Download The changing spectrum of pulmonary disease in patients with HIV

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 Masurb and the HOPS investigators!
AIDS 2006, 20:1095–1107
Keywords: AIDS, antiretroviral therapy, HIV, immune reconstitution, lung,
pulmonary disease
Introduction
The pulmonary manifestations of HIV disease in 2005 can
be divided into two sets of presentations. For patients who
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 chemoprophylaxis demonstrate very different manifestations compared
with patients in the 1980s who were 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, and other entities such as pulmonary hypertension.
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 the aNational Institutes of Allergy and Infectious Diseases, the bWarren G. Magnuson Clinical Center, National Institutes of
Health, Bethesda, MD, USA, the cNational Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention,
Atlanta, GA, USA, and the dCerner 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: [email protected]
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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AIDS 2006, Vol 20 No 8
12
90
Deaths per 100 person n years
70
8
60
50
6
40
4
30
20
2
Percentage of patients on HAART
80
10
10
0
0
1994
1995
1996
1997
1998
1999
2000
2001
2002
Jun-03
Year
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.
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].
Data from the HOPS study also demonstrate that
pulmonary disease has declined as a cause of hospitalization for HIV-infected patients compared with other
causes (Fig. 2). The increasing percentage of hospitalizations 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
25
Percentage of total hospitalizations
Percentage of total hospitalizations
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).
20
15
10
5
0
1994--1995
1996--1999
2000--June 2003
Years
Fig. 2. Pulmonary, cardiovascular, and hepatic hospitalizations as percentage of total hospitalizations of HIV Outpatient Study (HOPS) participants, fourth quarter, 2003
update. Total pulmonary diagnoses; total cardiovascular
diagnoses; total hepatic diagnoses; total renal diagnoses.
25
20
15
10
5
0
1994--95
1996--99
2000--June 2003
Years
Fig. 3. Specific pulmonary processes as a percentage of total
hospitalizations in the HIV Outpatient Study (HOPS) cohort,
fourth quarter, 2003 update. All pulmonary conditions;
Pneumocystis jiroveci pneumonia (PCP);
non-PCP pneumonia; asthma, bronchitis, chronic obstructive pulmonary
disease; tuberculosis; lung cancer.
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Changing spectrum of pulmonary disease and HIV: editorial review Grubb et al.
Deaths, hospitalizations, and total
cases per 100 person years
6
Antiretroviral therapy as a cause of
respiratory disease
5
4
3
2
1
0
1097
1994--1995
1996--1999
2000--June 2003
Years
Fig. 4. Pneumocystis jiroveci pneumonia deaths, hospitalizations, and total cases per 100 person-years, HIV Outpatient
Study (HOPS) cohort, fourth quarter, 2003 update. Total
Pneumocystis jiroveci pneumonia (PCP) cases; PCP hospitalizations; PCP deaths.
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.
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 the observation has not been explained.
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, antiretroviral agents can produce intense
immunological reactions (immune reconstitution syndromes) that can be clinically important, or life
threatening.
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 ART could be beneficial for patients with
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, the specific therapy for the pulmonary process, 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 concentrations 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 pharmacokinetics, irreversible HIV drug resistance may be promoted.
Stopping drugs does not 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, if patients are seriously 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 ART only 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
syndrome is based on small case series. The true incidence
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. It appears that the patients most likely to develop
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 infections who received ART developed immune reconstitution syndrome [16].
The syndrome may manifest in the first few days after the
initiation of ARTwhen the viral load has fallen but before
the CD4 T-cell count has increased as a result of an
improvement in qualitative T-cell function as CD4 T cells
become less activated. This improved qualitative T-cell
function leads to a more robust response against organisms
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 starting ART develop new manifestations, they merit a
methodical evaluation to determine whether the
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 reconstitution 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.
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
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Changing spectrum of pulmonary disease and HIV: editorial review Grubb et al.
