27: Pulmonary complications in the immunocompromised host
OUTLINE
Acquired Immunodeficiency Syndrome, 319
Etiology and Pathogenesis, 320
Infectious Complications of Acquired Immunodeficiency Syndrome, 321
Noninfectious Complications of Acquired Immunodeficiency Syndrome, 324
Diagnostic Evaluation of Pulmonary Infiltrates in Acquired Immunodeficiency
Syndrome, 325
Pulmonary Complications in Non–HIV Immunocompromised Patients, 325
Organ Transplant Recipients, 325
Treatment of Inflammatory Conditions, 326
Primary Immunodeficiencies, 327
Diagnostic Evaluation of Pulmonary Infiltrates in Non–HIV
Immunocompromised Patients, 327
Physicians are frequently faced with patients who have impaired host defense mechanisms that increase the risk of specific infections. HIV/AIDS, neutropenia, and depressed cellular and/or humoral immunity, as frequently occurs due to either chemotherapy (given for malignancy) or immunosuppressive agents (administered for inflammatory diseases or suppression of rejection following organ transplantation), all predispose patients to particular pathogens. This chapter is devoted to the spectrum of respiratory complications potentially associated with several of the more commonly encountered forms of impaired immunity.
Immunocompromised patients are extremely susceptible to respiratory tract infections with a variety of organisms, some of which rarely cause disease in the immunocompetent host. When the immunosuppressed patient has fever and new pulmonary infiltrates, the possibility of an “opportunistic” infection comes immediately to mind. However, immunocompromised patients are also susceptible to common respiratory pathogens and noninfectious complications, both of which must be seriously considered in the differential diagnosis.
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Acquired immunodeficiency syndrome
In 1981, a number of cases of immunodeficiency of unknown cause in men who had sex with men and in intravenous drug users were reported. These patients had a variety of unusual infections, including Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia, mucosal candidiasis, and several types of viral infections. In some cases, the unusual neoplasm Kaposi sarcoma also occurred. Evaluation of these patients revealed marked impairment of cellular immunity, characterized by anergy to skin tests for delayed hypersensitivity and decreased numbers of lymphocytes, specifically with loss of CD4+ T lymphocytes and a reversal in the normal ratio of CD4+ helper and CD8+ suppressor T cells. This disease subsequently was given the name acquired immunodeficiency syndrome (AIDS).
What initially seemed to be an unusual problem that might be relegated to the realm of medical curiosities has since become one of the major worldwide public health problems confronting the medical profession in the 21st century. Roughly 37 million individuals around the world (including approximately 1.2 million in the United States) are currently infected with HIV. With effective antiretroviral therapy (ART), the mortality from HIV/AIDS has declined in areas where the treatment is available. However, the World Health Organization estimates almost 700,000 deaths worldwide were attributable to HIV-related diseases in 2020. In some parts of sub-Saharan Africa, HIV/AIDS is the leading cause of death.
In the more than four decades since HIV/AIDS was recognized, an enormous amount of research has resulted in identification of the retrovirus responsible for this catastrophic attack on the cellular immune system. At the same time, a wide and unexpected spectrum of clinical problems has been posed by a myriad of opportunistic infections and neoplasms resulting from the profound immunodeficiency in these patients. Fortunately, the development of current antiretroviral therapies and effective prophylactic regimens against several opportunistic infections has significantly decreased many of the clinical complications of the disease, and the global death rate has declined by almost 40% since 2010. Nevertheless, although substantial and rapid progress has been made in therapy for the disease, as well as prevention and treatment of secondary complications, management of patients with AIDS continues to present a major challenge to the medical community. The critical concern is at the worldwide level, primarily because of limited availability of therapeutic and prophylactic agents for the large number of affected individuals in under-resourced regions.
In the United States, the largest category of individuals affected by AIDS is men who have sex with men, in whom HIV is transmitted by sexual contact. Heterosexual transmission also occurs, and intravenous drug users are at risk due to use of sharing of infected needles or syringes. In other areas of the world (e.g., sub-Saharan Africa and Asia), AIDS is common in both sexes and is transmitted primarily by heterosexual contact.
Although AIDS can lead to complications in almost any organ system, the lungs are the organ system most commonly affected.
