Cough and Dyspnea

in HIV Patients

Chinese Version

 

Alison Morris, M.D.,  Laurence Huang, M.D.

 

INTRODUCTION

               Respiratory complications are common among patients with HIV infection. The lungs are a frequent site of involvement, and pulmonary disease accounts for a significant proportion of the morbidity and mortality resulting from HIV. The Pulmonary Complications of HIV Infection study (PCHIS), a multicenter study of over one thousand HIV-infected patients, reported respiratory symptoms in about one quarter of patient visits, with the frequency of these complaints increasing as the patient's CD4 cell count declined (Huang, unpublished data). Given the wide spectrum of both HIV-associated and non-HIV-associated infections and neoplasms that can affect the lung, pulmonary disease among HIV-infected patients poses a significant diagnostic and therapeutic challenge for the clinician. The development of highly active antiretroviral therapy (HAART) to treat HIV infection has also influenced the frequency of various respiratory disorders and increased the difficulty of avoiding drug interactions.

               The spectrum of respiratory illnesses encompasses opportunistic infections (OIs), neoplasms, and other respiratory disorders (Table 1). Bacterial pneumonia (BP), Pneumocystis carinii pneumonia (PCP), mycobacterial disease, and fungal infections are the most common opportunistic infections. The most commonly encountered neoplasms of the lung are Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma. While these disorders frequently have characteristic clinical and radiographic presentations, there may be considerable variation in the presentation. No single constellation of clinical, radiographic, and laboratory findings can be considered pathognomonic for a specific disorder. Further, HIV-infected patients with incorrectly treated pulmonary disease may rapidly progress to respiratory failure. Therefore, a definitive microbiologic or pathologic diagnosis is preferable to empiric therapy whenever possible. This chapter will discuss the presentation of pulmonary disease encountered in HIV-infected persons and will present efficient diagnostic strategies for evaluation of these diseases.

EPIDEMIOLOGY

               Over the course of the AIDS epidemic, the spectrum of pulmonary disease has changed. For example, Pneumocystis carinii pneumonia was once the most common cause of pneumonia in AIDS patients. Recently, bacterial pneumonia is more commonly diagnosed in many places. However, Pneumocystis carinii pneumonia remains the leading serious AIDS-defining opportunistic infection in the United States, although its absolute incidence has decreased (1, 2). A similar decrease has occurred in the incidence of many other opportunistic infections as prophylaxis and HAART have become widely available (1, 2).

               The clinical setting in which the patient is evaluated influences the relative frequency of the respiratory disorders encountered. The PCHIS study found that patients presenting to outpatient clinics more commonly have illnesses such as upper respiratory tract infections (URIs), sinusitis, pharyngitis, and bronchitis than they do bacterial pneumonia, Pneumocystis carinii pneumonia, or tuberculosis (3). In contrast, patients requiring hospital admission more frequently have bacterial pneumonia, Pneumocystis carinii pneumonia, and mycobacterial or fungal disease. Throughout the course of the AIDS epidemic, those requiring admission to the intensive care unit were most likely to have Pneumocystis carinii pneumonia (4, 5). Data gathered during the time that HAART has been available show that Pneumocystis carinii remains the most frequent cause of respiratory failure among ICU patients; however, bacterial pneumonia and other non-respiratory (particularly non-AIDS-related) diagnoses have become more common (6, 7).

DIFFERENTIAL DIAGNOSIS

               The differential diagnosis of cough and dyspnea in an HIV-infected patient is quite extensive and includes both HIV-associated conditions as well as conditions unrelated to immunocompromise (Table 1). Both infectious and non-infectious entities can affect the respiratory system, and at times more than one disease may be present in the same patient.

               The differential diagnosis of cough without evidence of lower respiratory tract infection (i.e. normal arterial oxygen saturation and/or a normal chest radiograph) includes URIs and sinusitis. These two entities are more common in HIV-infected individuals. Other disorders that can present with cough in any population are cough-variant asthma and gastroesophageal reflux disease. Evaluation and treatment of these conditions is similar to that in the non-HIV-infected population.

               Lower respiratory tract disease may present with cough, dyspnea, or both. The various causes of lower respiratory tract disease can be categorized by conditions that are associated with HIV and those that are not associated with HIV. These categories can be further divided into infectious and non-infectious entities. HIV-associated infections include Pneumocystis carinii pneumonia, bacterial pneumonia, tuberculosis and other mycobacterial diseases, fungal infections, viruses, and other organisms (i.e. parasites). Non-infectious HIV-associated disorders include neoplasms such as Kaposi's sarcoma and lymphoma, and other disorders such as lymphocytic interstitial pneumonia (LIP) and pulmonary hypertension. The association of lung cancer with HIV infection has been debated. It may present at a younger age and behave more aggressively than in the general population, but this association has not been definitively proven (8-10). Respiratory disorders not associated with HIV infection are particularly important to remember as patients are surviving longer with intact immune systems. Such disorders include obstructive lung disease, interstitial lung diseases, and pulmonary emboli. Non-pulmonary disorders such as congestive heart failure can also lead to respiratory symptoms. This chapter will discuss those respiratory conditions that are directly related to HIV infection.

RISK FACTORS

               Many factors contribute to the risk of certain opportunistic infections and neoplasms in HIV-infected individuals with respiratory complaints. Knowledge of the patient's CD4 cell count, HIV risk group, travel history, past medical history, and presence of extrapulmonary findings can alter the likelihood of different diseases (Table 2).