1099
Table 1. Disease processes associated with immune reconstitution syndromes.
Infectious
Non-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–Barré syndrome
Appendicitis
Cholecystitis
Eosinophilic folliculitis
Hyperergic/allergic reactions
PML, Progressive multifocal leukoencephalopathy.
continue the therapy, and when to use non-steroidal antiinflammatory 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]. Histopathological findings of alveolar inflammatory infiltrate with a
Fig. 6. Chest computed tomography in a patient with fever
and chest pain after initiation of antiretroviral therapy found
to be cryptococcal infection.
few persistent Pneumocystis cysts were thought to be
consistent with an immune reconstitution 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 other opportunistic
processes are likely to occur.
Mycobacterium tuberculosis
Immune reconstitution syndrome is especially common
in patients with untreated tuberculosis, or patients with
tuberculosis who have initiated antituberculous therapy in
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 syndromes occurred 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 HIVpositive 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 log10 HIVRNA copies/ml in those without an exacerbation) and a
larger median increase in CD4 T-lymphocyte counts
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AIDS 2006, Vol 20 No 8
(71 cells/ml for those with a clinical exacerbation versus
51 cells/ml in those without an apparent immune
reconstitution syndrome).
The timing of ART initiation also affects the incidence of
immune reconstitution reactions. In a retrospective study
[24], seven out of 13 subjects starting ART less than 6
weeks after starting tuberculosis therapy developed
immunological reactions, whereas only one out of 15
subjects developed such reactions when starting after a
delay of more than 6 weeks.
For physicians treating patient populations in which
tuberculosis is common, the potential for immune
reconstitution syndromes poses a dilemma. It would
clearly be desirable to start ART promptly to enhance the
response to antituberculosis therapy and to prevent other
opportunistic infections from occurring. Until larger
studies are completed, there are no data-driven recommendations regarding when to start antiretroviral therapy
in the face of active tuberculosis. However, one
reasonable approach would be if a patient is simultaneously diagnosed with tuberculosis and HIV, the
antituberculosis therapy should be started first. Most
clinicians delay the initiation of ART for 4–8 weeks after
the start of antituberculosis therapy [25]. Patients with
lower CD4 T-lymphocyte counts should be considered
for early therapy with ART. Patients with higher CD4 Tlymphocyte counts should delay therapy; those with CD4
T-lymphocyte counts greater than 200 cells/ml can
probably defer until antituberculosis therapy is completed
[25,26].
Immune reconstitution syndrome and paradoxical reactions can also be associated with other mycobacterial
infections, such as focal pulmonary Mycobacterium avium
complex (MAC) infection [27] (Fig. 7). Immune
reconstitution syndromes may occur in patients with
latent MAC, i.e. those who have never had a clinically
apparent syndrome as a result of MAC. In contrast, as
noted above, it would appear that immune reconstitution
syndromes caused by Mycobacterium tuberculosis occur
predominantly in those who have recently had active
infection.
Neoplastic complications of HIV disease
In the United States and western Europe, Kaposi’s
sarcoma has been a hallmark cancer for HIV-infected
individuals; however, the incidence has markedly
decreased with the use of ART [28]. In the Swiss HIV
Cohort study, non-users of ART had a much higher
standardized incidence ratio (SIR) of Kaposi’s sarcoma
than users of ART [SIR 239, 95% confidence interval
(CI) 211–270 versus SIR 25.3, 95% CI 10.8–50.1] [29].
The EuroSIDA study, with over 9000 participants,
demonstrated similar findings; the incidence of Kaposi’s
sarcoma among patients receiving ART decreased with
the increasing time since the initiation of ART [28].
Overall, there was an estimated 39% reduction (95% CI
35–43%, P < 0.0001) in the incidence of Kaposi’s
sarcoma between 1994 and 2003 in the EuroSIDA
population [28].
