The changing spectrum of pulmonary disease in patients with HIV infection on antiretroviral therapy.

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EDITORIAL REVIEW
The changing spectrum of pulmonary disease in
patients with HIV infection on antiretroviral therapy
Jessica R. Grubba, Anne C. Moormanc, Rose K. Bakerd,
Henry Masurband the HOPS investigators?
AIDS 2006, 20:1095–1107
Keywords: AIDS, antiretroviral therapy, HIV, immune reconstitution, lung,
pulmonary disease
Introduction
ThepulmonarymanifestationsofHIVdiseasein2005can
bedividedintotwosetsofpresentations.For patientswho
do not have access to care, and who are not taking
antiretroviral or chemoprophylactic drugs, opportunistic
infections and neoplasms continue to occur. Pulmonary
disease caused by Streptococcus pneumoniae, Pneumocystis
carinii (now known as Pneumocystis jiroveci pneumonia;
PCP), Mycobacterium tuberculosis, lymphoma, and Kaposi’s
sarcoma present much as they did in the 1980s.
Management has improved in terms of new diagnostic,
therapeutic, and preventive strategies, as reviewed in
guidelines issued jointly by the National Institutes of
Health, Centers for Disease Control and Prevention, and
Infectious Disease Society of America (available online at
http://www.aidsinfo.nih.gov).
Patients in the United States who are taking combination
antiretroviral therapy (ART) and specific chemoprophy-
laxis demonstrate very different manifestations compared
with patients in the 1980s whowere receiving no ARTor
chemoprophylaxis. Some of these new manifestations are
caused by the augmented immune response that occurs
soon after ART is instituted, i.e. immune reconstitution
syndromes. Other new manifestations are facilitated by
prolonged patient survival at both high and low CD4
T-lymphocyte counts that result from ART. This
prolonged survival has allowed other processes to occur
after long periods of immunosuppression, e.g. neoplastic
processes such as lymphoma and perhaps various solid
tumors,andotherentitiessuchaspulmonaryhypertension.
This review will focus primarily on changing pulmonary
manifestations in the populations in the United States and
western Europe that have access to ART.
Current causes of pulmonary morbidity
and mortality in the USA:
epidemiological trends
The causes of mortality and morbidity in patients with
HIV have drastically changed over the past few years as a
result of the use of ART. Before the use of potent
antiretroviral drugs, pulmonary disorders caused an
enormous percentage of the overall mortality from
HIV. In one autopsy study from 1982 to 1988, all 75
patients had one or more pulmonary processes at the time
of death. Opportunistic infections were responsible for
76% of these pulmonary processes [1].
In a prospective multicenter trial investigating respiratory
complications from 1988 to 1994, HIV-infected patients
From theaNational Institutes of Allergy and Infectious Diseases, thebWarren G. Magnuson Clinical Center, National Institutes of
Health, Bethesda, MD, USA, thecNational Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention,
Atlanta, GA, USA, and thedCerner Corporation, Vienna, VA, USA.
?See acknowledgements section.
Correspondence and requests for reprints to Henry Masur, MD, Critical Care Medicine Department, Clinical Center, 9000
Rockville Pike, Bethesda, MD 20892, USA.
Tel: +1 301 496 9320; fax: +1 301 402 1213; e-mail: hmasur@cc.nih.gov
Received: 12 September 2005; revised: 15 November 2005; accepted: 30 November 2005.
ISSN 0269-9370 Q 2006 Lippincott Williams & Wilkins
1095

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had higher rates of both upper and lower respiratory
infections than HIV-uninfected controls [2]. Respiratory
infections were more common at all CD4 T-cell strata
than for HIV-uninfected controls. Over 98% of
respiratory complications were infectious [2]. The most
frequent respiratory complications were acute bronchitis,
bacterial pneumonia and PCP [2].
Since the introduction of ART, the overall mortality of
HIV-infected patients, and the mortality caused by
pulmonary processes, has dropped dramatically (Fig. 1).
An analysis of the Center for Disease Control and
Prevention’s HIV Outpatient Study (HOPS), in which
over 7300 patients have been followed in over 180 000
visits since 1993, found reductions in overall pulmonary
mortality and morbidity between 1994 and 2003 (Fig. 2,
Fig. 3, Fig. 4).
