Pulmonary Complications of HIV Infection
Report of the Fourth NHLBI Workshop

JAMES M. BECK, MARK J. ROSEN, and HANNAH H. PEAVY

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, and Veterans Affairs Medical Center, Ann Arbor, Michigan; Division of Pulmonary and Critical Care Medicine, Beth Israel Medical Center, New York, New York; and Lung Biology and Disease Program, Division of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

	INTRODUCTION

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The Fourth Workshop on the Pulmonary Complications of HIV Infection was sponsored by the Division of Lung Diseases (DLD), National Heart, Lung, and Blood Institute. Like previous DLD workshops led by Dr. John F. Murray (1, 2), a group of investigators met to assess the state of our knowledge of these disorders and make recommendations for new research. In the United States and Europe, the incidence and types of pulmonary disorders that develop in HIV-infected persons have changed since the last workshop in 1986. Prophylaxis for Pneumocystis carinii pneumonia (PCP) and effective combination chemotherapy for human immunodeficiency virus (HIV) infection (highly active antiretroviral therapy, or HAART) are now the standard of care, with a corresponding decline in the incidence of opportunistic infections, progression to acquired immunodeficiency syndrome (AIDS), and HIV-related mortality (3). In the last decade, the epidemiology of HIV-infected persons in the United States has also changed; an estimated 650,000 to 900,000 people are infected with HIV in the United States, and around 300,000 have AIDS (6). Approximately 40,000 people in the United States are infected with HIV each year, and cases of AIDS are increasingly likely to have acquired HIV through injection drug use and heterosexual contact (7). HAART and prophylaxis against opportunistic infections are not accessible to HIV-infected persons in many parts of the world, where pulmonary complications of HIV infection are undiminished as major causes of morbidity and mortality.

Our understanding of the basic mechanisms of HIV immunology and the biology of specific opportunistic pathogens and malignancies has increased dramatically in recent years (8). As part of the overall explosion in knowledge about HIV infection and replication, unique aspects of HIV infection in the lung have emerged. Furthermore, investigations of pulmonary defenses against infection and malignancy offer the prospect of new therapeutic approaches to these complications of HIV infection.

The purposes of this workshop were to summarize our current knowledge of HIV-associated lung disorders in an era of effective antiretroviral therapy, based on current investigation that is funded by the DLD, and to recommend and prioritize opportunities for research and training. Unlike the previous workshops that focused on clinical aspects, both clinical and basic scientists met together to summarize our current knowledge and offer recommendations. This report summarizes the presentations and major recommendations of the participants. Although not all pulmonary complications of HIV infection could be discussed within the context of this workshop, a recent volume in the Lung Biology in Health and Disease series provides a comprehensive overview of this field (8).

	EFFECTS OF HIV IN THE LUNG

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HIV Infection of Lung Cells

Infection of pulmonary macrophages and lymphocytes with HIV-1 plays a crucial role in the pathogenesis of pulmonary disease in AIDS (9). HIV variants in the lung may be genetically distinct from those in blood or other tissues, and this viral compartmentalization may be due to selective recruitment of particular variants to the lung or to localized viral evolution. HIV entry into cells is mediated by the CD4⁺ molecule on the cell surface, together with a chemokine coreceptor that is necessary for fusion. CCR5 is the coreceptor used by macrophage-tropic strains, which can infect macrophages and lymphocytes but are not able to infect T cell lines. In contrast, CXCR4 (fusin) is the coreceptor used by T cell-tropic strains, which can infect lymphocytes and cell lines, but are unable to infect macrophages. Monocyte-derived macrophages express both CCR5 and CXCR4, but only CCR5 functions to support entry for most strains. HIV infection of human alveolar macrophages is preferentially mediated by the CCR5 receptor, although alveolar macrophages also express CXCR4 (10). Although preferential coreceptor usage may contribute to compartmentalization of HIV in the lung, further investigation is needed to determine the exact mechanisms by which HIV enters lung cells (11). Additionally, the roles of other respiratory pathogens (including bacteria, fungi, and viruses) in control of HIV replication requires further study.

