Pulmonary Complications in the Immunocompromised Host

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Pulmonary Complications in the Immunocompromised Host



During the last several decades, physicians have been faced with increasing numbers of patients who have impaired host defense mechanisms, particularly due to infection with the virus causing HIV/AIDS. In addition, neutropenia (decreased polymorphonuclear neutrophils [PMNs]) or depressed cellular immunity occurs frequently as a result of either chemotherapy given for malignancy or immunosuppressive agents administered for inflammatory diseases or suppression of rejection following organ transplantation. This chapter is devoted to the spectrum of respiratory complications potentially associated with several of the more commonly encountered forms of immunodeficiency.


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 noninfectious complications, which must be seriously considered in the differential diagnosis.



Acquired Immunodeficiency Syndrome (AIDS)


In 1981, a number of cases of immunodeficiency of unknown cause in homosexual men and 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 helper-inducer CD4+ T lymphocytes and a reversal in the normal ratio of helper to suppressor T cells. This disease subsequently was given the name acquired immunodeficiency syndrome.


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 33 million individuals around the world (including >1.2 million in the United States) are currently infected with human immunodeficiency virus (HIV), with approximately 7000 new infections occurring worldwide each day. It has been estimated that there are nearly 2 million deaths worldwide per year from HIV/AIDS. In sub-Saharan Africa, HIV/AIDS is the leading cause of death.


During the past 30 years, 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 death rate in the United States declined 80% between 1990 and 2003. 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 challenge is at the worldwide level, primarily because of limited availability of therapeutic and prophylactic agents for the large number of affected individuals in developing nations.


In the United States, the largest category of individuals affected by AIDS is men who have sex with men, in whom the responsible virus is transmitted by sexual contact. Persons in the next largest group, intravenous drug users of either sex, introduce the virus into their circulation via infected needles or syringes. Recipients of contaminated blood products, including concentrates of factor VIII used for hemophilia, form another important group at risk for AIDS. Finally, a smaller number of patients in the United States contracted AIDS by heterosexual contact, generally with an individual in one of the aforementioned risk groups. 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 potentially leads to complications in almost any organ system, the lungs have been the organ system in which the largest number of complications has occurred.



Etiology and Pathogenesis


The etiologic agent responsible for AIDS is a retrovirus formerly called human T-cell lymphotropic virus type III (HTLV-III), now called human immunodeficiency virus. The virus appears to mediate its pathogenic effect by binding to the CD4 receptor on cells that carry this surface receptor. Although the most important cell type affected is the helper-inducer subset of T lymphocytes, 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. This loss of the helper-inducer cell population may be complicated by altered macrophage function, which probably is secondary to direct effects of the virus and impaired production of cytokines normally affecting macrophage activation and function.




The major consequence of the immunodeficiency is opportunistic infection with organisms normally handled by an adequately functioning cellular immune system. The most common infection involving the lungs in the absence of prophylaxis is pneumonia caused by P. jiroveci infection. Pulmonary infection can also result from a wide variety of other respiratory pathogens normally controlled by cell-mediated immune mechanisms, including cytomegalovirus, mycobacteria (Mycobacterium tuberculosis and nontuberculous or atypical mycobacteria), and fungi (especially Cryptococcus, Histoplasma, and Coccidioides). Certain types of bacterial pneumonia, primarily due to Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae, are also seen with increased frequency in AIDS. Whereas these types of bacterial pneumonia normally might not be predicted to result from the cellular immunodeficiency of AIDS, they probably can be explained by secondary dysregulation of the humoral immune system and impaired antibody production against these organisms.





Infectious Complications of AIDS



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.



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Jun 12, 2016 | Posted by in RESPIRATORY | Comments Off on Pulmonary Complications in the Immunocompromised Host

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