Clinical presentation and diagnosis of Pneumocystis pulmonary infection in HIV-

infected patients

Author:
Paul E Sax, MD
Section Editor:
John G Bartlett, MD
Deputy Editor:
Jennifer Mitty, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jan 2017. | This topic last updated: Nov 09, 2016.

INTRODUCTION The incidence of Pneumocystis jirovecii (previously

named Pneumocystis carinii) pneumonia has dramatically declined due to effective
antiretroviral therapy (ART) and, to a lesser extent, the use of prophylaxis. Despite this
decrease, it remains one of the leading causes of opportunistic infections among HIV-
infected persons with low CD4 cell counts, such as those who are unaware of their HIV
diagnoses or are not receiving medical care.

The general features of Pneumocystis pulmonary infection in the HIV-infected patient,

including clinical presentation and diagnosis, will be reviewed here. An overview of
extrapulmonary disease due to pneumocystic infection will also be discussed. Treatment
and prophylaxis of Pneumocystis infection in HIV-infected and non-infected individuals are
considered elsewhere. (See "Treatment and prevention of Pneumocystis infection in HIV-
infected patients" and "Treatment and prevention of Pneumocystis pneumonia in HIV-
uninfected patients".)

MICROBIOLOGY AND TERMINOLOGY Pneumocystis is currently recognized as a

fungus based upon ribosomal RNA and other gene sequence homologies, the composition
of their cell walls, and the structure of key enzymes [1]. Prior to being identified as a
fungus, the taxonomic classification of Pneumocystis as a genus of protozoan organisms
had been questioned for several years. However, Pneumocystis organisms are atypical
fungi as they do not grow in fungal culture, they respond to some antiparasitic agents, and
they have a cell wall that contains cholesterol rather than ergosterol [2]. The life cycle
consists of the trophic form, a precystic form, and the cystic form [3]. The trophic form
predominates over the cystic form during infection.

The nomenclature for Pneumocystis has also changed; the species that infects rats is
called P. carinii; and the one that infects humans, P. jirovecii [4]. P. jirovecii is now
designated as the species name to use in publications and references to human infections
[4,5]. However, the abbreviation of "PCP" is still used to refer to the clinical entity of
"Pneumocystis Pneumonia"; this allows for the retention of the familiar acronym and
maintains the accuracy of this abbreviation in older published papers.

PATHOGENESIS

Transmission The primary mode of transmission of P. jirovecii is via the airborne route.
Serologic studies show that primary infection occurs early in life, with 75 percent of
humans infected by the age of four years [6]. It was initially believed that PCP remained in
a latent state unless the patient became immunosuppressed; however, this may not
account for all cases of PCP. Animal and human studies have shown clearance of the
organism, and there is increasing evidence of transmission from person to person and
possibly through environmental reservoirs [7-11]. The role of colonization in humans may
also be of importance to Pneumocystis transmission. (See 'Colonization' below.)

Pathogen-host interaction Pneumocystis exists almost exclusively within the alveoli of

the lung [2]. The trophic forms first attach to the epithelium. Interaction
of Pneumocystis with alveolar epithelial cells and alveolar macrophages initiates a
cascade of cellular responses in both the organism and lung cells. Attachment
of Pneumocystis to lung epithelial cells enhances Pneumocystis proliferation.

Alveolar macrophages are the primary resident phagocytes that mediate the clearance of
the organisms from the lung. Phagocytosis, respiratory burst, and inflammatory activation
of alveolar macrophages in response to Pneumocystis are impaired in HIV-infected
persons, and may contribute to the pathogenesis of infection. Accumulating evidence
indicates that beta-glucan molecules, which are abundant in the cell wall
of Pneumocystis are important components that drive the initiation of the inflammatory
response during PCP. The most abundant surface protein of Pneumocystis is the major
surface glycoprotein (MSG) [12]. Variation of the expressed MSG may facilitate evasion of
host immune responses.

Host immunity Immune control of Pneumocystis involves production of chemokines

and inflammatory cytokines by alveolar macrophages and epithelial cells. In healthy
individuals, CD4+ T cells coordinate the host inflammatory response by recruiting and
activating additional immune effector cells including monocytes and macrophages, which
are responsible for elimination of the organism. In contrast to CD4+ T cells, the role of
CD8+ T cells in host defense against Pneumocystis is more controversial. However, CD8+
T cells may have some beneficial effect, particularly in a situation of chronic CD4+
depletion. In mice, the T-cell mediated inflammatory response can cause impaired lung
compliance and gas exchange; as such, both CD4+ and CD8+ T cells may result in
deleterious lung inflammation. In addition to T cells, neutrophils, recruited by CXCL2 and
IL-8, also participate in lung inflammation during PCP.

Colonization Healthy individuals, as well as those with HIV infection, underlying lung
disease, and immunosuppression, may harbor Pneumocystis in their respiratory tract
despite being without any signs or symptoms of disease. These colonized individuals have
generally been identified using experimental polymerase chain reaction assays.
(See 'Identifying the organism' below.)

The prevalence of Pneumocystis colonization among healthy adults ranges from 0 to 20

percent [2], and it has also been demonstrated to be a common colonizer in hospitalized
patients with bacterial and viral pneumonia [13].

The clinical significance of colonization is not well understood, but may be important for
several reasons [14]:

Colonized individuals may be at risk of developing pneumonia or transmitting

infection.
Colonized individuals receiving Pneumocystis prophylaxis may be at risk for
developing drug resistance mutations.
Ongoing colonization may trigger inflammation and local alveolar damage leading to
lung diseases, such as chronic obstructive pulmonary disease.

EPIDEMIOLOGY

Incidence The incidence of PCP has dramatically decreased after the administration of
potent ART, and the general adoption of recommendations for PCP prophylaxis [10,15-
19]. As examples:

In a United States cohort of HIV-infected patients, there was a decrease in PCP

incidence from 29.9 per 1000 person years between 1994 to 1997 to 3.9 per 1000
person years between 2003 to 2007 [18].
In Uganda, the frequency of PCP among HIV-infected patients hospitalized with
suspected pneumonia who had negative sputum acid-fast bacilli smears and
underwent bronchoscopy decreased from nearly 40 percent of bronchoscopies in
1999 to 2000 to less than ten percent in 2007 to 2008 [20,21].

The decrease in incidence with ART is due to both immunologic improvement as

measured by CD4 cell count increases and the suppression of HIV RNA. For example, in a
European cohort of HIV-infected individuals, the incidence of primary PCP was zero
among those with a CD4 count between 100 to 200 cells/microL who were receiving ART
and were virologically suppressed, independent of PCP prophylaxis [19].

Despite this decrease, PCP is still one of the leading causes of opportunistic infection in
HIV-infected individuals [18]. Most cases occur in patients who are undiagnosed or are not
receiving care [22,23].

Risk factors The main risk factor for PCP is advanced immunosuppression in patients
not taking antiretroviral therapy. Other risk factors include a CD4 cell count less than
200 cells/microL, a CD4 cell percentage of less than 14 percent, previous episodes of
PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and higher
plasma HIV RNA levels [24].

CLINICAL FEATURES OF PULMONARY DISEASE

Clinical manifestations The clinical manifestations of PCP are most commonly

gradual in onset, and are characterized by fever (80 to 100 percent), cough (95 percent),
and dyspnea (95 percent) progressing over days to weeks [25]. The average patient has
pulmonary symptoms for about 3 weeks before presentation. Patients may describe
fatigue with usual activities (climbing stairs, speaking on the telephone, shaving) that
previously were done without difficulty. The cough is generally nonproductive. Other
symptoms include fatigue, chills, chest pain, and weight loss. Approximately 5 to 10
percent of patients are asymptomatic.

