257

Fungal, Viral, and Parasitic Pneumonias

Associated with Human Immunodeficiency Virus
Joseph H. Skalski, MD1 Andrew H. Limper, MD1

1 Division of Pulmonary and Critical Care Medicine, Department of Address for correspondence Andrew H. Limper, MD, Division of
Internal Medicine, Mayo Clinic, Rochester, Minnesota Pulmonary and Critical Care Medicine, Department of Internal
Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905
Semin Respir Crit Care Med 2016;37:257–266. (e-mail: limper.andrew@mayo.edu).

Abstract Respiratory illness is an important cause of morbidity and mortality in patients with
Keywords human immunodeficiency virus (HIV). The spectrum of pulmonary disease that can
► opportunistic affect patients with HIV is wide and includes opportunistic infection with many fungal,

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infection viral, and parasitic organisms. This article reviews the clinical presentation; approach to
► acquired diagnosis; and management of fungal, viral, and parasitic pneumonias that can develop
immunodeficiency in patients with HIV including respiratory disease caused by Aspergillus, Cryptococcus,
syndrome Histoplasma, Coccidioides, Cytomegalovirus, Toxoplasma, and Strongyloides. Because
► aspergillosis clinical symptoms and radiographic patterns are often insensitive at distinguishing
► Cryptococcus these pulmonary infections, this review particularly focuses on specific host risk factors
► histoplasmosis and diagnostic testing to consider when approaching HIV patients with respiratory
► coccidioidomycosis illness.
► cytomegalovirus
► Strongyloides
► toxoplasmosis

Respiratory symptoms are common in patients with human
immunodeficiency virus (HIV). Although the incidence of
opportunistic infection has declined substantially with
increased use of antiretroviral therapy (ART) and prophylactic
antibiotics, respiratory infection due to opportunistic patho-
gens remains a significant cause of morbidity and mortality in
patients with HIV.
Respiratory illness usually presents with nonspecific signs
and symptoms such as fever, dyspnea, and cough. It is often
challenging to determine the specific diagnosis based on
clinical history and radiography alone. However, it is essential
to make a microbiological diagnosis, as the treatment of
pulmonary infection differs by organism and mortality is
often high if infection is left untreated. It is therefore essential
to consider host risk factors such as CD4 count and also obtain
appropriate diagnostic testing when evaluating HIV patients
with respiratory symptoms.
This review discusses risk factors, clinical presentation,
diagnosis, and management of selected fungal, viral, and
parasitic respiratory infections in patients with HIV
(►Table 1) with particular focus on diagnostic testing and
host risk factors for each infectious syndrome. As the spec-
trum of infectious pulmonary diseases that can affect patients
with HIV is wide, this review will not address all of the
important respiratory pathogens. Bacterial organisms and
Pneumocystis, the most important fungal pathogen in
patients with HIV, are discussed in detail elsewhere.
Fungal Pneumonias
Aspergillus
Aspergillus is a genus of fungi that can cause disease by a
variety of mechanisms in immunosuppressed patients. More
than 150 Aspergillus species have been described with
A. fumigatus, A. flavus, A. niger, and A. terreus reported as
the most common causes of disease in humans.1 Of these,
A. fumigatus is the cause of disease in more than 90% of HIV
patients.2 Aspergillus is ubiquitous in the environment and is
found on all continents including Antarctica, and we are
continually exposed to airborne Aspergillus conidia (spores)
in most indoor and outdoor environments.3–7 The mecha-
nisms by which Aspergillus-associated disease develops in

Issue Theme Pulmonary Complications Copyright © 2016 by Thieme Medical DOI http://dx.doi.org/
of HIV Infection; Guest Editors: Laurence Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0036-1578802.
Huang, MD, Alison Morris, MD, MS, and New York, NY 10001, USA. ISSN 1069-3424.
Kristina Crothers, MD Tel: +1(212) 584-4662.
258 Fungal, Viral, and Parasitic Pneumonias Associated with HIV
Table 1 Fungal, viral, and parasitic causes of opportunistic
respiratory infection in patients with HIV
Fungal Pneumocystis jirovecii
Aspergillus spp.
Cryptococcus spp.
Endemic fungi
- Histoplasmosis capsulatum
- Blastomyces dermatitidis
- Coccidioides spp.
- Paracoccidioides braziliensis
- Penicillium marneffei
Viral Cytomegalovirus
Human herpesvirus 8 (Kaposi sarcoma)
Herpes simplex virus
Varicella zoster virus
Parasitic Toxoplasma gondii
Strongyloides stercoralis
Cryptosporidium
some patients but not in others despite ubiquitous exposure
are largely unknown.