In patients with pulmonary Kaposi’s sarcoma, the mean
CD4 T-lymphocyte count is 19 cells/ml, although the
range was 0–520 cells/ml [30]. In one series, only 5% of
patients with Kaposi’s sarcoma had a CD4 T-lymphocyte
count greater than 200 cells/ml, emphasizing that most
cases occur at low CD4 T-cell counts [30].
Patients with pulmonary Kaposi’s sarcoma generally
present with cough, shortness of breath, and chest pain.
Fever also occurs, probably because of blood in the air
spaces. In a series of symptomatic pulmonary Kaposi’s
sarcoma, all 30 patients (100%) presented with dyspnea,
and 24 (80%) with cough. Chest pain was noted in 14
patients (47%), hemoptysis in nine patients (30%), and
fever in four patients (13%) [31].
Most patients have mucocutaneous involvement. In one
series, only 15.5% of 142 patients had isolated lung
involvement without mucocutaneous involvement [30].
Fig. 7. Chest computed tomography in a patient with dysphagia from mediastinal lymphadenopathy after initiation of
antiretroviral therapy found to be from Mycobacterium
avium complex. Photo with permission from Gary Decker,
MD.
Chest X-rays typically show patchy infiltrates; unilateral
effusions are sometimes present. In one case series, 24
patients (80%) had pleural effusions, 27 (90%) had a
diffuse interstitial pattern and 11 (37%) had nodules on
the chest radiograph [31]. Chest computed tomography
scans usually demonstrate nodules or consolidation in a
peribronchovascular distribution [32] (Fig. 8).
A diagnosis of Kaposi’s sarcoma is often suspected because
of the cutaneous or endobronchial lesions. The red or
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Changing spectrum of pulmonary disease and HIV: editorial review Grubb et al.
1101
the rate of NHL decreased from 61.8 per 1000 reported
AIDS cases in 1988 to 35.9 per 1000 AIDS cases in 2000.
Another study from Australia [42], found a decrease in the
incidence of NHL from 1994–1996 to 1996–1998 from
7.5 to 4.3 cases per 1000 person-years. Therefore, for
systemic NHL, the incidence appears to be decreasing.
However, given the longer duration of patient survival,
the lifetime risk of systemic lymphoma may not be
declining as impressively.
Fig. 8. Chest computed tomography of Kaposi’s sarcoma.
purple nodules are quite characteristic and are not easily
mistaken for other pathological manifestations [31–33].
A bloody pleural effusion is also suggestive [33]. Cytology
is not useful for establishing the diagnosis. Transbronchial
biopsy is also not helpful because the crush artifact can
easily be confused with the spindle cells of Kaposi’s
sarcoma. A definitive diagnosis usually depends on videoassisted biopsy or open-lung biopsy.
For patients with Kaposi’s sarcoma, the median survival in
the pre-ART era was approximately 6 months, although
patients often died of processes other than Kaposi’s
sarcoma [31]. With ARTand combination chemotherapy
regimens, such as those with liposomal doxorubicin,
bleomycin, or vincristine, the response rates have
improved [34–36]. ART therapy is also associated with
a markedly reduced risk of death (hazard ratio 0.09) in
HIV-positive patients with pulmonary Kaposi’s sarcoma
receiving chemotherapy [37]. There is thus a reason for
cautious optimism in offering chemotherapy to patients
with clinically important Kaposi’s sarcoma using current
treatment modalities.
Immune reconstitution syndromes have been reported in
association with Kaposi’s sarcoma treated with ART
[38,39].
Non-Hodgkin’s lymphoma
Non-Hodgkin’s lymphoma (NHL) has been the second
most common HIV-associated malignancy. Most studies
indicate a decrease in the incidence of systemic NHL in
the past few years since the introduction of ART [29,40–
44]. In the Swiss HIV Cohort study, the risk of
developing NHL, compared with the general population,
was much higher for non-ART users (SIR 99.3, 95% CI
85.8–114) compared with patients on ART (SIR 24.2,
95% CI 15.0–37.1) [29]. In one retrospective study [40],
NHL occurs in patients at all CD4 T-lymphocyte counts,
although the relative risk of NHL is higher at lower
CD4 T-lymphocyte counts [45]. The median CD4 Tlymphocyte count has been noted to be lower in patients
with pulmonary involvement than in those without such
involvement. In a small series of patients with pulmonary
involvement [46], the mean CD4 T-lymphocyte count
was 67 cells/ml.
