HIV-Associated Pneumocystis Pneumonia
Laurence Huang1,2, Adithya Cattamanchi1, J. Lucian Davis1, Saskia den Boon3, Joseph Kovacs4, Steven Meshnick5,
Robert F. Miller6,7, Peter D. Walzer8, William Worodria9, and Henry Masur4, on behalf of the International
HIV-associated Opportunistic Pneumonias (IHOP) Study and the Lung HIV Study
1Division of Pulmonary and Critical Care Medicine and2HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of
California, San Francisco, California;3Makerere University - University of California San Francisco Research Collaboration, Kampala, Uganda;4Critical
Care Medicine Department, National Institutes of Health, Bethesda, Maryland;5Department of Epidemiology and Department of Microbiology and
Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina;6Centre for Sexual Health and HIV Research, Research
Department of Infection and Population Health, Division of Population Health, University College London, London, United Kingdom;7Department
of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom;8Veterans Affairs Medical Center
and Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio;9Department of
Medicine, Mulago Hospital and Makerere University and Makerere University - University of California San Francisco Research Collaboration,
During the past 30 years, major advances have been made in our
understandingof HIV/AIDSandPneumocystis pneumonia (PCP),but
significant gaps remain. Pneumocystis is classified as a fungus and is
host-species specific, but an understanding of its reservoir, mode of
transmission, and pathogenesis is incomplete. PCP remains a fre-
quent AIDS-defining diagnosis and is a frequent opportunistic
pneumonia in the United States and in Europe, but comparable
with HIV/AIDS are limited. Pneumocystis cannot be cultured, and
bronchoscopy with bronchoalveolar lavage is the gold standard
procedure to diagnose PCP, but noninvasive diagnostic tests and
biomarkers show promise that must be validated. Trimethoprim-
sulfamethoxazole is the recommended first-line treatment and
prophylaxis regimen, but putative trimethoprim-sulfamethoxazole
drug resistance is an emerging concern. The International HIV-
associated Opportunistic Pneumonias (IHOP) study was established
to address these knowledge gaps. This review describes recent
advances in the pathogenesis, epidemiology, diagnosis, and man-
agement of HIV-associated PCP and ongoing areas of clinical and
translational research that are part of the IHOP study and the
Longitudinal Studies of HIV-associated Lung Infections and Compli-
cations (Lung HIV).
Keywords: acquired immune deficiency syndrome; HIV; Pneumocystis;
Pneumocystis pneumonia; dihydropteroate synthase
The pre-eminence of Pneumocystis pneumonia (PCP) as a her-
ald of the HIV/AIDS epidemic and as a major cause of HIV-
associated morbidity and mortality has focused considerable
attention and resources on this previously uncommon opportu-
nistic pneumonia. Over the past 30 years, major advances have
been made in our understanding of HIV/AIDS and PCP, but
significant gaps remain. This review describes recent advances
in the pathogenesis, epidemiology, diagnosis, and management
of HIV-associated PCP and ongoing areas of clinical and
translational research that are part of the International HIV-
associated Opportunistic Pneumonias (IHOP) study and the
Longitudinal Studies of HIV-associated Lung Infections and
Complications (Lung HIV).
BACKGROUND AND PATHOGENESIS
Pneumocystis is an opportunistic eukaryote that is classified as a
fungus (1). The genus Pneumocystis infects mammalian species
and is host-species specific. Infection in humans is caused by
Pneumocystis jirovecii; Pneumocystis carinii currently refers to
one of the Pneumocystis species that infects rats. Humans are
a reservoir of P. jirovecii, although the exact relationship is
incompletely understood, and environmental reservoirs have
also been suggested. Primary infection occurs early in child-
hood, likely manifesting as a self-limited upper respiratory tract
illness (2, 3), and the majority of children throughout the world
have detectable antibodies by 2 to 4 years of age (4–6). Studies
in animals demonstrate that Pneumocystis is transmitted from
animal to animal via an airborne route. Animal studies also
demonstrate that animals carrying Pneumocystis develop PCP
after being immunosuppressed (reactivation of latent infection)
and that immunocompromised Pneumocystis-free animals de-
velop PCP after exposure to immunocompromised animals
infected with Pneumocystis (new exogenous infection) and to im-
munocompetent animals that are colonized with Pneumocystis.