All of the major Aspergillus pulmonary syndromes have been
described in patients with HIV including invasive pulmonary
aspergillosis (IPA),2 chronic necrotizing (“semi-invasive”) asper-
gillosis,8 tracheobronchitis,9 allergic bronchopulmonary asper-
gillosis (ABPA),10 and aspergilloma (“fungus ball”).11 Of these, IPA
is the most commonly reported clinical syndrome, accounting
for 80% of cases of Aspergillus pulmonary disease in a large
review of patients with HIV.2 When compared with other
opportunistic fungal infections, IPA is generally considered to
be an uncommon infection in patients with HIV, but when does
occur, it carries high mortality.12 It may also be underdiagnosed;
in a series of HIV patients from Italy, aspergillosis was identified
as the second most common invasive fungal infection at autopsy,
and in 89% of cases the diagnosis was missed during life and only
discovered postmortem.13
In patients with HIV, major risk factors for IPA include CD4
count less than 50 cells/µL, neutropenia (such as either from
myelodysplasia or medication effect), and corticosteroid
use.2,12,14 Symptoms of IPA can include fever, cough, dyspnea,
chest pain, and hemoptysis.2 The lungs are involved in nearly
all HIV patients with invasive aspergillosis, and the central
nervous system (CNS) is the second most common organ
system affected.2,15 Other organ systems that can be involved
in disseminated disease include sinuses, skin, bones, eye,
kidneys, and heart.2,16–19 Chest radiographic findings are
variable and include focal alveolar opacity, nodular disease,
and bilateral alveolar or interstitial infiltrates.2,20 Upper lobe
cavitary disease is commonly seen in patients with chronic
necrotizing aspergillosis.20 The air crescent sign which has
been described in non-HIV patients with aspergillosis is
uncommon in HIV patients with Aspergillus disease.20
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 2/2016
Skalski, Limper
It is often challenging to establish a definitive diagnosis of
IPA. Aspergillus is frequently isolated in the culture of respi-
ratory specimens such as sputum and bronchoalveolar lavage
(BAL) in patients without IPA. Even in immunosuppressed
patients, the finding of Aspergillus in culture often represents
colonization rather than true invasive infection. Nearly 5% of
patients with advanced HIV and respiratory symptoms at one
institution grew Aspergillus from respiratory samples, but
most of these patients were not ultimately found to have IPA
even after autopsy examination.21 The gold standard for the
diagnosis of “proven IPA” is a lung biopsy documenting tissue
invasion of hyphal forms with associated tissue damage.22 If
biopsy is unavailable, the finding of Aspergillus in culture in a
host at risk for invasive infection with compatible symptoms
and imaging is described as “probable IPA” and usually
warrants treatment.22 Two assays are available to aid in the
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diagnosis of Aspergillus infection. Galactomannan is a cell-
wall polysaccharide that is found in Aspergillus but not in the
cell wall of other fungal pathogens. Galactomannan testing
has good performance characteristics for the diagnosis of
invasive aspergillosis in immunocompromised patients with
transplant or hematological malignancy.23 Galactomannan
testing can be performed on serum or BAL fluid samples, but
testing of BAL fluid is likely more sensitive.16 False-positive
galactomannan has been reported with certain antibacterials
(piperacillin-tazobactam) and histoplasmosis, although this
may no longer be a problem with newer formulations of
piperacillin-tazobactam.24–26 Beta-D-glucan is a cell wall
polysaccharide that is found in many fungal organisms.
