-to-arterial oxygen difference between rest and exercise was consistent with PCP [54]. By contrast, patients who did not have a decrease in the (A-a) oxygen gradient with exercise were unlikely to have the disorder. (See "Pulse oximetry" and "Treatment and prevention of Pneumocystis infection in patients with HIV", section on 'Initial assessment'.)

Diffusing capacity for carbon monoxide — Measurement of the diffusing capacity for carbon monoxide (DLCO) is a sensitive (though nonspecific) marker for pulmonary parenchymal disease [55]. In PCP, the DLCO may decrease before the development of interstitial infiltrates on chest radiograph and in the absence of resting hypoxemia. Thus, when the DLCO is abnormal (<80 percent of predicted) in a symptomatic patient, even with a normal chest radiograph, further diagnostic evaluation is indicated [56]. (See "Diffusing capacity for carbon monoxide".)

Sputum analysis — Analysis of spontaneously expectorated sputum is used primarily in patients with suspected bacterial infections or tuberculosis (TB). Induced sputum with histologic staining can be used for the diagnosis of PCP. The value of sputum induction and analysis in the setting of other pulmonary infections is unknown.

Detailed information on the role of sputum analysis for specific diseases is presented in individual topic reviews:

●(See "Bacterial pulmonary infections in patients with HIV", section on 'Sputum'.)

●(See "Diagnosis of pulmonary tuberculosis in adults".)

●(See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Choosing the optimal respiratory specimen'.)

●(See "Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV", section on 'Diagnostic evaluation'.)

Noninvasive tests — A variety of noninvasive diagnostic tests have been used in specific clinical settings.

Antibody, antigen, and beta-D-glucan testing — Assays designed to detect antigens (eg, urine histoplasma polysaccharide antigen, serum cryptococcal antigen, and serum galactomannan) may be useful for the diagnosis of certain fungal diseases. In addition, elevated plasma levels of 1-3-beta-d-glucan, a component of the cell wall of many fungi, have been found in the setting of invasive aspergillosis and PCP. By contrast, serologic testing is generally of little value in the diagnosis of acute pulmonary infections in patients with HIV. A detailed discussions of these tests are found within the individual topic reviews. (See "Cryptococcus neoformans infection outside the central nervous system", section on 'Pulmonary infection in immunocompromised adults' and "Diagnosis of invasive aspergillosis", section on 'Diagnostic modalities' and "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Choosing the diagnostic test' and "Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV", section on 'Approach to diagnosis'.)

Polymerase chain reaction testing — Polymerase chain reaction (PCR) testing is useful for diagnosis of certain infections (eg, viral infections, Pneumocystis).

Nasal swabs or washings may be used for the diagnosis of community-acquired viral infections due to influenza, parainfluenza, adenovirus, respiratory syncytial virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In a prospective study of 55 patients with HIV and pulmonary symptoms, nearly one-fifth of all patients were positive for at least one respiratory virus including coronavirus, influenza, and parainfluenza [57]. Since no other pathogens were found in the majority of cases, these were felt to be responsible for the pulmonary symptoms. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Testing for respiratory viruses' and "COVID-19: Diagnosis", section on 'NAAT (including RT-PCR)'.)

PCR of respiratory fluid, in particular bronchoalveolar lavage (BAL), is increasingly used to make the diagnosis of PCP [58]. The utility of PCR for the detection of Pneumocystis in oral washes and nasopharyngeal aspirates remains controversial [59]. The high sensitivity associated with PCR is its greatest drawback, since cutoff values to distinguish colonization from infection with PCP have not yet been established [59,60]. A more detailed discussion of PCR testing for the diagnosis of PCP is presented elsewhere. (See "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Choosing the diagnostic test'.)

Smear and culture of peripheral blood — Cultures of blood for Histoplasma capsulatum and mycobacteria may occasionally provide a definitive diagnosis. In patients with disseminated histoplasmosis, the highest yield is from bone marrow or blood cultures, which are positive in more than 75 percent of cases. Smears of peripheral blood can provide a rapid diagnosis in approximately 28 percent of cases [61]. Mycobacterial blood cultures are positive in 26 to 42 percent of patients with HIV and tuberculosis (TB), and the frequency of positive results is inversely related to the CD4 count [38].