Most patients with pulmonary NHL present with cough
(71%) and dyspnea (63%) [46]. The chest radiographs
usually demonstrate isolated or multiple peripheral nodules
[46,47]. In a case series of 38 patients [46], pleural effusions
occurred in 68% and thoracic lymphadenopathy in 54% of
the cases. Infiltrates and masses with cavitations have also
been reported [47]. There are no major differences in the
diagnostic approach to suspected NHL in patients with
HIV compared with patients without HIV: a diagnosis of
non-Hodgkin’s disease may be made with a pleural
cytological study, transbronchial biopsy, percutaneous
transthoracic needle biopsy or open-lung biopsy, whereas
bronchial brushings are not usually helpful [46–48].
The most important change in the ART era has been the
recognition of the importance of aggressive chemotherapy treatment for HIV-positive patients. During the preART era, patients were often treated with a conservative
low-dose chemotherapy regimen. More recently, treatment for HIV-infected patients has approximated regimens for high-grade NHL of HIV-non-infected
populations [49–51].
As chemotherapy has become more successful, other
aggressive modalities of therapy for lymphoma are being
assessed. Peripheral blood stem cell transplantation is
being investigated in some centers [52–54].
There has been some debate as to whether to continue
ART during chemotherapy. In one study of 39 patients
[55], holding antiretroviral therapy while patients underwent chemotherapy with EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin)
was associated with high response rates, with complete
remission in 74% of patients, but tolerable toxicities. The
median CD4 T-lymphocyte cell count returned to the
baseline value in the 30 patients followed within 12
months after therapy [56]. Another trial demonstrated
similar response rates with simultaneous ARTand CHOP
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AIDS 2006, Vol 20 No 8
complete remission were treated with both chemotherapy and ART, and one patient treated with ART alone
also had a complete response [59]. In that series, the five
patients treated before ART had a much poorer survival
rate (survival time range 0.5–4.5 months) compared with
those treated after ART therapy (survival time range 1–
35 months) [59]. Another series of 28 patients with
primary effusion cell lymphoma [60] found that the
absence of ART before primary effusion cell lymphoma
diagnosis was an independent predictor of shorter survival
by multivariate analysis (hazard ratio 3.26, 95% CI 1.14–
9.34). Several different chemotherapy regimens have
been attempted [60]. Rituximab has also been used [62].
Multicentric Castleman’s disease
Fig. 9. Chest radiograph of primary effusion cell lymphoma.
(cyclophosphamide, hydroxydaunomycin, oncovin and
prednisone) compared with suspending ART during
chemotherapy [56]. Some toxicities such as anemia and
the need for colony-stimulating factor support were
greater in patients receiving antiretroviral agents with
chemotherapy; however, opportunistic infection rates
decreased compared with patients not on concomitant
antiretroviral therapy. Protease inhibitor use may change
the pharmacokinetics of chemotherapy, and the impact of
drug interactions must be carefully considered [57].
Regardless of whether ART is continued during
chemotherapy, it should be re-instituted after chemotherapy is completed [58].
Prophylaxis against opportunistic infections based on
CD4 T-cell thresholds is an important component of
therapy for these patients.