Etiology and pathogenesis
The etiologic agent responsible for AIDS is the human immunodeficiency virus (HIV), a retrovirus formerly called human T-cell lymphotropic virus type III (HTLV-III). The virus appears to mediate its pathogenic effect by binding to the CD4 receptor on cells that carry this surface receptor, then entering and destroying the cells. Although the predominant cell type affected is the CD4+ helper T lymphocyte, cells of the monocyte-macrophage series and certain neural cells are also infected because they carry the CD4 receptor on their cell surface.
The immunodeficiency occurring with HIV infection results primarily from lysis and depletion of infected CD4+ T lymphocytes. Macrophages and monocytes are also infected, leading to dysfunctional
cytokine production. Because macrophages are relatively resistant to the cytotoxic effects of the virus, they appear to provide a viral reservoir.
HIV binds to the CD4 receptor of T lymphocytes.
The major consequence of the immunodeficiency is opportunistic infection with organisms normally handled by an adequately functioning cellular immune system. When CD4+ T lymphocytes fall below 200/mm3, the most common infection involving the lungs in the absence of prophylaxis is pneumonia caused by P. jiroveci infection. Pulmonary infection can similarly result from a wide variety of other respiratory pathogens normally controlled by cell-mediated immune mechanisms, including cytomegalovirus (CMV), mycobacteria (Mycobacterium tuberculosis and nontuberculous or atypical mycobacteria), and fungi (especially Cryptococcus, Histoplasma, and Coccidioides). Patients with HIV have also been more likely to develop severe illness if they contract COVID-19.
Certain types of bacterial pneumonia, primarily due to Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae, are also seen with increased frequency in AIDS. Although these types of bacterial pneumonia normally might not be predicted to result from the cellular immunodeficiency of AIDS, these infections probably can be explained by secondary dysregulation of the humoral immune system and impaired antibody production against these organisms.
Major pulmonary infections with AIDS:
1.Pneumocystis jiroveci (formerly carinii)
2.Cytomegalovirus
3.Mycobacteria (tuberculosis, nontuberculous mycobacteria)
4.Fungi (Cryptococcus, Histoplasma, Coccidioides)
5.Bacteria (Streptococcus pneumoniae, Haemophilus influenzae)
Infectious complications of acquired immunodeficiency syndrome
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 in the United States, 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 associated with a 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 26. Although Pneumocystis is a fungus, it is discussed separately from other fungi (see later in this chapter) due to its distinct clinical characteristics. 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 is commonly described as looking like “ground glass” (see Fig. 26.3).
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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.
Pneumocystis jiroveci pneumonia often has an indolent onset in AIDS.
A presumptive diagnosis of Pneumocystis pneumonia may be made in a patient with HIV/AIDS who develops dyspnea and hypoxemia if the CD4+ T-lymphocyte count is less than 200 cells/mm3, chest radiology is consistent, and the serum 1,3-β-D-glucan is more than 80 pg/mL. However, a definitive diagnosis requires demonstrating the organism in respiratory secretions or tissue—typically by immunofluorescent staining with a monoclonal antibody or by nucleic acid amplification methods. Patients with Pneumocystis pneumonia in the setting of AIDS often have a large burden of organisms, making specimens that are diagnostic easier to obtain than from patients without AIDS. Inducing sputum by having the patient inhale a solution of hypertonic saline is frequently effective and often is 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.
Definitive diagnosis of Pneumocystis jiroveci is made most commonly on samples obtained by induction of sputum or bronchoalveolar lavage.
Trimethoprim-sulfamethoxazole, given either orally or intravenously, is the preferred treatment of pneumonia due to Pneumocystis. For patients unable to tolerate trimethoprim-sulfamethoxazole, the combination of clindamycin and primaquine, the combination of trimethoprim and dapsone, or either atovaquone or pentamidine as single agents are considered. Because patients with HIV/AIDS have a higher incidence of allergic reactions to sulfonamides, making a switch from trimethoprimsulfamethoxazole to other drugs is necessary in a relatively high proportion of patients. In patients without AIDS treated for Pneumocystis pneumonia, the combination trimethoprim-sulfamethoxazole also is generally preferred and tends to be complicated by fewer drug reactions.