Testing for beta-D-glucan is not specific for Aspergillus, but
it may have a good negative predictive value for excluding
invasive infection.27 Both galactomannan and beta-D-glucan
testing have been primarily described in patients with
hematological malignances, and the performance character-
istics of these tests are less certain in patients with HIV.16
The mortality of IPA is extremely high with a case fatality rate
reported to be 85.7% in patients with HIV.28 The preferred
treatment for invasive aspergillosis is intravenous voricona-
zole.1,16 The duration of treatment in HIV-positive patients
has not been systematically studied, but consensus guidelines
recommend prolonged treatment until the infection is resolved
and CD4 count is >200 cells/µL.16 Presently, no antibiotic
prophylaxis is recommended for primary prevention of Asper-
gillus infection in patients with HIV.16
Cryptococcus
Cryptococcus is a genus of encapsulated budding yeast that is
an important cause invasive fungal infection in patients with
HIV. Cryptococcus neoformans is the species that most com-
monly causes human disease, and nearly 1 million HIV
patients will develop infection each year.29 C. neoformans is
endemic throughout the world and is found in the soil,
particularly soil contaminated by pigeon dropping.30,31 Infec-
tion occurs by inhalation of yeast cells or spores. Exposure is
widespread and nearly 70% of children older than 5 years in
some urban areas have detectable antibodies to C. neofor-
mans.32 Nonneoformans cryptococcal species can also cause
human disease, but it is much less common. Cryptococcus
 Fungal, Viral, and Parasitic Pneumonias Associated with HIV
gattii is found in tropical and subtropical climates and is an
emerging cause of disease in both immunocompetent hosts
and patients with HIV.33 Rarely, Cryptococcus laurentii and
Cryptococcus albidus have been reported to cause human
disease in patients with HIV.32 Nonneoformans cryptococcal
disease can present with clinical syndromes that are similar
to C. neoformans disease.34
Cryptococcal infection in HIV patients usually presents as
meningoencephalitis, but cryptococcal pneumonia is also
relatively common and is likely underdiagnosed. Patients
with CD4 counts less than 100 cells/µL are at highest risk of
cryptococcal infection.16,35 The presenting symptoms of pul-
monary cryptococcal infection are nonspecific and include
fever, cough, chest pain, and dyspnea.36,37 There is a spectrum
of disease severity ranging from mild symptoms to severe
pneumonia with respiratory failure.31 Chest radiography
findings are variable and can include nodules with or without
cavitation, alveolar consolidation, bilateral interstitial infil-
trates, and/or pleural effusion.37–40 Although isolated pulmo-
nary infection can occur, cryptococcal pneumonia often
coexists with meningoencephalitis. Therefore, all HIV
patients with a diagnosis of cryptococcal pneumonia should
undergo lumbar puncture to exclude CNS involvement.34
Similarly, in patients with cryptococcal meningoencephalitis,
it should be recognized that anywhere from 10 to 55% of
patients will have evidence of pulmonary involvement.31
Disseminated infection is common in patients with HIV,
and the involvement of the skin, eye, bone, and prostate
have also been described.1,16
There are multiple modalities available to establish the
diagnosis of cryptococcal infection including direct visualiza-
tion of the organism, culture, or Cryptococcus antigen (CrAg)
detection. CrAg testing refers to direct testing of blood, urine,
or cerebrospinal fluid (CSF) samples for the presence of
cryptococcal capsular polysaccharides. Newer techniques
such as lateral flow assay (LFA) allow CrAg testing to be
performed rapidly in resource-limited settings.41,42 Testing
of CSF samples for CrAg has good performance characteristics
for the diagnosis of meningoencephalitis.27 Elevated serum
CrAg titer may be one of the earliest manifestations of disease,
and patients with HIV and cryptococcal pneumonia will
frequently have elevated serum CrAg titers.27,42 Direct testing
of respiratory samples such as sputum or BAL for CrAg is less
valuable, as there can be a high rate of false-positive results.43
Definitive diagnosis of cryptococcal pneumonia usually relies
on direct observation or growth in culture of Cryptococcus
spp. from a respiratory sample in a patient with compatible
clinical history and imaging.31 Although asymptomatic colo-
nization can occur in immunocompetent hosts, the finding of
Cryptococcus in a patient with HIV should generally be
treated as a true pathogen. Bronchoscopy with BAL offers a
very high diagnostic yield, and the addition of transbronchial
biopsies is generally not necessary to establish the diagnosis
of cryptococcal pneumonia.44
The standard initial treatment for severe cryptococcal
pneumonia, meningoencephalitis, or disseminated disease
is amphotericin B and flucytosine.1 If there is clinical
improvement including negative CSF cultures at 2 weeks,
Skalski, Limper 259
treatment can be switched to fluconazole for 8 weeks. If
HIV patients present with only mild pulmonary disease, they
can be treated with a 6- to 12-month course of fluconazole
therapy.1 All HIV patients with CD4 cell counts <200 cells/µL
should continue to receive chronic secondary prophylaxis
therapy with fluconazole after completion of treatment of the
acute infection.1 Secondary prophylaxis should only be
discontinued after initiation of ART therapy if they are disease
free with sustained CD4 count >200 cells/µL for at least
3 months.1
Endemic Mycoses
The endemic mycoses are a group of fungal pathogens local-
ized to specific geographic regions around the world. Most
are dimorphic fungi that exist as mold in the environment
and yeast at body temperature. They can generally cause
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disease in both immunocompetent patients and immunosup-
pressed hosts. Cell-mediated immunity is important for
clearance of these fungal pathogens, and patients with
HIV are therefore particularly susceptible to severe and
disseminated disease from endemic mycoses.45 Infection
usually occurs by the inhalation of spores from contaminated
soil while a patient is residing in an endemic area. More
rarely, it can present as reactivation of latent infection after a
patient has left an endemic area.46
Histoplasma capsulatum is among the most important
endemic fungi in patients with HIV, and it is the endemic
mycosis that most commonly causes severe illness requiring
hospitalization in the United States.47 It is found in temperate
climates worldwide including the Ohio and Mississippi River
Valleys, central Africa (Histoplasma duboisii), Mexico, and
Central America.48 Histoplasma can cause infection of immu-
nocompetent hosts and patients with HIV with a normal CD4
count, where it usually presents as a respiratory illness that is
often mild and self-limited. In patients with HIV and a low
CD4 count, it can present as a systemic syndrome called
progressive disseminated histoplasmosis. Progressive dis-
seminated histoplasmosis is an AIDS-defining illness, and is
sometimes the initial presentation of previously unrecog-
nized HIV infection. The annual incidence of disseminated
histoplasmosis in HIV patients living in endemic areas has
been reported to be as high as 5% in patients not receiving
antibacterial prophylaxis.49 Disseminated disease most com-
monly presents with pulmonary symptoms such as cough and
dyspnea and also with constitutional symptoms such as fever
and weight loss.50 Other common presenting signs and
symptoms include hepatosplenomegaly, lymphadenopathy,
skin lesions, meningitis, bone marrow failure, and gastroin-
testinal symptoms.49,50 Disseminated disease can progress to
a sepsis-like syndrome with high fevers and respiratory
failure. Chest radiograph usually shows a diffuse interstitial
infiltrate, but can be normal in up to 40% of cases.50,51
Multiple tests are available to establish a diagnosis of
disseminated histoplasmosis. In the setting of disseminated
disease, the organism can often be detected by direct micro-
scopic examination or culture of blood or other bodily fluids.
