Pneumocystis jiroveci Pneumonia

Since the first identification of cases in 1981, Pneumocystis infection has been the most common respiratory complication in untreated patients with AIDS, frequently representing the initial opportunistic infection that establishes the diagnosis of AIDS in the absence of other known causes of immunosuppression. The risk of developing this opportunistic infection is highly dependent on the patient’s peripheral blood CD4⁺ count, with a level less than 200 cells/mm³ the cutoff below which patients are at high risk for infection. Fortunately the availability of increasingly effective antiretroviral agents and more frequent use of prophylaxis against Pneumocystis have significantly decreased the likelihood of infection and death resulting from this opportunistic infection.

A general discussion of Pneumocystis as a respiratory pathogen was given in Chapter 25. In patients with AIDS, onset of the disease is often more indolent than in immunosuppressed patients without AIDS. Fever, cough, and dyspnea are the usual symptoms bringing the patient to medical attention. The typical chest radiograph shows diffuse interstitial or alveolar infiltrates. Often the lung fields look hazy, a pattern that may be difficult to characterize specifically as either interstitial or alveolar and commonly described as looking like “ground glass” (see Fig. 25-3). However, atypical radiographic presentations are clearly recognized with documented Pneumocystis pneumonia, including even the finding of a normal chest radiograph. High-resolution computed tomographic (CT) scanning is particularly sensitive for demonstrating subtle changes associated with Pneumocystis pneumonia and generally shows abnormal results even in patients with a normal chest radiograph.

Diagnosis is generally based on finding the organism in respiratory secretions by any number of techniques, especially immunofluorescent staining with a monoclonal antibody. Patients with AIDS often have a surprisingly large burden of organisms, making the organisms easier to obtain than from patients without AIDS. Inducing sputum by having the patient inhale a solution of hypertonic saline is frequently effective and now often used as the initial diagnostic method when Pneumocystis is suspected. Flexible bronchoscopy with bronchoalveolar lavage (BAL) is another means for recovering the organism, with a positive yield of greater than 85% in patients eventually proven to have Pneumocystis pneumonia. Transbronchial biopsy provides a small incremental increase in sensitivity over BAL alone.

Treatment of severe pneumonia caused by Pneumocystis organisms usually involves one of four regimens: the combination antimicrobial trimethoprim-sulfamethoxazole, the combination of clindamycin and primaquine, or trimetrexate or pentamidine as single agents given intravenously. These four regimens appear to be equally effective; each is successful in about 80% of cases. In patients without AIDS treated for Pneumocystis pneumonia, the combination trimethoprim-sulfamethoxazole is generally preferred because of fewer side effects. However, patients with AIDS have a peculiar predisposition to allergic reactions to sulfonamides, making the frequency of adverse side effects equivalent to that seen with pentamidine and making necessary a switch to therapy with other drugs in a relatively high proportion of patients. Other agents such as atovaquone or the combination of trimethoprim and dapsone have been used, especially in patients who do not respond to or cannot tolerate one of the more standard agents or have less severe disease.

In patients with moderate to severe disease caused by Pneumocystis pneumonia, adjunctive therapy with corticosteroids is often helpful in averting significant respiratory failure. Although corticosteroid therapy might be expected to cause more immunosuppression and make the infection worse, this has not been the case, and the presumed benefit of reducing the inflammatory response in the lung to lysing organisms outweighs any negative effects of the corticosteroids.

In patients with AIDS, oral administration of trimethoprim-sulfamethoxazole (in low doses) or dapsone (either alone or with pyrimethamine) can be used with reasonable effectiveness to prevent Pneumocystis pneumonia. Alternatively, patients can receive aerosolized or intravenous pentamidine once a month or daily oral atovaquone. Such prophylactic therapy is routinely recommended in HIV-infected patients who have a CD4⁺ count less than 200 cells/mm³ and in selected other circumstances. Unfortunately, the propensity for development of allergic reactions to trimethoprim-sulfamethoxazole frequently makes this regimen difficult to use in patients with AIDS, so many patients are maintained on one of the other forms of prophylaxis. When Pneumocystis pneumonia develops despite use of aerosolized pentamidine prophylaxis, the clinical presentation may be atypical. Unusual radiographic patterns are often seen, especially pulmonary infiltrates limited to the upper lung zones rather than the more typical pattern of diffuse pulmonary infiltrates.