Trimethoprim-sulfamethoxazole is the preferred therapy for Pneumocystis jiroveci pneumonia.
In patients with moderate to severe disease caused by Pneumocystis pneumonia, adjunctive therapy with corticosteroids is indicated to avert respiratory failure. Although corticosteroid therapy might be expected to cause more immunosuppression and make the infection worse, this has not been the case when administered along with antimicrobial agents directed at the organism. 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) is used 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. 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.
Atypical presentations of Pneumocystis jiroveci infections are commonly seen in patients receiving aerosolized pentamidine.
Mycobacterial infection
M. tuberculosis is an important respiratory pathogen in patients with AIDS. Clinical disease may result from primary infection, reactivation of previous infection, or exogenous reinfection. Disease due to M. tuberculosis is a particular problem in those groups of individuals with a high background prevalence of tuberculosis—for example, much of the population of sub-Saharan Africa, intravenous drug users, homeless or incarcerated individuals, and some immigrant populations in the United States.
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 HIV infection. The clinical presentation is similar to that seen in the non-HIV-infected patient with tuberculosis. However, it also may occur in HIV/AIDS patients who are in an advanced 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. Importantly, 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 symptoms from 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 known as immune reconstitution inflammatory syndrome.
Tuberculosis may be an early opportunistic infection in HIV/AIDS.
Treatment considerations for tuberculosis in AIDS patients are 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. Similar to recommendations in patients without HIV infection, treatment of latent tuberculosis is indicated. For patients with HIV infection who have a positive tuberculin skin test reaction (defined as 5 mm or more of induration) or a positive interferon-γ release assay but no evidence of active disease, one of the recommended treatment regimens for latent tuberculosis should be administered.
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. Previously, in patients with HIV/AIDS, prophylactic treatment against MAC with a macrolide antibiotic such as azithromycin or clarithromycin was indicated when the CD4+ count fell below 50/mm3. However, with potent antiretroviral therapy, the risk of disease due to MAC is significantly reduced and routine prophylaxis is no longer recommended.
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Other bacterial infection
Patients with AIDS, particularly intravenous drug users, 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. As with other opportunistic infections in HIV disease, the risk of bacterial pneumonia is also greatly decreased with the use of antiretroviral therapy.
Bacterial pneumonias might not be predicted as 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 CD4+ cells results in alteration of the normal interaction between these cells and B lymphocytes that regulates antibody production.
Viral infection
One of the most common viruses afflicting patients with AIDS is CMV, a member of 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 BAL 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.
Evidence regarding the interaction between HIV infection and infection with COVID-19 is rapidly evolving. HIV, especially with a low CD4+ count, appears to be an independent risk factor for the development of severe COVID-19, even in patients on effective antiretroviral therapy. Individuals with HIV infection should receive COVID-19 vaccination on the same schedule as recommended for non-HIV individuals.
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
In addition to Pneumocystis, discussed previously, several other fungi are recognized as causes of respiratory involvement in patients with advanced 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. Although the initial infection starts in the lungs, meningitis is the most common clinical manifestation rather 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. Optimal treatment consists of amphotericin B combined with flucytosine.
Histoplasmosis and coccidioidomycosis, fungal infections that occur in specific endemic regions, are described in detail in Chapter 26. Consequently, histoplasmosis and coccidioidomycosis in AIDS patients are seen primarily but not exclusively in their respective endemic areas. 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, in those with advanced AIDS, from progressive primary infection. Treatment with antiretroviral therapy greatly decreases the risk from either of these organisms. 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.
Noninfectious complications of acquired immunodeficiency syndrome
Although infectious complications affecting the respiratory system are much more common, noninfectious complications are also recognized in patients with AIDS. They fall into the broad categories of neoplastic disease (which includes Kaposi sarcoma and non-Hodgkin lymphoma), inflammatory disease (which includes lymphocytic interstitial pneumonitis and nonspecific interstitial pneumonitis), and pulmonary vascular disease (pulmonary hypertension). As with infections, the incidence of these noninfectious complications is also markedly decreased in patients receiving antiretroviral therapy. A brief discussion of each of these potential complications follows.