CD4 Cell Count

               The CD4 cell count is one of the most useful pieces of information in determining a patient's risk for respiratory diseases. Although many disorders can occur at any cell count, most of them are typically seen in certain ranges (Table 3). With the widespread use of HAART, patients are experiencing prolonged increases in their CD4 cell counts accompanied by improved morbidity and mortality (11). Multiple studies now indicate that if patients, in response to HAART, sustain CD4 cell counts above 200 cells/ul over the course of 3-6 months, the risk of many opportunistic infections is reduced (12-15). These findings may not hold true in all patients, and those with histories of particular OIs or a history of advanced AIDS before starting therapy may remain at increased risk of developing these disorders (16).

               Approximately 95% of cases of Pneumocystis carinii pneumonia occur in individuals with CD4 cell counts below 200 cell/ul (17, 18). The Multicenter AIDS Cohort Study (MACS) found that subjects with a CD4 count below 200 cells/ul had a nearly fivefold greater risk of developing Pneumocystis carinii compared to those above 200 cells/ul (17). As the CD4 count falls below 200 cells/ul, the risk increases. The PCHIS study found that patients with a CD4 cell count under 100 cells/ul had nearly double the risk of developing Pneumocystis carinii pneumonia as those with CD4 counts between 100 and 200 cells/ul (18). Bacterial pneumonia may occur at any CD4 cell count; however, its frequency increases as the count decreases below 500 cells/ul (19). The incidence of bacteremia associated with pneumonia increases with declining CD4 cell count as well and is higher in HIV-infected individuals than in the general population (20). Similar to bacterial pneumonia, tuberculosis can affect HIV-positive patients at any CD4 cell count and increases in frequency at lower counts. Tuberculosis is more likely to present with extrapulmonary sites of infection or with "atypical" radiographic findings at low CD4 cell counts (21). Other types of mycobacterial infection such as Mycobacterium avium complex (MAC) and M. kansasii are frequently seen only at very low CD4 cell counts (22, 23). Fungal diseases, including cryptococcosis, histoplasmosis, and coccidioidomycosis, typically occur at CD4 cell counts below 100 cells/ul and especially below 50 cells/ul (24, 25). Aspergillosis, however, seems to be more related to neutropenia and other causes of immunosuppression than to the CD4 cell count (26).

               Neoplasms of the lung may also be related to the CD4 cell count. In one study of patients with pulmonary Kaposi's sarcoma, the median CD4 cell count was 19 cells/ul and 68% of the patients had a count below 50 cells/ul (27). In contrast, non-Hodgkin's lymphoma can present at a wide range of CD4 cell counts, with a median CD4 count of 100 cells/ul in one study (28). Similarly, bronchogenic carcinoma can develop at any CD4 cell count. In the PCHIS study, patients with lung cancer presented with counts ranging from 127 to 1,026 cells/ul (8).

HIV Risk Group

               The patient's risk group for HIV infection also alters the probability of different respiratory diseases. For example, Kaposi's sarcoma is seen almost exclusively in men who report sex with other men. Over 90 percent of the cases occur in this group (29). This association has been explained by the finding of human herpesvirus 8 in biopsy specimens of KS (30). It has been postulated that this virus is sexually transmitted and that it plays a central role in the pathogenesis of KS (31-33). Intravenous drug users (as well as cigarette smokers) are at increased risk for bacterial pneumonia (19). Patients who use intravenous drugs are also at an increased risk for tuberculosis, likely because of their social situations (19).

Travel History

               Travel history can be an important piece of information, particularly in the diagnosis of fungal diseases. For example, a patient who presents with fever, cough and dyspnea, and radiographic infiltrates who has just traveled through the Midwest may have histoplasmosis. The same patient who has just traveled through the Central Valley of California is at risk for coccidioidomycosis. The fungus Penicillium marneffei is a common cause of disease among patients who live in or have traveled to Southeast Asia. HIV-infected patients without a history of travel to endemic areas are unlikely to have been exposed and therefore unlikely to develop disease from these fungal pathogens.

               Mycobacterium kansasii also has a geographic distribution. The disease is more common in the southern and central United States (34). There has been an increase in the number of cases in non-endemic areas, however, so lack of an appropriate travel history does not exclude the diagnosis (35). Travel to areas with high rates of M. tuberculosis such as Asia or Africa also places the HIV-infected person at risk of developing tuberculosis.

Past Medical History

               Many HIV-related opportunistic infections are recurrent, and knowledge of a patient's prior pulmonary history may suggest the etiology of the current illness. Bacterial pneumonia frequently recurs in HIV-positive patients, and two or more episodes in a 12 month period constitute an AIDS-defining diagnosis (36). Patients with a history of Pneumocystis carinii pneumonia are at high risk of recurrence, as are those with previous fungal disease. However, risk of relapse decreases significantly in those patients with sustained improvement in CD4 cell counts in response to HAART. Respiratory complications in an HIV-infected patient who is non-adherent with recommended therapy will frequently be due to recurrent or relapsed disease.

               A patient's social situation or exposures can also contribute to the risk of disease. Patients who are homeless or are housed in group situations have an increased risk of tuberculosis (37, 38). If respiratory symptoms develop in these patients, tuberculosis should be suspected. Patients should be placed in isolation and three sputum samples collected for AFB. Other exposures in the patient's environment may also contribute to the risk of diseases. For example, exposure to pigeons is a risk factor for the development of cryptococcal disease. Recent data suggest that soil exposure may be an independent risk factor for the development of Pneumocystis carinii pneumonia and that risk of PCP may vary by geographic location (39-41). It is possible that person-to-person transmission of Pneumocystis occurs; however, current data are inconclusive and patients with Pneumocystis carinii pneumonia are not routinely isolated.