Mycobacterial Infection

Mycobacterium tuberculosis has emerged as an important respiratory pathogen in patients with AIDS, not only because it is common but also because it is potentially treatable. Clinical disease may result from primary infection, reactivation of previous infection, or exogenous reinfection. Rather than occurring in all categories of AIDS patients, disease due to M. tuberculosis is a particular problem in those groups of individuals with a high background prevalence of tuberculosis—for example, intravenous drug users and indigent and immigrant populations.

Because M. tuberculosis is a relatively virulent organism that does not require the same degree of immunosuppression to produce disease as do many of the other opportunistic infections, it is often seen early in the course of the disease in patients with AIDS. In this setting, its clinical presentation is similar to that seen in the typical patient with tuberculosis who does not have AIDS. However, it also may occur in AIDS patients who are in a late stage of their disease with more severe immunosuppression, in which case the clinical manifestations are often atypical. In this latter circumstance, upper lobe cavitary disease is less frequent, and disseminated disease is more frequent than is usually seen in patients without AIDS. Interestingly, for patients with AIDS and tuberculosis (or for that matter, with other opportunistic infections), improvement in the patient’s overall immune status, particularly as a result of antiretroviral therapy, can be associated with a paradoxical clinical worsening of the opportunistic infection. In these cases, “reconstitution” of the immune system results in an augmented inflammatory reaction to the opportunistic infection, leading to the apparent clinical worsening.

Treatment considerations for tuberculosis in AIDS patients are generally similar to those for patients without AIDS, but with some differences. Because of the risk for disease with nontuberculous mycobacteria, an expanded list of drugs is sometimes given initially to AIDS patients until the organism and its sensitivities are firmly identified. In addition, treatment may be given for a longer duration to AIDS patients, especially if the response to therapy appears slow. Drug interactions with antiretroviral therapy must be carefully considered. Patients with HIV infection who have positive tuberculin skin test reactions (defined as 5 mm or more of induration) but no evidence of active disease should receive 9 months of treatment with isoniazid (or an alternative regimen), similar to the treatment of latent tuberculosis infection in individuals without HIV infection.

The other types of mycobacteria that frequently cause opportunistic infection in AIDS are members of the Mycobacterium avium complex (MAC). What is surprising in patients with MAC infection is that the organism is associated primarily with disseminated disease, not with pulmonary disease. Even when disseminated disease is present, pulmonary involvement is not generally a significant part of the clinical picture. Because the risk of MAC infection is associated with extremely low CD4⁺ counts, prophylactic treatment against MAC, typically with a newer macrolide antibiotic such as azithromycin or clarithromycin, is indicated when the CD4⁺ count falls below 50/mm³.

Other Bacterial Infection

Patients with AIDS appear to have an increased frequency of bacterial pneumonia, primarily due to either S. pneumoniae or H. influenzae. The risk is increased at all levels of CD4⁺ count and is highest when the count falls below 200 cells/mm³. Intravenous drug users also appear to be at particularly high risk.

Bacterial pneumonias might not be predicted to be a complication of AIDS, because impairment in cellular immunity should not by itself predispose an individual to these infections. However, dysregulation of the humoral immune system accompanies the impairment in cellular immunity. Patients frequently have polyclonal hyperglobulinemia at the same time they demonstrate a poor antibody response after antigen exposure. Presumably, loss of helper-inducer cells results in alteration of the normal interaction between helper-inducer cells and B lymphocytes that regulates antibody production.

Viral Infection

The most common virus afflicting patients with AIDS is cytomegalovirus (CMV), one of the viruses in the herpesvirus family. The most common sites of clinical involvement are the eye (CMV retinitis) and gastrointestinal tract. Although CMV can frequently be cultured from lung tissue or bronchoalveolar fluid of patients with AIDS, its role as a clinically important respiratory pathogen is not clear. When patients with CMV in the lungs have clinical respiratory system disease, they almost always have a coexistent organism such as Pneumocystis that is thought to be the primary pathogen. Even when typical nuclear and cytoplasmic inclusions are present, the role played by CMV is uncertain in the presence of these other important pathogens, and the usefulness of adding specific treatment for CMV in this setting is unclear.

Other viruses such as herpes simplex, varicella-zoster, and Epstein-Barr virus have been described as potential respiratory pathogens in AIDS, but they are distinctly uncommon and are not considered here.