The yield of blood culture has been variably reported to be 50
to 75% in HIV patients with disseminated disease,52,53 but it
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 2/2016
260 Fungal, Viral, and Parasitic Pneumonias Associated with HIV
can take weeks for growth, making blood culture a less useful
test for guiding acute patient management. Assays are avail-
able to test directly for Histoplasma polysaccharide antigen,
and these can often provide more rapid diagnosis.54 Histo-
plasma antigen testing can be performed on urine or blood
and is highly sensitive for diagnosis of disseminated histo-
plasmosis, with the urine test being described in multiple
case series to have a 95 to 97% sensitivity for diagnosis of
disseminated disease in HIV patients.53,55 Testing for Histo-
plasma antigen can also be performed on CSF or BAL samples
if indicated. It is important to note that Histoplasma antigen
testing can be falsely positive in the setting of blastomyco-
sis.55 Serology testing for histoplasmosis is available but is
less valuable when evaluating HIV patients for disseminated
infection. It is often positive due to prior exposure in HIV
patients living in endemic areas and some HIV patients with
disseminated disease have been described to have negative
serologic testing.
Disseminated disease is generally fatal without antifungal
therapy, and rapid initiation of treatment is essential.
Amphotericin, either amphotericin B or a lipid formulation,
is the initial treatment of choice.1 Itraconazole is the azole
antifungal with highest activity against Histoplasma, and
patients can be transitioned to itraconazole maintenance
therapy after 2 weeks of amphotericin induction therapy if
there is clinical improvement.1,16 Patients who survive
disseminated histoplasmosis infection have a high rate of
relapse, and itraconazole maintenance therapy should be
continued for at least 12 months or even longer if CD4 count
remains suppressed or there is evidence of relapse.1 It is
important to monitor serum drug levels during itraconazole
therapy, as gastrointestinal absorption can be variable and
there are multiple drug interactions that affect serum con-
centration. One randomized controlled trial has evaluated
primary prophylaxis against histoplasmosis for HIV patients
living in endemic areas. The trial showed decreased incidence
of disease but no mortality benefit.54 Primary prophylaxis
with itraconazole should therefore be considered on an
individualized basis. The Infectious Disease Society of
America (IDSA) 2013 guidelines recommend primary pro-
phylaxis in HIV patients with CD4 count <150 cells/µL who
live in selected communities with “hyperendemic” rates of
histoplasmosis.16
Coccidioidomycosis is an endemic mycosis caused by
fungal pathogens Coccidioides immitis and Coccidioides pos-
adasii. Coccidioides has a narrow geographic range, occurring
almost exclusively in the Southwest United States and
Mexico, but it is an extremely important fungal pathogen
in these regions.56 More than 50% of the general population in
highly endemic areas of California, Arizona, and Texas shows
immunological evidence of prior coccidioidomycosis expo-
sure.57 In immunocompetent patients, coccidioidomycosis
can present with a wide range of manifestations, from
asymptomatic or self-limited infection to acute pneumonia
requiring hospitalization. In endemic areas, coccidioidomy-
cosis is extremely common, with one observational study
reporting that 29% of all patients presenting to outpatient
clinic with lower respiratory symptoms were ultimately
Seminars in Respiratory and Critical Care Medicine Vol. 37
Skalski, Limper
found to have coccidioidomycosis.58 HIV patients with CD4
count greater than 250 cells/µL present similarly to immuno-
competent patients with a focal pneumonia as the most
common clinically significant disease.16 Fluconazole for at
least 3 months is the treatment of choice for mild infection
when antibiotics are needed.1
HIV patients with CD4 count <250 cells/µL or nonsup-
pressed HIV virus replication are at risk of distinct and more
severe manifestations of infection.59 Pulmonary involvement
in these patients most commonly presents as a diffuse
pneumonia with reticulonodular infiltrates on chest X-ray,
and focal pneumonia is less common.60,61 Other syndromes
that can occur in these patients include meningitis (up to
15% of patients), cutaneous disease, lymphadenopathy, or
liver involvement.60,61 Most patients will report constitu-
tional symptoms such as fevers and chills, fatigue, weight loss,
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or night sweats. Amphotericin B liposomal is the treatment of
