Comprehensive, up-to-date information on HIV/AIDS treatment and prevention from the University of California San Francisco

Respiratory symptoms are a frequent complaint among HIV-infected individuals. This fact was borne out by the Pulmonary Complications of HIV Infection Study, a large, prospective, observational cohort study of more than 1,150 HIV-infected subjects conducted at 6 sites across the United States where large numbers of HIV-infected patients received care.(1) The enrolled cohort was similar in composition to AIDS cases reported in the United States as of 1990 with regard to gender, race or ethnicity, and HIV transmission category. Subjects had a wide range of CD4 counts at enrollment (<200 cells/�L: 19%; 200-499 cells/�L: 44%; ≥500 cells/�L: 37%). The subjects were evaluated at enrollment and at scheduled intervals (randomized to either 3 or 6 months). In addition, subjects who developed new or worsening respiratory symptoms between these scheduled visits were instructed to present to a study site for evaluation. At each visit, subjects underwent a thorough history review and physical examination, routine laboratory studies (complete blood count with differential, CD4 cell count), chest radiography (posteroanterior and lateral views), and pulmonary function tests (lung volumes, spirometry, and diffusing capacity for carbon monoxide). Subjects in whom a pulmonary illness was suspected underwent sputum induction, bronchoscopy, or both.

The focus of the study was pulmonary disease. Researchers collected clinical and radiographic data prospectively and in a standardized fashion and, in subjects who developed new or worsening respiratory symptoms and in whom there was a suspicion of pulmonary disease, pursued definitive microbiologic and pathologic diagnoses whenever possible. HIV-related, non-HIV-related, AIDS-defining, and non-AIDS-defining respiratory illnesses were recorded. The study provided clinicians with an unparalleled source of information on pulmonary diseases in HIV-infected patients.

The Pulmonary Complications of HIV Infection Study demonstrated that respiratory symptoms are a common complaint among HIV-infected individuals and are increasingly frequent as CD4 counts decline to <200 cells/�L (Table 1). Study subjects reported cough at 27%, shortness of breath at 23%, and fever at 9% of more than 12,000 clinic visits.(2) These symptoms were even more frequent in the subset of subjects with a CD4 count of <200 cells/�L at the time of or previous to their visit. In that group, subjects reported cough at 34%, shortness of breath at 34%, and fever at 17% of the more than 4,000 visits.

The findings of the Pulmonary Complications of HIV Infection Study have been replicated in a single-center cohort of HIV-infected and HIV-uninfected subjects.(3) In this cohort, respiratory symptoms were frequent complaints in the HIV-infected group and were significantly more common than in the HIV-uninfected group. These included dyspnea (41.6% vs 7.7%), cough (40% vs 25%), and phlegm production (41.9% vs 23.1%). The researchers found that current or past cigarette smoking was the most important predictor of respiratory symptoms among the HIV-infected group.

Respiratory symptoms may result from a wide spectrum of pulmonary illnesses that includes both HIV-related and non-HIV-related conditions (Table 2). The HIV-related conditions include both OIs and neoplasms. The OIs include bacterial, mycobacterial, fungal, viral, and parasitic pathogens. OIs and neoplasms may be limited to the lungs, but pulmonary involvement may be only one manifestation of a multiorgan disease. Because prompt diagnosis and institution of appropriate therapy are essential for successful treatment of many of these HIV-related conditions, the initial focus of the evaluation of respiratory symptoms frequently and appropriately is placed on the diagnosis of an HIV-related OI or neoplasm. It is important to remember, however, that HIV-infected patients may have preexisting conditions or may develop conditions (eg, pulmonary embolism, asthma, or bronchogenic carcinoma in a cigarette smoker) unrelated to HIV infection that may cause respiratory complaints. In addition, factors that contribute to HIV infection, such as injection drug use (IDU), may contribute to respiratory disease (eg, pulmonary vascular disease). Clinicians should carefully consider these non-HIV-related respiratory conditions before embarking on an exhaustive search for an HIV-related OI or neoplasm.

The Pulmonary Complications of HIV Infection Study demonstrated that upper respiratory tract infections (URIs) such as sinusitis, pharyngitis, and acute bronchitis were more commonly the cause of respiratory symptoms than Pneumocystis jiroveci pneumonia (PCP), bacterial pneumonia, tuberculosis (TB), or pulmonary Kaposi sarcoma combined (Table 3).(4) This spectrum of pulmonary illnesses dominated by URIs and acute bronchitis in an outpatient-based clinical setting clearly shifts toward the opportunistic pneumonias in an inpatient- or hospital-based clinical setting, and it shifts toward PCP in an intensive care unit-based clinical setting.(5,6) In addition, demographic and regional differences will affect the spectrum of pulmonary illnesses seen. Therefore, the diagnostic approach to the evaluation of respiratory symptoms in an HIV-infected patient must take all these factors into consideration.