Primary effusion lymphoma
Primary effusion cell lymphoma is a human herpes virus 8
(HHV-8)-associated B-cell lymphoma, which occurs in
body cavities. Pleural effusions are the most common
manifestations; peritoneal and pericardial effusions also
occur [59,60] (Fig. 9). At the time of presentation,
patients’ CD4 T-lymphocyte cell counts are usually less
than 150 cells/ml, but can range from 2 to 291 cells/ml
[59,60]. Primary effusion lymphoma is diagnosed by
cytology or biopsy [61]. The detection of HHV-8 by insitu hybridization or in-situ polymerase chain reaction
provides supportive evidence for this diagnosis [61].
Primary effusion lymphoma has a very poor prognosis. It
is not yet clear what therapy is most likely to be effective.
In one series of 11 patients, two of the three patients with
Multicentric Castleman’s disease (MCD) is an HHV-8associated lymphoproliferative disorder associated with
IL-6 dysregulation [63,64]. MCD presents at any CD4 Tlymphocyte count: patients have presented with counts
ranging from 56 to 1086 cells/ml [65]. Patients can
present with fever and cough and interstitial infiltrates,
often with polyadenopathy, splenomegaly, hepatomegaly,
and weight loss [63]. Pulmonary imaging may demonstrate diffuse mediastinal lymphadenopathy, as well as
pleural effusions and bronchovascular nodularity [66].
Diagnosis can be difficult to establish, but is usually
established by lymph node or bone marrow biopsy in
conjunction with HHV-8 testing [63–66].
MCD has been treated with a variety of regimens,
including various combinations of zidovudine, interferon, ganciclovir, cidofovir, and thalidomide [67–70].
ART appears to improve survival. In a case series of seven
patients, the mean survival was 48 months, compared
with a historical pre-ART median survival of 14 months
[63,64]. Anti-CD20 monoclonal antibody has also been
successful in inducing prolonged remission, possibly by
decreasing the IL-6 and TNF-a levels [71–74].
Patients with MCD often also develop NHL as well as
other HHV-8-related diseases [75]. In one prospective
study of 60 patients with HIV and MCD [75], 14 patients
developed NHL 0–76 months after the diagnosis of
MCD, with a median follow-up of 20 months. MCD is
also associated with a high rate of concurrent Kaposi’s
sarcoma [64,66]. Therefore, much needs to be learned
about the ultimate prognosis of patients with this disorder,
and the optimal approach to therapy.
Bronchogenic carcinoma
Patients with HIV infection may have an increased risk
of bronchogenic carcinoma [5–8,76–87]. When a
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Changing spectrum of pulmonary disease and HIV: editorial review Grubb et al.
population of 7893 HIV-infected patients in Chicago was
compared with general population databases, the adjusted
relative risk of lung cancer for HIV-infected patients was
3.63 for the years 1992–2002 [76]. Another study of
26 861 HIV-infected patients found an observed/
expected ratio of 6.5 for primary lung cancer for the
years 1990–1995 [8]. What factors other than HIV might
have contributed to this increased risk, such as an
increased use of tobacco, have not been carefully assessed
[76].
Bronchogenic carcinoma has occurred at CD4 Tlymphocyte counts ranging from 3 to 835 cells/ml
[77,78]. There is thus not a definite association between
CD4 T-lymphocyte counts and occurrence. It is also not
clear what effect ART has on the epidemiology of lung
cancer. In one prospective database comparing HIVinfected patients with the general population in southeast England [79], there was a dramatic increase in the
incidence of HIV-related lung cancer from 0.8 per 10 000
patient years (95% CI 0.2–3.2) in the pre-ART period to
6.7 per 10 000 patient years (95% CI 3.1–13.9) in the
post-ART period (post-1996). The relative risk of HIVinfected patients in the post-ART period was 8.93 (95%
CI 4.92–19.98) compared with the control population
[79]. Another retrospective study comparing HIVinfected patients in France with the observed rate in
the French general population [80], found a twofold
increase in the risk of lung cancer between the pre-ART
period (1992–1995) and the ARTera (1996–1999) (SIR
2.05, 95% CI 1.62–2.65). Strikingly, in the same study,
the risk for women increased from 1992–1995 (SIR 1.08,
95% CI 0.01–5.98) to 1996–1999 (SIR 6.59, 95% CI
3.40–11.52) [80]. However, a similar study from the
United States [44] found an increased risk of lung cancer
compared with the general control population in HIVinfected women both pre-ART (SIR 6.8, 95% CI 0.8–
18.9 from 1994 to 1995) and post-ART (SIR 6.2, 95% CI
2.3–12.1 from 1997 to 2001).