Non-Pulmonary Findings

               The presence of disease at sites outside of the lung provides important clues about respiratory problems. For example, altered mental status and headache accompanying respiratory symptoms may signal cryptococcal meningitis and cryptococcal pneumonia. As mentioned previously, at low CD4 cell counts, tuberculosis tends to present with extrapulmonary manifestations such as lymphadenopathy, mycobacteremia, and bone marrow involvement. Fungal infections may present similarly with typical signs of systemic infection. Mucocutaneous lesions are often seen in patients who have pulmonary Kaposi's sarcoma, although the absence of skin findings does not rule out the presence of pulmonary disease (27). Those patients with a history of oral candidiasis are also at increased risk for Pneumocystis carinii pneumonia (17).

 

CLINICAL MANIFESTATIONS

Signs and Symptoms

Pneumocystis carinii pneumonia: One of the most important clinical decisions in treating patients with HIV-associated respiratory disease is distinguishing between Pneumocystis carinii pneumonia and bacterial pneumonia (Table 4). Unlike the course of the disease in other immunocompromised patients, Pneumocystis carinii in an HIV-infected adult typically presents with a prolonged prodromal illness. The median duration of symptoms in some series ranges from 21 to 28 days (42, 43). In contrast to patients with bacterial pneumonia, the cough from Pneumocystis carinii pneumonia is usually nonproductive (42). Dyspnea is extremely common and found in up to 95% of patients (42). High fevers, rigors, purulent sputum, and pleuritic chest pain are uncommon in Pneumocystis carinii pneumonia and can be used to distinguish P. carinii from bacterial infection (44). Caution must be used in applying these clinical predictors as patients may have more than one disease or have atypical presentations.

Bacterial pneumonia: Streptococcus pneumoniae and Haemophilus species are the most frequently identified causes of community-acquired bacterial pneumonia in the HIV-infected population (19, 45, 46). Staphylococcus aureus also causes pneumonia in HIV-infected patients, producing pleural effusions in up to one third of patients (47). Pseudomonas aeruginosa is a more frequent pathogen among those patients with end stage AIDS and a history of frequent hospitalizations (48, 49). Pseudomonas now may also be more common among the general HIV-infected population hospitalized with pneumonia (6). The presentation of these infections in an HIV-infected patient is similar to that in the nonimmunocompromised population. Bacterial pneumonia characteristically presents with fever, cough that is often productive of purulent sputum, dyspnea, and pleuritic chest pain (Table 4). The onset of symptoms is usually acute, occurring over three to five days. Physical examination often reveals signs of focal lung consolidation or pleural effusions.

Mycobacteria: Tuberculosis is a major source of morbidity and mortality among HIV-infected patients worldwide (50, 51). Unlike most other opportunistic infections in the HIV-positive patient, tuberculosis is readily transmissible to both immunocompetent and immunocompromised individuals. HIV infection dramatically increases the likelihood that latent M. tuberculosis infection will progress to active disease; those patients who are tuberculin skin test-positive and fail to receive adequate treatment will almost certainly develop active disease if their immunity declines (44). HIV-infected patients are also at an increased risk of contracting rifampin mono-resistant strains of tuberculosis (52). The clinical symptoms of tuberculosis in an HIV-infected patient typically vary according to the patient's CD4 cell count. Patients with a relatively high CD4 count often present with symptoms of classic reactivation disease (53). These patients will complain of fevers, cough, night sweats, and weight loss. The course of the disease is usually subacute. In contrast, those patients with low CD4 cell counts typically present with a clinical picture consistent with primary tuberculosis infection or with disseminated disease (53). Extrapulmonary tuberculosis has been reported in as many as 70% of patients with a CD4 cell count below 100 cells/ul (54). Any extrapulmonary site may be involved. Common sites of infection include lymph nodes (usually cervical, supraclavicular, and axillary), bone marrow, central nervous system, and liver (55). Tuberculosis may worsen several weeks into treatment, particularly if HAART is started around the time of initiation of antituberculosis treatment (56, 57). In one series, this paradoxical worsening occurred in 36 percent of patients started on HAART and in only 7 percent of those not receiving HAART (57). Symptoms include increases in fevers, sweats, and respiratory complaints. These symptoms are presumably due to improvements in the patient's immune system and subsequent response to the infection. The chest radiograph may worsen as well. Steps should be taken to confirm that the patient is not failing therapy or has not developed another respiratory disorder.

Cain KP, et al.  An Algorithm for Tuberculosis Screening and Diagnosis in People with HIV.  N Engl J Med 2010;362(8):707-716.

               Although Mycobacterium avium complex (MAC) is a common cause of disseminated infection among HIV-positive patients, MAC pulmonary disease is rare (58). The disease probably results from primary acquisition of the microorganism through the gastrointestinal tract, but the lungs may serve as a portal of entry as well (59-61). Pulmonary disease may be asymptomatic and detected only on sputum cultures. Although patients may feel well, treatment is often recommended as the presence of MAC in the lungs usually heralds the onset of disseminated disease. Patients with disseminated MAC present with the usual symptoms of fevers, night sweats, fatigue, and weight loss. Patients may also have involvement of the bone marrow, lymph nodes, liver, and gastrointestinal system (59, 61-63).

               Mycobacterium kansasii is another mycobacterium that can cause pulmonary disease in patients with end-stage HIV infection. It is the second most common cause of non-tuberculous pulmonary disease in the United States (34). Its clinical presentation is indistinguishable from that of tuberculosis and includes fever, cough, weight loss, and night sweats. Extrapulmonary disease is less common than in tuberculosis and occurs mainly at very low CD4 counts.