The most common findings on physical examination are fever (over 80 percent of patients
have a temperature exceeding 38.1C) and tachypnea (60 percent). The most common
adventitial sounds are crackles and rhonchi, but a normal chest examination occurs in 50
percent of cases. Oral thrush is a common co-infection.

Laboratory findings There are several laboratory findings that are observed in HIV-
infected patients with PCP.

Low CD4 counts The incidence of PCP in HIV-infected patients increases as the CD4
count decreases [15,26,27], with most cases occurring when the CD4 count drops below
200 cells/microL [26,28]. A CD4 cell count percentage of less than 14 percent is also
commonly observed.

Oxygenation Hypoxia occurs with progression of PCP. The alveolar-arterial oxygen

gradient is widened in more than 90 percent of patients, ranging from mild (alveolar-arterial
O2 difference <35 mmHg) to severe (alveolar-arterial O2 difference >45 mmHg) [29].
Oxygen desaturation can occur with exercise and is highly suggestive of a diagnosis of
PCP [30-32]. (See "Approach to the HIV-infected patient with pulmonary symptoms",
section on 'Pulse oximetry or arterial blood gas analysis'.)

Lactate dehydrogenase level In studies done before the availability of effective ART,
an elevated lactate dehydrogenase (LDH) level was present in 90 percent of HIV-infected
patients with PCP and had some prognostic significance. In one study, the mean LDH of
PCP survivors was 340 IU, while the mean level of non-survivors was 447 IU [33]. More
importantly, a rising LDH level despite appropriate treatment portends a poor prognosis
[33,34].

1-3-beta-d-glucan Elevated plasma levels of 1-3-beta-d-glucan, a component of the

cell wall of P. jirovecii, have been found in HIV-infected patients with PCP. In a study of
282 HIV-infected patients, those with a diagnosis of PCP had significantly higher median
beta-D-glucan levels than patients without the disease (408 versus 37 pg/mL) [35]. The
use of this assay in supporting the diagnosis of PCP is discussed elsewhere.
(See 'Presumptive diagnosis' below.)

Diffusion capacity PCP is highly unlikely if the diffusion lung capacity for carbon
monoxide (DLCO) is normal (eg 70 percent of the predicted value or greater). One
prospective study of 306 HIV-positive patients with 467 episodes of worsening respiratory
symptoms found that PCP pneumonia was present in less than 2 percent of patients with a
normal or unchanged chest x-ray and a single breath DLCO >75 percent of the predicted
value [36].

Radiographic manifestations

Chest radiographs Chest x-rays are initially normal in up to one-fourth of patients with
PCP. The most common radiographic abnormalities are diffuse, bilateral, interstitial, or
alveolar infiltrates [37] (image 1). Upper lobe infiltrates and pneumothoraces can be seen
de novo; however, a higher incidence of both of these findings can be seen in patients
using aerosolized pentamidine prophylaxis [38-40]. (See "Pneumothorax in HIV-infected
patients".)

Other less common radiographic presentations include [25,39]:

Lobar or segmental infiltrates

Cysts
Nodules
Pleural effusions

High resolution computed tomography High resolution computed tomography

(HRCT) has a high sensitivity for PCP among HIV-positive patients [41-43]. One study, for
example, evaluated 51 patients with suspected PCP and normal, equivocal, or nonspecific
chest x-ray findings; HRCT had a sensitivity of 100 percent and a specificity of 89 percent
when the presence of patchy or nodular ground-glass attenuation was used to indicate
possible PCP [42]. While such findings are suggestive, they are not diagnostic. However, a
negative high resolution computed tomography scan makes the diagnosis of PCP highly
unlikely.

Gallium-67 citrate scanning Gallium-67 citrate scanning is sometimes used to screen

for PCP in suspected individuals with a normal chest radiograph but in whom a HRCT
cannot be obtained. Nuclear scanning is a highly sensitive test in patients with PCP,
demonstrating intense, diffuse bilateral uptake [44]. This test is rarely used for diagnosis
today.

EVALUATION AND DIAGNOSIS The initial approach to the HIV-infected patient with
pulmonary symptoms is discussed separately (see "Approach to the HIV-infected patient
with pulmonary symptoms"). If PCP is a consideration, we measure CD4 cell counts,
oxygen saturation, and 1-3-beta-d-glucan levels (if available). We also obtain a chest
radiograph and, if the plain film is nondiagnostic, a high resolution CT scan of the lung.

PCP is strongly suspected in the HIV-infected patient with a CD4 cell count less than
200 cells/microL, 1-3-beta-d-glucan levels greater than 80 pg/mL (especially if markedly
elevated), and symptoms/signs characteristic of the infection; particularly dyspnea,
hypoxemia, and cough, and diffuse, bilateral, interstitial, or alveolar infiltrates on chest
radiograph or HRCT.

Definitive diagnosis A definitive diagnosis of PCP requires visualization of the cystic

or trophic forms in respiratory secretions. Obtaining a definitive diagnosis of PCP is usually
important since treatment requires a prolonged course of possibly toxic therapy, and a
significant percentage of patients with PCP have an alternative or co-
occurring infection/disease. Approximately 15 percent have a concurrent cause of disease
[24]; this rate may be higher in resource-limited settings where coinfection with
Mycobacterium tuberculosis is more likely to occur [45]. However, some clinicians may
elect to forego obtaining a definitive diagnosis if the clinical presentation and radiographic
findings are highly consistent with PCP, especially if the beta glucan is markedly elevated.
(See 'Presumptive diagnosis' below and "Treatment and prevention of Pneumocystis
infection in HIV-infected patients".)

Empiric treatment should be initiated in acutely ill patients in whom there is a high clinical
suspicion for PCP. This is because:

The definitive diagnosis of PCP can be problematic since obtaining appropriate

specimens may be difficult to obtain and quickly process. Processing and
interpretation of an adequate specimen may require several days.
Many patients are acutely ill due to PCP and require definitive therapy before a
diagnosis can be confirmed.
The initiation of empiric therapy does not preclude obtaining a definitive diagnosis
since cysts may persist for days to weeks after appropriate therapy has been
administered [46,47].

Identifying the organism Since Pneumocystis cannot be cultured, the diagnosis relies
upon the visualization of the cystic or trophic forms in appropriate specimens. Stains that
have commonly been used selectively stain the cell wall of the cystic form, and include
Gomori-methenamine silver, cresyl violet, Gram-Weigert and toluidine blue O. Wright-
Giemsa and Diff-Quick detect both the cystic and trophic forms, but does not stain the cell
wall. Other agents that can be useful include the Papanicolaou stain and Calcofluor white.
Immunofluorescent staining using fluorescein-labeled monoclonal antibodies represents
the preferred technique for the diagnosis of PCP and is more sensitive than the general
stains [2,24,29].
Polymerase chain reaction (PCR) of respiratory fluid, in particular bronchoalveolar lavage
(BAL), is increasingly used to make the diagnosis of PCP in HIV-uninfected patients who
are immunocompromised [48]. Experience in patients with HIV is limited [29,49,50],
although several clinical laboratories offer the test. Advantages to PCR testing include
confirming the diagnosis in clinically suspect cases with negative sputum or BAL smears,
and using alternative specimens such as oral washes and nasopharyngeal aspirates
[50,51]. A disadvantage is that PCR cannot distinguish between colonization and disease
[10].