HIV and Lung Host Defenses

As in all tissues, progressive HIV infection decreases numbers of lung CD4⁺ T cells. However, the presence of HIV in the lung may cause intense infiltration of CD8⁺ T cells in the interstitial and alveolar spaces. This "lymphocytic alveolitis" exists in all stages of HIV infection, but is most pronounced in patients with early to middle stage disease, and is caused mainly by the compartmentalization of HIV-specific cytotoxic T cell (12). As CD4-derived signals for T cell proliferation are decreased, recent investigations demonstrate that alveolar macrophage products are responsible for T cell chemotaxis and proliferation. These mediators include chemokines that are CXCR3 ligands (IP-10) and interleukin-15 (IL-15). IL-15 mediates the development of T cell alveolitis by inducing T cell proliferation and by stimulating T cell migration (13). With HAART, it is possible to reduce HIV burden and to down-regulate activation of peripheral blood CD8⁺ T cells. Current investigations seek to determine whether HAART is associated with a parallel down-regulation of cytokine expression, and return of normal CD8⁺ T cell activation, in pulmonary tissue.

In addition to T cell destruction and impaired cell-mediated immune responses, HIV infection is also associated with defects in humoral (B cell) immunity. Whereas immunoglobulin production undergoes a generalized increase, the ability to generate antigen-specific responses is impaired. The increased incidence of bacterial pneumonia in HIV-infected persons suggests that antibody production is decreased in the lung, but absolute numbers of B cells in bronchoalveolar lavage (BAL) fluid from asymptomatic HIV-infected subjects are comparable to numbers present in uninfected subjects. A major defect in antigen-specific immunoglobulin production may lie at the level of effector T cells, both by clonal deletion of antigen-specific T cells and by an impaired ability of HIV-infected T cells to activate B cells (14).

The participants in the workshop identified several areas for future research focused on the effects of HIV in the lung: (1) What role do immunomodulators play in the lung to enhance innate defense and to enhance specific immunity? These investigations should be conducted in animal models first, to determine whether their therapeutic benefits warrant eventual trials in humans. (2) What is the role of humoral immunity in the lung in defense against bacterial and other pathogens? (3) What are the mechanisms by which different pathogens accelerate HIV-related disease? Specifically, improved understanding of how bacteria, mycobacteria, and other pathogens modulate HIV replication and mutation in the lung is needed. (4) As HIV-infected persons survive longer with HAART, do chronic and latent infections produce long-term consequences in the lung? (5) How does the lung serve as a model for organ-specific viral compartmentalization, both as a reservoir for viral persistence and as a locus in which HIV strains evolve independently from other organs? (6) How is lung immunity influenced by chemokine/cytokine networks, inducible inhibitors, different classes of cytokines, and early events in immune responses?

	IMPACT OF HAART

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HIV-infected persons who adhere to a regimen of HAART are likely to enjoy suppression of HIV replication, and preservation or improvement in immunological function, with a reduced incidence of opportunistic events and mortality. Enhanced immunity is reflected both in the decline in rates of PCP and other infections, and the fact that prophylaxis against PCP and other infections may be discontinued successfully in patients who have a sustained increase in CD4⁺ lymphocyte counts to > 200/µl (15, 16). However, HAART does not appear to reduce the risk of all HIV-associated disorders, including lymphoma and invasive cervical cancer (17).

Despite the benefits of HAART, successful treatment poses formidable challenges. Adherence to therapy is vital to its success but difficult to achieve because these regimens are complex and expensive. Suboptimal adherence leads to inadequate viral suppression and the emergence of resistant strains of HIV. Antiretrovirals often interact with other medications, including antituberculosis chemotherapy, imidazoles, and lipid-lowering drugs (18, 19). They also have adverse effects, including hyperlipidemia, insulin resistance, accelerated atherosclerosis, changes in body habitus, and lactic acidosis (20).

When HAART inhibits viral replication, there is a corresponding increase in the population of memory and naive T cells, enhancement of lymphoproliferative responses, and increased IL-2 receptor expression (21). These proinflammatory effects probably underlie newly recognized syndromes associated with immunological reconstitution, some involving the lung. Some patients develop a granulomatous disorder that resembles sarcoidosis, whereas others with latent or active mycobacterial infections may develop fever, lymphadenopathy, and opacities on the chest radiograph following immune restoration with HAART (22, 23).