Data from the HOPS study also demonstrate that
pulmonary disease has declined as a cause of hospital-
ization for HIV-infected patients compared with other
causes (Fig. 2). The increasing percentage of hospitali-
zations for cardiac etiologies also highlights the need to
recognize the potential for chest complaints to represent
atherosclerotic disease. A large, prospective study
demonstrated that cardiovascular events increase with
each year of ART [3].
The rates and causes of hospitalizations associated with
pulmonary disease from the HOPS cohort have also
1096 AIDS 2006, Vol 20 No 8
0
2
4
6
8
10
12
Jun-03
2002 200120001999 1998 1997
1996
19951994
Year
Deaths per 100 person n years
0
10
20
30
40
50
60
70
80
90
Percentage of patients on HAART
Fig. 1. Mortality and HAART use over time in HIV Outpatient Study (HOPS) cohort, fourth quarter, 2003 update.
Deaths per 100 person-years; pulmonary deaths per 100 person-years;percentage of patients on HAART.
0
5
10
15
20
25
Percentage of total hospitalizations
2000--June 2003
1996--1999
1994--1995
Years
Fig. 2. Pulmonary, cardiovascular, and hepatic hospitaliz-
ations as percentage of total hospitalizations of HIV Out-
patient Study (HOPS) participants, fourth quarter, 2003
update.
Total pulmonary diagnoses;
diagnoses;
total hepatic diagnoses;
total cardiovascular
total renal diagnoses.
0
5
10
15
20
25
Percentage of total hospitalizations
2000--June 2003
1996--99
Years
1994--95
Fig. 3. Specific pulmonary processes as a percentage of total
hospitalizations in the HIV Outpatient Study (HOPS) cohort,
fourth quarter, 2003 update.
Pneumocystis jiroveci pneumonia (PCP);
monia;
asthma, bronchitis, chronic obstructive pulmonary
disease;
tuberculosis; lung cancer.
All pulmonary conditions;
non-PCP pneu-

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changed since the beginning of the HIV epidemic
(Fig. 3). PCP is responsible for a declining fraction of the
pulmonary processes requiring hospitalization compared
with other types of pulmonary pathology (Fig. 3). In
particular, total cases, hospitalizations and deaths from
PCP have decreased since the beginning of the epidemic
(Fig. 4, Fig. 5). Some non-infectious etiologies, in
contrast, have not decreased as significantly since the
widespread use of ART (Fig. 3). Other studies have
corroborated these findings [4–8]. Practitioners are thus
seeing a very different spectrum of disease presenting in
HIV-infected patients.
Antiretroviral therapy as a cause of
respiratory disease
There are four specific issues regarding ART that deserve
special attention regarding respiratory manifestations.
First, patients may present with unexplained tachypnea
and dyspnea in the absence of pulmonary pathology.
Clinicians must recognize that the tachypnea and dyspnea
may be caused by nucleoside-induced lactic acidosis [9].
This lactic acidosis can be reversed by discontinuing the
offending agents if the clinician recognizes the etiological
link before end-organ damage is irreversible.
Second, enfuvirtide, or T-20, has been associated with an
increased incidence of bacterial pneumonias [10]. The
biological basis of theobservation has not beenexplained.
There is little guidance available as to the need to stop
enfuvirtide if a bacterial pneumonia occurs in patients
taking this drug.
Third, abacavir can produce a hypersensitivity reaction,
with fever, rash, and myalgias. Patients can manifest
dyspnea (13%), cough (27%), and pharyngitis (13%) [11].
In approximately 20% of patients, pulmonary infiltrates
are seen [12]. If patients stop abacavir, and then restart it,
distributive shock and death can occur [13–15].
Clinicians thus need to consider this syndrome in their
differential diagnosis so that patients are not rechallenged
with abacavir, leading to disastrous consequences.
Fourth,
immunological reactions (immune reconstitution syn-
dromes) that can be clinically important, or life
threatening.
antiretroviralagentscanproduceintense
Changing spectrum of pulmonary disease and HIV: editorial review Grubb et al.1097
0
1
2
3
4
5
6
Deaths, hospitalizations, and total
cases per 100 person years
2000--June 20031996--1999
Years
1994--1995
Fig. 4. Pneumocystis jiroveci pneumonia deaths, hospitaliz-
ations, and total cases per 100 person-years, HIV Outpatient
Study (HOPS) cohort, fourth quarter, 2003 update.