Fungal Infections: The budding encapsulated yeast Cryptococcus neoformans causes cryptococcosis. Infection occurs after inhalation of a yeast-containing aerosol. The organism enters the lung where it may cause local disease or proceed to disseminate. The most common manifestation of cryptococcal infection is meningitis. Isolated pulmonary disease can often be asymptomatic or minimally symptomatic, and the serum cryptococcal antigen is often negative in those patients with only cryptococcal pneumonia. Patients with respiratory symptoms who also present with altered mental status and headache should undergo evaluation for both cryptococcal pneumonia and meningitis. Pulmonary cryptococcosis in the absence of CNS infection is often discovered by chance when a patient has an abnormal chest radiograph. Patients who do have symptoms often report productive cough, dyspnea, and fevers. Pleuritic chest pain is somewhat more common than in other pulmonary infections with approximately 30% of patients reporting this symptom at presentation (64).

               Histoplasmosis is a disease caused by the fungus Histoplasma capsulatum. The fungus is endemic to many parts of North America and the Caribbean, although it has been found on all continents except Antarctica. Inhalation of the microconidial form of the fungus leads to primary pulmonary infection that is usually clinically silent. Once in the lung, the organism transforms into its yeast phase and spreads through the lymph nodes and reticuloendothelial system. The most common presentation of Histoplasma infection among HIV-infected individuals is a febrile, wasting illness (65-67). Patients may also present with a sepsis-like syndrome (67). When pulmonary symptoms are present, they are most frequently cough and dyspnea. The presence of respiratory symptoms is associated with an abnormal chest radiograph. Lung examination may also be abnormal with findings of crackles. Signs of disseminated fungal infection are often present and include lymphadenopathy, hepatosplenomegaly, cutaneous lesions, and CNS involvement (67).

               Coccidioidomycosis is caused by the fungus Coccidioides immitis. As with most fungi, the portal of entry is the lung. Dissemination occurs after rupture of spherules. Signs and symptoms of disseminated disease dominate the clinical presentation and include fevers, weight loss, lymphadenopathy, and meningitis (25). The most frequent sign of respiratory involvement is cough. Dyspnea is less common, occurring in less than 10% of patients.

               Disease caused by Aspergillus species is less common among those with HIV infection than is infection with most other pathogenic fungi. HIV-positive patients with aspergillosis usually have other risk factors such as neutropenia, corticosteroid use, or marijuana smoking (26). Aspergillus pulmonary infection produces a variety of manifestations including colonization of the respiratory tract, tracheobronchitis, aspergilloma, and invasive aspergillosis (68). Patients with invasive disease typically present with cough, dyspnea, and occasionally with pleuritic chest pain. Hemoptysis is common, particularly with the development of an aspergilloma in a pre-existing cavity.

               Penicilliosis is caused by the fungus Penicillium marneffei. Although rare in the United States and Europe, infection with this fungus is common in Southeast Asia where cases of AIDS are increasing (69, 70). Infection is acquired through inhalation and is associated with soil exposure, particularly during the rainy season (May to October)(71, 72). The clinical presentation is similar to that of other fungal diseases and includes fever, weight loss, night sweats, and cough. Skin lesions may be present and typically have a central umbilication (70).

Cytomegalovirus: Cytomegalovirus (CMV) is a herpes virus that remains latent in the non-  immunocompromised population. Reactivation of latent infection in HIV-positive patients generally leads to retinitis and gastrointestinal manifestations. Because CMV is shed from respiratory secretions, it is frequently present in the lung, but not responsible for clinical disease. Patients with true CMV pneumonia will often complain of cough and dyspnea over a time course of two to four weeks (73). Physical examination of the chest may be normal or may reveal crackles or pleural effusions. Because of the high frequency of disseminated disease in this population, pulmonary CMV infection should prompt a retinal examination even if visual symptoms are not present.

Neoplasms: Kaposi's sarcoma is the most common HIV-associated malignancy and its incidence in men who report sex with other men is much higher than in any other risk group (29). Mucocutaneous lesions are the most common presenting symptom in patients with Kaposi's sarcoma. Approximately one third of patients with cutaneous Kaposi's sarcoma will have pulmonary Kaposi's sarcoma detected clinically. As many as 50 to 70% of patients with cutaneous disease will have pulmonary Kaposi's sarcoma on autopsy (10, 74). Pulmonary Kaposi's sarcoma may present in the absence of mucocutaneous lesions in as many as 15% of cases (27). Patients with pulmonary Kaposi's sarcoma often complain of cough, dyspnea, and fever. Chest pain and hemoptysis may be present, especially in extensive disease. The time course of the symptoms is usually subacute. Symptoms may occur more rapidly if an opportunistic infection is present because OIs can accelerate the progression of KS. Chest examination is frequently normal, but crackles, wheezes, or signs of pleural effusion may be present.

               Non-Hodgkin's lymphoma (NHL) is also a frequent complication of HIV disease, and the development of HAART has had less impact on the incidence of lymphoma than on Kaposi's sarcoma and OIs (21). NHL in HIV-infected patients is almost always of B-cell origin. Most cases present with disseminated disease and extranodal involvement. Frequent sites of involvement include the liver, spleen, bone marrow, and gastrointestinal system. Intrathoracic adenopathy is present in up to 31 percent of patients at time of clinical diagnosis (10, 74). As with many pulmonary processes in HIV infection, symptoms are nonspecific with cough and dyspnea being the most common complaints (28). B symptoms of fevers, sweats, and weight loss are also a common feature. Physical examination is similarly nonspecific with crackles, rhonchi, wheezes, or signs of consolidation all possible findings.