choice for patients with diffuse pneumonia, but even with
treatment, mortality is nearly 70%.1,60,61
Coccidioidomycosis can be diagnosed by direct observation
or culture of the organism from respiratory samples, tissue, or
CSF. Blood cultures are rarely positive. Coccidioides has not been
described as a colonizer, so observation of the organism is
diagnostic of infection. In host lungs, the organism can grow
into a specialized spore-filled structure called a giant spherule
which is unique to Coccidioides and, if observed, is pathogno-
monic.56 Spherules are observed in the BAL sample of approxi-
mately 40% of HIV patients with pneumonia.62 Serology testing
for immunoglobulin G (IgG) and IgM is highly specific and useful
for diagnosis, but serology will not be positive early in the illness
and some patients with advanced HIV will not produce detect-
able antibodies.63 Antigen testing is available, and antigen
testing of urine has been reported to have moderate (71%)
sensitivity for diagnosis in a mixed population that included
patients with HIV.64 Polymerase chain reaction (PCR) testing is
more recently described and not widely available, but it appears
to have a high sensitivity and specificity for diagnosis of
coccidioidomycosis.65,66
Most immunocompetent patients will develop durable
lifelong immunity after Coccidioides infection, and therefore
vaccination to prevent coccidioidomycosis has become the
subject of increasing study. Presently, no vaccine has yet
reached clinical trials and there is no way to prevent coccidi-
oidomycosis infection. Because it is found in the soil, HIV
patients living in endemic areas cannot completely avoid
exposure to Coccidioides, but they should be counseled to
avoid extensive exposure to disturbed natural soil such as
excavation or dust storms, as this may increase risk of
acquiring acute infection. Primary prophylaxis has limited
benefit for patients with HIV living in endemic areas, even
those with low CD4 counts.16,67 However, yearly serology
testing for Coccidioides in patients with HIV living in endemic
areas may be reasonable, as positive serology can suggest
imminent active disease, and these patients may warrant
treatment with fluconazole.16
Other endemic fungi that can cause disease in patients
with HIV include Blastomyces dermatitidis, Paracoccidioides
braziliensis, and Penicillium marneffei. Blastomyces is endemic
No. 2/2016
 Fungal, Viral, and Parasitic Pneumonias Associated with HIV
to North America including the Mississippi and Ohio River
Valleys and can cause respiratory infection in both immuno-
competent and immunosuppressed hosts.68 In patients with
HIV, Blastomycosis disease tends to be more severe with
higher incidence of respiratory failure and disseminated
disease.69,70 Similar to other endemic fungi, Blastomycosis
can be diagnosed by identification of the organism by direct
observation or culture from a respiratory, blood, or tissue
sample. Blastomyces antigen testing of serum or urine is
available, but it is not specific for Blastomycosis, as it can
cross-react with other endemic fungi.71 Paracoccidioides,
endemic to rural areas of Brazil and Latin America, has also
been described as an opportunistic infection in patients with
HIV.72,73 Nearly all HIV patients with Paracoccidioidomycosis
will present with pulmonary disease and constitutional
symptoms such as fever and weight loss. The majority of
patients will also have extrapulmonary disease at presenta-
tion that most commonly involves the skin (painful mucocu-
taneous ulcers), CNS, lymph nodes, spleen, and liver.62,72
P. marneffei is endemic to Southeast Asia and southern China
and is among the most common opportunistic infections for
HIV patients who live in or have traveled to these areas.74,75
Similar to other endemic fungi, the typical presentation in
patients with HIV is pulmonary and constitutional symptoms
along with extrapulmonary disease that commonly involves
the skin, bone marrow, and lymph nodes.74,75 Fungemia is
relatively common with positive blood cultures described in
approximately 50 to 75% of patients.74,75
Viral Pneumonias
Cytomegalovirus
Cytomegalovirus (CMV), also known as human herpesvirus
5 (HHV-5), is a double-stranded DNA virus that can cause disease
in immunosuppressed patients including those with advanced
HIV.16 After an initial primary infection that may occur early in
life, CMV persists as a lifelong latent infection that can periodi-
cally reactivate.76 Prevalence of CMV in the general population
varies geographically, ranging from 45% to nearly 100% depend-
