Am J Respir Crit Care Med 2001.164:2120-2126.
NHLBI Workshop Summary
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
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 previ-
ous 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 combina-
tion 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 mortal-
ity (3–5). 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 un-
diminished as major causes of morbidity and mortality.
Our understanding of the basic mechanisms of HIV immu-
nology 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 pulmo-
nary defenses against infection and malignancy offer the pros-
pect of new therapeutic approaches to these complications of
HIV infection.
The purposes of this workshop were to summarize our cur-
rent knowledge of HIV-associated lung disorders in an era of
effective antiretroviral therapy, based on current investigation
(Received in original form February 13, 2001; accepted in final form August 7, 2001)
Workshop held October 25–26, 1999 in Washington, DC.
Supported by the National Heart, Lung and Blood Institute, National Institutes of
Health.
Correspondence and requests for reprints should be addressed to James M. Beck,
M.D., Pulmonary and Critical Care Medicine (111G), Veterans Affairs Medical Cen-
ter, 2215 Fuller Road, Ann Arbor, MI 48105-2300. E-mail: jamebeck@umich.edu
Am J Respir Crit Care Med Vol 164. pp 2120–2126, 2001
DOI: 10.1164/rccm2102047
Internet address: www.atsjournals.org
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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 knowl-
edge 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 re-
cent volume in the Lung Biology in Health and Disease series
provides a comprehensive overview of this field (8).
EFFECTS OF HIV IN THE LUNG
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 geneti-
cally 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 nec-
essary for fusion. CCR5 is the coreceptor used by macro-
phage-tropic strains, which can infect macrophages and lym-
phocytes 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 mac-
rophages is preferentially mediated by the CCR5 receptor,
although alveolar macrophages also express CXCR4 (10). Al-
though preferential coreceptor usage may contribute to com-
partmentalization of HIV in the lung, further investigation is
needed to determine the exact mechanisms by which HIV en-
ters 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 inter-
stitial and alveolar spaces. This “lymphocytic alveolitis” exists
in all stages of HIV infection, but is most pronounced in pa-
tients 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 de-
creased, recent investigations demonstrate that alveolar mac-
rophage products are responsible for T cell chemotaxis and
 Am J Respir Crit Care Med 2001.164:2120-2126.
NHLBI Workshop Summary
proliferation. These mediators include chemokines that are
CXCR3 ligands (IP-10) and interleukin-15 (IL-15). IL-15 me-
diates 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-reg-
ulate activation of peripheral blood CD8 T cells. Current in-
vestigations seek to determine whether HAART is associated
with a parallel down-regulation of cytokine expression, and re-
turn 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 de-
fects 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 compara-
ble 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-spe-
cific 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 en-
hance innate defense and to enhance specific immunity? These
investigations should be conducted in animal models first, to
determine whether their therapeutic benefits warrant even-
tual trials in humans. (2) What is the role of humoral immu-
nity in the lung in defense against bacterial and other patho-
gens? (3) What are the mechanisms by which different
pathogens accelerate HIV-related disease? Specifically, im-
proved 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 compartmentaliza-
tion, 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
HIV-infected persons who adhere to a regimen of HAART
are likely to enjoy suppression of HIV replication, and preser-
vation or improvement in immunological function, with a re-
duced incidence of opportunistic events and mortality. En-
hanced 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/l (15, 16). However, HAART does not ap-
pear to reduce the risk of all HIV-associated disorders, includ-
ing 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 inade-
quate 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, includ-
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2121
ing hyperlipidemia, insulin resistance, accelerated atheroscle-
rosis, changes in body habitus, and lactic acidosis (20).
When HAART inhibits viral replication, there is a corre-
sponding increase in the population of memory and naive T
cells, enhancement of lymphoproliferative responses, and in-
creased IL-2 receptor expression (21). These proinflammatory
effects probably underlie newly recognized syndromes associ-
ated with immunological reconstitution, some involving the
lung. Some patients develop a granulomatous disorder that re-
sembles sarcoidosis, whereas others with latent or active my-
cobacterial infections may develop fever, lymphadenopathy,
and opacities on the chest radiograph following immune resto-
ration with HAART (22, 23).
Among the questions that emerged from our discussion of
the impact of HAART on the lung were: (1) Which lung dis-
eases are most likely to occur in patients who take HAART, and
what are the epidemiologic and immunologic factors that influ-
ence 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 se-
vere opportunistic infections who are not taking HAART,
should clinicians start antiretroviral medications immediately, or
wait until the complicating infection is treated? (4) Which pro-
cesses cause the immune restoration syndromes that follow the
use of HAART? (5) How can the immune restoration syn-
dromes be distinguished from other inflammatory disorders, and
how should they be treated? (6) Do immune reconstitution syn-
dromes have an impact on pulmonary function, and on the risk
and course of subsequent HIV-associated disorders?