Lymphocytic Interstitial Pneumonitis: The diagnosis of lymphocytic interstitial pneumonitis as a distinct entity has not been definitively established. Although clearly more common among children with HIV infection, its occurrence among adults is less well-documented. Symptoms include slowly progressive dyspnea, nonproductive cough, and fever. Chest examination may be normal or may have crackles. In children, extrapulmonary findings include finger clubbing, lymphadenopathy, and hepatosplenomegaly.

Pulmonary Hypertension: Although the association of pulmonary hypertension with HIV infection is not completely clear, there are a number of reports of an increased incidence of the disorder in patients with HIV infection (75-77). The disease presents with progressive dyspnea as in the non-HIV-infected patient. Patients may also complain of cough, chest pain, and dizziness. Lung examination is normal, but signs of increased pulmonary pressure and right heart strain are common in the cardiac examination. Often, patients with HIV infection have other risk factors for pulmonary hypertension such as injection drug use, hepatitis C infection, or chronic pulmonary disease, making the diagnosis of primary pulmonary hypertension difficult to establish. There is some evidence that the disease occurs at a younger age and is more aggressive in the HIV-infected population. Interestingly, it is often present at higher CD4 cell counts.

 

RADIOGRAPHIC MANIFESTATIONS

               The chest radiograph is one of the most useful diagnostic tools available for evaluating respiratory complaints in an HIV-infected patient. A chest radiograph should be performed in all HIV-infected patients with respiratory complaints that are not clearly confined to the upper respiratory tract. Although radiographic presentations of HIV-associated lung disease may vary and overlap, each disease has a characteristic radiographic appearance that can aid the clinician. Common chest radiograph findings for each disease are listed in Table 5. The patient's CD4 count needs to be considered when interpreting the radiographic findings. For example, diffuse interstitial infiltrates are very suggestive of Pneumocystis carinii in patients with CD4 cell counts below 200 cells/ul. However, in a patient with a higher CD4 cell count, Pneumocystis carinii is still possible, but its likelihood is decreased. The impact of the CD4 count on the spectrum of disease should be remembered when interpreting Table 5.

Pneumocystis carinii pneumonia

               Pneumocystis carinii classically presents with bilateral reticular or granular opacities (Figure 1). Occasionally, infiltrates are unilateral or asymmetric. In our experience, the pattern seen (reticular or granular) is more suggestive of the diagnosis than the distribution of the abnormalities. In patients with mild disease, changes may be limited to the perihilar region or the radiograph may be normal (78). Patients who have used aerosolized pentamidine for Pneumocystis carinii prophylaxis are somewhat more likely to have changes confined to the upper lobes. Thin-walled cysts or pneumatoceles are seen in 10-20% of cases (79, 80). These cysts may occur with initial presentation or develop during therapy. They are initially thin-walled, but can coalesce over time to form bizarre-shaped, thick-walled cysts. The cysts generally resolve over the course of weeks to months, but may persist despite the eradication of infection. The cysts predispose patients to pneumothoraces that can be life-threatening (Figure 2). The findings of intrathoracic adenopathy or pleural effusion are rarely due to Pneumocystis carinii. These findings in a patient with documented Pneumocystis carinii pneumonia suggest a concurrent process.

               In patients with a clinical history suggestive of Pneumocystis carinii pneumonia who have a normal chest radiograph, high resolution computed tomography (HRCT) of the chest is helpful in determining the need for further diagnostic evaluation. Patients with Pneumocystis carinii pneumonia will have patchy areas of ground glass opacities on HRCT (Figure 3). Because these opacities can be seen in a number of respiratory diseases, their presence does not establish the diagnosis of Pneumocystis carinii pneumonia and further testing should be done (i.e. bronchoscopy). On the other hand, the absence of ground glass opacities on an HRCT, in our experience, virtually rules out the diagnosis of Pneumocystis carinii and other conditions should be considered (81).

Bacterial Pneumonia

               Bacterial pneumonia characteristically presents with focal consolidation of lung segments or lobes (Figure 4). Although the disease may involve a single area, multifocal disease appears to be more common than in the non-HIV-infected population. Often, there is an associated pleural effusion. Bacterial pneumonia may also have a reticulonodular appearance on the chest radiograph, especially if due to Haemophilus species. Patients with Pseudomonas pneumonia or Rhodococcus equi may have cavitary infiltrates (82-84).

Mycobacteria

               The radiographic presentation of tuberculosis varies with the patient's CD4 cell count. In patients with a relatively high CD4 cell count, tuberculosis presents with the typical pattern of reactivation disease seen in the immunocompetent population. These patients' radiographs will have upper lung zone infiltrates often with cavitation (Figure 5)(21, 85, 86). As the CD4 cell count decreases, cavitary lesions become less common, particularly in patients with CD4 cell counts below 50 cells/ul (87). Middle or lower lung zone consolidation is more common at lower CD4 counts as is intrathoracic adenopathy (which is typically necrotic) (Figure 6) (21, 53). The radiographic appearance of tuberculosis in patients with a more severe degree of immunosuppression can be mistaken for bacterial pneumonia, leading to delays in diagnosis and treatment as well as possible transmission to others.

               The radiographic findings of pulmonary MAC are nonspecific. Given that pulmonary disease is not a major part of the clinical presentation of MAC, the chest radiograph is usually not helpful in establishing the diagnosis. The patients who do have pulmonary involvement may have diffuse reticulonodular opacities, alveolar consolidation, and lymphadenopathy.

               The radiographic picture of M. kansasii is quite varied and may be indistinguishable from that of tuberculosis. The most common findings include diffuse alveolar infiltrates, cavities, interstitial infiltrates, or even a normal radiograph (88).