Serum lactate dehydrogenase — Measurement of serum lactate dehydrogenase (LDH) is helpful in screening patients suspected of having PCP. One study of 54 patients with PCP found that 93 percent had an abnormal LDH value [62]. Although LDH is sensitive for the diagnosis of PCP, its specificity is quite low. Thus, a normal LDH value makes the diagnosis unlikely. Other diseases associated with markedly elevated LDH values include lymphoma, TB, and toxoplasmosis. (See "Toxoplasmosis in patients with HIV".)

Skin testing — With the exception of the tuberculin skin test, other skin testing in patients with HIV is not useful. Therapy for latent tuberculosis infection (LTBI) is indicated for patients with HIV who have a positive tuberculin skin test (>5 mm) without active TB [63]. Since the positivity of the tuberculin test depends upon the CD4 count, a negative test in patients with CD4 counts <300 cells/microL does not rule out either active or latent infection. Tuberculin skin tests should not be relied upon to make or rule out the diagnosis of active pulmonary TB. A detailed discussion of skin testing and other noninvasive tests (ie, interferon-gamma release assays) for TB screening is found elsewhere. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

Invasive tests — On rare occasion, invasive diagnostic tests may be needed to help in the evaluation of patients with HIV and pulmonary disease. The major invasive tests that are used to diagnose pulmonary disease in patients with HIV include fiberoptic bronchoscopy (FOB), CT-guided transthoracic needle aspiration (TTNA), and surgical lung biopsy using either video-assisted thoracoscopic surgery (VATS) or open thoracotomy.

Fiberoptic bronchoscopy — FOB remains the procedure of choice for diagnosing certain pulmonary diseases in patients with HIV because of its high yield and low complication rate [64]. (See "Flexible bronchoscopy in adults: Indications and contraindications".)

Evaluation of infectious causes — The organisms most commonly identified using FOB include Pneumocystis jirovecii (which causes PCP), as well as other fungal, mycobacterial, and viral pathogens. By contrast, FOB is rarely performed for the routine diagnosis of bacterial infection in patients with HIV.

●Pneumocystis pneumonia – The yield of BAL for the diagnosis of PCP is between 96 and 98 percent. Hence, the value of routine transbronchial biopsy in addition to BAL is controversial. Although biopsies slightly increase the risks of pneumothorax and hemorrhage, they may incrementally improve the diagnostic yield in PCP and other infections [65]. If transbronchial biopsy is contraindicated, BAL alone continues to have a good overall diagnostic yield, justifying its use as a sole procedure. (See "Flexible bronchoscopy in adults: Overview" and "Epidemiology, clinical presentation, and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Evaluation and diagnosis'.)

●Tuberculosis – The role of FOB in the rapid diagnosis of TB in patients with HIV remains controversial. Several studies have shown that bronchoscopy provided an early diagnosis in patients who had negative sputum smears 34 to 38 percent of the time [66,67]. In one study, transbronchial biopsy provided the exclusive means for rapid diagnosis in 6 of 59 patients with HIV [66]. However, studies directly comparing induced sputum to bronchoscopy have found the yield of induced sputum superior or equal to that of bronchoscopy [68]. If bronchoscopy is to be used for rapid diagnosis of TB, a transbronchial biopsy should be considered in addition to washings and lavage [66,67]. (See "Diagnosis of pulmonary tuberculosis in adults".)

●Cytomegalovirus infection – The clinical relevance of CMV retrieved bronchoscopically is questionable since BAL culture or cells showing cytopathic changes compatible with CMV in patients with HIV are not specific for CMV pneumonitis or morbidity [69]. In general, treatment is not warranted when CMV is isolated in bronchoscopic specimens from an asymptomatic person (eg, if bronchoscopy was performed for evaluation of noninfectious disorder).