Optimal specimens There are several respiratory and lung tissue specimens that are
optimal for immunofluorescent staining. The type of specimen that should be obtained
depends on the respiratory status of the patient, concern for alternative pathogens, the
institution where the specimen is being processed, and the risks of the various procedures.
In most cases, sputum induction is the initial step in the attempt to obtain an adequate
specimen. In many cases, however, bronchoalveolar lavage (BAL) specimens are required
to make the diagnosis of PCP. The ability to detect Pneumocystis can be reduced in
patients receiving prophylactic therapy, particularly those receiving
aerosolized pentamidine [38,52].

Infrequently, a more invasive technique, such as a lung biopsy, is necessary. However,

most patients are treated empirically without resorting to these more invasive methods
because of the significant morbidity associated with their use. In patients in whom an
alternative diagnosis is likely, the use of these techniques may be necessary.

Sputum induction The least invasive method of definitively diagnosing PCP in HIV-
infected individuals is by analysis of sputum induced via the inhalation of hypertonic saline.
While the specificity of this method can approach 100 percent, the sensitivity is highly
variable, ranging from 55 to approximately 90 percent [53-55]. Factors that affect the
accuracy of sputum induction include the type of staining that is used, the quality of the
specimen, the burden of organisms (particularly in the setting of prophylactic therapy), and
the expertise of the laboratory in interpreting the specimen.

Bronchoalveolar lavage In HIV infected individuals, BAL is highly sensitive for the
diagnosis of PCP. Therefore, if sputum induction is nondiagnostic or cannot be performed
(eg, the patient cannot cooperate, is too dyspneic, or is unable to produce a specimen),
fiberoptic bronchoscopy with BAL is the next recommended step.

BAL alone has a diagnostic yield of 90 to 100 percent in HIV-infected patients. To increase
its sensitivity, site-directed lavage can be used in patients with focal infiltrates; this involves
sampling the most heavily involved lobes on chest radiograph. One group has shown that
the combination of site-directed lavage and immunofluorescent antibody staining
increased the sensitivity of BAL from 80 to 98 percent [56]. Transbronchial biopsy, which
has a diagnostic yield of up to 100 percent, can be added if necessary.
The major concerns with using BAL are the potential risks of the procedure. These include
respiratory failure (rare) and fever (common). Transbronchial biopsy can be complicated
by hemoptysis and pneumothorax (the latter occurring in less than 2 percent).

Tissue biopsy If sputum induction, BAL, and a transbronchial biopsy are nondiagnostic
or cannot be performed, more invasive techniques may be necessary to diagnose PCP.
Options include transthoracic needle biopsy or lung biopsy performed either via
thoracotomy or by video-associated thoracoscopic surgery. However, the risks with these
procedures, which are significant, must be weighed against the need for an accurate and
definitive diagnosis:

Transthoracic needle biopsy, which has a high diagnostic yield, is associated with a
30 percent incidence of pneumothorax.
Lung biopsy, either by thoracotomy or by video-assisted thoracoscopic surgery, can
be performed with a sensitivity of 95 to 100 percent for the diagnosis of PCP [24].
Histology on lung biopsy demonstrates the formation of a foamy, eosinophilic alveolar
exudate; severe cases are associated with edema and interstitial fibrosis [57].

Endotracheal aspirates Endotracheal aspirates from intubated and mechanically

ventilated patients have a high sensitivity for the detection of PCP. As an example, one
study of 31 intubated patients found that endotracheal aspirates examined with
immunostaining techniques had a sensitivity of 92 percent for PCP, with immunostained
BAL specimens serving as the reference standard [58]. Thus, examination of endotracheal
aspirates in intubated patients may obviate the need for bronchoscopy in many cases.

Presumptive diagnosis There are times when a definitive diagnosis cannot be made
due to a low burden of organisms and/or the inability to obtain the necessary specimen. In
those situations, a decision must be made whether or not to continue treatment.

Clinical and radiographic findings can be highly suggestive of a diagnosis of PCP in

patients with low CD4 cell counts. Increasingly, elevated levels of 1-3-beta-d-glucan are
used to help support this diagnosis. Thus, some clinicians may choose to forego obtaining
a definitive diagnosis if beta glucan levels are markedly elevated and the clinical
presentation and radiographic findings are highly consistent with PCP. Others, however,
recommend obtaining a definitive diagnosis if possible [24].

Support for the diagnostic utility of 1-3-beta-d-glucan levels is provided by a study of 282
HIV-infected patients in which levels greater than 80 pg/mL were associated with a
sensitivity and specificity of 92 and 65 percent for the diagnosis of PCP, respectively [35].
Further analysis showed that, among individuals with advanced immunosuppression and
respiratory symptoms, the positive and negative predictive values for PCP of a beta-glucan
level of greater than 80 pg/mL was 96 and 60 percent, respectively [59]. Elevated levels
can also be observed in patients infected with other fungi (in particular histoplasmosis),
and false positives can be seen as a result of other clinical variables. Therefore, potential
confounding factors must be considered when interpreting the results of this test.
(See "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay'.)

In patients without evidence of an alternative and/or concurrent diagnosis, we continue

therapy for presumed PCP in individuals with all of the following clinical features:

Advanced immunosuppression (CD4 cell count less than 200 cells/microL)

Clinical signs and symptoms such as cough, fever, dyspnea, hypoxemia (especially
with exercise)
Radiographic findings consistent with PCP on chest x-ray (interstitial, or alveolar
infiltrates) or HRCT (patchy or nodular ground-glass attenuation)
An elevated 1-3-beta-D-glucan level (defined as greater than 80 pg/mL) [59].

These patients must be closely monitored for failure to respond to treatment or clinical
deterioration. In those cases, a more extensive work up may be indicated. (See 'Optimal
specimens' above and 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS

Overview HIV-infected patients may have symptoms and/or signs that mimic PCP
which are due to a wide variety of disease processes. Considerations include acute
bronchitis, pneumonia due to bacteria, fungi, viruses and mycobacteria, neoplasm, drug
hypersensitivity, pulmonary hypertension, and cardiomyopathy. These diseases may
present with atypical signs and/or symptoms in patients with advanced
immunosuppression and the clinician must be diligent in ensuring that they are not
responsible for the underlying clinical presentation. This is discussed separately.
(See "Approach to the HIV-infected patient with pulmonary symptoms".)

Pulmonary infections with specific organisms are a significant concern in HIV infected
patients with CD4 counts less than 200 cells/microL. These include tuberculosis,
nontuberculosis mycobacteria, several different fungi, toxoplasma, cytomegalovirus, and
influenza. Kaposis sarcoma involving the lung is also a concern, particularly in patients
with CD4 counts less than 100 cells/microL.

Tuberculosis Patients with tuberculosis (TB) present with fever, cough, weight loss,
night sweats and malaise. As immunity declines, the frequency of pulmonary cavitation,
which is the hallmark of pulmonary TB in adults, becomes progressively less common
[60,61]. In HIV-infected individuals with advanced immunosuppression, the findings on
chest radiographs can vary, ranging from no evidence of disease to a miliary pattern.
(See "Epidemiology, clinical manifestations, and diagnosis of tuberculosis in HIV-infected
patients".)