ing on the population studied.76 In patients with HIV, CMV
disease typically occurs only in patients with advanced immu-
nosuppression including CD4 count less than 50 cells/µL and
those who have failed ART.16,77,78 CMV retinitis is the most
common clinical syndrome caused by CMV in patients with HIV
and can result in vision loss if untreated.16
CMV pneumonitis is uncommon in patients with HIV, even
in those with advanced disease.16 This is in contrast to other
immunosuppressed patient populations such as transplant
recipients, where CMV is an important respiratory
pathogen.79 Establishing a diagnosis of CMV pneumonitis
in HIV patients can be challenging, and the optimal approach
to diagnosis and management remains controversial. CMV is
commonly detected in the BAL in patients with HIV, but the
presence of CMV in BAL in an HIV patient with respiratory
illness is not sufficient to establish the diagnosis of CMV
pneumonitis. In case series of HIV patients with respiratory
illness who underwent bronchoscopy, CMV was found in the
BAL in anywhere from 19 to 51% of all patients.80–82 Often,
Skalski, Limper 261
CMV is found to coexist with other pathogens such as
Pneumocystis that are more likely to be the cause of the
patient’s pneumonia.81–83 In these cases, CMV may be a
marker for worsening immune function related to the infec-
tion rather than the primary cause of respiratory disease.
Therefore, the finding of CMV in BAL should be considered to
have low specificity for the diagnosis of CMV pneumonitis.
The diagnosis of CMV pneumonitis is generally established
only when an HIV patient with compatible respiratory illness
undergoes a lung biopsy showing cytopathic effects consis-
tent with CMV infection and other causes of respiratory
illness are excluded.16,84 Regardless of whether or not the
patient has true CMV pneumonitis, the finding of CMV in the
BAL likely portends a poor prognosis for long-term survival. In
a case series of 40 HIV patients who underwent BAL, the
finding of CMV was associated with 46% mortality at 6 months
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compared with 15% mortality in patients without detectable
CMV in the BAL. Interestingly, this and other case series have
shown no change in short-term mortality between patients
with and without CMV in the BAL.81,82 This observation
further supports the idea that CMV in the BAL is, in most
cases, a marker for immune deterioration rather than a
pathogenic contributor to the patient’s acute pneumonitis.
Signs and symptoms of CMV pneumonitis are nonspecific
and can include fever, hypoxemia, cough, and shortness of
breath.84 Patients typically have very low CD4 counts, with
mean value of 17 cells/µL reported in one case series.85
Variable radiographic patterns have been described including
interstitial infiltrate, alveolar infiltrate, nodular disease, and
bronchial wall thickening.84,86 However, the significance of
these radiology patterns is difficult to interpret due to varia-
tion in the case definitions used for CMV pneumonitis in the
literature. The use of antivirals targeted at CMV such as
ganciclovir have not been conclusively shown to improve
outcomes in patients with CMV, although some case series
have suggested that patients with true isolated CMV pneu-
monitis may benefit from antiviral treatment.84,87,88
Other Viral Infections
Human herpesvirus 8 (HHV-8) is a virus that is closely
associated with Kaposi sarcoma (KS). Pulmonary involve-
ment of KS usually occurs in association with extensive KS
mucocutaneous disease but can also occur in isolation. 89
Pulmonary KS usually presents with nonspecific respira-
tory symptoms such as cough, dyspnea, and wheezing
that are sometimes indistinguishable from other HIV-
associated pneumonias.89 Pulmonary KS can involve the
lung parenchyma, large airways resulting in endobronchial
lesions, and the pleura. Multiple radiographic patterns can
be observed in lung parenchymal KS, but the finding of
bilateral hilar opacities with extension along the broncho-
vascular bundle into the lung parenchyma is highly char-
acteristic.90–92 Pleural effusion will also occur in about
two-thirds of patients with lung parenchymal KS.90 Endo-
bronchial KS has a characteristic appearance on bronchos-
copy and does not necessarily require biopsy for diagnosis.
The mainstay of treatment for pulmonary KS is ART with
restoration of immune function.
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 2/2016
262 Fungal, Viral, and Parasitic Pneumonias Associated with HIV
Herpes simplex virus (HSV) and varicella zoster virus (VZV)
may very rarely cause respiratory infection in patients with HIV.