Pneumocystis jiroveci pneumonia (PCP) cases;
talizations;
PCP deaths.
Total
PCP hospi-
Fig. 5. Chest computed tomography of Pneumocystis jiroveci pneumonia at initial diagnosis and after 20 days of therapy.

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Should antiretroviral therapy be initiated
or continued when patients develop
pulmonary disease?
When patients present with acute pulmonary disease,
healthcare practitioners must decide how to manage
ART.Initiating ARTcouldbebeneficialfor patientswith
acute pulmonary disease: improving immunological and
inflammatory responses could hasten recovery. However,
there are several reasons to consider withholding ART.
First, as described below, intense inflammatory responses
can exacerbate lung dysfunction. Second, antiretroviral
agents are all associated with toxicities. When patients
with acute pulmonary processes develop rash, liver
function abnormalities, or cytopenias, for example,
clinicians often have difficulty determining whether
the toxicity is caused by HIV, the acute pathogenic
process,thespecifictherapyfor thepulmonaryprocess,or
the newly prescribed ART.
Third, many antiretroviral agents cause drug interactions.
The protease inhibitors and the non-nucleoside reverse
transcriptase inhibitors have complex interactions with
the cytochrome p-450 system, making serum concen-
trations of concurrent drugs unpredictable, and making
their own pharmacokinetics difficult to anticipate.
Withholding antiretroviral agents may thus be a safer
option than initiating them in terms of avoiding
undesirable drug–drug interactions. If such patients are
administered ART and have unpredictable pharmacoki-
netics,irreversible HIVdrug resistance maybe promoted.
Stopping drugs doesnot promote resistance, and may be a
preferable strategy for patients who may not have
predictable absorption or kinetics. Such a strategy also
prevents drug toxicities and drug interactions from
becoming problems superimposed on the issues being
acutely managed.
In addition, most antiretroviral agents (except zidovudine
and enfuvirtide) are only available as oral agents.
Therefore, ifpatients areseriously ill,e.g.with respiratory
failure, they may not be able to absorb oral drugs
adequately. There are thus many reasons to adopt a
conservative strategy and withhold ART from patients
with acute respiratory processes, and to initiate or
continue ARTonly if there is clear and well thought out
benefit, and if the drug pharmacokinetics are carefully
considered.
Immune reconstitution syndrome
When ART is initiated, patients with HIV infection may
demonstrate new clinical manifestations as a result of
enhanced immune response, i.e. immune reconstitution
syndrome. Much of the current information about this
syndromeis basedonsmallcase series.Thetrueincidence
of immune reconstitution syndrome is not yet clear,
although it will presumably differ in various populations
depending on the pathogens the patient has been exposed
to and the degree of immune deficit when ART was
initiated.Itappearsthatthepatientsmostlikelytodevelop
this syndrome are patients with low CD4 T-cell counts
(e.g. < 50 cells/ml) and high viral loads (> 100 000
copies/ml) who have had a good virological response to
ART. At least one retrospective review found that 31.7%
of patients with known underlying opportunistic infec-
tions who received ART developed immune reconstitu-
tion syndrome [16].
The syndrome may manifest in the first few days after the
initiation of ARTwhen theviral load has fallen but before
the CD4 T-cell count has increased as a result of an
improvement in qualitative T-cell function asCD4 T cells
become less activated. This improved qualitative T-cell
functionleadstoamorerobustresponseagainstorganisms
or antigens [17].
The range and severity of manifestations is wide, as
indicated in Table 1. Some patients have clinically
apparent but trivial syndromes, such as the appearance of
an asymptomatic pulmonary nodule or mediastinal
lymph node, wheereas other patients develop extensive
organ dysfunction (Fig. 6). Many of the listed syndromes
are clearly related to recognized microbial pathogens.
However, some are related to tumors or to syndromes of
uncertain cause. As there is not a clear case definition for
immune reconstitution syndrome, it is difficult to
determine if all of the listed syndromes are true examples
of immune reconstitution syndrome, or if some are
unrelated coincidental occurrences.