PNEUMOCYSTIS CARINII PNEUMONIA
Despite the declining incidence of PCP, it remains the most
common AIDS-defining indicator condition among opportu-
nistic 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 patho-
gen. Although the organism has been cultured successfully
for short periods, extended culture without mammalian feeder
cells has been unsuccessful. Recently, the use of specialized me-
dia 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-immu-
nosuppressed rats resulted in PCP (24). Because P. carinii ob-
tained from one species does not cause pneumonia when inoc-
ulated 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 trans-
mission is assumed but unproven. Nucleotide sequence varia-
tions 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 re-
infected with new strains, rather than reactivating latent infec-
tions (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 infec-
 Am J Respir Crit Care Med 2001.164:2120-2126.
2122 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
tion, such as vaccines (26). Serological studies show that hu-
mans 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 pro-
tective 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 im-
munization 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 immu-
nological responses. Thus, the major problems with develop-
ing 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 de-
termines host susceptibility to PCP in animal models, as these
cells are required to clear P. carinii, and their absence facili-
tates 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 in-
tact 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 mac-
rophage-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 pro-
liferative and cytokine responses when stimulated with P. cari-
nii. Several investigations suggest that cytokine responses dur-
ing 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 investi-
gated, but interactions among them seem critical to host de-
fense (33). Adenovirus vectors administered to the lung, which
increase or inhibit cytokine effects, could provide an alterna-
tive 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 patho-
genesis of PCP. The hydrophobic surfactant proteins SP-B and
SP-C regulate alveolar surface tension. In animal models, P. cari-
nii 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 con-
trast, 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 aggrega-
tion of the microbe, increasing its adherence to alveolar macro-
phages, but impairing phagocytosis and suppressing TNF- re-
sponses (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.
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VOL 164 2001
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, nei-
ther HAART nor specific prophylaxis is widely available.
It is still not known if there are differences in the presenta-
tion 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 de-
creased risk of developing P. carinii pneumonia (38). Accord-
ingly, recent guidelines emphasize that primary PCP prophy-
laxis may be discontinued under these circumstances (16).
Additionally, recent data indicate that secondary prophylaxis
may also be discontinued safely, provided a prolonged re-
sponse 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 ap-
proach results in a better outcome than the other, and some
institutions do not have the resources to obtain definitive di-
agnoses. Polymerase chain reaction identification of P. carinii
DNA is very sensitive, and may identify the organism nonin-
vasively. 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 en-
zyme 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 indi-
viduals (43), other investigators have not demonstrated any
increase in mortality.
The participants recommended several areas for future inves-
tigation 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 multi-
ple strains? (3) What are the essential mechanisms of immune re-
sponse to P. carinii in HIV-infected hosts, and do they remain lo-
calized within the lung or do they occur systemically? (4) How
does P. carinii modulate HIV replication? (5) Does initial diag-
nostic 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
The collision of the tuberculosis and HIV epidemics created a
devastating international public health crisis. Millions of
 Am J Respir Crit Care Med 2001.164:2120-2126.
NHLBI Workshop Summary
people around the world are infected with both HIV and My-
cobacterium tuberculosis, especially in underdeveloped coun-
tries. In Africa, tuberculosis may be the most common pulmo-
nary complication of HIV infection, with at least one-third of
all cases of tuberculosis occurring in patients with HIV infec-
tion. 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 opportu-
nistic 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 mortal-
ity 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 tubercu-
losis in AIDS patients in several ways. By improving cellular
immune function, clearance of mycobacteria may be acceler-
ated and the natural history of AIDS patients with tuberculo-
sis might be improved. On the other hand, complex drug inter-
actions between antituberculosis drugs (primarily rifamycins)
and antiretroviral agents (both protease inhibitors and nonnu-
cleoside reverse transcriptase inhibitors) have led to treat-
ment 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 per-
sons using HAART? (3) What is the optimal strategy for inte-
grating antituberculosis and antiretroviral treatment in pa-
tients with AIDS and tuberculosis? (4) Would other agents
(interferon, thalidomide, IL-12) be useful? (5) How can treat-
ment of tuberculosis be better monitored so as to predict re-
lapse? (6) Can latent tuberculous infection be identified in pa-
tients with HIV infection with cutaneous anergy?
BACTERIAL PNEUMONIA
Bacterial pneumonia is a common complication of HIV infec-
tion, occurring at all stages of HIV disease, but more fre-
quently 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 Le-
gionella) has not been studied systematically. The risk of de-
veloping bacterial pneumonia is higher in injection drug users
than in gay men, and increases with declining immune func-
tion, especially in smokers. The use of TMP-SMZ prophylaxis
* Recent reports of serious hepatotoxicity may limit the utility of short course reg-
imens.