Neoplastic disease
Kaposi sarcoma, a vascular tumor that is associated with human herpesvirus-8, is an AIDS-defining illness and the most common malignancy in patients with HIV. Prior to the AIDS epidemic, it was a rare diagnosis in the United States, typically occurring in elderly men and characterized by slowly progressive cutaneous lesions of the lower extremities. A more aggressive form with frequent visceral involvement was seen in certain parts of Africa. In the early descriptions of AIDS patients in 1981, Kaposi sarcoma was one of the unusual clinical manifestations accompanying the profound cellular immunodeficiency. Since then, Kaposi sarcoma is recognized as one of the common manifestations, typically occurring with skin involvement but often complicated by dissemination to the lungs and other organ systems. The incidence of HIV-related Kaposi sarcoma has decreased substantially with antiretroviral therapy.
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 slit-like vascular spaces. Visceral involvement indicates the presence of dissemination, and 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 helpful diagnostically to distinguish pulmonary Kaposi sarcoma from Pneumocystis pneumonia because pleural effusions are uncommon with the latter diagnosis. Involvement of the airways or mediastinal lymph nodes can be seen with intrathoracic Kaposi sarcoma.
Kaposi sarcoma in the thorax can manifest with parenchymal, airway, lymph node, and pleural involvement.
Definitive diagnosis of Kaposi sarcoma in the lung may be difficult, because BAL and even transbronchial biopsy infrequently provide sufficient diagnostic material. A surgical lung biopsy typically provides sufficient 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. Although rarely used now, a gallium lung scan may provide another useful clinical clue by demonstrating pulmonary uptake in most opportunistic infections but not in Kaposi sarcoma.
The primary therapy for Kaposi sarcoma in patients with AIDS is antiretroviral treatment. Prior to
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effective antiretroviral medications, the prognosis for AIDS-associated Kaposi sarcoma was quite poor, with typical survival of less than 1 year. For patients who show progression of disease despite antiretroviral therapy, systemic chemotherapy is considered.
Another common neoplasm associated with AIDS is non-Hodgkin lymphoma. Although extranodal involvement and advanced disease are common when this malignancy occurs in AIDS patients, isolated intrathoracic involvement is uncommon. Lung cancer also appears to occur with increased frequency in AIDS patients. As with Kaposi sarcoma, antiretroviral therapy does appear to significantly diminish the incidence of non-Hodgkin lymphoma and lung cancer, but to a lesser extent.
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 perinatally acquired HIV infection who do not receive antiretroviral therapy. The primary treatment for these children is the institution of antiretroviral therapy, with the addition of corticosteroids when necessary.
Lymphocytic interstitial pneumonitis is a common pulmonary complication of AIDS in children.
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
Pulmonary arterial hypertension (PAH) is a potential complication of HIV infection, although the exact pathophysiologic explanation is poorly understood. A number of viral proteins have been implicated, and one hypothesis holds that circulating monocytes infected with HIV abnormally release high levels of endothelin-1, leading to pulmonary artery vasoconstriction and remodeling. The histopathology and clinical features are indistinguishable from those of idiopathic pulmonary arterial hypertension (IPAH). Antiretroviral therapy is indicated as part of the therapeutic approach, although the effect of antiretroviral agents on progression of PAH is unclear. Treatment is similar to that of IPAH (see Chapter 14), but use of endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors is frequently problematic because of concerns about drug interactions.
Diagnostic evaluation of pulmonary infiltrates in acquired immunodeficiency syndrome
Pulmonary infiltrates, often accompanied by fever, dyspnea, and cough, present a common problem in patients known to have either HIV infection or risk factors for exposure to HIV. Although typical radiographic presentations may suggest a particular diagnosis, findings are often nonspecific. In addition, with accumulation of experience with AIDS, more atypical presentations of many of these respiratory complications have been recognized. For example, with Pneumocystis infection, use of aerosolized pentamidine decreases the likelihood of infection but increases the frequency of atypical radiographic presentations when the infection occurs despite prophylactic therapy. Likewise, pulmonary tuberculosis in patients with advanced HIV infection may present with minimal or atypical radiographic manifestations.