Transbronchial biopsies are more likely to be specific for CMV pneumonitis but are insensitive due to the patchy nature of the disease.

The diagnostic utility of specific types of testing for CMV include:

•Culture – Cultures of BAL fluid are neither sensitive nor specific for CMV pneumonitis [70-75]. One study of 54 patients with HIV and CMV pneumonitis at autopsy found a sensitivity of BAL culture of only 50 percent [70], while a second study involving 40 autopsies found a sensitivity of 61 percent [71]. The specificity of a positive result also appears unacceptably low, and the presence of CMV on BAL culture does not correlate with gas exchange or chest radiographic abnormalities or with acute morbidity due to pulmonary disease [72,73]. One study of asymptomatic persons with HIV found that BAL culture was positive for CMV in 9 out of 19 subjects (47 percent) [74].

A particular problem is posed by the coexistence of CMV with other pathogens found in BAL fluid, particularly P. jirovecii (the causative agent of PCP). BAL fluid cultures or PCR testing may be positive for CMV in many patients with HIV and PCP [73], but it is not clear that clinical sequelae can be attributed to the presence of CMV [73,76]. In a study of 111 patients with AIDS and a first episode of PCP, 48 percent had CMV demonstrated on BAL fluid culture, but there was no difference between CMV culture-positive and culture-negative patients in terms of initial presentation, long-term survival, hospital mortality, or length of hospital stay [77]. Thus, when CMV is isolated from bronchoscopic specimens and concomitant pathogens are also present, treatment of only the concomitant pathogens is usually recommended.

•Polymerase chain reaction testing – The usefulness of CMV-PCR testing in BAL fluid has not been fully evaluated in patients with HIV and CMV pneumonitis. In one study of patients without HIV, CMV-PCR-BAL provided significantly higher sensitivity and specificity compared with shell vial cultures and conventional cultures for CMV [78]. However, the use of this test remains controversial.

•Cytology – BAL cytology that is positive for a cytopathic effect is presumably a more specific test than BAL fluid culture or PCR for CMV. However, there is no good correlation of cytopathic effect with either pneumonia attributable to HIV or with morbidity, above and beyond that associated with the presence of a positive BAL culture [69].

Evaluation of noninfectious etiologies — Bronchoscopic biopsies can provide tissue specimens allowing diagnosis of noninfectious disorders including Kaposi sarcoma [79], lymphocytic interstitial pneumonitis, and nonspecific interstitial pneumonitis, which cannot be reliably diagnosed on the basis of BAL findings. The diagnostic yield of endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) is high with experienced operators, and it is the preferred diagnostic procedure in patients for thoracic lymphadenopathy and lung cancer staging. (See "Bronchoscopy: Transbronchial needle aspiration" and "Endobronchial ultrasound: Indications, contraindications, and complications".)

Transbronchial lung cryobiopsy — Transbronchial lung cryo biopsy has been reported to be a valid and safe alternative to surgical lung biopsy in patients with diffuse parenchymal lung disease (DPLD). The reported diagnostic yield has been between 70 and 80 percent. (See "Bronchoscopic cryotechniques in adults".)

Although there are no large studies in persons with HIV, it might be considered a viable alternative to open lung biopsy in those suspected of having noninfectious diffuse pneumonitis and malignancies such as lymphoma, Kaposi sarcoma, lung cancer, and other causes of DPLD [80].

CT-guided TTNA — Transthoracic needle aspiration (TTNA) using CT guidance has a high yield in diagnosing the cause of peripheral nodules and localized infiltrates; however, the yield is much lower in patients with diffuse disease. In a study of patients with focal chest or mediastinal abnormalities on CT scan, a diagnosis was established in 27 of 32 cases (84 percent) using TTNA [81]. Although infectious agents were isolated in most of these patients, bronchogenic carcinoma was also diagnosed.

Although TTNA has been shown to be a safe and effective procedure for the evaluation of focal thoracic disease, it is not widely used for diffuse/interstitial disease. The reasons for this include:

●The small size of the samples obtained limits the number of studies that can be performed.