Numerous reports of cluster outbreaks of PCP among different
immunocompromised populations support person-to-person trans-
mission and recent acquisition of infection in the pathogenesis of
PCP in humans. In addition, molecular typing of P. jirovecii
genetic loci from persons with PCP has demonstrated the
diversity of P. jirovecii infecting humans and has provided
molecular evidence in support of interhuman transmission and
recent infection (7–9).
Before the HIV/AIDS epidemic, PCP was uncommon. From
November 1967 to December 1970, a total of 194 patients were
diagnosed with PCP and reported to the Centers for Disease
Control, which was the sole supplier of pentamidine isethionate,
the only treatment for PCP at that time (10). In 1981, two
reports of PCP in 15 previously healthy men who had sex with
other men and/or who were injection drug users heralded the
onset of the HIV/AIDS pandemic (11, 12) that currently affects
an estimated 33.4 million people worldwide and has caused an
estimated 25 million deaths (13).
PCP is a frequent AIDS-defining diagnosis in the United
States and in Europe. At its peak in the United States, PCP was
the leading AIDS-defining diagnosis and was responsible for
more than 20,000 new AIDS cases per year from 1990 to 1993
(14–17). In Europe, PCP was the leading AIDS-indicator dis-
ease in the World Health Organization 2008 HIV/AIDS Sur-
veillance in Europe Report, accounting for 16.4% of the AIDS
(Received inoriginal form September 30, 2010; acceptedinfinal form November 26,2010)
Supported by National Heart Lung and Blood Institute grants HL087713,
HL090335, and HL090335-02S1.
Correspondence and requests for reprints should be addressed to Laurence
Huang, M.D., HIV/AIDS Division, Ward 84, San Francisco General Hospital, 995
Potrero Avenue, San Francisco, CA 94110. E-mail: firstname.lastname@example.org
Proc Am Thorac Soc
Internet address: www.atsjournals.org
Vol 8. pp 294–300, 2011
cases diagnosed in adults and adolescents that year (18). PCP
remains a leading cause of AIDS in North American and
European HIV cohorts. In the Antiretroviral Therapy Cohort
Collaboration, a network comprised of 15 North American and
European cohorts established in 2000, PCP was the second most
frequent AIDS-defining event after esophageal candidiasis (19).
PCP remains an important cause of HIV-associated pneu-
monia, but rates of PCP have decreased. At San Francisco
General Hospital, nearly 1,000 cases of HIV-associated PCP
were microscopically diagnosed from 1990 to 1993 (average, 250
cases per year) (Figure 1) (20). This number has decreased to 20
to 30 cases per year. Most of these cases occurred in persons
who were not receiving antiretroviral therapy or PCP pro-
phylaxis, and many were unaware of their HIV infection at the
time of presentation (21, 22). This experience is similar at other
institutions, where 23 to 31% of reported PCP cases occurred in
patients who were newly diagnosed with HIV infection at the
time of PCP (21, 23, 24).
HIV-associated PCP is reported at varying rates throughout
the world (25, 26). Clinical studies from Africa that performed
bronchoscopy with bronchoalveolar lavage (BAL) in HIV-
infected patients with pneumonia report that PCP accounted
for 0.8 to 38.6% of cases (26–28). At Mulago Hospital in
Kampala, Uganda, the frequency of PCP among HIV-infected
patients hospitalized with suspected pneumonia who had neg-
ative sputum acid-fast bacilli smears and underwent bronchos-
copy has decreased from nearly 40% of bronchoscopies to less
than 10% (28, 29). However, the mortality associated with PCP
remains high. Although its current incidence is low in Uganda,
patients with PCP had a higher mortality (75%, 3/4) than did
those with culture-positive pulmonary TB (31%, 59/190) or
cryptococcal pneumonia (10%, 1/10) (30).