A large percentage of HIV-infected patients with
bronchogenic cancer smoke tobacco, similar to the
non-infected population with lung cancer [78,81–83].
Some experts have speculated that smoking accounts for
the risk of lung cancer [76]. Adenocarcinoma has been
the most common histology accounting for 36–80% of
cases [8,77,78,84–86]. The mean or median age at
diagnosis of bronchogenic carcinoma for HIV-positive
patients is much younger (38–49 years) than expected in
HIV-negative patients [77,86]. Survival has been noted to
be significantly shorter for HIV-infected patients compared with HIV-uninfected individuals with similar stages
of lung cancer [77,85,87].
No literature has suggested that therapy for HIVinfected patients with bronchogenic carcinoma should
differ from that for non-HIV-infected individuals. It
would seem logical to treat patients with ART as well as
1103
chemotherapy, possibly holding ART during the period
of active chemotherapy administration, as with lymphoma above.
In a large retrospective study from New York City [88],
the 24-month survival in patients with lung cancer and
HIV did not significantly change from the time periods
1980–1989 (5%) to 1996–2000 (10%) (death hazard 2.2
and 2.5, respectively). In comparison, the 24-month
survival for a non-HIV-infected population was much
higher at 31% [88].
Pulmonary hypertension
There is an increasing suspicion that pulmonary
hypertension is overrepresented in patients with HIV
infection. It has been difficult to dissect out other risk
factors such as methamphetamine abuse and chronic
obstructive pulmonary disease. Therefore, until large
prospective studies with appropriate controls are completed, the role of HIV in causing or predisposing to
pulmonary hypertension is unclear.
The incidence of pulmonary hypertension in HIVinfected patients is estimated to be 0.5%, compared with
0.02% in the general population [89–91]. Pulmonary
hypertension occurs at all CD4 T-lymphocyte counts
[89–91]. In 82% of 131 cases reviewed from the literature,
HIV was the sole identified cause of the pulmonary
hypertensive occlusive disease [92].
It is not clear what the clinical importance of pulmonary
hypertension is in this setting. There is yet no evidence that
patients are dying as a result of pulmonary hypertension,
but what will happen as patients live longer will have to be
determined [91–95]. The pathological findings are similar
to primary pulmonary hypertension, and are generally
plexogenic pulmonary arteriopathy and occasionally
thrombotic pulmonary arteriopathy and pulmonary venoocclusive disease [89,94,96,97].
In one small prospective study of long-term echocardiographic follow-up in 13 patients [91], the right
ventricular systolic pressure decreased by 3.2 mmHg in
six patients treated with either zidovudine or didanosine,
and increased by 19 mmHg in the seven untreated
patients (P ¼ 0.026). A retrospective analysis of 47
patients found a decrease in right ventricular systolic
pressure of 21 mmHg in 14 patients receiving HAART
compared with an increase of 25 mmHg in nine patients
not receiving ART [98]. In that analysis, the use of
HAART also significantly decreased mortality by multivariable Cox regression analysis (hazard ratio 0.075, 95%
CI 0.02–0.28, P < 0.001) [98]. Another series of 82
patients with HIV and primary pulmonary hypertension
[99] also found that combination antiretroviral therapy,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1104
AIDS 2006, Vol 20 No 8
including the use of a protease inhibitor, was associated
with improved survival on univariate analysis; however,
this was not validated in multivariate analysis or in
subgroup populations with concurrent epoprostenol.