Among the questions that emerged from our discussion of the impact of HAART on the lung were: (1) Which lung diseases are most likely to occur in patients who take HAART, and what are the epidemiologic and immunologic factors that influence the risk of developing these disorders? (2) Do the clinical features and outcomes of these disorders differ from those that occur in patients not taking HAART? (3) In patients with severe opportunistic infections who are not taking HAART, should clinicians start antiretroviral medications immediately, or wait until the complicating infection is treated? (4) Which processes cause the immune restoration syndromes that follow the use of HAART? (5) How can the immune restoration syndromes be distinguished from other inflammatory disorders, and how should they be treated? (6) Do immune reconstitution syndromes have an impact on pulmonary function, and on the risk and course of subsequent HIV-associated disorders?

	PNEUMOCYSTIS CARINII PNEUMONIA

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Despite the declining incidence of PCP, it remains the most common AIDS-defining indicator condition among opportunistic infections, and knowledge about the organism, its mode of transmission, the pathogenesis of disease, and the impact of HAART on its clinical expression remains inadequate.

Microbiology and Epidemiology

Difficulty achieving a reliable in vitro culture methodology for P. carinii has significantly slowed investigation of this pathogen. Although the organism has been cultured successfully for short periods, extended culture without mammalian feeder cells has been unsuccessful. Recently, the use of specialized media and culture plates with porous membranes yielded long-term culture of P. carinii obtained from rats, and transfer of the cultured organisms into the lungs of corticosteroid-immunosuppressed rats resulted in PCP (24). Because P. carinii obtained from one species does not cause pneumonia when inoculated into other species, it will be important to extend these observations to organisms obtained from mice and humans.

The ability to identify strains of P. carinii is central to studies of its transmission and epidemiology. Person-to-person transmission is assumed but unproven. Nucleotide sequence variations of the P. carinii genome show polymorphisms in a number of genetic loci, and transmission of P. carinii in humans has been studied in cases of recurrent PCP by genotyping. Approximately 50% of cases were infected with strains of a different genotype than the primary infection strain, suggesting that patients are reinfected with new strains, rather than reactivating latent infections (25). More discriminative, sensitive, and cost-efficient methods for strain identification of P. carinii are needed.

Host Responses to P. carinii

Improved understanding of host defense against P. carinii could produce novel therapeutic or prophylactic approaches to infection, such as vaccines (26). Serological studies show that humans are exposed to P. carinii at an early age, but it is difficult to use serology to distinguish present from past infection or to make conclusions about the role of antibody responses in protective immunity. Immunization to protect against PCP seems problematic in humans, given the difficulty of cultivation of P. carinii and the host species-specific serotypes of P. carinii. Active or passive immunization may be possible using selected P. carinii antigens, as experiments in mice show that active immunization against P. carinii can be effective and prolonged if given before CD4⁺ T cell depletion (27). However, the critical antigens required for immunity against P. carinii are unknown, and infection may progress despite prompt and marked immunological responses. Thus, the major problems with developing effective immunization strategies include identification of protective immunogens, determination of the source and route of immunization, and examining the duration of immunity.

Studies of host defense against P. carinii require animal models and in vitro approaches because the methodology for human investigations is still inadequate. The CD4⁺ T cell determines host susceptibility to PCP in animal models, as these cells are required to clear P. carinii, and their absence facilitates progression of PCP in otherwise immunocompetent mice (28). However, some animal models show that CD4⁺ T cells can also induce inflammation, lung injury, and death (29). CD8⁺ T cells are not required for clearance of infection in intact mice, but have a partial host defense role in the setting of CD4⁺ T cell deficiency (30). Although it is clear that alveolar macrophages participate in defense against P. carinii, as macrophage-depleted rats demonstrate markedly impaired lung clearance of P. carinii (31), the exact mechanisms by which macrophages participate in defense remain unclear.

An approach to augmentation of host defense against P. carinii could exploit modulation of cytokines. Peripheral blood mononuclear cells from most healthy adults have vigorous proliferative and cytokine responses when stimulated with P. carinii. Several investigations suggest that cytokine responses during HIV infection shift from Th1-like to Th2-like patterns, and so restoration of a Th1 phenotype could be beneficial (32). The roles of individual cytokines, particularly interferon-gamma and tumor necrosis factor-alpha (TNF-), have been investigated, but interactions among them seem critical to host defense (33). Adenovirus vectors administered to the lung, which increase or inhibit cytokine effects, could provide an alternative approach to immune modulation (34). However, gene therapy with adenoviral vectors remains experimental and will require further study before being placed into clinical use.