PRESENTATION AND DIAGNOSIS
Classically, HIV-associated PCP presents with fevers, nonpro-
ductive cough, and dyspnea. Symptoms may be subtle at first but
gradually progress and may be present for several weeks before
diagnosis. This presentation differs from that typically seen in
non-HIV immunocompromised patients with PCP in whom the
duration of symptoms is often much shorter (31). The lung
examination is often normal, but, when abnormal, inspiratory
crackles are the most common finding. The chest radiograph is
the cornerstone of the diagnostic evaluation and demonstrates
bilateral, symmetric, reticular (interstitial), or granular opacities
(Figure 2) (32, 33). PCP may also present with a pneumothorax
or bilateral pneumothoraces. Although relatively uncommon,
pneumothorax presents a difficult problem, often requiring pro-
longed chest tube management. Occasionally, PCP presents with
a normal chest radiograph. In these cases, chest high-resolution
computed tomography (HRCT) may be useful. Chest HRCT
demonstrates patchy areas of ground glass opacity (Figure 3)
(34). Although the presence of ground glass opacities is non-
specific for PCP, their absence strongly argues against the diag-
nosis of PCP, and no further diagnostic testing for PCP or PCP
treatment is generally warranted in these cases (34). There is no
universal approach to the management of suspected PCP. Some
institutions empirically treat these individuals, whereas others pur-
sue a definitive diagnosis. Regardless of the approach selected,
close follow-up is recommended because the presentation of PCP
can overlap with those of other HIV-associated pneumonias,
and HIV-infected patients can have more than one concurrent
Pneumocystis cannot be cultured, and the diagnosis of PCP
relies on microscopic visualization of characteristic cystic or
trophic forms in respiratory specimens obtained most often
from sputum induction or bronchoscopy. Bronchoscopy with
BAL is regarded as the gold standard procedure to diagnose
PCP in HIV-infected patients and has a reported sensitivity of
98% or greater (20). However, bronchoscopy requires special-
ized personnel, rooms, and equipment, and it is also expensive
and carries an associated risk of complications. Thus, bronchos-
copy is limited in its availability throughout many areas of the
world that are burdened with HIV/AIDS, and an accurate
noninvasive procedure to diagnose PCP would be a significant
The development of specific PCR assays has revolutionized
the diagnosis of many infectious diseases, and PCR assays for P.
jirovecii have been developed. P. jirovecii PCR assays combined
with BAL specimens have been shown to be sensitive for the
diagnosis of PCP. The availability of sensitive PCR-based assays
led to studies that examined whether these assays could be
combined with a noninvasive pulmonary procedure to effectively
diagnose PCP. Two studies from San Francisco General Hospital
examined oropharyngeal wash (OPW; i.e., gargling) specimens
and tested three different PCR-based assays, comparing results
firmed cases of Pneumocystis pneumonia (PCP) diag-
nosed at San Francisco General Hospital, 1990–2009.
ART 5 antiretroviral therapy.
Annual number of microscopically con-
Huang, Cattamanchi, Davis, et al.: HIV-Associated PCP 295
with induced sputum or BAL specimens and microscopic exam-
ination after Diff-Quik staining as the gold standard. These
studies found that OPW-PCR had a diagnostic sensitivity of up
to 88% and a specificity of up to 90% for PCP (35, 36).