Case reports have described HSV tracheobronchitis or pneumo-
nia in patients with HIV.93,94 The infection likely occurs via direct
extension of oral mucocutaneous HSV infection from the upper
airway in profoundly immunosuppressed patients. Pneumonitis
caused by VZV has been described in case reports of patients
with advanced HIV, and it generally occurs in the setting of
disseminated disease such as VZV disease with recurrence of
characteristic “chicken pox” cutaneous lesions.95,96
HIV patients are also at risk of the common viral respira-
tory infections that affect the general population such as
influenza virus, parainfluenza virus, respiratory syncytial
virus, and adenovirus. These infections should remain in
the differential diagnosis when evaluating an HIV patient
with respiratory symptoms. Yearly influenza vaccination with
the inactivated formulation is safe and recommended for
patients with HIV, but patients with low CD4 count may not
mount a response.97,98 Therefore, influenza should be
considered in the differential diagnosis for HIV patient pre-
senting with compatible respiratory symptoms even if they
have received the seasonal influenza vaccination.
Parasitic Pneumonias
Toxoplasmosis
Toxoplasma gondii is an important opportunistic protozoal
parasite in patients with HIV. Latent and asymptomatic
infection with Toxoplasma is common in the general popula-
tion, with serologic prevalence of antibodies to T. gondii
ranging from 10 to 80% of adults depending on the population
and geographic location studied.99–102 Risk factors for latent
toxoplasma infection include ingestion of food contaminated
by cat feces or consuming raw or undercooked meat, but up to
50% of individuals with primary infection may not have an
identifiable risk factor.103 Clinically significant toxoplasmosis
disease usually occurs when a latent infection acquired earlier
in life is reactivated after a patient enters an immunosup-
pressed state.16 In HIV patients, the primary risk factor for
toxoplasmosis reactivation is a low CD4 count. Reactivation
usually occurs only in patients whose CD4 count is less than
200 cells/µL, with patients having CD4 count less than
50 cells/µL at the greatest risk.104–107 The most common
clinical presentation of toxoplasmosis infection is toxoplasma
encephalitis, but it can rarely present as infection involving
other organ system including the lungs.
The clinical presentation of toxoplasma pneumonia is
nonspecific but often resembles Pneumocystis pneumonia.
Patients usually present with cough, dyspnea, and fever
with chest X-ray showing diffuse bilateral interstitial infil-
trates.108,109 Other radiological patterns have been reported
including nodular infiltrates, cavitary lesions, or pleural
effusion.108 Diagnosis is established when T. gondii organisms
are directly observed in BAL fluid or lung biopsy specimens or
grown in culture. Serologic response during acute infection is
variable, and serology alone should not be used to rule out the
diagnosis, as some patients with toxoplasma pneumonia will
not have detectable antibodies.109 Toxoplasma pneumonia is
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 2/2016
Skalski, Limper
a relatively rare cause of respiratory illness in patients with
HIV. In a retrospective French study, only 4% of patients with
HIV who underwent BAL for evaluation of acute respiratory
illness were found to have toxoplasma pneumonia.110 It
should be noted that the population prevalence of seroposi-
tivity to Toxoplasma is higher in France compared with the
United States (59 vs. 11%), so the incidence of toxoplasma
pneumonia is likely even lower in the United States.102
The optimal treatment for toxoplasma pneumonia is
unknown, and antibiotic regimens effective for toxoplasma
encephalitis such as pyrimethamine plus sulfadiazine are
often used.16,108 Even with treatment, toxoplasma pneumo-
nia has a high mortality (40–58%) in HIV-positive patients
and relapse is common.108,110 Prophylaxis is highly effective
at preventing toxoplasmosis CNS disease, and all Toxoplasma
seropositive patients with CD4 count <100 cells/µL should
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receive antibiotic prophylaxis. Trimethoprim sulfamethoxa-
zole (TMP-SMX) is the preferred agent and dapsone-pyri-
methamine plus leucovorin is the recommended alternative
for patients unable to take TMP-SMX.16 These regimens are
primarily used to protect against toxoplasma encephalitis,
but may also offer protection against toxoplasma pneumonia.
Strongyloides
Strongyloides stercoralis is a parasitic nematode that can cause
gastrointestinal, pulmonary, and disseminated disease in
humans. Worldwide, anywhere from 3 to 100 million people
are estimated to be infected.111 It is more prevalent in hot and
humid tropical climates, but can be found almost everywhere
in the world except for extreme cold climates.111 In the United
States, it is most prevalent in the southeast.112,113 The Strong-
yloides larval form lives in the soil and infects the human host
by crossing through the skin of the feet. The larva then likely
migrate to the venous blood system where they are hema-
togenously transferred to the lung and then ascend the
tracheobronchial tree to access the gastrointestinal tract.114
The organism matures in the small intestine where it lays
eggs that hatch into more larva. Most of these larvae are
excreted in the stool, but some can reinfect the same host
causing perpetuation of infection.