Surfactant proteins have also been implicated in the pathogenesis of PCP. The hydrophobic surfactant proteins SP-B and SP-C regulate alveolar surface tension. In animal models, P. carinii infection reduces the expression of SP-B and SP-C and alters the biophysical properties of surfactant, leading to hypoxemia, decreased lung compliance, and microatelectasis (35). In contrast, the hydrophilic surfactant proteins SP-A and SP-D have a primary role in host defense. The exact role of SP-A in mediating attachment of P. carinii to alveolar macrophages is controversial (36). Intraalveolar SP-D accumulates in PCP, enhancing aggregation of the microbe, increasing its adherence to alveolar macrophages, but impairing phagocytosis and suppressing TNF- responses (37). Thus, SP-D may provide a mechanism by which P. carinii escapes host recognition and elimination.

Clinical features of P. carinii Pneumonia

Patients still develop PCP in the era of HAART and anti-PCP prophylaxis for several reasons. Some do not know they have HIV infection until they present with an opportunistic infection. Others are aware of their HIV infection, but choose not to use these treatments or use them improperly. Other patients adhere to treatment, but it is ineffective. In other parts of the world, neither HAART nor specific prophylaxis is widely available.

It is still not known if there are differences in the presentation and risk factors for PCP in patients who take or do not take prophylaxis against this infection. However, it has become clear that HIV-infected individuals who respond to HAART with immunological improvement have a substantially decreased risk of developing P. carinii pneumonia (38). Accordingly, recent guidelines emphasize that primary PCP prophylaxis may be discontinued under these circumstances (16). Additionally, recent data indicate that secondary prophylaxis may also be discontinued safely, provided a prolonged response to HAART occurs (39, 40). The diagnostic evaluation of patients with suspected PCP usually involves identifying the organism in induced sputum or bronchoscopic specimens, but many clinicians prefer to treat patients empirically, reserving invasive procedures for those who do not respond well in a few days (41). There is no conclusive evidence that one approach results in a better outcome than the other, and some institutions do not have the resources to obtain definitive diagnoses. Polymerase chain reaction identification of P. carinii DNA is very sensitive, and may identify the organism noninvasively. Amplification of P. carinii DNA from oropharyngeal washings has been used to identify P. carinii in HIV-infected individuals, and also suggests that a carrier state may exist for this organism (42).

Trimethoprim-sulfamethoxazole (TMP-SMZ) is the agent of choice to treat and to prevent this infection in susceptible persons, but the best choice of alternative agents has not been established. It is also not known whether drug resistance or host factors account for cases in which there is a poor response to treatment. Some strains of P. carinii have mutations in the gene for dihydropteroate synthase (DHPS), an essential enzyme that is inhibited by sulfonamides. The DHPS mutation is associated with use and duration of TMP-SMZ prophylaxis, but these mutations may only reflect exposure to the drug, as TMP-SMZ treatment in these cases is usually still effective. Although a recent study demonstrates that DHPS mutations are associated with decreased survival in HIV-infected individuals (43), other investigators have not demonstrated any increase in mortality.

The participants recommended several areas for future investigation of P. carinii: (1) Which factors determine the organism's virulence, what are the mechanisms of drug resistance, and how can we test for resistance in the clinical setting? (2) How is PCP acquired, and what are the consequences of infection with multiple strains? (3) What are the essential mechanisms of immune response to P. carinii in HIV-infected hosts, and do they remain localized within the lung or do they occur systemically? (4) How does P. carinii modulate HIV replication? (5) Does initial diagnostic evaluation, including bronchoscopy, differ in outcome from empiric therapy in patients with suspected PCP? (6) Which test (if any) should be performed before proceeding to fiberoptic bronchoscopy in patients with suspected PCP who have a normal chest radiograph? (7) Does analysis of oropharyngeal washings have a role in the diagnosis? (8) Which second line agents are preferred for treatment and prevention of this infection? (9) What are the criteria for restarting P. carinii prophylaxis in persons who are failing HAART?