Fungal Infections

               The fungal diseases have a wide range of radiographic presentations. Cryptococcus, Histoplasma, and Coccidioides typically present with diffuse interstitial or reticulonodular infiltrates (Figure 7, a and b)(18, 64, 67). In the largest series of patients with cryptococcosis (n=37), diffuse interstitial infiltrates were the most common finding, seen in 76% of patients (64). This radiographic pattern also predominates in those with coccidioidomycosis (25). The radiograph in any fungal infections may be normal, particularly in the case of histoplasmosis (67, 89). Cavitary lesions, pleural effusions, and intrathoracic adenopathy have also been reported (18, 64, 67). Aspergillosis can present with a spectrum of findings including bronchial wall thickening, nodules, and aspergillomas seen in pre-existing cavities.

Cytomegalovirus

               CMV pneumonitis typically causes a reticular pattern on the chest radiograph. Ground glass opacities, nodules, and pleural effusions may also be seen (80).

Neoplasms

               Patients with pulmonary Kaposi's sarcoma usually have bilateral opacities on chest radiograph which have a central or perihilar distribution. Almost all patients have peribronchial cuffing and "tram track" opacities corresponding to the tendency of the tumor to spread along the bronchovascular bundle (Figure 8, a and b) (81). Many patients also have nodules, Kerley B lines, and pleural effusions. CT scanning often reveals small or coalescent nodules and intrathoracic adenopathy.

               The most common radiographic findings in patients with pulmonary involvement with NHL are nodular opacities or masses, lobar infiltrates, or diffuse interstitial infiltrates (Figure 9)(28, 90). NHL may also present as a solitary pulmonary nodule, although this presentation is uncommon (91, 92). Pleural effusions are quite common and are seen in 40 to 70% of cases (28, 93). Hilar adenopathy is also common, although this finding alone is rare in HIV-associated NHL (94). The nodules seen in NHL are distinct in that they are larger (>1cm) than those typically seen in infectious diseases and have clearly defined borders, unlike the nodules of Kaposi's sarcoma.

               The chest radiograph of lymphocytic interstitial pneumonia is nonspecific. Bilateral reticulonodular interstitial infiltrates are common and often predominate in the lower lung zones (95). Alveolar opacities and adenopathy are possible, but less common (89).

 

DIAGNOSIS

Laboratory Testing

               Laboratory tests may provide important clues to the diagnosis of respiratory complications; however, HIV-infected patients often have a host of laboratory abnormalities that may be due to unrelated conditions. As a result, few laboratory findings are pathognomonic for a specific disease, and test results must be interpreted in the context of the patient's overall clinical picture.

               White blood cell count (WBC): The white blood cell count is frequently elevated relative to the individual's baseline during episodes of bacterial pneumonia. A leftward shift of the white blood cell count differential is often present as well. The presence of neutropenia raises the possibility of Aspergillus infection. In Pneumocystis carinii pneumonia, the white blood cell count may be normal, elevated, or decreased, and is therefore not useful in the diagnosis. Pancytopenia suggests the presence of bone marrow infiltration by mycobacterial or fungal disease or by NHL.

Lactate dehydrogenase (LDH): An elevated LDH may suggest the diagnosis of Pneumocystis carinii pneumonia, but is more useful as a prognostic rather than diagnostic marker. Although the LDH is frequently elevated in Pneumocystis carinii pneumonia with a sensitivity of 83% to 100%, the test is nonspecific and may be elevated in many pulmonary (including bacterial pneumonia and tuberculosis) and nonpulmonary conditions. Patients with Pneumocystis carinii pneumonia may also have a normal or minimally elevated LDH; therefore, a normal LDH does not rule out the possibility of Pneumocystis carinii pneumonia. Despite its diagnostic limitations, the degree of elevation of the serum LDH has been shown to correlate with prognosis and response to therapy (96). Patients with Pneumocystis carinii pneumonia and an initial markedly elevated LDH or a rising LDH despite treatment have a worse prognosis and decreased survival.

Arterial blood gas (ABG): The ABG is frequently abnormal in patients with respiratory disease. Hypoxemia indicates involvement of the lower respiratory tract. Patients with pneumonia also commonly have an increased alveolar-arterial oxygen gradient and a respiratory alkalosis. Clearly, these types of abnormalities are non-specific for any respiratory disease in an HIV-infected or non-HIV-infected patient. Therefore, the ABG is more useful in assessing the severity of the illness and the need for rapid diagnosis and treatment and in establishing an indication for hospital or ICU admission.

Microbiology

               Blood cultures for bacteria are necessary in any HIV-infected patient presenting with fever and respiratory complaints in whom bacterial pneumonia is suspected. Given the high rate of bacteremia among HIV-infected patients with bacterial pneumonia, blood cultures are often the easiest way to diagnose a specific pathogen in these cases. In patients with lower CD4 cell counts, blood cultures for fungi as well as two blood cultures for AFB should also be performed.

               Sputum examination and culture can establish the diagnosis of many HIV-associated respiratory infections. Sputum samples to evaluate a patient for bacterial pneumonia, tuberculosis, or fungal disease may be either spontaneously expectorated or induced. If Pneumocystis carinii pneumonia is a possibility, induced, not expectorated, sputum should be sampled. The sensitivity of induced sputum for Pneumocystis carinii pneumonia varies depending on the hospital and the type of test used (Giemsa stain, antibody immunofluorescence). Because the sensitivity of sputum induction for Pneumocystis carinii pneumonia can be as high as 80% to 90% and the specificity is close to 100%, it is often the initial diagnostic test of choice (97, 98). At our hospital, a negative sputum induction is not sufficient to rule out a diagnosis of Pneumocystis carinii pneumonia (sensitivity of 83%); therefore, diagnosis with bronchoscopy and bronchoalveolar lavage (BAL) is pursued. Institutions with very high sensitivity may chose not to pursue bronchoscopy in those patients with negative sputum inductions; alternatively, those hospitals with lower sensitivity often omit sputum induction and proceed directly to bronchoscopy.