In the current era of combination antiretroviral therapy, the frequency of HIV-associated OIs and neoplasms has decreased.(7,8) In contrast, the frequency of noninfectious complications such as chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), and lung cancer may be increasing. HIV infection appears to be an independent risk factor for COPD and PAH.(9)

The diagnostic approach begins with a thorough history review and physical examination. On this basis, patients in whom there is suspicion of pulmonary illness should undergo selected laboratory tests and chest radiography. The radiograph result should be compared with previously obtained images, if available. Frequently, the clinical and radiographic presentations will suggest a differential diagnosis and a diagnostic and management plan. Occasionally, additional tests such as chest CT scan, chest high-resolution CT (HRCT) scan, and pulmonary function tests may be needed to further evaluate the cause of the symptoms and to further refine the differential diagnosis. Whenever possible, the diagnostic approach should include tests that may provide a definitive microbiologic or pathologic diagnosis. These tests include cultures of sputum and blood. They also include cultures from respiratory specimens obtained by bronchoscopy (with bronchoalveolar lavage, transbronchial biopsies, brush biopsies, or forceps/needle biopsies), pleural fluid (with or without pleural biopsies), CT-guided transthoracic needle aspiration, thoracoscopy, mediastinoscopy, and occasionally, open-lung biopsy. Specimens may be examined microscopically or cultured for bacterial, mycobacterial, fungal, viral, and parasitic pathogens, and they may be sent for cytopathologic and pathologic studies.

Occasionally, specimens from other sites (eg, skin, lymph node, bone marrow, cerebrospinal fluid) will provide evidence for the diagnosis of extrapulmonary or disseminated disease. For certain OIs, blood or urine serologies (eg, serum cryptococcal antigen, urine Histoplasma antigen) or molecular techniques such as analyses based on polymerase chain reaction (PCR) can provide or strongly suggest the diagnosis. The decision regarding which tests to obtain and which treatments to initiate relies on an accurate differential diagnosis derived from a thorough history and physical examination, selected laboratory data, and imaging studies.

The goal of the history review and physical examination should be to establish a differential diagnosis and to assess the need for further evaluation (eg, laboratory tests, chest radiography). Although each of the OIs and neoplasms has a characteristic clinical presentation, these presentations can vary and overlap significantly. As a result, no combination of symptoms or signs is diagnostic of a particular disease. Nevertheless, certain clinical information is useful for suggesting a particular diagnosis or diagnoses, perhaps none more so than the CD4 cell count.

The CD4 cell count is an excellent indicator of an HIV-infected patient's risk of developing a specific OI or neoplasm, presumably because it reflects the stage of HIV disease and degree of immunocompromise. Each of the HIV-related respiratory illnesses typically develops at or below a characteristic CD4 cell count range and uncommonly or rarely occurs above these ranges (Table 4). Respiratory illnesses such as URIs, obstructive airway disease, bacterial pneumonia, TB, non-Hodgkin lymphoma, pulmonary embolus, and bronchogenic carcinoma can occur in immunocompetent persons. Many of these diseases, however, are more common in HIV-infected persons than in immunocompetent ones. These diseases occur in HIV-infected patients at all CD4 cell count ranges. As the CD4 cell count declines, the incidence of many of these diseases increases. For example, there is a higher incidence of bacterial pneumonia in HIV-infected patients with a CD4 count of <250 cells/�L compared with patients with a CD4 count of >250 cells/�L.(10)

As the CD4 count declines to <500 cells/�L, episodes of bacterial pneumonia may be recurrent and mycobacteria other than M tuberculosis (eg, M kansasii) may occur.(11,12)

At a CD4 count of <200 cells/�L, bacterial pneumonia is often accompanied by bacteremia and sepsis, and M tuberculosis infection is often extrapulmonary or disseminated. In addition, PCP and pneumonia/pneumonitis caused by Cryptococcus neoformans become significant considerations.

At a CD4 count of <100 cells/�L, bacterial pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa and pulmonary involvement from Kaposi sarcoma or Toxoplasma gondii are increasingly diagnosed.(13)

At a CD4 count of <50 cells/�L, respiratory diseases caused by endemic fungi (eg, Histoplasma capsulatum, Coccidioides immitis), certain viruses (most commonly cytomegalovirus), mycobacteria (Mycobacterium avium complex), and nonendemic fungi (eg, Aspergillus spp) occur. Often, these diseases are associated with extrapulmonary or disseminated disease that dominates the clinical presentation. With the exception of the endemic fungal pathogens, identification of these organisms in sputum or bronchoalveolar lavage fluid can represent either airway colonization or actual pulmonary disease. In these cases, careful consideration of the clinical situation and the value of more invasive procedures (eg, lung biopsy) is crucial before initiating treatment.

Because each of the OIs and neoplasms typically develops at or below a characteristic CD4 cell count range, knowledge of an HIV-infected patient's CD4 cell count can be extremely useful in defining the possible diagnoses. For example, bacterial pneumonia (and possibly TB, depending on the demographic and region) but not PCP should be a top consideration for the differential diagnosis with an HIV-infected patient whose CD4 count is significantly higher than 200 cells/�L. All three of these pneumonias, but not pneumonias caused by the endemic fungi or cytomegalovirus, should be considered with an HIV-infected patient whose CD4 count is <200 cells/�L but well above 50 cells/�L. Finally, most or all of the diseases discussed above are diagnostic possibilities (although some are more frequent than others) with an HIV-infected patient whose CD4 count is <50 cells/�L. In each of these examples, information on the relative frequencies of the various OIs and neoplasms within a certain CD4 cell count range is essential for further refining the differential diagnosis.

The Centers for Disease Control and Prevention's Adult and Adolescent Spectrum of HIV Disease Project has provided statistics on which conditions occur at or below certain CD4 cell count ranges as well as which conditions are more common within a particular CD4 cell count range.(14) The project was a prospective, multicenter study conducted in 10 U.S. cities involving more than a hundred medical facilities that provide outpatient or inpatient care for HIV-infected individuals. The project reviewed medical records of enrolled subjects at 6-month intervals for the development of AIDS-defining and non-AIDS-defining infections, neoplasms, and illnesses. As of August 1993, more than 22,000 HIV-infected patients had been enrolled, and 18,062 of these patients had at least one 6-month follow-up medical record review. The median duration of follow-up at that time was 12 months.