Procedural factors, such as collecting the OPW specimen before
PCP treatment initiation or within 1 day of initiation and having
the patient cough vigorously before specimen collection, in-
creased the sensitivity of the test. Although the sensitivity of
OPW-PCR for PCP approaches that of BAL-microscopy and
may exceed that of induced sputum-microscopy, OPW-PCR can
detect P. jirovecii DNA in the absence of PCP, resulting in false-
positive PCR results. The imperfect specificity of PCR for PCP
likely relates to the highly sensitive nature of these assays and the
fact that HIV-infected patients and other patients can be
colonized with Pneumocystis (i.e., Pneumocystis DNA is detected
by PCR in the absence of PCP) (37, 38). Further study is needed
to determine whether the application of a ‘‘cut-off’’ in quantita-
tive PCR assays can be used to distinguish between PCP and
Plasma and serum assays have been studied for the diagnosis
of PCP. One assay examined plasma S-adenosylmethionine
(SAM or AdoMet) as a potential biomarker for PCP. SAM is
an important biochemical intermediate involved in methylation
reactions and polyamine synthesis (39, 40). The original ratio-
nale for developing a SAM assay was that Pneumocystis lacks
a SAM synthetase and therefore is unable to synthesize its own
SAM and must scavenge this intermediate from its host (a
subsequent study has demonstrated that Pneumocystis has
a functional SAM synthetase) (41). Thus, patients with PCP
might be expected to have low SAM levels. A series of studies
from New York found that plasma AdoMet levels could be used
to distinguish between HIV-infected patients with PCP and
those with non-PCP pneumonia and healthy control subjects
(39, 40). In one study, patients with PCP had significantly lower
plasma AdoMet levels compared with patients with non-PCP
pneumonia (bacterial pneumonia or TB), and there was no
overlap in AdoMet levels between these two groups of patients
(40). A subsequent study that measured serum SAM found
overlapping levels between HIV-infected patients with PCP and
those with non-PCP pneumonia (42). Whether the differing
results from these studies relates to differences between plasma
and serum SAM levels, as has been hypothesized, or to other
factors, is unclear, and further studies are needed. More re-
cently, serum (1–3)-b-D-glucan, a cell wall component of all
fungi including Pneumocystis, has been investigated as a bio-
marker for PCP because patients with PCP might be expected
to have high levels (43, 44). One report found that patients with
PCP with and without underlying HIV infection had signifi-
cantly higher serum (1–3)-b-D-glucan levels compared with
patients without PCP (43). Using a 100 pg/ml cutoff, another
study reported a diagnostic sensitivity of 100% and a specificity
of 96.4% (44). (1–3)-b-D-glucan is elevated in a number of
fungal pneumonias, and this test cannot distinguish among
fungal etiologies (e.g., PCP and Aspergillus species). Thus, al-
though results from these noninvasive diagnostic or biomarker
tests are promising, additional validation is needed, and bron-
choscopy with BAL remains the gold standard diagnostic test
Trimethoprim-sulfamethoxazole is the recommended first-line
treatment for PCP in HIV-infected patients with mild, moder-
ate, and severe PCP, with intravenous therapy generally rec-
ommended for inpatients with moderate to severe disease and
oral therapy used for outpatients with milder disease (45).
Alternative regimens include intravenous pentamidine, clinda-
mycin plus primaquine, trimethoprim plus dapsone, and atova-
quone suspension. Adjunctive corticosteroids are recommended
for patients with moderate to severe PCP as demonstrated by a
PaO2less than 70 mm Hg or an alveolar-arterial oxygen gradient
greater than 35 mm Hg (45). Patients should be started on
adjunctive corticosteroids at the same time that PCP therapy is
initiated. The recommended duration of treatment is 21 days
(45). However, a substantial proportion of individuals cannot
complete a full course of trimethoprim-sulfamethoxazole due to
treatment-limiting toxicity or are switched to an alternate
treatment regimen due to perceived treatment failure (46).
Although there are only limited data from prospective, ran-
domized clinical trials comparing second-line PCP treatments,
a tri-center observational study, and a systematic review suggest
that the combination of clindamycin plus primaquine is an
effective alternative to intravenous pentamidine as second-line
PCP treatment (47, 48).