There is no consensus or specific laboratory marker
regarding the optimal method for diagnosing these
immune reconstitution syndromes. When patients start-
ing ART develop new manifestations, they merit a
methodical evaluation to determine whether
syndrome represents a new, active, infectious process, a
new neoplastic process, or some other disease entity in
need of specific intervention. The distinction between a
new opportunistic infection and an immune reconstitu-
tion syndrome can be subtle. The histology of immune
and inflammatory response does not distinguish the acute
opportunistic infections from immune reconstitution
syndromes: responses to either may be composed of
lymphocytes and monocytes with or without granulomas
and necrosis. Negative cultures can be useful, although
there is inconsistency in the published literature,
emphasizing the lack of consistency in defining this
syndrome.
the
In the absence of data to direct the optimal management
approach, clinicians are left to make a clinical judgement
about when to use anti-infectious therapy, how long to
1098 AIDS 2006, Vol 20 No 8

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continue the therapy, and when to use non-steroidal anti-
inflammatory agents or corticosteroids. This decision
should be influenced by the severity of the syndrome, the
robustness of the virological and CD4 T-cell response to
ART, and the specific pathogen identified.
Pneumocystis jiroveci pneumonia
Immune reconstitution syndromes can occur in patients
with active infectious processes such as PCP [18,19]. In
one small case series, three patients presented with PCP
(median CD4 T-lymphocyte count of 26 cells/ml),
improved on conventional anti-PCP therapy, and started
ART therapy within 15–18 days of PCP diagnosis [18].
All three developed acute respiratory failure within a
median of 5 days (range 3–17 days) [18]. Histopatho-
logical findings of alveolar inflammatory infiltrate with a
few persistent Pneumocystis cysts were thought to be
consistent with an immunereconstitution syndrome [19].
How often this occurs when ART is initiated soon after
PCP is unknown, but there are enough such cases to
make concern over an immune reconstitution syndrome
one reason to consider delaying ART for many weeks
after PCP therapy. The optimal time to wait has not been
defined, i.e. enough time to diminish the likelihood that
an immune reconstitution syndrome will occur, but not
an excessive amount of time such that otheropportunistic
processes are likely to occur.
Mycobacterium tuberculosis
Immune reconstitution syndrome is especially common
in patients with untreated tuberculosis, or patients with
tuberculosiswhohaveinitiatedantituberculoustherapyin
the past few weeks or months [20]. In one prospective
study of patients with active tuberculosis treated with
antituberculosis therapy [21], 36% of HIV-infected
patients treated with ART versus 7% of HIV-infected
patients not taking ART developed clinical exacerbations
consistent with immune reconstitution syndromes after
the initiation of therapy. These syndromesoccurred 2–40
days after the initiation of ART. In another retrospective
study [22], transient radiographic worsening occurred
during the first 1–5 weeks of ART in 45% of 31 HIV-
positive patients who had received at least two initial
weeks of antituberculosis therapy. A similar series from
Spain reported transient exacerbations in 35% of 17
patients [23]. These exacerbations appeared to be
particularly likely in those patients who had a substantial
fall in HIV viral load (2.4 log drop in patients with
immune reconstitution syndrome versus 0.4 log10HIV-
RNA copies/ml in those without an exacerbation) and a
larger median increase in CD4 T-lymphocyte counts
Changing spectrum of pulmonary disease and HIV: editorial review Grubb et al. 1099
Table 1. Disease processes associated with immune reconstitution syndromes.
InfectiousNon-infectious
Mycobacterium tuberculosis
Cryptococcus neoformans
Mycobacterium avium complex
Mycobacterium leprae
Leishmania major
Cytomegalovirus
Varicella zoster virus
Herpes simplex virus
Human papillomavirus (Condyloma acuminata)
Pneumocystis jiroveci
Histoplasma capsulatum
Hepatitis B and C
JC virus (PML)
Bartonella henselae
Microsporidiosis
Toxoplasma gondii
Lymphoma
Sarcoidosis
Graves disease
Rheumatoid arthritis/vasculitis
Polymyositis
Systemic lupus erythematosis
Reiter’s syndrome
Alopecia universalis
Guillain–Barre ´ syndrome
Appendicitis
Cholecystitis
Eosinophilic folliculitis
Hyperergic/allergic reactions
PML, Progressive multifocal leukoencephalopathy.
Fig. 6. Chest computed tomography in a patient with fever
and chest pain after initiation of antiretroviral therapy found
to be cryptococcal infection.