In immunocompetent hosts, the most common manifes-
tation of strongyloidiasis is a chronic infection with mild
waxing and waning pulmonary and gastrointestinal symp-
toms.114 Strongyloidiasis is usually only recognized as a
serious disease if it progresses to the hyperinfection syn-
drome. Hyperinfection occurs when there is rapid increase in
organism burden with ongoing auto-reinfection. Strongy-
loides hyperinfection typically develops when a patient
with chronic Strongyloides infection enters into an immuno-
suppressed state, particularly immunosuppression that
blunts the Th2 response such as initiation of corticosteroid
therapy, HLTV-1 infection, or onset of a hematologic malig-
nancy.115 Strongyloidiasis was initially described as an AIDS-
defining illness,116 but it is now increasingly recognized that
Strongyloides hyperinfection provoked solely by HIV/AIDS is
actually rare.114 HIV patients are primarily at risk of hyper-
infection syndrome if they develop an additional concurrent
immunosuppressing condition.114
 Fungal, Viral, and Parasitic Pneumonias Associated with HIV
Strongyloides hyperinfection typically presents with acute or
subacute onset of gastrointestinal, pulmonary, and systemic
symptoms. The specific symptoms are highly variable and can
include cough, wheezing, chest pain, tachypnea, crampy abdom-
inal pain, and/or diarrhea.114,117 The chest X-ray is usually
abnormal showing focal or bilateral interstitial infiltrates.117–119
Disseminated disease, defined as involvement of organs outside
of the pulmonary–gastrointestinal autoinfective cycle, com-
monly occurs in association with hyperinfection syndrome.
Organ systems involved in disseminated disease can include
the skin, CNS, heart, kidneys, liver, and other abdominal
organs.114,117 Eosinophilia often occurs with chronic Strong-
yloides infection, but it should be noted that not all patients with
Strongyloides hyperinfection syndrome will have elevated
peripheral eosinophil count. In fact, eosinophil count is often
suppressed, and an elevated eosinophil count can be a sign of a
better prognosis.114,120
Diagnosis of hyperinfection syndrome can usually be
confirmed by a stool or sputum examination showing
numerous larva.121 Chronic infection can be more difficult
to diagnosis, as stool examination will be positive less than
50% of the time due to lower organism burden.121 Serology
testing for IgG to S. stercoralis is available to aid in the
diagnosis of chronic infection, but it can be falsely negative
in immunosuppressed patients or falsely positive in the
setting of other parasitic infection.114,121 The optimal
treatment for Strongyloides hyperinfection syndrome is
unknown. Multiple anthelminthic drugs including ivermec-
tin and albendazole appear to have activity against Strong-
yloides, and multiple different treatment regimens have been
described using these medications.
Other Parasitic Infections
Cryptosporidium is a protozoal parasite that can cause enteri-
tis with watery diarrhea in patients with HIV.122 In patients
with profound immunosuppression, cryptosporidium has
been rarely reported to cause extraintestinal disease includ-
ing pneumonia.123–125 Cryptosporidial pneumonia likely
occurs as an extension of severe intestinal disease rather
than in isolation. Respiratory tract infection is typically
diagnosed when Cryptosporidium oocysts are observed in
respiratory secretions in a patient with signs and symptoms
of respiratory infection. Many case reports describe the
presence of other coexisting pathogenic organisms in the
respiratory sample making it difficult to determine whether
Cryptosporidium is the primary cause of respiratory illness.124
Antibiotic medications are incompletely effective against
Cryptosporidium. Therefore, the optimal therapy for Crypto-
sporidial infection in HIV patients is antiretroviral therapy
with restoration of CD4 count to greater than 100 cells/uL.16
Other parasitic organisms have only rarely been reported
to cause respiratory tract disease in patients with HIV.126
Microsporidiosis and Leishmaniasis are important parasitic
infections in patients with HIV, but both rarely cause direct
pulmonary disease.126,127 Other pulmonary parasitic infec-
tions such as Echinococcus and Paragonimus can affect
patients with HIV, but they are not necessarily considered
opportunistic infections, as they more commonly cause
Skalski, Limper 263
pulmonary disease in immunocompetent hosts.128–130 The
differences in presentation of these infections between HIV
and immunocompetent patients are largely unknown.
Conclusion
Fungal, viral, and parasitic infections are important and
highly morbid causes of respiratory infection in patients
with advanced HIV. Even with appropriate anti-infective
treatment, mortality is high with some infectious syndromes,
but it is essential to make an accurate microbiological diag-
nosis to give each patient the best chance of survival. Consid-
eration of host risk factors such as CD4 count and geographic
region as well as the correct use and interpretation of
diagnostic testing is essential to establishing a definitive
diagnosis.
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