Trimethoprim-sulfamethoxazole is also the recommended first-
line regimen for primary and secondary prophylaxis against
PCP (45). Alternative regimens include dapsone with or with-
out pyrimethamine and leucovorin, atovaquone suspension, and
aerosolized pentamidine. HIV-infected adolescents and adults,
including pregnant women, should receive PCP prophylaxis if
their CD41 cell count is below 200 cells/ml or if they have a
history of oral candidiasis (primary prophylaxis) and after an
episode of PCP (secondary prophylaxis) (45). Persons with
a CD41 cell count below 14% and those with a history of an
AIDS-defining illness should also be considered candidates for
PCP prophylaxis (45).
Once initiated, PCP prophylaxis is recommended for life, but
it can be discontinued in HIV-infected adolescents and adults
who are receiving combination antiretroviral therapy and have
responded with an increase in their CD41 cell count from
below 200 cells/ml to above 200 cells/ml for at least 3 months
(45). One potential exception is patients who developed PCP
when their CD41 cell count was above 200 cells/ml; these
individuals should probably remain on PCP prophylaxis regard-
less of their CD41 cell count (45). After discontinuation of PCP
prophylaxis, the risk of subsequent PCP on combination anti-
Figure 2. Chest radiograph demonstrating the characteristic bilateral,
symmetric granular opacities in an HIV-infected patient with Pneumo-
cystis pneumonia (courtesy of L. Huang, used with permission).
296 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETYVOL 82011
retroviral therapy with a sustained CD41 cell count above 200
cells/ml (and generally accompanied by a sustained suppression
of plasma HIV RNA below the limits of detection) has been
shown to be extremely low, but rare cases have been described
(49). Prophylaxis should be resumed if the CD41 cell count
declines below 200 cells/ml (45). Recent data from a 12-cohort
collaboration suggest that PCP incidence is low in HIV-infected
persons with CD41 cell counts of 100 to 200 cells/ml and HIV
RNA levels less than 400 copies/ml irrespective of PCP pro-
phylaxis use, suggesting that it may be safe to stop prophylaxis
earlier, though additional data are needed (50).
DRUG RESISTANCE IN P. JIROVECII
The widespread use of trimethoprim-sulfamethoxazole for PCP
prophylaxis has been associated with increases in trimethoprim-
sulfamethoxazole–resistant bacteria (51) and has raised concerns
over potential trimethoprim-sulfamethoxazole drug resistance in
P. jirovecii (52). Similar concerns have been raised related to the
use of atovaquone and potential atovaquone drug resistance (53).
Trimethoprim-sulfamethoxazole drug resistance might also result
in resistance to trimethoprim plus dapsone (a sulfone), thereby
further limiting the therapeutic options available to treat (and
prevent) PCP. The inability to culture P. jirovecii has hindered
efforts to document drug resistance in Pneumocystis, but re-
searchers have explored this important question by examining
genetic mutations within the dihydrofolate reductase (DHFR)
and dihydropteroate synthase (DHPS) genes, the enzymatic targets
of trimethoprim and sulfa (sulfamethoxazole and dapsone) med-
ications, respectively, and by correlating the observed genetic
mutations with clinical outcomes (52). This approach was chosen
because DHFR and DHPS genetic mutations have been shown
to cause drug resistance as demonstrated in other microorgan-
isms, such as Plasmodium falciparum (54).