The vast majority (>80%) of bacterial pneumonias and pulmonary M tuberculosis pneumonias occurred in subjects with a CD4 count of <400 cells/�L. Therefore, both of these diseases should be considered at any CD4 cell count but are more common when the count is <400 cells/�L. Results showed, however, that bacterial pneumonia (1,418 episodes; 8.4%) was a more common cause of pulmonary disease than TB (149 episodes; 0.8%) in this cohort. In contrast, the majority of PCP episodes occurred in subjects with a CD4 count of <200 cells/�L (1,097 episodes; 7.3%).

Knowledge of the CD4 cell count can be useful in narrowing the scope of the differential diagnosis, and knowledge of the relative frequencies of these pulmonary diseases can be useful in ranking potential diagnoses and suggesting a diagnostic and therapeutic plan. For example, if an HIV-infected patient presents with respiratory symptoms and a CD4 count of >200 cells/�L, PCP is unlikely and bacterial pneumonia is more likely than TB. In that case, the diagnostic plan should include sputum and blood cultures for bacteria, and therapy probably should target the most common bacterial pathogens.

Respiratory symptoms include cough, dyspnea, and pleuritic chest pain, either alone or in combination. Cough may be nonproductive or productive of clear phlegm/sputum, purulent sputum, blood-streaked sputum, or even frank hemoptysis. Dyspnea may be mild or severe and present at rest. Constitutional complaints such as fever, chills, night sweats, fatigue, anorexia, and weight loss also may be present. In addition, extrapulmonary symptoms (eg, headache, stiff neck, abdominal tenderness or fullness) may be present and could aid in differentiating the various OIs and neoplasms.

In many clinical settings (including San Francisco General Hospital), the two most likely HIV-related syndromes producing significant respiratory symptoms and pneumonia are PCP and pneumonia caused by bacterial pathogens (most commonly Streptococcus pneumoniae and Haemophilus influenzae). At San Francisco General Hospital, these two diseases account for the majority of the pulmonary diseases seen. Thus, distinguishing these two pneumonias often becomes the focus of the diagnostic approach (Table 5).

This author's firsthand experience indicates that these pneumonias often differ by the presence or absence of purulent sputum and the duration of respiratory symptoms.(15) PCP characteristically presents with fever, shortness of breath, and a dry, nonproductive cough. When the cough is productive, it is productive of clear phlegm/sputum. Respiratory symptoms are usually subacute and are present for weeks. Kovacs and colleagues reported in an early review that the median duration of symptoms was 28 days.(16)

In contrast, pneumonia caused by S pneumoniae or H influenzae characteristically presents with fevers, shaking chills or rigors, shortness of breath, pleuritic chest pain, and a productive cough with purulent sputum. Symptoms usually are acute and present for 3-5 days. In an HIV-infected patient with a CD4 count of <200 cells/�L (and therefore at risk of both pneumonias), the absence of purulent sputum and a duration of symptoms of a few weeks strongly favors a diagnosis of PCP rather than bacterial pneumonia. In contrast, the presence of purulent sputum and a duration of symptoms of a few days favors a diagnosis of bacterial pneumonia. Patients who have PCP and report a productive cough or purulent sputum often have a concurrent bacterial infection (bronchitis or pneumonia). Patients diagnosed with bacterial pneumonia who initially respond to antibiotics but subsequently worsen often have PCP that has become clinically symptomatic.

A thorough review of the patient's past medical history is essential and can provide important clues to the etiology of the current respiratory symptoms.

HIV Transmission Category and Habits

A patient's HIV transmission category and habits (eg, cigarette smoking) provide insights into the relative frequency of various HIV-related OIs and neoplasms and non-HIV-related conditions. Bacterial pneumonia is more common in HIV-infected patients who are injection drug users than in patients without a history of IDU.(17) Similarly, TB is more common in HIV-infected patients who use injection drugs than in patients without a history of IDU. On the other hand, Kaposi sarcoma is seen in the United States almost exclusively in men who have sex with men (MSM). Use of injection drugs or other illicit drugs can cause a variety of non-HIV-related pulmonary diseases (eg, endocarditis-related septic emboli or pneumonitis, respiratory depression, pulmonary edema). As with immunocompetent persons, HIV-infected patients who are cigarette smokers are at increased risk of a variety of respiratory illnesses. Both bacterial bronchitis and bronchopneumonia are more common in HIV-infected cigarette smokers than in nonsmokers or former smokers.(17,18) HIV-infected patients who report a long history of cigarette use may present with manifestations of chronic obstructive lung disease as the etiology of their respiratory symptoms.(19,18) Finally, HIV-infected smokers are more likely than nonsmokers to develop bronchogenic carcinoma.(20) As a result, it is critical for clinicians caring for HIV-infected persons to assess cigarette use among their patients.(18)

Travel and Residence

A travel and residence history may provide information about exposures to certain organisms and the possibility of disease from them. Travel to or residence in a geographic region that is endemic for one of the endemic fungi (H capsulatum, C immitis) is a strong determinant of the risk of exposure/infection and disease. HIV-infected patients without such a history are unlikely to be exposed and become infected with these organisms; therefore, they are unlikely to develop disease as a manifestation of their HIV infection. TB is more common in certain geographic areas and in certain populations (eg, immigrants from Asia and Latin America, homeless or unstably housed, incarcerated). HIV-infected patients who were born in or have traveled to a country with a high prevalence of TB and patients who are homeless, unstably housed, or previously incarcerated are at higher risk of exposure to M tuberculosis. Clearly, patients who report or have a positive result (defined as >5 mm of induration in HIV-infected persons) on purified protein derivative (PPD) testing are at increased risk of developing TB,(21) as are injection drug users who are anergic.(22)