Compared with PCP, tuberculosis is associated with more severe constitutional symptoms.
The incidence of TB in HIV-infected individuals varies markedly depending on
epidemiology. Most cases in the United States now occur in individuals originally from
countries where TB is highly endemic, or in those with risk factors for exposure (eg,
prisoners, injection drug users, household contacts of active TB cases).

Nontuberculous mycobacteria There are a variety of nontuberculous mycobacteria

(NTM) that can cause disease in patients with HIV, especially in those with CD4 cell
counts less than 50 cells/microL. Most disease in HIV secondary to NTM presents as
disseminated disease, without respiratory symptoms or pulmonary involvement; this is
particularly the case for Mycobacterium avium complex (MAC). This manifestation of MAC
is far different from the multifocal nodular disease (with "tree in bud" radiographic
opacities) seen in immunocompetent hosts, such as those with bronchiectasis. However,
on rare occasions disease due to M. kansasii and M. xenopi can present with localized
pulmonary findings.

Fungi HIV-infected patients who are from regions known to have endemic fungal
infections can present with disseminated diseases that may mimic PCP. The most
important of these is disseminated histoplasmosis. Both diagnoses should be considered
in a patient with fever, cough, and diffuse interstitial infiltrates who is from a
histoplasmosis-endemic area. Elevated beta-glucan levels are observed in both PCP and
histoplasmosis. Findings suggestive of histoplasmosis include adenopathy,
hepatosplenomegaly, and/or the presence of oral or other mucosal ulcerations. The
diagnosis is confirmed with histoplasmosis antigen testing. Other fungi, including
cryptococcus and coccidioides, can also mimic PCP. (See "Epidemiology and clinical
manifestations of histoplasmosis in HIV-infected patients" and "Cryptococcus neoformans
infection outside the central nervous system", section on 'HIV-positive patients'.)

Toxoplasma Pneumonitis, as an extracerebral manifestation of toxoplasmosis,

presents with fever, dyspnea and non-productive cough [62]. Chest radiographs typically
have reticulonodular infiltrates. The clinical picture may therefore be indistinguishable from
PCP. Toxoplasma, which is a much less common respiratory pathogen
than Pneumocystis in HIV-infected patients with low CD4 counts, can be identified in
bronchoalveolar lavage (BAL) fluid [62,63]. (See "Toxoplasmosis in HIV-infected patients",
section on 'Pneumonitis'.)

Cytomegalovirus Pneumonitis due to Cytomegalovirus (CMV) typically occurs in HIV-

infected patients with CD4 cell counts less than 50 cells/microL. CMV pneumonitis and
PCP have similar clinical presentations, but CMV pneumonitis is much less common in
HIV-infected patients. A definitive diagnosis of CMV pneumonitis requires observing CMV
inclusion bodies on biopsy. (See "Cytomegalovirus infection as a cause of pulmonary
disease in HIV-infected patients".)

Influenza HIV-infected individuals are considered at high risk for complications of

influenza, one of which is primary influenza pneumonia. This presents with the acute onset
of a severe viral syndrome (fever, myalgias, headache) followed by progressive respiratory
symptoms such as dyspnea and possibly cyanosis. Typical radiographic manifestations
include bilateral reticular or reticulonodular opacities with or without superimposed
consolidation. High-resolution computed tomography may show multifocal
peribronchovascular or subpleural consolidation and/or ground glass opacities. Unlike the
acute onset of influenza pneumonia, symptoms associated with PCP occur in a subacute
fashion. (See "Clinical manifestations of seasonal influenza in adults", section on
'Pneumonia'.)

Kaposi's sarcoma Kaposis sarcoma may cause a multifocal nodular disease in HIV-
infected individuals with CD4 counts less than 100 cells/microL. Although most patients
with pulmonary symptoms have skin findings, up to 20 percent have no evidence of
cutaneous disease. Direct visualization of characteristic lesions on bronchoscopy remains
the gold standard for diagnosis; if bronchoscopy cannot be performed, findings with
nuclear scans can help differentiate KS from PCP. (See "Pulmonary involvement in AIDS-
related Kaposi sarcoma".)

EXTRAPULMONARY DISEASE Extrapulmonary manifestations

of Pneumocystis infection are rare and have been observed in patients with very advanced
HIV infection, as well as in those receiving second-line therapy for PCP prevention,
including dapsone and aerosolized pentamidine. Current or prior PCP does not need to be
present at the time of presentation, and disease can be restricted to a single site.
However, when multiple noncontiguous sites are involved, pulmonary disease is often
present [64].

Extrapulmonary Pneumocystis has been reported to involve the eye (typically the choroid
layer), ear, thyroid, spleen, as well as multiple other sites. In most cases, the diagnosis is
made by detection of cysts in GMS-stained, formalin fixed tissue. In some situations, such
as when disease is localized to the eye, the diagnosis is based on the characteristic
appearance of the lesion on exam and supported by the appropriate response to therapy.
The prognosis is better when disease is limited to the eye or ear compared with
disseminated disease at noncontiguous sites [64].

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SUMMARY AND RECOMMENDATIONS

Although the incidence is decreasing, PCP remains one of the leading causes of
opportunistic infection in HIV-infected individuals. Most cases occur in patients who
are not receiving antiretroviral therapy (ART), either because they are newly
diagnosed with HIV or not engaged in care. (See 'Epidemiology' above.)
Pneumocystis is currently recognized as a fungus based upon ribosomal RNA and
other gene sequence homologies, the composition of their cell walls, and the
structure of key enzymes. (See 'Microbiology and terminology' above.)
Risk factors include not receiving ART, a CD4 cell count less than
200 cells/microL, a CD4 cell percentage of less than 14 percent, previous episodes of
PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and higher
plasma HIV RNA levels. (See 'Risk factors' above.)
The clinical manifestations, which are most commonly gradual in onset, are
characterized by fever, cough, and dyspnea progressing over days to weeks.
(See 'Clinical manifestations' above.)
If PCP is a consideration, we measure CD4 counts, oxygen saturation, and 1-3-
beta-d-glucan levels (if available). We also obtain a chest radiograph and, if the plain
film is nondiagnostic, a high resolution CT scan of the lung. (See 'Evaluation and
diagnosis' above.)
A definitive diagnosis of PCP requires visualization of the cystic or trophic forms in
respiratory secretions. Empiric treatment should be initiated in acutely ill patients in
whom there is a high clinical suspicion for PCP. (See 'Evaluation and
diagnosis' above.)
In most cases, sputum induction is the initial step in the attempt to obtain an
adequate specimen. In many cases, however, bronchoalveolar lavage (BAL)
specimens are required to make the diagnosis of PCP. (See 'Optimal
specimens' above.)
There are times when a definitive diagnosis is unable to be made due to a low
burden of organisms and/or the inability to obtain the necessary specimen. In those
situations, we make a presumptive diagnosis of PCP in the patient with a clinical
presentation and radiographic findings that are highly consistent with PCP,
particularly if beta glucan levels are marked elevated. (See 'Presumptive
diagnosis' above.)
The differential diagnosis is broad, and includes acute bronchitis, pneumonia due to
bacteria, fungi, viruses and mycobacteria, neoplasm, drug hypersensitivity, pulmonary
hypertension, and cardiomyopathy. (See 'Differential diagnosis' above.)
Topic 3704 Version 15.0
Treatment and prevention of Pneumocystis infection in HIV-infected patients

Author:
Paul E Sax, MD
Section Editor:
John G Bartlett, MD
Deputy Editor:
Jennifer Mitty, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jan 2017. | This topic last updated: Aug 27, 2015.