Six studies have examined P. jirovecii DHFR mutations
from patients with PCP with and without underlying HIV
infection in the United States, Japan, Europe, South Africa,
and Thailand (55–60). The first two studies reported that
DHFR mutations were uncommon and unrelated to trimeth-
oprim use as part of PCP prophylaxis (i.e., trimethoprim-
sulfamethoxazole) (55, 56). In these studies, nonsynonymous
DHFR mutations, resulting in amino acid substitution(s), were
found in 0% (0/37) and 7% (2/27) of PCP samples. A similar
proportion (4%, 5/128 samples) was found in the largest study
to date, which also failed to find an association between tri-
methoprim use and the presence of nonsynonymous DHFR
mutations (59). In contrast, a European study reported non-
synonymous DHFR mutations in 33% (11/33) of PCP samples
(57). This study found that use of DHFR inhibitors (trimetho-
prim or pyrimethamine) for PCP prophylaxis was associated
with the presence of DHFR mutations (P 5 0.008) and that
most of the patients with DHFR mutations were receiving
pyrimethamine (n 5 7) rather than trimethoprim (n 5 2) as part
of their prophylaxis regimen. This study raises the possibility
that different DHFR inhibitors may select for different DHFR
mutations or may select nonsynonymous DHFR mutations at
different frequencies. Because no outcomes were reported in
this study, it is unknown whether the presence of DHFR gene
mutations is associated with increased morbidity, mortality,
or PCP treatment failure in persons receiving trimethoprim-
sulfamethoxazole or trimethoprim plus dapsone.
Compared with six DHFR studies, more than 20 studies have
examined P. jirovecii DHPS mutations from patients with PCP
with and without underlying HIV infection in North America,
Europe, Asia, Africa, South America, and Australia. The
preponderance of studies on DHPS compared with DHFR
relates to the fact the sulfamethoxazole is more active against
Pneumocystis compared with trimethoprim in animal models of
PCP, and therefore DHPS mutations would be expected to be
more important than DHFR mutations to the development of
These studies report a wide range in the frequency of DHPS
mutations (from 3.7 to 81%) (58, 61, 62). In general, these
studies also reveal a geographic variation in the proportions of
DHPS mutations observed, with the highest proportions
reported in the United States (San Francisco) and the lowest
proportions reported in Spain and South Africa. In addition,
some studies report an increase in the proportion of DHPS
mutations over time (63). Specifically, two nonsynonymous
mutations that result in amino acid substitutions at amino acid
position 55 (Thr/Ala) and/or position 57 (Pro/Ser) are
almost exclusively reported (64, 65). Overall, these studies have
generally demonstrated a significant association between sulfa
(sulfamethoxazole or dapsone) use as part of PCP prophylaxis
and the presence of nonsynonymous DHPS mutations (52). This
finding is noteworthy because the DHPS locus is well conserved
in Pneumocystis obtained from other mammals and because
DHPS mutations are rarely encountered in nonhuman primates
(66), suggesting that use of sulfa drugs by humans has selected
for P. jirovecii DHPS mutations.
In several studies, the presence of DHPS mutations has been
associated with poor outcomes in HIV-infected persons with
PCP. One study reported that the presence of DHPS mutations
was an independent predictor associated with an increased 3-
month mortality (adjusted hazard ratio, 3.10; 95% confidence
interval, 1.19–8.06; P 5 0.01) (67). Another study noted that the
presence of DHPS mutations was associated with an increased
risk of PCP treatment failure with trimethoprim-sulfamethox-
azole or trimethoprim plus dapsone (RR 5 2.1; P 5 0.01) (68).
Finally, a small study reported that all four patients with DHPS
mutations who were treated with trimethoprim-sulfamethoxa-
zole failed PCP therapy (69). In contrast, other studies have
failed to demonstrate these associations and instead have
reported that risk factors such as low serum albumin and early
ICU admission were stronger predictors of PCP mortality than
the presence of DHPS mutations (62).
Thus, a seeming paradox exists regarding the clinical signif-
icance of DHPS mutations and inferences related to putative
trimethoprim-sulfamethoxazole drug resistance. Studies consis-
tently report that the majority of patients with PCP and DHPS
Figure 3. Chest high-resolution computed tomograph demonstrating
the characteristic ground glass opacities in an HIV-infected patient with
Pneumocystis pneumonia who had a normal chest radiograph (courtesy
of L. Huang, used with permission).