	TUBERCULOSIS

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The collision of the tuberculosis and HIV epidemics created a devastating international public health crisis. Millions of people around the world are infected with both HIV and Mycobacterium tuberculosis, especially in underdeveloped countries. In Africa, tuberculosis may be the most common pulmonary complication of HIV infection, with at least one-third of all cases of tuberculosis occurring in patients with HIV infection. HIV-associated tuberculosis is also common in the United States, especially in injection drug users (44). Although active tuberculosis in AIDS patients appears to be curable in most instances, survival of HIV-infected patients with multidrug-resistant tuberculosis remains dismal. Tuberculosis also appears to accelerate the course of HIV disease, as development of tuberculosis predicts the development of subsequent opportunistic infections (45). A large study of over 5,000 HIV-infected individuals in Europe demonstrated that the development of tuberculosis increases overall mortality by approximately one-third (46). However, what proportion of this increased mortality is attributable to tuberculosis itself is unknown. Treatment of latent tuberculosis infection in patients with HIV may be improved by the advent of ultrashort course regimens, such as 2 mo of rifampin and pyrazinamide (47).*

The use of HAART has affected the challenge of tuberculosis in AIDS patients in several ways. By improving cellular immune function, clearance of mycobacteria may be accelerated and the natural history of AIDS patients with tuberculosis might be improved. On the other hand, complex drug interactions between antituberculosis drugs (primarily rifamycins) and antiretroviral agents (both protease inhibitors and nonnucleoside reverse transcriptase inhibitors) have led to treatment of many patients with a variety of logical but unproven combinations of antituberculosis and antiretroviral regimens (48). The development of faster, molecular diagnostic tests and new treatments for tuberculosis would allow for earlier and more effective therapy, and better contain the spread of this infection in persons with and without HIV infection. An effective vaccine would be even more valuable.

Several other important questions about tuberculosis in HIV-infected persons are unanswered: (1) Which components of the cellular immune response are most critical to protect against tuberculous infection and disease? For example, the relative importance and function of CD8⁺ T cells, CD4⁺ T cells, dendritic cells, and NK cells remain unknown. (2) Which features of immunity against M. tuberculosis change in persons using HAART? (3) What is the optimal strategy for integrating antituberculosis and antiretroviral treatment in patients with AIDS and tuberculosis? (4) Would other agents (interferon, thalidomide, IL-12) be useful? (5) How can treatment of tuberculosis be better monitored so as to predict relapse? (6) Can latent tuberculous infection be identified in patients with HIV infection with cutaneous anergy?

	BACTERIAL PNEUMONIA

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Bacterial pneumonia is a common complication of HIV infection, occurring at all stages of HIV disease, but more frequently as immune function declines (49). The pathogens and clinical features of bacterial pneumonia are generally similar in patients with and without HIV infection, although the role of atypical pathogens (Mycoplasma, Chlamydia, and Legionella) has not been studied systematically. The risk of developing bacterial pneumonia is higher in injection drug users than in gay men, and increases with declining immune function, especially in smokers. The use of TMP-SMZ prophylaxis for P. carinii pneumonia is associated with a substantial reduction in the risk of developing bacterial pneumonia, but vaccination with pneumococcal vaccine did not appear to reduce risk in the era prior to HAART. Long-term survival in HIV-infected persons following bacterial pneumonia is reduced significantly, compared with HIV-infected persons without an episode of bacterial pneumonia (50).

Unanswered questions about bacterial pneumonia in HIV-infected persons include the following: (1) Does HAART reduce the risk of developing bacterial pneumonia? (2) Which pathogens cause bacterial pneumonia, and how common are pneumonias caused by Chlamydia, Mycoplasma, and Legionella species in HIV-infected persons? (3) Which pathogens cause bacterial pneumonia in patients who use TMP-SMZ and macrolide prophylaxis, and are they likely to be resistant to these and other antibiotics? (4) How effective is pneumococcal vaccine in preventing pneumonia, bacteremia, and extrapulmonary disease in patients who respond to HAART with immunological reconstitution? Which factors predict effectiveness, and how should vaccination be timed in relation to the administration of HAART?

	VIRAL PNEUMONIA

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Although the clinical significance of isolating cytomegalovirus from respiratory specimens of HIV-infected persons has always been controversial, it is clear that viruses can produce clinical pneumonia and may be cofactors in producing other patterns of disease, including neoplasms (51). The interaction of HIV within the pulmonary compartment of immune cells and the role of HIV in the lungs on the systemic progression of HIV-related disease are still of interest. Questions to be answered include the following: (1) What is the incidence of viral infections of the lung? (2) What is the role of Epstein-Barr virus in the development of lymphoma? (3) How does HIV infection of the lung influence the development of subsequent pulmonary disorders? (4) Do viral infections of the lung, such as those caused by cytomegalovirus, have an impact on the course of HIV disease?