Fungal Infection

Several fungi are recognized as causes of respiratory involvement in patients with AIDS, either as isolated respiratory system disease or as part of a disseminated infection. The most common of these fungal infections is due to Cryptococcus neoformans, which more commonly causes meningitis than clinically apparent respiratory disease. When respiratory involvement is present, the radiograph may show localized or diffuse disease, and sometimes an associated pleural effusion or intrathoracic lymph node involvement. The lung may be the only organ involved, or involvement may be accompanied by meningitis or disseminated disease. Treatment traditionally has been with amphotericin B, but fluconazole has been used as an alternative agent.

Histoplasmosis and coccidioidomycosis, fungal infections that occur in specific endemic regions, are described in detail in Chapter 25. In patients with AIDS, pulmonary involvement with these organisms is most commonly a manifestation of disseminated disease that resulted either from reactivation of previous disease or from progressive primary infection. Consequently, histoplasmosis and coccidioidomycosis are seen primarily but not exclusively in their respective endemic areas. As is the case in patients without AIDS, amphotericin B (or an oral azole such as itraconazole) is the primary agent used to treat either of these infections.

Other fungal infections of the lung are much less common in AIDS patients. Perhaps surprisingly, even though oral candidiasis (thrush) is extremely common in AIDS, pulmonary infection with Candida albicans is extremely uncommon and rarely described except at autopsy. Aspergillus infection has been described in AIDS but generally it occurs in patients who have other predisposing factors for invasive aspergillosis, especially neutropenia.

Neoplastic Disease

Kaposi sarcoma is one of the most common of the neoplastic diseases affecting AIDS patients. In patients without AIDS, typically elderly men, it is characterized by slowly progressive cutaneous lesions of the lower extremities. It was formerly a rare diagnosis in the United States and was seen in a more aggressive form with frequent visceral involvement in certain parts of Africa. In the early descriptions of AIDS patients in 1981, Kaposi sarcoma was one of the peculiar clinical manifestations accompanying the profound cellular immunodeficiency. Since then, Kaposi sarcoma has been recognized as one of the common manifestations, occurring generally with skin involvement but often complicated by dissemination to the lungs and other organ systems. Data from a variety of studies, including identification of herpesvirus-like DNA sequences in patients with Kaposi sarcoma (either with or without AIDS) but not in control subjects, indicate that human herpesvirus 8 is the causative agent responsible for Kaposi sarcoma.

Kaposi sarcoma is most commonly observed in AIDS patients as violaceous vascular-appearing skin lesions. Histologically, these lesions consist of spindle-shaped cells with intervening slitlike vascular spaces. When visceral involvement indicates the presence of dissemination, commonly involved organ systems include the gastrointestinal tract and lungs. Pulmonary involvement has a variable presentation on chest radiograph. It can appear as diffuse infiltrates, localized disease, or pulmonary nodules. Pleural involvement with resulting pleural effusions can be present and is often a helpful diagnostic point against Pneumocystis pneumonia, since pleural effusions are uncommon with the latter diagnosis. Involvement of the airways or mediastinal lymph nodes can be seen with intrathoracic Kaposi sarcoma.

Definitive diagnosis of Kaposi sarcoma in the lung may be difficult because BAL and even transbronchial biopsy infrequently provide sufficient diagnostic material. A more invasive surgical lung biopsy generally provides diagnostic material but is preferably avoided because of its invasive nature. When endobronchial involvement is present, the gross appearance of airway lesions may be highly suggestive of the diagnosis. A gallium lung scan may provide another useful clinical clue by demonstrating pulmonary uptake in most opportunistic infections but not in Kaposi sarcoma.

Therapy for Kaposi sarcoma involving the lungs is palliative rather than curative, although treatment options have improved greatly in recent years. Patients may have progressive respiratory involvement, often complicated by pulmonary hemorrhage. Although patients may die of disseminated Kaposi sarcoma, they frequently succumb to coexisting opportunistic infections rather than to the neoplasm.

Another common neoplasm associated with AIDS is non-Hodgkin lymphoma. Although extranodal involvement and disseminated disease are common when this malignancy occurs in AIDS patients, intrathoracic involvement is uncommon. Lung cancer also appears to occur with increased frequency in AIDS patients. In contrast to Kaposi sarcoma, antiretroviral therapy does not appear to significantly diminish the incidence of non-Hodgkin lymphoma or lung cancer.