Huang, Cattamanchi, Davis, et al.: HIV-Associated PCP297
mutations who are treated with trimethoprim-sulfamethoxazole
respond to this treatment (62, 67, 68, 70). However, patients
with DHPS mutations who are treated with trimethoprim-
sulfamethoxazole tend to have worse outcomes compared with
those with wild-type DHPS who are treated with trimethoprim-
sulfamethoxazole and compared with those with DHPS muta-
tions who are treated with a non–sulfa-based regimen (62). The
precise explanation for these observations is unclear, but concur-
rent DHFR mutations, low serum trimethoprim-sulfamethoxazole
levels, and host factors have been postulated as potential co-
factors for trimethoprim-sulfamethoxazole treatment failure in
patients with PCP and DHPS mutations. No study has examined
all of these postulated factors at the same time in patients with
PCP. Until the clinical significance of DHPS and possibly DHFR
mutations can be further defined, clinicians treating patients with
PCP should use trimethoprim-sulfamethoxazole as first-line ther-
apy in all patients unless contraindicated by allergic reaction or
THE LUNG HIV AND IHOP STUDIES
The Longitudinal Studies of HIV-associated Lung Infections
and Complications (Lung HIV) Study is a novel, collaborative,
multi-R01 consortium of research projects established by the
National Heart, Lung, and Blood Institute (NHLBI) to examine
a broad range of infectious and noninfectious pulmonary dis-
eases that affect people living with HIV/AIDS. The Lung HIV
Study’s specific aims, study design, and study protocols are de-
scribed in the online supplement to this issue. Within the Lung
HIV Study, eight clinical centers conduct their own separate
research studies but also join under the stewardship of the
NHLBI and a data coordinating center to conduct multisite and
group level collaborative studies. Each clinical site has its own
research focus. The IHOP Study focuses on opportunistic pneu-
monias, primarily PCP, but includes the establishment of a
clinical database and specimen bank that seamlessly enables
research on tuberculosis, bacterial pneumonia, and other op-
portunistic pneumonias. For example, studies on tuberculosis,
the dominant opportunistic pneumonia in sub-Saharan Africa,
are incorporated within the IHOP infrastructure. The IHOP
Study’s specific aims include (1) to determine the frequency and
mortality of HIV-associated opportunistic pneumonias in an
international, longitudinal cohort and to test the hypothesis that
PCP is associated with increased mortality; (2) to estimate the
sensitivity and specificity of molecular tools for PCP and TB di-
agnosis and to test the hypotheses that OPW specimens com-
bined with PCR assays are sensitive tests to diagnose PCP and
TB; and (3) to test the hypothesis that DHPS gene mutations
are associated with an increased morbidity and mortality and to
explore potential mechanisms for these outcomes. IHOP and
Lung HIV have established specimen banks linked to clinical
data, and investigators interested in studying HIV-associated
opportunistic pneumonias are encouraged to contact the au-
thors of this review.
The HIV/AIDS pandemic has witnessed significant advances in
our understanding of HIV/AIDS and PCP, one of the prominent
diseases associated with the pandemic. This review describes
recent advances in the pathogenesis, epidemiology, diagnosis,
and management of HIV-associated PCP and ongoing areas of
clinical and translational research that are part of the IHOP and
the Lung HIV Studies. The IHOP and Lung HIV Studies have
established a clinical specimen bank accompanied by clinical
data for future studies. Given the decline in the incidence of
PCP but its enduring importance as a cause of morbidity and
mortality in HIV-infected and other immunosuppressed patients,
this specimen bank may accelerate and further our understanding
of P. jirovecii and PCP.
Author Disclosure: L.H. received grant support from the Foundation for In-
novative New Diagnostics (FIND). A.C. and J.L.D. received grant support from
the WHO and the FIND. S.d.B. and J.K. do not have a financial relationship with
a commercial entity that has an interest in the subject of this manuscript. S.M.
received grant support from Abbott and the Gates Foundation. R.F.M. received
lecture fees from Gilead and Merck. P.D.W., W.W., and H.M. do not have
a financial relationship with a commercial entity that has an interest in the subject
of this manuscript.
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