	FUNGAL INFECTIONS

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Pulmonary histoplasmosis, blastomycosis, and coccidioidomycosis occur in patients with HIV infection, either with progressive primary infection, or by reactivation of latent disease once an individual is immunosuppressed (52). The incidence of these infections in endemic areas was never fully elucidated because no surveillance systems have been in place. Therefore, it is also not known whether the incidence is declining in the era of HAART. Diagnosis of fungal infections in HIV-infected individuals remains problematic, despite published guidelines (53). No effective prophylaxis is available for HIV-infected persons who live in endemic areas, and limiting exposure seems to be the best way to prevent these infections. To evaluate the effectiveness of prophylaxis, surveillance in endemic areas will be needed. Also, better drugs are needed to treat these infections, given the toxicity of amphotericin B. These infections are probably never eradicated in immunocompromised persons, so lifetime therapy is also recommended. Whether this is necessary following immunological recovery with HAART should be investigated.

	AIRWAY DISEASE AND EMPHYSEMA

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An increasing body of evidence indicates that airway disease and emphysema are associated with HIV infection and opportunistic infections. In the Pulmonary Complications of HIV Infection Study, the incidence of acute bronchitis was increased in HIV-infected persons compared with control subjects, especially in those with less advanced HIV disease (54). Smaller series show that episodes of bronchitis tend to be recurrent, and sometimes progress to bronchiectasis (55). The recognition of an emphysema-like condition in the lungs of young HIV-infected smokers has implicated cytotoxic lymphocytes in the pathogenesis of emphysema. A pathogenic synergy between HIV infection and smoking has been identified by comparing lung lymphocyte counts and physiology in a cohort of HIV-infected individuals with those of age and smoking matched control subjects (56). Computed tomographic studies show that emphysema in HIV disease correlates with increased numbers of cytotoxic lymphocytes in the alveoli. Insights into the pathogenesis of emphysema in HIV-infected persons may also lead to a better understanding of emphysema in other populations.

The role of airway disease and emphysema in HIV-infected persons should be clarified: (1) How common are these disorders? (2) What factors increase the risk of developing obstructive airway diseases? These may include demographic groups, immune function, prior opportunistic infections, and the use of HAART. (3) What are the underlying mechanisms of emphysema in HIV-infected persons?

	NEOPLASMS

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Kaposi's sarcoma (KS), non-Hodgkin's lymphoma (NHL), and invasive carcinoma of the cervix are recognized as AIDS-defining conditions. However, other malignancies may also be more common in HIV-infected persons than in the general population. These include Hodgkin's lymphoma and cancers of the lung, penis, testicle, and soft tissues (57).

The development of Kaposi's sarcoma is now clearly linked to infection with human herpes virus type 8 (HHV8) (58). The underlying mechanisms are not known, but immunosuppression in HHV8-infected persons is presumed to lead to the expression of this malignancy. The use of HAART is associated with a reduction in the incidence of KS as an AIDS-defining illness, most likely as a result of immune reconstitution. The diagnosis of KS involving the lungs remains difficult. It is usually diagnosed by finding typical lesions on inspection of the airways during fiberoptic bronchoscopy, but identification of HHV8 DNA by PCR in bronchoalveolar lavage (BAL) fluid is a sensitive and specific marker of pulmonary KS (59). Involvement of the lung by lymphoma is still uncommon. However, HAART does not seem to reduce the incidence of NHL as much as it does the incidence of opportunistic infections. Primary effusional lymphoma is a newly recognized disorder, characterized by effusions without tumor masses in peritoneal, pleural, and pericardial spaces (60). This disorder may be associated with HHV8 or Epstein-Barr virus.

Questions for new investigations include the following: (1) How does HHV8 infection in the lung lead to malignancy? (2) What is the role of HHV8 PCR, as well as MRI and PET scanning in the diagnosis of pulmonary Kaposi's sarcoma? (3) What is the incidence of primary lung cancer in HIV-infected persons, and what factors predict its development?

	PULMONARY DISORDERS IN CHILDREN

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The rate of maternal-child transmission of HIV is declining with the use of antiretroviral therapy and avoidance of breast feeding. Nevertheless, several important pulmonary disorders still occur in HIV-infected children. A prospective multicenter study followed 600 infants of HIV-infected mothers, and found that the rate of decline for CD4⁺ T cells was the most important predictor of the development of PCP (61). Also, many children developed chronic radiographic changes (CRC) not associated with a diagnosed infection or malignancy. These children tended to have lower CD4⁺ T cell counts, and more than half resolved spontaneously. Unanswered questions include the following: (1) What is the nature of CRC, and what are the immunological changes associated with its resolution? (2) Does HAART affect the development and resolution of CRC? (3) Is there a relationship between CRC and viral agents like HIV or Epstein-Barr virus? (4) Do uninfected children born of HIV-infected mothers grow and develop normally? (5) What is the best way to screen for and diagnose tuberculosis in HIV-infected children?