Previous Pulmonary Conditions and Prophylaxis Use

Some HIV-related OIs recur frequently, and knowledge of a patient's past pulmonary history may suggest the etiology of the current illness. Recognition that bacterial pneumonias are common and frequently recurrent (recurrent bacterial pneumonia being defined as >2 episodes within a 12-month period) in HIV-infected patients (23) led to inclusion of bacterial pneumonia as an AIDS-defining condition beginning in 1993.(24) Patients with a history of PCP are at high risk of recurrence and must be offered secondary PCP prophylaxis regardless of their CD4 cell count.(25) Similarly, HIV-infected patients with a history of cryptococcosis, coccidioidomycosis, or histoplasmosis are at high risk of relapse/recurrence and should receive fluconazole (for cryptococcosis and coccidioidomycosis) or itraconazole (for histoplasmosis) lifelong maintenance therapy after completing treatment of the acute infection.(25) The exceptions to these rules involve patients whose CD4 cell count rises above a specific critical threshold for a minimum of 3-6 months as a result of antiretroviral therapy. In these individuals, multiple studies have documented that secondary prophylaxis/maintenance therapy may be discontinued safely in the vast majority of patients. Respiratory symptoms in an HIV-infected patient who is nonadherent with the recommended prophylaxis/maintenance therapy frequently are attributable to recurrent or relapsed disease.

A complete physical examination, including vital signs, may provide important clues to the nature and severity of the disease. HIV-infected patients with pneumonia may be febrile, tachycardic, and tachypneic. Evidence of systemic hypotension would be concerning for a fulminant disease process. Pulse oximetry often reveals decreased oxygen saturation and provides an estimate of disease severity. The presence of exercise-induced desaturation, hypoxia, or an increase in the alveolar-arterial oxygen gradient is reported to be a sensitive finding for PCP.(26)

Examination of the lungs may suggest an etiology for the respiratory symptoms. At least 50% of patients with PCP have lung examinations that are clear to auscultation and percussion (Table 5). In contrast, patients with bacterial pneumonia often have focal lung findings. Evidence of wheezing in an HIV-infected patient who has a history of asthma suggests an asthma exacerbation, whereas findings of decreased breath sounds in a patient who has a long history of cigarette use may indicate emphysema. In a patient with sudden onset of pleuritic chest pain or shortness of breath, findings of absent breath sounds would be worrisome for pneumothorax. Occasionally, abnormal findings on the lung examination are the result of a nonpulmonary etiology. For example, the finding of rales in association with a cardiac S3 gallop and elevated jugular venous pressure suggests a cardiac etiology for the respiratory symptoms. Pulmonary embolic disease should be considered in a hypoxic patient, especially if there are predisposing factors (eg, previous history, deep vein thrombosis).

The remainder of the physical examination also may suggest an etiology for the respiratory symptoms, because many of the OIs and neoplasms that affect the lung can also cause extrapulmonary or disseminated disease. For example, the finding of an altered mental status in an HIV-infected patient whose CD4 count is <200 cells/�L may suggest C neoformans as the cause of both the neurologic and pulmonary diseases. New cutaneous lesions may reflect a disseminated fungal disease, whereas hepatosplenomegaly suggests either disseminated mycobacterial or fungal disease or non-Hodgkin lymphoma. Patients with mucocutaneous Kaposi sarcoma may develop significant pulmonary involvement; however, the absence of mucocutaneous involvement does not rule out significant pulmonary Kaposi sarcoma. Huang and colleagues found that 15% of 168 consecutive HIV-infected patients diagnosed with pulmonary Kaposi sarcoma on bronchoscopy had no evidence of mucocutaneous disease at the time of their bronchoscopy.(27) The observed extent of tracheobronchial Kaposi sarcoma ranged from isolated tracheal lesions to diffuse/extensive involvement. No clinical symptoms or signs could distinguish patients with pulmonary Kaposi sarcoma from those with pulmonary Kaposi sarcoma and a concurrent pulmonary OI.

Selected laboratory tests may provide important clues to the diagnosis. HIV-infected patients often have a host of laboratory abnormalities that may result from HIV infection itself, from an HIV-related OI or neoplasm, or from medications used to treat HIV infection or an HIV-related condition. Accordingly, no laboratory abnormality is specific for a particular pulmonary disease and the clinician must be cautious before attributing a laboratory abnormality to a pulmonary illness.

Laboratory tests that may be useful include the complete blood count (CBC) with white blood cell (WBC) count and differential, the serum lactate dehydrogenase (LDH) level, and the arterial blood gas (ABG) concentration. These tests serve as a prognostic marker and as a baseline value for subsequent measurements. Serial measurements are useful with any patient who fails to exhibit a clinical response in an appropriate time interval and with any patient who is worsening clinically despite seemingly appropriate therapy.

WBC Count

The WBC count frequently is elevated relative to the patient's baseline value in those with bacterial pneumonia (Table 5). Often, this relative elevation is accompanied by a left shift. HIV-infected patients with neutropenia are at higher risk of bacterial and certain fungal (Aspergillus spp) infections. In contrast, persons with PCP may have an elevated, normal, or even decreased WBC count. In these patients, the WBC count more frequently reflects the degree of underlying immunosuppression, the use of bone marrow suppressive medications, or the presence of an infiltrative marrow infection or neoplasm rather than the presence of PCP.