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2123
for P. carinii pneumonia is associated with a substantial reduc-
tion in the risk of developing bacterial pneumonia, but vacci-
nation 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 sig-
nificantly, 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 re-
duce 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 mac-
rolide prophylaxis, and are they likely to be resistant to these
and other antibiotics? (4) How effective is pneumococcal vac-
cine in preventing pneumonia, bacteremia, and extrapulmo-
nary disease in patients who respond to HAART with immu-
nological reconstitution? Which factors predict effectiveness,
and how should vaccination be timed in relation to the admin-
istration of HAART?
VIRAL PNEUMONIA
Although the clinical significance of isolating cytomegalovirus
from respiratory specimens of HIV-infected persons has al-
ways 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 an-
swered include the following: (1) What is the incidence of viral
infections of the lung? (2) What is the role of Epstein–Barr vi-
rus in the development of lymphoma? (3) How does HIV in-
fection 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
Pulmonary histoplasmosis, blastomycosis, and coccidioidomy-
cosis occur in patients with HIV infection, either with progres-
sive 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. There-
fore, 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 expo-
sure seems to be the best way to prevent these infections. To
evaluate the effectiveness of prophylaxis, surveillance in en-
demic 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 immuno-
compromised persons, so lifetime therapy is also recom-
mended. Whether this is necessary following immunological
recovery with HAART should be investigated.
AIRWAY DISEASE AND EMPHYSEMA
An increasing body of evidence indicates that airway disease
and emphysema are associated with HIV infection and oppor-
tunistic infections. In the Pulmonary Complications of HIV
 Am J Respir Crit Care Med 2001.164:2120-2126.
2124 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Infection Study, the incidence of acute bronchitis was in-
creased in HIV-infected persons compared with control sub-
jects, especially in those with less advanced HIV disease (54).
Smaller series show that episodes of bronchitis tend to be re-
current, and sometimes progress to bronchiectasis (55). The
recognition of an emphysema-like condition in the lungs of
young HIV-infected smokers has implicated cytotoxic lym-
phocytes in the pathogenesis of emphysema. A pathogenic
synergy between HIV infection and smoking has been identi-
fied 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 tomo-
graphic studies show that emphysema in HIV disease corre-
lates 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 disor-
ders? (2) What factors increase the risk of developing obstruc-
tive airway diseases? These may include demographic groups,
immune function, prior opportunistic infections, and the use
of HAART. (3) What are the underlying mechanisms of em-
physema in HIV-infected persons?
NEOPLASMS
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 immunosuppres-
sion in HHV8-infected persons is presumed to lead to the ex-
pression 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 usu-
ally 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). In-
volvement of the lung by lymphoma is still uncommon. How-
ever, HAART does not seem to reduce the incidence of NHL
as much as it does the incidence of opportunistic infections. Pri-
mary effusional lymphoma is a newly recognized disorder,
characterized by effusions without tumor masses in peritoneal,
pleural, and pericardial spaces (60). This disorder may be as-
sociated 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 scan-
ning 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
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
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VOL 164 2001
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 ques-
tions 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 unin-
fected children born of HIV-infected mothers grow and de-
velop normally? (5) What is the best way to screen for and di-
agnose tuberculosis in HIV-infected children?
CONSIDERATIONS FOR CLINICAL STUDIES
The use of HAART led to changes in the incidence and pre-
sentation of HIV-associated pulmonary diseases, and new dis-
orders (such as emphysema and immune reconstitution syn-
dromes) are recognized. A multicenter prospective cohort
study, similar to the Pulmonary Complications of HIV Infec-
tion Study, would be the ideal vehicle to determine the preva-
lence, incidence, and types of lung diseases that occur in peo-
ple 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, viro-
logical, and other variables associated with the development
of specific HIV-associated lung diseases, and describe the clin-
ical 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 investi-
gate the influence of specific opportunistic events and comor-
bidities on the course of HIV disease. We may also encounter
an era of HAART “failures,” when immunological deteriora-
tion would increase the risk of developing opportunistic infec-
tions. 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 stud-
ied 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 collabo-
ratively with basic scientists to answer different sets of ques-
tions. When biological materials (serum, bronchoalveolar lav-
age fluid, biopsies) are collected, they should be shared with
other investigators who are studying specific pathogens and
mechanisms of disease.
Acknowledgment : 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 Ar-
bor, MI, and Mark J. Rosen, New York, NY, Co-Chairs; Veena B. Antony, In-
dianapolis, IN; Allen B. Clarkson, Jr., New York, NY; Arturo Casadevall,
Bronx, NY; Ronald G. Collman, Philadelphia, PA; Waafa M. El-Sadr, New
 Am J Respir Crit Care Med 2001.164:2120-2126.
NHLBI Workshop Summary
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, Syl-
mar, CA; Peter D. Walzer, Cincinnati, OH; Dorothy White, New York, NY;
and Mark D. Wewers, Columbus, OH.
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