	CONSIDERATIONS FOR CLINICAL STUDIES

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The use of HAART led to changes in the incidence and presentation of HIV-associated pulmonary diseases, and new disorders (such as emphysema and immune reconstitution syndromes) are recognized. A multicenter prospective cohort study, similar to the Pulmonary Complications of HIV Infection Study, would be the ideal vehicle to determine the prevalence, incidence, and types of lung diseases that occur in people in selected HIV transmission categories, and to describe the course and outcome of these disorders (62). Such a study could also identify demographic, clinical, immunological, virological, and other variables associated with the development of specific HIV-associated lung diseases, and describe the clinical variables associated with specific lung diseases at the time they are diagnosed. A study that spans several years would be needed to determine the significance and consequences of chronic pulmonary disorders like emphysema, and to investigate the influence of specific opportunistic events and comorbidities on the course of HIV disease. We may also encounter an era of HAART "failures," when immunological deterioration would increase the risk of developing opportunistic infections. A cohort followed prospectively would be uniquely poised to identify and to characterize such trends, particularly as they relate to the development of pulmonary diseases.

A study cohort could be recruited de novo, or a study could be designed to be nested within an existing multicenter effort. Regardless, its composition should reflect groups that are likely to have HIV infection currently, but who were not studied in detail previously. These include people who acquired HIV infection through injection drug use and heterosexual contact, people from the southern United States, women, and children. Any new studies of HIV-infected cohorts should be designed to cooperate with existing cohort studies to promote the efficient collection of data and use of resources. There should be a standardized protocol to assess the prevalence and incidence of different pulmonary disorders, along with serial studies of immune function, viral load, pulmonary function, and possibly high-resolution computerized tomography of the chest. In addition, clinical studies should be designed collaboratively with basic scientists to answer different sets of questions. When biological materials (serum, bronchoalveolar lavage fluid, biopsies) are collected, they should be shared with other investigators who are studying specific pathogens and mechanisms of disease.

	Footnotes

Correspondence and requests for reprints should be addressed to James M. Beck, M.D., Pulmonary and Critical Care Medicine (111G), Veterans Affairs Medical Center, 2215 Fuller Road, Ann Arbor, MI 48105-2300. E-mail: jamebeck{at}umich.edu

(Received in original form February 13, 2001 and accepted in revised form August 7, 2001).

Acknowledgments: The workshop participants acknowledge the pioneering work of Dr. John F. Murray in encouraging the systematic study of HIV-related pulmonary complications. The authors wish to thank the workshop participants, who provided the information and formulated the questions presented in this report. These participants were: James M. Beck, Ann Arbor, MI, and Mark J. Rosen, New York, NY, Co-Chairs; Veena B. Antony, Indianapolis, IN; Allen B. Clarkson, Jr., New York, NY; Arturo Casadevall, Bronx, NY; Ronald G. Collman, Philadelphia, PA; Waafa M. El-Sadr, New York, NY; Francis Gigliotti, Rochester, NY; Jeffrey L. Glassroth, Madison, WI; Allen G. Harmsen, Saranac Lake, NY; Laurence Huang, San Francisco, CA; Meyer Kattan, New York, NY; Jay K. Kolls, New Orleans, LA; Joseph Kovacs, Bethesda, MD; Andrew H. Limper, Rochester, MN; Bettina Lundgren, Copenhagen, Denmark; William J. Martin, II, Indianapolis, IN; Hannah H. Peavy, Bethesda, MD; George A. Sarosi, Indianapolis, IN; Neil W. Schluger, New York, NY; Gianpietro Semenzato, Padua, Italy; Judd E. Shellito, New Orleans, LA; Homer L. Twigg, III, Indianapolis, IN; Jeanne M. Wallace, Sylmar, CA; Peter D. Walzer, Cincinnati, OH; Dorothy White, New York, NY; and Mark D. Wewers, Columbus, OH.

Supported by the National Heart, Lung and Blood Institute, National Institutes of Health.

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