INTRODUCTION Pneumocystis jirovecii pneumonia (formerly called Pneumocystis

carinii pneumonia or PCP) is the most common opportunistic respiratory infection in
patients infected with AIDS. It typically occurs in HIV-infected patients with a CD4 count
<200 cells/microL who are not receiving potent antiretroviral therapy or appropriate
prophylaxis.

This topic will review the treatment and prevention of PCP in patients with HIV infection.
Topic reviews on the clinical presentation and diagnosis of PCP in HIV-infected individuals
and PCP in the HIV-uninfected host are discussed separately. (See "Clinical presentation
and diagnosis of Pneumocystis pulmonary infection in HIV-infected
patients" and "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis
pneumonia in HIV-uninfected patients" and "Treatment and prevention of Pneumocystis
pneumonia in HIV-uninfected patients".)

TREATMENT Antimicrobial therapy directed against P. jirovecii is the mainstay of

treatment for Pneumocystis pneumonia (PCP). In addition, some patients will require
adjunctive corticosteroids. Antiretroviral therapy (ART) should be initiated to restore
cellular immunity. For those patients already receiving ART, we continue their ART
regimen while they are being treated for PCP. (See "Selecting antiretroviral regimens for
the treatment-nave HIV-infected patient" and 'Timing of ART initiation' below.)

Empiric therapy for PCP should be initiated pending the results of the diagnostic
evaluation if there is a high clinical suspicion for PCP (eg, CD4 count
<200 cells/microL, hypoxemia, interstitial infiltrates). In certain situations, it is not possible
to confirm the diagnosis, and patients are treated and monitored for clinical response
(see 'Monitoring patients on treatment' below). A detailed discussion on the clinical
manifestations and diagnosis of PCP is found elsewhere. (See "Clinical presentation and
diagnosis of Pneumocystis pulmonary infection in HIV-infected patients".)

After patients complete their initial treatment regimen, antimicrobial therapy should be
continued at lower doses to prevent recurrent infection (ie, secondary prophylaxis). This
preventive therapy can be discontinued after immune recovery has been achieved for a
prolonged period of time. (See 'Secondary prophylaxis' below.)

Initial assessment Several factors impact the approach to treatment for patients with
PCP. Thus, prior to initiating therapy, we assess the following:

Drug allergies Trimethoprim-sulfamethoxazole (TMP-SMX), a sulfa-containing

regimen, is the preferred treatment for PCP. For patients with a sulfa allergy, a
second-line regimen is generally used. However, we may desensitize certain patients
to TMP-SMX, such as those with severe PCP, if their sulfa allergy is non-life
threatening. (See 'Preferred regimen' below and 'Alternative regimens' below
and 'Desensitization for patients with a sulfa allergy' below.)
Respiratory status We evaluate the patients respiratory status to help assess
the severity of disease. We first assess the patient clinically by measuring their
respiratory rate and evaluating the use of accessory muscles of respiration. We then
measure arterial oxygenation using pulse oximetry. (See "Approach to the HIV-
infected patient with pulmonary symptoms", section on 'Pulse oximetry or arterial
blood gas analysis'.)
Guidelines suggest obtaining an arterial blood gas in patients with evidence of
respiratory distress, tachypnea, and/or hypoxia to further assess the severity of
disease (eg, alveolar to arterial oxygen [A-a] gradient) [1]. However, with the reliability
of pulse oximetry, we no longer obtain a blood gas solely to determine the need for
corticosteroids if a patient has clear evidence of hypoxemia (eg, resting room air
oxygen saturation <92 percent). A blood gas may still be useful to help determine if
the patient requires placement in the intensive care unit and/or if an intravenous
regimen should be used. (See 'Severe disease' below.)
Factors that impact absorption Many patients with PCP can be treated with an
oral regimen. However, some individuals may have a concurrent condition that
impacts their ability to take an oral medication (eg, severe esophageal candidiasis,
diarrhea). Such patients will require intravenous (IV) therapy until these other
conditions have improved.

Approach The initial approach to treatment (eg, the choice of agent, the mode of
administration, and the use of adjunctive corticosteroids) is determined primarily by the
level of oxygenation and/or the A-a gradient. An overview of the management of patients
with mild, moderate, or severe disease is reviewed here. A discussion of the specific
antimicrobial agents is found below. (See 'Antimicrobial regimens' below.)

Mild disease Patients with mild disease have an A-a O2 gradient <35 mmHg and/or a
partial pressure of arterial oxygen 70 mmHg.

We administer oral therapy to such patients unless they have a concurrent infection or
comorbidity that would impact absorption. We suggest TMP-SMX for treatment of mild
disease; alternative regimens include trimethoprim-dapsone, clindamycin-primaquine,
or atovaquone. Such patients do not require corticosteroids. (See 'Preferred
regimen' below and 'Alternative regimens for mild to moderate disease' below and 'Whom
to treat with corticosteroids' below.)

Moderate disease Patients with moderate disease have an A-a O2 gradient 35 and
<45 mmHg and/or a partial pressure of arterial oxygen 60 and <70 mmHg.

As with mild disease, we administer oral therapy unless the patient has a concurrent
infection or comorbidity that would impact absorption. We suggest TMP-SMX for treatment
of moderate disease. Alternative regimens include trimethoprim-dapsone or clindamycin-
primaquine; we generally do not use atovaquone as initial treatment for moderate disease.
In addition, individuals with moderate disease require adjunctive corticosteroids.
(See 'Preferred regimen' below and 'Alternative regimens for mild to moderate
disease' below and 'Corticosteroid regimen' below.)

Severe disease A patient has severe disease when the A-a O2 gradient is 45 mmHg,
the partial pressure of arterial oxygen is <60 mmHg, and/or there is potential for fatigue
leading to respiratory failure (eg, a high respiratory rate or a partial pressure of arterial
carbon dioxide that is normal or higher than normal in a patient with hypoxia).

We recommend TMP-SMX for patients with severe disease. Individuals should receive
intravenous therapy until they are clinically stable (eg, PaO2 60 mmHg, respiratory rate
<25) and are able to be transitioned to oral treatment. Adjunctive corticosteroids should
also be administered. (See 'Preferred regimen' below and 'Alternative regimens for severe
disease' below and 'Corticosteroid regimen' below.)

For those with a sulfa allergy, we suggest pentamidine. Patients should be switched to a
less toxic regimen as soon as they can tolerate oral therapy. For such patients, we also
obtain a detailed history to assess the type and severity of their past reaction since certain
individuals can be desensitized to TMP-SMX. (See 'Desensitization for patients with a
sulfa allergy' below.)

Indications for hospitalization Patients with PCP sometimes worsen after two to three
days of therapy. This must be taken into consideration when deciding who requires
hospitalization. In general, the following are indications for inpatient therapy: disease
severe enough to warrant treatment with corticosteroids, regardless of whether
intravenous or oral anti-Pneumocystis therapy is used; initial treatment with
intravenous pentamidine given the potential side effects of therapy (in particular,
hypoglycemia and hypotension); and patients for whom compliance with therapy or
laboratory monitoring is likely to be difficult.

Antimicrobial regimens

Preferred regimen TMP-SMX is the preferred regimen for the treatment of PCP in HIV-
infected patients (table 1). Therapy should be administered for 21 days. Trimethoprim is a
dihydrofolate reductase inhibitor, and sulfamethoxazole is a dihydropteroate synthetase
inhibitor; when coupled together they are synergistic in eradicating P. jirovecii.
(See "Trimethoprim-sulfamethoxazole: An overview".)