               Examination and culture of three morning sputum samples for AFB is also useful in establishing a diagnosis of tuberculosis or non-tuberculous mycobacterial disease. Sputum samples should be collected even in those patients with mostly non-pulmonary disease because HIV-infected patients may have positive sputum samples in the absence of pronounced lung involvement.

Invasive Diagnostic Tests

               Fiberoptic bronchoscopy is the cornerstone of the diagnostic evaluation of respiratory complaints in HIV-infected patients. In general, bronchoscopy with BAL should be performed in any patients whose pulmonary disease warrants timely, definitive diagnosis. Patients who deteriorate on therapy should also undergo bronchoscopy.

               The decision to perform bronchoscopy with transbronchial biopsy depends on the diseases under consideration. For Pneumocystis carinii pneumonia in an HIV-infected patient, transbronchial biopsy is not always needed because the sensitivity of BAL for Pneumocystis carinii pneumonia can approach 95% at many institutions (97). In hospitals where BAL is less sensitive, transbronchial biopsy may be required for the diagnosis of Pneumocystis carinii pneumonia. Transbronchial biopsy does improve the sensitivity of bronchoscopy for diagnosing tuberculosis or fungal infections. These diseases may be cultured from sputum and/or BAL fluid alone, so the decision to perform transbronchial biopsy as the initial diagnostic modality depends on the clinical severity of the patient and the need for a rapid diagnosis. Diseases in which transbronchial biopsy is always necessary for diagnosis include CMV pneumonitis, invasive aspergillosis, and pulmonary non-Hodgkin's lymphoma. If these diseases are strongly suspected, initial transbronchial biopsy with BAL may be the most efficient diagnostic strategy. Bronchoscopy is the procedure of choice for diagnosing pulmonary Kaposi's sarcoma because the lesions of Kaposi's sarcoma are unique. Biopsy is not required if the typical Kaposi's sarcoma lesions are seen. In those patients with atypical appearing lesions or with normal airways, transbronchial biopsies should be performed.

               Open lung biopsy is rarely necessary in the evaluation of HIV-associated pulmonary disease. Given the invasiveness of this procedure, it should only be undertaken when all other methods including BAL with transbronchial biopsy, biopsy of extrapulmonary sites, and cultures of sputum, blood, and other fluids have failed to yield a diagnosis. The overall condition of the patient and the speed of disease progression should be considered in deciding to pursue an open lung biopsy.

               Other invasive procedures that may be done to diagnose pulmonary disease include fine needle aspiration and pleural biopsy. Fine needle aspiration of a lung mass can be performed as an outpatient and is often helpful in making a diagnosis of malignancy or infection. Pleural biopsy increases the sensitivity of thoracentesis for culturing tuberculosis.

Radiology

               An additional radiological study that may occasionally be useful in the diagnosis of pulmonary disease is the gallium scan. The use of gallium scanning was more common in the early part of the AIDS epidemic. It allows differentiation between infectious and non-infectious diseases, specifically Kaposi's sarcoma. Typically, infectious processes are gallium-avid, while Kaposi's sarcoma will be negative on gallium scanning. The use of CT has largely replaced the need for gallium scanning, however, and the test is now rarely used at our institution.

Pulmonary Function Testing

               The use of pulmonary function testing (PFTs) for the diagnosis of respiratory disease in HIV infection is mostly similar to that in the general population. Pulmonary function testing should be performed in any patient in whom obstructive or restrictive lung diseases or pulmonary vascular disease are considerations. PFTs may also aid in the diagnosis of Pneumocystis carinii since most patients will experience a decline in the diffusing capacity for carbon monoxide (DLCO) (97, 99, 100). PFTs are also helpful to evaluate lingering respiratory complaints after episodes of pulmonary infection as it has been found that permanent obstructive changes occur after Pneumocystis carinii or bacterial pneumonia (101).

               Algorithm-based approaches to diagnosis can help direct the work-up of pulmonary complaints and avoid unnecessary testing or treatment. The evaluation should be focused on diagnosing the disease(s) most suggested by the combination of the patient's history, physical, radiographic, and laboratory findings. Approaches to diagnosis of respiratory diseases are outlined in Table 6 and Figures 10 and 11.

 

MANAGEMENT

Empiric Therapy

               The differential diagnosis of respiratory complaints in HIV-infected persons is extensive. Further, many diseases, although they have typical presentations, often present in an atypical manner. Unfortunately, clinicians are not always as accurate in their estimate of a patient's diagnosis as they would like. Studies of bronchoscopy in cases where Pneumocystis carinii pneumonia was the leading diagnosis revealed the presence of Pneumocystis in only 57% of cases (102). Also, many drug therapies have side effects to which the patients may be exposed unnecessarily, and appropriate therapy may be delayed by empiric treatment. Given these facts, the definitive microbiological or pathological diagnosis of respiratory disease is always preferred. However, there are some circumstances under which definitive diagnosis may not be possible or advisable. Empiric therapy should always be started while awaiting diagnostic evaluation particularly in the severely ill patient or in those suspected to have tuberculosis. In patients with bacterial pneumonia, definitive microbiologic diagnosis is often not possible and treatment must be based on clinical history and radiographic findings. Some centers may not have access to bronchoscopy, or laboratory techniques for diagnosing Pneumocystis carinii pneumonia may be inadequate. Patients with mild disease who have not been taking anti-Pneumocystis prophylaxis and have low CD4 cell counts with a clinical picture consistent with Pneumocystis carinii pneumonia may be treated empirically. However, failure to respond to treatment or clinical worsening should prompt a more definitive evaluation.