Inflammatory Disease

An occasional patient with AIDS and diffuse pulmonary infiltrates has neither an opportunistic infection nor a neoplasm affecting the lung. Instead, the process is an inflammatory one without any known cause, although viral etiologies (especially Epstein-Barr virus and HIV) have been proposed. In some cases the microscopic appearance is notable for the prominence of lymphocytes and plasma cells infiltrating alveolar septa. In these cases a diagnosis of lymphocytic interstitial pneumonitis is made. This particular histologic pattern is a relatively common pulmonary complication seen in children with AIDS but is found infrequently in adults. When treatment is necessary, corticosteroids are used with variable success.

The other histologic pattern is a nonspecific one with a mixed inflammatory cell infiltrate. Patients with this pattern are diagnosed as having nonspecific interstitial pneumonitis. This is an uncommon complication of AIDS about which little is known.

Pulmonary Vascular Disease

A number of cases of pulmonary arterial hypertension (PAH) in patients with HIV infection have been reported. Although the association is believed to be a true rather than a coincidental relationship, no clear mechanistic or pathophysiologic explanation is known. The histopathology and clinical features are typically similar to those of idiopathic pulmonary arterial hypertension (IPAH), but the disease may have a more rapid progression than is generally seen in patients without HIV infection. Treatment is similar to that of IPAH (see Chapter 14), but use of endothelin-1 receptor antagonists is frequently problematic because of concomitant hepatic disease or concerns about drug interactions. Antiretroviral therapy is generally indicated as part of the therapeutic approach.

Solid Organ Transplantation

Lung transplantation is increasingly performed to treat a variety of end-stage lung diseases (see Chapter 29). In addition to the effects of immunosuppressive medications, the immunologic milieu in the transplanted lung is quite abnormal, leading to an increased risk of pulmonary infections of a variety of types. The propensity of specific organisms to cause infections in the post–lung transplant period varies somewhat during the time course following transplantation.

In the first month after lung transplantation, pulmonary infections are most commonly caused by healthcare-associated pneumonia organisms such as gram-negative rods and Staphylococcus aureus. Between months 1 and 6 after transplantation, patients are at maximal risk for opportunistic infections such as cytomegalovirus, P. jiroveci, toxoplasmosis, Aspergillus, endemic fungi, and mycobacteria. By 6 months post transplant, most patients are receiving stable and reduced levels of immunosuppression. These patients are most frequently subject to community-acquired pneumonias due to pneumococcus, Mycoplasma, Legionella, respiratory viruses (e.g., influenza, parainfluenza, RSV, adenovirus, metapneumovirus), or other common respiratory pathogens.

Similar patterns are observed among patients who receive transplants of other solid organs, such as heart, liver, or kidney. However, the overall incidence of pneumonia is less common in these groups, both because their native lung defenses remain intact and because lower levels of immunosuppression are required. Notably, the widespread practice of prophylaxis against P. jiroveci, cytomegalovirus, and other pathogens has helped reduce the overall incidence of pulmonary infections among solid organ transplant recipients over the past decade.

Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) has largely replaced bone marrow transplantation as a treatment modality because of the ease of harvesting circulating hematopoietic stem cells by pheresis. HSCT is used to treat primary hematopoietic malignancies such as acute myelogenous leukemia and is also indicated for treating some solid organ malignancies and some chronic nonmalignant diseases of the bone marrow.

Most patients receiving HSCT undergo pretransplant treatment with antineoplastic agents or radiation therapy to destroy the native bone marrow so that transplanted bone marrow precursors can take residence with less risk of immunologic destruction. This usually imparts a prolonged period of neutropenia in addition to other impairment of cell-mediated and humoral immunity.

As a consequence, HSCT recipients are at very high risk for infections, including respiratory tract infections. During the several weeks of profound neutropenia that follow transplantation, pulmonary infections are most commonly due to bacteria such as S. aureus and gram-negative rods or to fungi such as Aspergillus. After approximately 30 days, when neutrophil numbers have returned to normal but additional immunosuppression may be required to suppress graft-versus-host disease, viral infections become more common. Community-acquired pneumonia due to organisms such as S. pneumoniae is a constant concern. As with solid organ transplant recipients, appropriate prophylaxis against cytomegalovirus and P. jiroveci has reduced the incidence of these specific infections in this population.