LDH Level

An elevated serum LDH level may suggest a diagnosis of PCP, but the LDH measurement has greater utility as a prognostic test than as a diagnostic test. LDH is frequently elevated in patients with PCP (Table 5).(28,29,30) Studies report the diagnostic sensitivity of an elevated serum LDH level for PCP to be in the range of 83-100%. It must be emphasized, however, that serum LDH level is nonspecific for PCP and may be elevated as a result of many pulmonary and nonpulmonary conditions (including bacterial pneumonia). Furthermore, patients with PCP may have a normal or a minimally elevated serum LDH level, and there can be overlap between the serum LDH value in patients with PCP and that of patients with other pneumonias. Most of the published studies consisted of hospitalized patients with PCP, some of whom had respiratory failure and were mechanically ventilated. The study that reported the lowest diagnostic sensitivity of an elevated serum LDH level for PCP consisted of ambulatory outpatients presenting to an urgent care clinic,(31) which suggests that the severity of disease and the patient population being studied may affect the diagnostic sensitivity. Despite its limitations as a diagnostic marker, the degree of elevation of the serum LDH has been shown to correlate with a prognosis and response to therapy.(29) Patients with PCP and an initial markedly elevated serum LDH level or a rising serum LDH level despite PCP treatment have a worse prognosis and decreased survival rate.

ABG Concentration

The ABG concentration is frequently abnormal in patients with significant pulmonary disease. Typically, patients have hypoxemia, an increased alveolar-arterial oxygen difference, and a respiratory alkalosis. Clearly, these abnormalities are nonspecific for any OI or neoplasm of the lung. Thus, similar to the serum LDH test, the ABG measurement has greater utility as a prognostic test and as a marker of the severity of the pulmonary disease than as a diagnostic test.

The chest radiograph is the cornerstone of the diagnostic evaluation of respiratory symptoms in HIV-infected patients. Because each of the HIV-related OIs and neoplasms has a characteristic radiographic presentation, the radiograph (combined with information derived from the history, physical examination, and selected laboratory tests) can narrow the diagnostic possibilities and suggest a diagnostic approach.

Characteristic chest radiographic findings for the most common HIV-related OIs and neoplasms are presented in Table 6. For each radiographic finding, the OIs and neoplasms are listed according to their approximate frequency at San Francisco General Hospital. For example, PCP is a more common cause of a reticular or granular pattern of opacities than pulmonary disease resulting from C neoformans, bacterial pathogens (H influenzae), fungal pathogens (H capsulatum), cytomegalovirus, or non-Hodgkin lymphoma (Table 6). Thus, when presented with such a radiograph finding in a patient with a CD4 count of <200 cells/�L, the diagnostic approach usually focuses on diagnosing PCP. In contrast, PCP is a much less common cause of a miliary pattern than either M tuberculosis or fungal pathogens (H capsulatum, C immitis, C neoformans). With the presence of a miliary pattern, the diagnostic approach would shift to these pathogens.

The differential diagnoses presented in Table 6 can be altered by a number of factors. Demographic and regional differences can alter the differential diagnoses presented. For example, patients who are injection drug users have an increased incidence of TB and bacterial pneumonia compared with nonusers of drugs.(17,22,32,33) Clinical settings in regions endemic for H capsulatum or C immitis report a higher proportion of these pathogens. Furthermore, patients often present with combinations of these radiographic findings.

Consideration of radiographic combinations also can dramatically alter the differential diagnoses presented. For example, PCP is the most common cause of diffuse infiltrates. The combination of diffuse infiltrates and pleural effusions, however, is more suggestive of a bacterial pneumonia, TB, fungal pathogens, and pulmonary Kaposi sarcoma than it is of PCP because these diseases also can present with pleural effusions, which are relatively uncommon in PCP.

Finally, consideration of the CD4 cell count and the chest radiograph together also can alter the differential diagnosis. For example, PCP is extremely uncommon in an HIV-infected patient with a CD4 count significantly higher than 200 cells/�L. In such a patient, a chest radiograph with diffuse infiltrates may be more suggestive of a fulminant bacterial pneumonia (H influenzae) than of PCP. Table 6 should be used as a reminder of syndromes to consider rather than as a guide for a rigid approach to the diagnosis.

In most cases, a chest CT scan is unnecessary because the clinical and chest radiographic presentation suggests a single diagnosis or a few diagnoses to consider. However, HRCT can be useful in cases of clinically suspected PCP in which the chest radiograph is normal or unchanged.(34) Patients with PCP and a normal chest radiograph have patchy areas of ground-glass opacity (GGO) on HRCT. Although the presence of GGO is nonspecific and may be seen with a number of pulmonary disorders, its absence argues strongly against the diagnosis of PCP.(34)

Chest CT also can be useful in cases in which the chest radiograph reveals multiple pulmonary nodules.(35,36) A predominance of nodules <1 cm in diameter in a centrilobular distribution strongly suggests the presence of an OI (bacterial pneumonia, TB, fungal pneumonia), whereas a predominance of nodules >1 cm in diameter is suggestive of a neoplasm (pulmonary Kaposi sarcoma, non-Hodgkin lymphoma). If the nodules are mostly <1 cm in diameter, the presence of intrathoracic adenopathy, especially if low attenuation (another potential use for CT), indicates that mycobacterial (or fungal) disease is probable.(37) If the nodules are mostly >1 cm in diameter, the finding of associated peribronchovascular thickening strongly suggests pulmonary involvement from Kaposi sarcoma. Finally, chest CT scans can guide diagnostic procedures such as bronchoscopy, CT-guided transthoracic needle aspiration, and surgical procedures.