Another retrospective study [100] found a higher risk of
pulmonary artery hypertension in patients treated with
ART (including a protease inhibitor) than in patients
treated with ART (with only one or two nucleoside
reverse transcriptase inhibitors; 2.0 versus 0.7%,
P ¼ 0.048). Whether HIV is directly linked to pulmonary hypertension, and whether effective and durable ART
therapy will reduce the morbidity potentially caused by
this condition remains to be determined.
A prominent report linked pulmonary hypertension in
HIV-uninfected patients to HHV-8 [101]. This was
particularly intriguing because HHV-8 is sexually
transmitted, and causes neoplastic disease in HIV-infected
patients (Kaposi’s sarcoma, multicentric Castleman’s
syndrome, and primary effusion cell lymphoma). This
observation needs to be confirmed before a link between
HHV-8 and pulmonary hypertension is definitively
established [102].
Conclusion
Over the next decade in the United States and western
Europe, as more patients have access to ART and
chemoprophylaxis, the pulmonary manifestations of HIV
will continue to evolve. How much impact pulmonary
hypertension, neoplastic processes such as lymphoma
and bronchogenic carcinoma, and atherosclerosis will
have on morbidity and mortality remains to be defined.
An unfortunate reality of the healthcare system in the
United States is that there will continue to be large
numbers of individuals who do not know they have HIV,
or who cannot access care. Healthcare providers will thus
continue to play an important role in managing
pulmonary complications in patients receiving ART
and in those who present without previous therapeutic
intervention.
Acknowledgements
The HIV Outpatient Study (HOPS) Investigators: The
HOPS Investigators include the following investigators
and sites: Anne C. Moorman, Tony Tong, John T.
Brooks, and Kate Buchacz, Division of HIV/AIDS
Prevention, National Center for HIV, STD, and TB
Prevention (NCHSTP), Centers for Disease Control and
Prevention (CDC), Atlanta, GA; Kathleen C. Wood,
Rose K. Baker, Carl Armon, James T. Richardson,
Cerner Corporation., Vienna, VA; Frank J. Palella, Joan
S. Chmiel, Katharine A. Kirby, Janet Cheley, and Tiffany
Murphy, Feinberg School of Medicine, Northwestern
University, Chicago, IL; Kenneth A. Lichtenstein,
University of Colorado Health Sciences Center, Denver,
CO; Kenneth S. Greenberg, Benjamin Young, Barbara
Widick, Cheryl Stewart, and Peggy Zellner, Rose
Medical Center, Denver, CO; Bienvenido G. Yangco,
Kalliope Halkias, and Arletis Lay, Infectious Disease
Research Institute, Tampa, FL; Douglas J. Ward and
Charles A. Fiorentino, Dupont Circle Physicians Group,
Washington, DC; Jack Fuhrer, Linda Ording-Bauer, Rita
Kelly, and Jane Esteves, State University of New York
(SUNY), Stony Brook, NY; Ellen M. Tedaldi, Ramona
A. Christian, and Linda Walker-Kornegay, Temple
University School of Medicine, Philadelphia, PA; Joseph
B. Marzouk, Roger T. Phelps, and Mark Rachel, Adult
Immunology Clinic, Oakland, CA; Silver Sisneros and
Mark Rachel, Fairmont Hospital, San Leandro, CA;
Richard M. Novak, Jonathan P. Uy and Andrea
Wendrow, University of Illinois at Chicago, Chicago, IL.
Sponsorship: This work was supported by intramural
National Institutes of Health (NIH) funds from the
Critical Care Medicine Department, Clinical Center,
NIH and intramural funds from the Centers for Disease
Control and Prevention.
The authors have no financial, consultant, institutional,
or other relationships that would constitute a conflict of
interest. The findings and conclusions in this paper are
those of the authors and do not necessarily represent the
views of the National Center for HIV, STD, and TB
Prevention, Centers for Disease Control and Prevention.
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