The standard dose of TMP-SMX is 15 to 20 mg/kg/day orally or intravenously in three or

four divided doses. Dosing of TMP-SMX is based upon the TMP component and
expressed as mg/kg per day of TMP. Dose modifications for renal impairment may be
needed; detailed dosing recommendations are available in the TMP-SMX drug information
monograph included within UpToDate.

The severity of disease dictates whether oral or intravenous therapy should be used:

For patients with mild to moderate disease, we prefer oral therapy since TMP-SMX
has excellent oral absorption. For most patients, this turns out to be two double-
strength tablets given every eight hours.
For patients with severe disease, we administer IV therapy. (See 'Severe
disease' above.)

We treat with TMP-SMX even if the patient was prescribed TMP-SMX for PCP prophylaxis
(see 'Preventing initial infection' below). Most patients who break through TMP-SMX
prophylaxis do so because of non-adherence to their medication [2]. Although sulfa-
containing agents can result in resistance mutations in the dihydropteroate synthase
(DHPS) gene of P. jirovecii [3], drug resistance leading to treatment failure is unlikely [4].

The efficacy of TMP-SMX for treating PCP has been most clearly demonstrated in
individuals with severe disease [5-9]. As an example, in a randomized trial of 70 patients
with severe PCP that compared TMP-SMX with pentamidine, the survival rate was
significantly higher in those receiving TMP-SMX (86 versus 61 percent) [6]. Among those
with mild to moderate disease, there are no high quality data to support the use of TMP-
SMX over one of the other agents. However, based upon our clinical experience, and the
experience of other experts [1], we suggest TMP-SMX for initial treatment of mild to
moderate PCP. (See 'Alternative regimens for mild to moderate disease' below.)

Alternative regimens For those who are unable to take TMP-SMX, the choice of which
alternative agent to use is based upon the severity of disease, the patients intolerances
and allergies, and the ease of administration (table 1). Dose modifications for renal
impairment may be needed for certain agents; detailed dosing recommendations are
available in the specific drug information monographs included within UpToDate.

Alternative regimens for mild to moderate disease Several alternative regimens can
be used for the treatment of mild to moderate disease; the available data do not favor one
over the other. This was illustrated in a multicenter trial that randomly assigned 181
patients with mild to moderate PCP (defined as an A-a O2 gradient <45 mmHg) to therapy
with TMP-SMX, TMP-dapsone, or clindamycin-primaquine for 21 days [2]. Patients with an
A-a O2 gradient between 35 and 45 mmHg also received corticosteroids. There was no
significant difference between groups in the rate of treatment failure or mortality
(approximately 5 percent in each treatment arm). However, the risk of hematologic and
hepatotoxicity were significantly more frequent in those receiving clindamycin-primaquine
and TMP-SMX, respectively.

The following oral regimens should be administered for 21 days, and are listed in order of
our preference:

Trimethoprim-dapsone Oral trimethoprim is administered at a dose of

5 mg/kg (typically rounded to the nearest 100 milligrams) three times per day with
dapsone 100 mg per day. Dapsone is a sulfone that is usually tolerated by persons
who have adverse reactions to TMP-SMX [10,11]. (See "Sulfonamide allergy in HIV-
uninfected patients", section on 'Cross-reactivity'.)
Clindamycin-primaquine Oral clindamycin-primaquine is administered as
clindamycin (450 mg every six hours or 600 mg every eight hours) along with
primaquine base 30 mg per day.
Atovaquone Atovaquone suspension can be used for the treatment of mild PCP
(see 'Mild disease' above). The dose is 750 mg twice daily and should be taken with
food [12]. In general, we do not use this agent for the initial treatment of moderate
disease since atovaquone was less effective than TMP/SMX in a comparative clinical
trial [13]. However, we may switch a patient with moderate to severe disease to
atovaquone if they are clinically improved on a more potent agent, but have
developed an adverse reaction.

Patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency

when using a regimen that contains dapsone or primaquine since patients with G6PD
deficiency are at risk for developing hemolytic anemia when exposed to these agents.
Patients with G6PD deficiency and mild disease should receive atovaquone. For those
with G6PD deficiency and moderate disease, the decision to use atovaquone, desensitize
to TMP-SMX, or switch to IV therapy with pentamidine depends upon the severity of their
disease and their past reaction to TMP-SMX. Although it is best if G6PD results are
available prior to initiating treatment, therapy may be initiated simultaneously with testing
as the risk for this deficiency is quite low. (See "Initial evaluation of the HIV-infected adult",
section on 'G6PD deficiency' and "Diagnosis and management of glucose-6-phosphate
dehydrogenase deficiency".)

Alternative regimens for severe disease We suggest intravenous pentamidine for

patients with severe disease who cannot take TMP-SMX based upon extensive clinical
experience with this agent compared with other regimens for severe disease. Clindamycin-
primaquine can be used for those who have contraindications or adverse reactions to
pentamidine; however, primaquine must be administered orally.
 Pentamidine Pentamidine is administered intravenously at a dose of 4 mg/kg daily.
We avoid pentamidine in patients with renal insufficiency (estimated glomerular
filtration rate <60 mL/min/1.73m2), as well as those with concurrent pancreatitis
because of its potential toxicities (see 'Adverse reactions' below). Patients who
require treatment with pentamidine should be admitted to the hospital and closely
monitored with bedside telemetry and frequent measurement of blood pressure. The
drug should be administered over at least 60 minutes while the patient is supine and
adequately hydrated.
Adverse reactions to pentamidine are common and can be severe. Individuals who
improve while on pentamidine should be switched to a safer oral regimen as soon as
clinically feasible. However, the pentamidine dose can be reduced to 3 mg/kg IV daily
for patients who experience toxicity if no other treatment option is possible.
(See 'Adverse reactions' below and 'Alternative regimens for mild to moderate
disease' above.)
Clindamycin-primaquine Clindamycin can be administered intravenously at a dose
of 600 mg every six hours or 900 mg every eight hours. Primaquine base is given
orally at a dose of 30 mg daily. Patients should be tested for G6PD when initiating this
regimen since patients with G6PD deficiency are at risk for developing hemolytic
anemia when exposed to primaquine. (See "Initial evaluation of the HIV-infected
adult", section on 'G6PD deficiency' and "Diagnosis and management of glucose-6-
phosphate dehydrogenase deficiency", section on 'Acute hemolytic anemia'.)

For patients with a sulfa allergy, we obtain a detailed history to assess the type and
severity of their past reaction; this will allow us to determine if it is safe for them to be
desensitized to TMP-SMX. Patients who undergo desensitization should continue
treatment with one of these alternative regimens until they are able to tolerate treatment
doses of TMP-SMX. (See 'Desensitization for patients with a sulfa allergy' below.)

Use of corticosteroids Corticosteroids given in conjunction with anti-Pneumocystis

therapy can decrease the incidence of mortality and respiratory failure associated with
PCP [14]. Without steroids, patients with PCP may worsen clinically after two to three days
of therapy, presumably due to increased inflammation in response to dying organisms.
(See "Clinical presentation and diagnosis of Pneumocystis pulmonary infection in HIV-
infected patients", section on 'Clinical Features of Pulmonary disease'.)