Non-Antimicrobial Therapy

               Despite the availability of effective treatment for Pneumocystis carinii, there is still a substantial mortality from this disease. The use of adjunctive corticosteroids in the treatment of moderate and severe Pneumocystis carinii pneumonia has been shown to lessen mortality. Much of the lung damage that occurs in Pneumocystis carinii pneumonia results from the body's immune response to the organism, not the organism itself. This response typically occurs several days into therapy and results in worsening oxygenation. Multiple studies have reported improved mortality and decreased hypoxemia in patients treated with steroids (103-105). Current guidelines recommend the use of adjunctive corticosteroids in adults and adolescents with documented or suspected Pneumocystis carinii pneumonia when the arterial pO2 is less than 70mm Hg or the alveolar-arterial oxygen gradient is greater than 35mm Hg. Either oral prednisone or intravenous methylprednisolone should be started when anti-Pneumocystis treatment is begun, and the dose should be tapered over the 21 day course of treatment.

               HAART may become another adjunctive therapy for PCP in the future. Continuation or initiation of HAART in critically ill patients with PCP has been debated. While there have been some case reports of paradoxical worsening of PCP upon HAART initiation (106), a recent study found an improvement in mortality from 63% to 25% among those admitted to the ICU with PCP who were either taking HAART or were started on HAART (107). Also, some authors have found that protease inhibitors have an anti-Pneumocystis effect that may provide additional benefit in treatment (108). A prospective study of HAART initiation in the intensive care unit is currently ongoing to answer this question.

 

CONCLUSIONS

               In this chapter, we have summarized the clinical features of common pulmonary disorders in HIV-infected patients and suggested methods for efficient diagnosis. Accurate diagnosis of respiratory disease requires integration of information from the history and physical, laboratory data, and the chest radiograph. Because of the diversity of findings in HIV-associated respiratory illnesses, no disease has a single pathognomonic presentation. Therefore, empiric therapy should be avoided and definitive diagnosis pursued whenever possible. The clinician should be aware of the typical presentations of the most common respiratory diseases and focus the diagnostic evaluation appropriately.

 

Tables and Figures 

Table 1. Spectrum of Respiratory Complications  [Download PDF]

Table 2. Evaluation of Respiratory Complications: Diagnostic Clues   [Download PDF]
 Table 3. HIV-associated Respiratory Complications According to CD4 Cell Count   [Download PDF]

Table 4. Comparison of Clinical, Laboratory, and Chest Radiographic Findings in Pneumocystis carinii and Bacterial Pneumonias 

Table 5. Characteristic Chest Radiographic Findings in Selected HIV-associated Respiratory Complications Listed in Order of Decreasing Frequency (San Francisco General Hospital)

Table 6.  Diagnostic Tests for Evaluation of Respiratory Diseases in HIV-Infected Individuals.  [Download PDF]

Figure 1. Frontal chest radiograph of an HIV-infected patient with Pneumocystis carinii pneumonia (PCP).  The bilateral, diffuse reticular infiltrates are typical of PCP (with permission from L. Huang).

Figure 2. Frontal chest radiograph of an HIV-infected patient with Pneumocystis carinii pneumonia (PCP) demonstrating a right-sided pneumothorax (horizontal arrow) and an air-containing cyst (vertical arrow).  There are diffuse granular opacities in the left lung characteristic of PCP (with permission from L. Huang).

Figure 3. High resolution chest computed tomograph of an HIV-infected patient with Pneumocystis carinii pneumonia demonstrating characteristic patchy ground glass opacities (with permission from L. Huang).

Figure 4. Frontal chest radiograph of an HIV-infected patient with bacterial pneumonia.  There are bilateral areas of focal consolidation (arrows) (with permission from L. Huang).

Figure 5. Frontal chest radiograph of an HIV-infected patient with tuberculosis.  The pattern of an upper lung zone infiltrate with cavitation (arrow) is typical of reactivation disease (with permission from L. Huang).

Figure 6. Frontal chest radiograph of an HIV-infected patient with tuberculosis and a CD4 cell count less than 50 cells/ul.  The radiograph demonstrates that patients with low CD4 cell counts typically present with mid or lower lung zone consolidation (arrow) in contrast to the radiographic presentation shown in Figure 5 (with permission from L. Huang).

Figure7. Frontal chest radiograph and chest computed tomograph of an HIV-infected patient with fungal pneumonia.  There are bilateral diffuse reticulonodular infiltrates.  Also typical is the presence of hilar adenopathy (arrow) (with permission from L. Huang).

Figure 8. Frontal chest radiograph and chest computed tomograph of an HIV-infected patient with Kaposi’s sarcoma demonstrating peribronchial cuffing and bilateral poorly-defined nodules (with permission from L. Huang).

Figure 9. Frontal chest radiograph of an HIV-infected patient with non-Hodgkin’s lymphoma revealing a left-sided mass (with permission from L. Huang).

Figure 10.  Algorithm for diagnosing suspected PCP

Figure 11a.  Diagnostic Evaluation of Respiratory Complaints in HIV-Infected Individuals Based on Radiographic Findings.

Figure 11b. Diagnostic Evaluation of Respiratory Complaints in HIV-Infected Individuals Based on Radiographic Findings

 

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