The characteristic chest radiographic presentations of the most common OIs--PCP and bacterial pneumonia--should be familiar to clinicians because of their frequency. Given the public health risks of a missed diagnosis, clinicians should be familiar with the two most characteristic radiographic presentations of M tuberculosis pneumonia. Finally, because it is the most common pulmonary neoplasm, clinicians should be familiar with the characteristic presentation of pulmonary Kaposi sarcoma. The following is a brief summary of classic radiographic findings for these 4 pulmonary diseases.

Classically, PCP presents with bilateral reticular or granular opacities (Figure 1).(38,39,40,41) In mild cases, the radiographic findings may be normal. In patients with clinically suspected PCP who have a normal chest radiograph result, HRCT of the chest is a useful test. HRCT will reveal patchy areas of GGO in patients with PCP (Figure 2). These opacities are not diagnostic for PCP, however, and may be seen in a variety of other pulmonary infections and diseases. Therefore, patients with suspected PCP and GGO on HRCT should undergo sputum induction or bronchoscopy in an attempt to establish a definitive diagnosis. Importantly, the absence of GGO on HRCT makes PCP extremely unlikely. Gruden and colleagues at San Francisco General Hospital reported that the diagnostic sensitivity of HRCT with GGO for PCP was 100% (HRCT revealed GGO in all 6 patients with PCP) and that its specificity was 89%.(34) In addition, the negative predictive value of an HRCT without GGO was 100% (none of the 40 patients whose HRCT scan revealed no GGO had PCP). Thus, chest HRCT can be a useful test to "rule out" or at least make unlikely the diagnosis of PCP, but it cannot be used to "rule in" this disease.

PCP reticular or granular infiltrates characteristically are bilateral and symmetric. Occasionally, the infiltrates are unilateral or asymmetric (Figure 3). A greater emphasis should be placed on the pattern seen (reticular or granular) than on the distribution (bilateral, symmetric, or diffuse). Patients with these chest radiographic findings should have induced sputum or bronchoscopy specimens (usually bronchoalveolar lavage) examined for Pneumocystis organisms.

In patients with milder disease, the findings may be limited to the perihilar region. As the disease progresses, chest radiograph findings will progress from predominantly perihilar involvement to more diffuse involvement, and an alveolar or mixed reticular-alveolar pattern can result. Thin-walled, air-containing cysts or pneumatoceles are seen in approximately 15-20% of radiograph images from patients with PCP (Figure 4, arrows). The combination of bilateral granular opacities and pneumatoceles in an HIV-infected patient with a CD4 count of <200 cells/�L is strongly suggestive of PCP (Figure 4). Pneumatoceles may be single or multiple, small or large, and may predispose patients to the development of pneumothorax, another radiographic presentation suggestive of PCP. PCP occasionally presents with focal opacities, with a miliary pattern, with a nodular pattern or discrete nodules, or with cavities. However, the findings of either intrathoracic adenopathy or pleural effusions are rarely a manifestation of PCP. In a patient with PCP, these radiographic findings usually represent a concurrent process.

Among HIV-infected persons with PCP, radiographic improvement often is seen after 7-14 days.(42)

Bacterial pneumonia caused by S pneumoniae characteristically presents with a bronchopneumonic pattern or with a focal segmental or lobar alveolar pattern. The radiographic presentation is similar to that of pneumococcal pneumonia in an HIV-uninfected person. Often, there is an associated pleural effusion. Occasionally, the radiographic presentation is indistinguishable from those of other OIs.(43) In severe cases of pneumonia, the findings may be multifocal or diffuse. Patients with a focal segmental or lobar alveolar pattern (with or without pleural effusions) on chest radiograph should have sputum and blood cultures sent for bacterial analysis as a part of their diagnostic evaluation. Thoracentesis also should be considered for patients with pleural effusion. Bacterial pneumonia resulting from H influenzae has been reported to present with diffuse opacities similar to those associated with PCP.(44) In HIV-infected patients with advanced immunosuppression, pneumonias resulting from P aeruginosa and S aureus increase in frequency and may present with a cavitary infiltrate.(45)

TB can have a variety of radiographic findings and presentations.(46,47,48) The characteristic presentation depends partly on the degree of immunosuppression. Early in the course of HIV infection (when the patient has a relatively high CD4 cell count), TB typically presents in a pattern of reactivation, namely, upper lung zone infiltrates (apical and posterior segments of the upper lobes and superior segment of the lower lobes), often with cavities.

In contrast, cavities are a less common presentation of TB in HIV-infected patients with low CD4 cell counts. These patients are more likely to present either with diffuse disease that may be miliary or with predominantly middle and lower lung zone infiltrates that may be mistaken for bacterial pneumonia (Figure 5). In the case illustrated in Figure 5, the "key" to the differential diagnosis is knowledge of the patient's CD4 cell count and the fact that this chest radiographic presentation of TB may occur at a low CD4 cell count. Pleural effusions can be seen with TB at both high and low CD4 cell counts, but intrathoracic adenopathy is seen much more commonly in patients with low CD4 cell counts (Figure 6).