Several randomized trials have demonstrated the benefits of administering corticosteroids

to patients with PCP who have abnormalities in oxygen exchange at the time of
presentation [15-17]. These findings were illustrated in a Cochrane Database review of
seven randomized controlled trials that evaluated the effects of adjunctive corticosteroids
in HIV-infected patients with moderate to severe disease [14]. Compared with placebo, the
risk ratios for overall mortality in patients receiving adjunctive corticosteroids were 0.56
(95% CI 0.32-0.98) at one month and 0.59 (95% CI 0.41-0.85) at three to four months of
follow-up.
Whom to treat with corticosteroids We recommend the use of adjunctive
corticosteroids for patients with moderate to severe disease (table 1). (See 'Moderate
disease' above and 'Severe disease' above.)

If blood gas data are available, we agree with guideline panels and initiate steroids in
patients with [1,18]:

A partial pressure of oxygen of <70 mmHg on room air and/or

An alveolar-arterial (A-a) oxygen gradient of 35 mmHg

However, with the reliability of pulse oximetry, we no longer obtain a blood gas solely to
determine the need for corticosteroids if a patient has clear evidence of hypoxemia (eg,
resting room air oxygen saturation <92 percent). A blood gas may still be useful to help
determine if the patient requires placement in the intensive care unit and/or if an
intravenous regimen should be used. (See 'Severe disease' above.)

We also administer corticosteroids to patients with worsening respiratory symptoms after

starting treatment. Although there are no controlled studies evaluating the use of
corticosteroids in this setting, one case series suggested there may be some benefit [19].

Corticosteroid regimen Corticosteroids should be initiated concurrently with anti-

Pneumocystis therapy. Although studies have not demonstrated the optimal dose or
duration of therapy, we administer the following 21-day oral regimen [1,18]:

Prednisone 40 mg twice daily for 5 days

followed by
Prednisone 40 mg daily for 5 days
followed by
Prednisone 20 mg daily for 11 days

Intravenous methylprednisolone can be substituted for oral prednisone at 75 percent of the

prednisone dose if IV therapy is necessary.

Pregnancy TMP-SMX is the preferred therapy for PCP in pregnant women. If an

alternative regimen must be used, we prefer trimethoprim-dapsone since there is clinical
experience with this regimen in pregnancy [1]. (See 'Preferred regimen' above
and 'Alternative regimens for mild to moderate disease' above.)

However, there are risks associated with the use of TMP-SMX and dapsone in pregnancy.
As examples:

First-trimester exposure to TMP-SMX has been associated with an increased risk for
neural tube defects and cardiovascular, urinary tract, and other anomalies [20]. Folic
acid supplementation may reduce this risk [21], but there are concerns that folic acid
can lead to increased treatment failures in patients being treated for PCP. Thus, we
 administer folic acid only to women in the first trimester. In addition, we obtain a
follow-up ultrasound at 18 to 20 weeks to assess fetal anatomy [1].
If sulfa drugs or dapsone are used near delivery, neonatal providers should be
informed since there is an increased risk of kernicterus.

We do not use intravenous pentamidine in pregnant women since animal studies suggest
that pentamidine can cause embryonic toxicity and death when administered at doses
similar to those used in humans [22]. (See 'Alternative regimens for severe
disease' above.)

The indications for corticosteroids are the same as in nonpregnant patients; however,
pregnant women should be followed closely for gestational diabetes when treated with
corticosteroids during the third trimester. Some women may also require stress dose
corticosteroids during delivery [1]. (See "The management of the surgical patient taking
glucocorticoids".)

More detailed discussions on the use of TMP-SMX in pregnancy are found elsewhere.
(See "Trimethoprim-sulfamethoxazole: An overview", section on 'Pregnancy and
breastfeeding' and "Prenatal evaluation of the HIV-infected woman in resource-rich
settings", section on 'Chemoprophylaxis for opportunistic infections'.)

Prognosis Most patients being treated for PCP will improve on therapy. However,
some patients develop progressive respiratory failure, even with appropriate treatment.
Studies done prior to the widespread use of antiretroviral therapy found that response to
treatment depends, in part, upon the degree of hypoxia at presentation [2,17,23,24]. As
examples:

Patients with mild to moderate disease (A-a O2 gradient 45 mmHg) had a case
fatality rate <10 percent [2], whereas patients with more severe abnormalities in gas
exchange had a case fatality >20 percent [17].
The mortality among patients with PCP and respiratory failure requiring intensive
care admission or mechanical ventilation was reported to be as high as 60 percent
[25-28].

Other factors that correlate with poor outcome include increasing age, a prior episode of
PCP, an elevated serum lactate dehydrogenase concentration, a low CD4 cell count, and
the presence of cytomegalovirus in bronchoalveolar lavage fluid [23,24,29-31].

Initiating antiretroviral therapy (ART) improves the prognosis of patients with PCP and
advanced HIV-related immunosuppression [31-33]. In an observational study that included
5222 episodes of PCP occurring among 4412 patients, the 12-month survival increased
from 40 percent in 1992 to 1993 to 63 percent in 1996 to 1998 (ie, after the introduction of
potent ART) [31]. Administering antiretroviral therapy soon after treatment for PCP is
initiated provides the best benefit. (See 'Timing of ART initiation' below.)
Monitoring patients on treatment Patients should be monitored for adverse events
related to their treatment regimen, as well as their response to therapy.

For patients with mild to moderate disease being treated as an outpatient, we

schedule a follow-up visit within one week of starting treatment to perform a clinical
assessment and obtain laboratory testing. At that visit, we measure the oxygen
saturation, obtain a complete blood count, and measure renal function, electrolytes,
and aminotransferase levels.
For patients with severe disease requiring hospitalization, daily clinical assessments
and more frequent laboratory monitoring are needed. For such patients, we monitor
complete blood counts, electrolytes, and liver function tests at least two to three times
per week. Individuals receiving pentamidine should have renal function, glucose,
calcium, and electrolyte concentrations monitored daily; such patients should be
switched to a less toxic regimen as soon as they can tolerate oral therapy.
(See 'Alternative regimens' above.)
Individuals who receive corticosteroids should be monitored for the development of
new opportunistic infections, especially candidiasis [34-37]. In an observational study
of 174 patients with PCP, adjunctive corticosteroids increased the likelihood of
subsequent esophageal candidiasis [36].

Adverse reactions Several of the antimicrobial regimens used to treat PCP are
associated with significant side effects. A change in regimen may be needed for patients
who develop severe adverse reactions (eg, Stevens Johnson syndrome with TMP-SMX,
pancreatitis or renal failure with pentamidine).