●The diagnostic yield is lower than that of FOB for the diagnosis of interstitial disease.

●There is a higher complication rate compared to FOB.

Surgical lung biopsy — Surgical lung biopsy remains the procedure with the greatest sensitivity in the diagnosis of parenchymal lung disease. Thoracotomy and VATS can both be performed safely in patients with HIV. One study showed that in patients who had a nondiagnostic bronchoscopy, a definitive diagnosis was found in 13 of 18 patients (72 percent) who underwent open lung biopsy [82]. Another study showed that results of an open lung biopsy led to a change in therapy in 15 of 25 patients, eight of whom improved clinically and were discharged from the hospital [83]. The authors outlined the following indications for open lung biopsy in patients with HIV:

●Nondiagnostic bronchoscopy

●Failed medical therapy after a diagnostic bronchoscopy

●Failed empiric medical therapy after a nondiagnostic bronchoscopy

●Any of the above, in combination with a worsening chest radiograph

Even though no formal comparison of VATS and open lung biopsy has been made in patients with HIV, both procedures appear to be equivalent for obtaining diagnostic lung tissue. There may be less morbidity associated with VATS, as these patients generally require fewer days in hospital and less time with chest tube drainage [83]. If the patient cannot tolerate single lung ventilation, which is necessary during VATS, or if the lesion cannot be reached through a thoracoscope, then an open thoracotomy should be performed. In general, the choice of procedure is best left to the surgeon. (See "Preoperative physiologic pulmonary evaluation for lung resection".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults and adolescents with HIV".)

SUMMARY AND RECOMMENDATIONS

●Causes of pulmonary disease – Persons with HIV are at increased risk of both infectious and noninfectious pulmonary diseases. Infectious etiologies include bacterial pneumonia, viral pneumonia, Pneumocystis pneumonia (PCP), and tuberculosis (TB). Noninfectious pulmonary diseases include lung cancer, Hodgkin lymphoma, constrictive bronchiolitis, bronchiectasis, and emphysema. (See 'Causes of pulmonary disease in persons with HIV' above.)

●Clinical assessment – When evaluating a patient with HIV and pulmonary disease, attention should be paid to the specific signs and symptoms, likely exposures, physical examination findings, and HIV-associated factors (eg, CD4 cell count, viral load level, and antiretroviral history). (See 'Clinical assessment' above.)

●Imaging studies – Chest radiographs, CT scanning, and (on occasion) nuclear imaging scans all may play a role in the diagnostic evaluation of a patient with HIV and pulmonary symptoms. (See 'Imaging studies' above.)

Plain chest radiography is an appropriate initial imaging study for those who present with unexplained pulmonary or constitutional symptoms. Chest CTs are more sensitive than plain chest radiographs in the detection of early interstitial lung disease, lymphadenopathy, and nodules. (See 'Chest radiography' above and 'Chest CT' above.)

●Additional evaluation

•Physiologic studies – Physiologic studies, such as measurements of pulmonary function and gas exchange, may be useful for diagnosis of certain pulmonary diseases (eg, PCP), especially when chest radiographs are normal. (See 'Physiologic studies' above.)

•Sputum analysis – Analysis of spontaneously expectorated sputum is used primarily for the diagnosis of bacterial infections or TB. (See 'Sputum analysis' above.)

•Noninvasive testing – A variety of noninvasive diagnostic tests have been used in specific clinical settings. These include antigen tests and testing for beta-D-glucan to help diagnose fungal infections, and the use of polymerase chain reaction (PCR) testing to diagnose viral infections and PCP. (See 'Noninvasive tests' above.)

•Invasive tests – On rare occasion, invasive diagnostic tests may be needed to help in the evaluation of patients with HIV and pulmonary disease. The major invasive tests include fiberoptic bronchoscopy (FOB), transbronchial cryobiopsy, CT-guided transthoracic needle aspiration (TTNA), and surgical lung biopsy using either video-assisted thoracoscopic surgery (VATS) or open thoracotomy. (See 'Invasive tests' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.