A CT scan of the chest sometimes can be useful for evaluating patients with intrathoracic adenopathy and for investigating findings suspicious for adenopathy on chest radiograph. Low attenuation of lymph nodes suggests central necrosis and thus a diagnosis of mycobacterial or fungal disease. Patients with clinically suspected TB and a consistent radiographic presentation should have up to 3 examinations of sputum for acid-fast organisms and sputum and blood and cultures sent for mycobacterial analysis as a part of their diagnostic evaluation. Thoracentesis (with pleural biopsy) should be considered for patients with pleural effusion. Careful physical examination may reveal peripheral lymph nodes amenable to biopsy.(46,47,48,49) Occasionally, more invasive diagnostic procedures such as bronchoscopy (with bronchoalveolar lavage and transbronchial biopsies) and mediastinoscopy (if significant intrathoracic adenopathy is accessible to procedure) are necessary. Laboratory evidence of a bone marrow infiltrative disease may warrant bone marrow aspiration and biopsy.

Pulmonary Kaposi sarcoma characteristically presents with bilateral opacities in a central or perihilar distribution (Figure 7, Figure 8). Gruden and colleagues at San Francisco General Hospital reviewed the chest radiographic presentation of 76 consecutive patients with pulmonary Kaposi sarcoma diagnosed by bronchoscopy.(50) All of these patients had a bronchoalveolar lavage that was negative for Pneumocystis, M tuberculosis, M avium complex, and any bacterial, fungal, or viral pathogen. In this study, 95% of the chest radiographs had peribronchial cuffing and tram track opacities with or without more extensive perihilar coalescent opacities. Small nodules or nodular opacities were seen in 78%, Kerley B lines in 71%, and pleural effusions in 53% of the radiographs. Of note, no patient presented with either Kerley B lines or pleural effusions without concurrent parenchymal findings. As the radiographic abnormalities tended to be central or perihilar in distribution, precise evaluation of possible intrathoracic adenopathy was difficult. Nevertheless, 16% of these patients had clear hilar or mediastinal lymph node enlargement seen on their radiograph.

Patients with these radiographic findings should undergo bronchoscopy as part of the diagnostic evaluation. Visualization of the characteristic tracheobronchial Kaposi lesions will confirm the diagnosis, and bronchoalveolar lavage will serve to exclude a concurrent OI.

Basic Differential Diagnosis:

• Bacterial pneumonia (S pneumoniae, H influenzae)

• TB

• Non-Hodgkin lymphoma

• Bronchogenic carcinoma (if cigarette smoker)

The differential diagnosis of respiratory symptoms in an HIV-infected patient includes non-HIV-related respiratory illnesses such as URI and acute bronchitis. Individuals with these upper respiratory tract illnesses, however, have a normal, unchanged radiograph unless complicated by a concurrent lower respiratory tract process. In most clinical settings, bacterial pneumonia is a more frequent cause of pulmonary disease than TB, non-Hodgkin lymphoma, or bronchogenic carcinoma, and is the most likely diagnosis if the chest radiograph reveals a focal segmental or lobar infiltrate in an alveolar pattern. The suspicion for bacterial pneumonia is increased if the patient reports acute onset, fevers, chills/rigors, pleuritic chest pain, or a cough productive of purulent sputum, and if the patient has focal findings on lung examination, an elevated WBC with a left shift, a history of cigarette smoking or IDU, or a history of bacterial pneumonias.

In this case, the diagnostic approach would typically include sputum and blood cultures for bacteria and empiric therapy to cover the most common bacterial organisms: S pneumoniae and H influenzae.(51,52) The presence of a pleural effusion should prompt consideration of a thoracentesis. Clinical response to antibiotics and outcomes are similar in HIV-infected and HIV-uninfected persons with bacterial pneumonia.(52) HIV-infected persons with bacterial pneumonia who have shock, a CD4 count of <100 cells/�L, and pleural effusion, cavities, or multilobar involvement on chest radiograph have a higher mortality rate.(53)

If the chest radiograph instead reveals upper lung zone infiltrates with cavities and the patient reports subacute onset of fevers, cough, and associated constitutional complaints (night sweats, anorexia, weight loss), then TB becomes the major consideration, especially if the patient is at increased risk of exposure to M tuberculosis. In this case, the diagnostic approach probably would include respiratory isolation (if the patient were hospitalized), examination of 3 sputum samples for acid-fast bacilli (AFB), sputum and blood cultures for mycobacteria, and empiric TB therapy (usually with 4 drugs plus pyridoxine).(51,54,55,56)

In contrast, if the chest radiograph demonstrated multiple nodular opacities or masses (with or without pleural effusions) and there was evidence of extrapulmonary sites of disease (eg, abdominal, bone marrow), non-Hodgkin lymphoma could be the leading diagnosis. In this case, the diagnostic approach likely would focus on the acquisition of tissue for pathologic examination.

Basic Differential Diagnosis:

• Bacterial pneumonia (S pneumoniae, H influenzae but also gram-negative bacilli and S aureus as the CD4 cell count declines; providers should be alert for bacteremia/sepsis)

• TB (providers should be alert for disseminated or extrapulmonary disease)

• Fungal pneumonia (C neoformans; Aspergillus spp if CD4 count is <50 cells/�L or associated risk factors [eg, neutropenia] are present)

• Non-Hodgkin lymphoma

• PCP

In many clinical settings, the two most common pulmonary diseases in HIV-infected patients with CD4 counts of <200 cells/�L are PCP and bacterial pneumonia. Among these patients, the presence of a focal opacity on chest radiographs is more suggestive of a bacterial pneumonia than of PCP. Therefore, a patient with the characteristic clinical and radiographic presentation of bacterial pneumonia should have sputum and blood cultures (high incidence of bacteremia and sepsis) sent for bacterial analysis and should begin empiric antibiotic therapy.(51)

At CD4 counts of ≤100 cells/�L, organisms such as P aeruginosa and S aureus are increased in incidence. In a patient with such a CD4 count (especially if accompanied by a history of recurrent pneumonia, or prior antibiotic treatment), consideration for broad-spectrum antibiotics to cover these organisms may be prudent.

At lower CD4 cell counts, TB also can manifest with a focal opacity on chest radiographs (usually middle-lower lobes) (Figure 5). Because of the public health risk, TB always should be considered, especially if the patient is at increased risk of exposure to M tuberculosis on the basis of HIV transmission category (eg, IDU) or residence/travel history (eg, born in or traveled to an area with a high incidence of TB, living in such an area, homeless/unstably housed, incarcerated). If the clinical presentation is subacute, TB should be the focus of the diagnostic and management plans. Because of the higher incidence of mycobacteriosis and disseminated or extrapulmonary disease, blood cultures should be sent for mycobacterial analysis, and patients should have a careful physical examination for extrapulmonary sites of disease (eg, peripheral lymphadenopathy should prompt a lymph node aspiration/biopsy that may provide the diagnosis).

HIV-infected patients (usually those with CD4 counts of <150 cells/�L) with evidence of concomitant neurologic dysfunction (headache, altered mental status) or constitutional complaints (fever, fatigue, malaise) may have concurrent C neoformans meningitis and pneumonia. In this case, a test for serum cryptococcal antigen (CrAg) is an excellent screening tool; a positive result should prompt analysis of cerebrospinal fluid. In addition, the diagnosis of cryptococcal disease can be made by fungal culture of blood and respiratory specimens from sputum or bronchoscopy. A positive test result for serum CrAg, however, will not occur if cryptococcosis is confined to the lung.

PCP occasionally presents with a focal opacity. Consider this diagnosis if the chest radiograph shows a focal opacity and a reticular or granular pattern; the patient complains of the subacute onset of fever, shortness of breath, and a dry, nonproductive cough; and the serum LDH level is elevated. In cases of suspected PCP, the diagnostic approach usually includes sputum induction or bronchoscopy.

Basic Differential Diagnosis:

• PCP

• Bacterial pneumonia (multifocal)

• TB (multifocal or miliary)

• Fungal pneumonia (C neoformans, H capsulatum, C immitis)

• Pulmonary Kaposi sarcoma

• Non-Hodgkin lymphoma

• Cytomegalovirus

The two most common pulmonary diseases in such a patient are PCP and bacterial pneumonia. Diffuse infiltrates on chest radiographs are more suggestive of Pneumocystis infection than of a bacterial infection. PCP is likely in a patient whose chest radiograph reveals diffuse reticular or granular opacities (with or without pneumatoceles) and whose symptoms include the subacute onset of fevers, shortness of breath, and a dry, nonproductive cough. The diagnostic approach should include sputum induction or bronchoscopy and empiric PCP therapy (with corticosteroids if disease is moderate or severe).(57,51) The use of a 60-second noninvasive oropharyngeal washing specimen combined with a PCR assay to diagnose PCP has been reported.(58)

Bacterial pneumonia becomes a more likely diagnosis, however, in a patient whose chest radiograph reveals multifocal alveolar opacities (with or without pleural effusions), especially if accompanied by the acute onset of fevers, chills/rigors, pleuritic chest pain, or productive cough with purulent sputum. The associated finding of a pleural effusion would favor the diagnosis of bacterial pneumonia over that of PCP. The initial approach should include sputum, blood, and pleural fluid cultures for bacteria and the use of empiric broad-spectrum antibiotics.(51)

At the lowest CD4 counts (<50 cells/�L), the presence of any (and often more than one) of the HIV-related OIs and neoplasms is possible. Furthermore, diffuse opacities may result from any severe pulmonary disease. At this stage, the radiographic presentation resembles that seen in acute respiratory distress syndrome (ARDS) and, as with ARDS, there is no radiographic finding that is specific for a particular disease.

A patient with a CD4 count of <200 cells/�L (usually <50 cells/�L) and a chest radiograph demonstrating a miliary pattern (Figure 9) likely has either mycobacterial disease (eg, miliary TB) or disseminated fungal disease. A history of risk factors for exposure to M tuberculosis or residence in or travel to a geographic region that is endemic for one of the fungal diseases may be useful in deciding which is most likely and whether to begin empiric 4-drug anti-TB therapy or antifungal therapy.(51)

Finally, a patient with a CD4 count of <100 cells/�L and a chest radiograph showing bilateral, diffuse coalescent opacities in a central distribution (usually with associated smaller nodules, Kerley B lines, pleural effusions, and occasionally intrathoracic adenopathy) likely has pulmonary Kaposi sarcoma (Figure 7). This diagnosis would be further supported by the presence of mucocutaneous Kaposi lesions and could be confirmed by bronchoscopy and visualization of the characteristic Kaposi lesions.

--------------------------------------------------------------------------------------------------------------------

These case scenarios illustrate the most common HIV-related OIs and neoplasms. HIV-infected patients can develop a wide spectrum of pulmonary illnesses that include non-HIV-related conditions; HIV-related OIs caused by bacterial, mycobacterial, fungal, viral, and parasitic pathogens; and HIV-related neoplasms. Usually, these diseases occur singly, but clinical experience with HIV has reinforced the fact that, occasionally, diseases may present at the same time or develop one after another in rapid succession (Figure 10). Clinicians caring for HIV-infected patients must be ever vigilant for these situations and must have a low threshold for investigating any signs of clinical deterioration that may be attributable to a concurrent process that was missed initially.

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