TMP-SMX Adverse reactions to TMP-SMX are common in patients being treated

for PCP [38]. Reactions can range from mild to severe and include gastrointestinal
intolerance, photosensitivity, rash, and fever. Laboratory testing can reveal
leukopenia and marked hyperkalemia, as well as evidence of acute kidney injury and
hepatotoxicity [39]. Sulfonamides should be immediately discontinued if any of the
following conditions are present [40]:
Persistent rash and/or fever for more than five days
Absolute neutrophil count <500 cells/mm3
Hypotension
Intractable hyperkalemia
Fever and flu-like symptoms, followed by conjunctival irritation, mucous
membrane involvement, painful skin, target lesions, blistering, or desquamation
of the skin
We try to continue treatment in patients who have adverse reactions to TMP-SMX
that are not life threatening [1]. Antihistamines may be helpful in controlling minor
reactions. Hydration or sodium polystyrene can be used to treat hyperkalemia caused
by the renal tubular resorption of potassium. A more detailed discussion on adverse
 reactions to TMP-SMX is found elsewhere. (See "Trimethoprim-sulfamethoxazole: An
overview", section on 'Adverse effects and precautions'.)
TMP-dapsone Side effects of TMP-dapsone include gastrointestinal upset, rash,
fever, hemolytic anemia, and methemoglobinemia. Laboratory testing can also reveal
neutropenia, hyperkalemia, and transaminase elevations. An interaction
between trimethoprim and dapsone appears to increase the levels of both drugs in
patients being treated for PCP, and this may increase the risk of side effects such as
anemia and methemoglobinemia [41].
Clindamycin-primaquine Side effects include rash, fever, diarrhea
(including Clostridium difficile-associated colitis), hemolytic anemia, neutropenia, and
methemoglobinemia.
Atovaquone The most common side effect is gastrointestinal distress. Other
adverse reactions include fever and transaminase elevations. Rash may also occur,
but is less common than with other regimens.
Pentamidine Adverse reactions occur in up to 70 percent of patients and include
nausea, taste disturbance, cardiac arrhythmias, hyperkalemia, nephrotoxicity,
pancreatitis, hypokalemia, hypocalcemia, hypoglycemia, and hyperglycemia. Patients
can develop permanent insulin-requiring diabetes mellitus after treatment with
pentamidine [42]. The nephrotoxicity of pentamidine is cumulative and is usually
evidenced by a gradual increase in the creatinine concentration over the course of
therapy. Concomitant use of other nephrotoxic drugs such as amphotericin B,
aminoglycosides, and foscarnet potentiate the renal toxicity of pentamidine. Certain
adverse events, particularly hypoglycemia and hypotension, may be life threatening.

Treatment failure Patients who do not show any improvement (eg, tachypnea,
hypoxemia) after four to eight days of therapy are considered treatment failures [1].
Treatment failure may be due to the severity of disease at the time of diagnosis or to a
concurrent infection that was not previously identified. It is possible that P. jirovecii can
develop mutations associated with resistance to sulfa drugs; however, the impact of drug
resistance on treatment outcomes has not been established [3,4].

Our approach to treatment failure is as follows:

We modify the treatment regimen for patients failing therapy, especially those with
severe disease and those who do not improve after eight days. However, this
approach is based upon clinical experience and the findings of uncontrolled studies,
since there are no controlled clinical trials to guide whether to continue or change
initial therapy. Examples of treatment modifications include:
If a patient progresses to severe disease while receiving oral therapy, we
administer an IV regimen. For those receiving oral TMP-SMX, we change to IV
TMP-SMX. Patients unable to tolerate TMP-SMX should be switched
to pentamidine or clindamycin-primaquine. (See 'Preferred regimen' above
and 'Alternative regimens for severe disease' above.)
 For patients failing therapy with an alternative regimen, we determine if
desensitization and changing to TMP-SMX is an option. (See 'Desensitization for
patients with a sulfa allergy' below.)
For those failing therapy with intravenous TMP-SMX, we initiate clindamycin-
primaquine based upon the results of uncontrolled studies that suggest this
regimen improves clinical outcomes when used as salvage therapy for the
treatment of PCP [9,43,44].
Patients with treatment failure should be evaluated for a concurrent infection since
approximately 15 percent of patients with PCP will have more than one opportunistic
infection. This may involve more invasive testing such as bronchoalveolar lavage. For
patients with severe respiratory failure, empiric therapy directed at one or more of
these infections may be indicated while the results of diagnostic tests are pending. A
more detailed discussion of respiratory infections in patients with HIV is found
elsewhere. (See "Clinical presentation and diagnosis of Pneumocystis pulmonary
infection in HIV-infected patients", section on 'Differential diagnosis' and "Approach to
the HIV-infected patient with pulmonary symptoms", section on 'Invasive tests'.)
We initiate adjunctive corticosteroids if a patients respiratory status worsens and
they require supplemental oxygen. Some patients may be stable initially (eg, mild
disease), and then worsen clinically two to three days after starting anti-
Pneumocystis therapy. Such patients typically have an increase in the alveolar-
arterial oxygen gradient due to increased inflammation in the lungs as the organisms
are killed. However, there are no controlled studies evaluating the use of
corticosteroids in this setting. (See 'Use of corticosteroids' above.)

Respiratory failure Patients who show progressive respiratory failure (eg, increased
respiratory rate, worsening oxygen saturation) may require mechanical ventilatory support.
For such patients, low tidal volumes and plateau pressures should be used given the
potential presence of pneumatoceles, which increase the risk of pneumothorax [45].
(See "Overview of mechanical ventilation".)

Patients with respiratory failure should also be assessed for pneumothorax since
individuals with PCP are at risk for pneumothorax, both spontaneously or in the setting of
mechanical ventilation [46-48]. Such patients who develop pneumothorax in the setting of
mechanical ventilation have a poor prognosis [46]. A discussion on the management of
pneumothorax in HIV-infected patients is found elsewhere. (See "Pneumothorax in HIV-
infected patients".)

Timing of ART initiation Most patients who present with PCP are not receiving ART at
the time of their diagnosis. For such patients, we recommend ART be initiated within two
weeks of PCP treatment [1]. The use of early versus deferred ART was supported in a trial
that enrolled 282 patients who presented with an opportunistic infection (OI), of whom the
majority (63 percent) had PCP. Patients were randomly assigned to early ART (initiation
within two weeks of starting OI therapy) or deferred ART (initiation after completing OI
therapy) [49]. Early therapy reduced the risk of AIDS progression and death by almost half,
and was not associated with an increase in adverse events or an increase in the incidence
of immune reconstitution inflammatory syndromes (IRIS). (See "Immune reconstitution
inflammatory syndrome".)

A detailed discussion on selecting an antiretroviral regimen is found elsewhere.

(See "Selecting antiretroviral regimens for the treatment-nave HIV-infected patient".)

Secondary prophylaxis After completing an initial 21-day course of treatment, patients

should continue to receive antimicrobial therapy at a reduced dose to prevent recurrent
infection (ie, secondary prophylaxis). The risk of developing recurrent PCP without
secondary prophylaxis is 60 to 70 percent per year in patients who are not receiving ART
[50]. The antimicrobial regimens used for secondary prophylaxis are the same as those
used to prevent initial infection and are described below. (See 'Regimens for
prophylaxis' below.)

Secondary prophylaxis can be discontinued in patients receiving ART if they have an

undetectable viral load and a rise in their CD4 count to 200 cells/microL for at least three
months. This approach has been supported by several studies [51-53]. As an example, in
a randomized trial of 113 HIV-infected patients with prior PCP on ART, secondary
prophylaxis was safely discontinued after the CD4 cell count had increased to
>200 cells/microL for more than three months [52]. Among the 60 patients who
discontinued prophylaxis, there were no episodes of PCP during a median follow-up of 12
months (95% CI 0 to 4.5 episodes per 100 person-years).

It is unclear if prophylaxis should be discontinued in patients who were diagnosed with

PCP when their CD4 count was 200 cells/microL. Guideline panels suggest continuing
PCP prophylaxis indefinitely for such patients [1]. However, we discuss the option of
discontinuing PCP prophylaxis with individuals who have achieved virologic suppression
for at least one year, since control of HIV viremia improves immune function independent
of the absolute CD4 cell count [54,55].

PREVENTING INITIAL INFECTION Patients with advanced immune suppression are at

risk for developing Pneumocystis pneumonia (PCP). PCP is most likely to occur in patients
who have a CD4 count <200 cells/microL and are not receiving antiretroviral therapy
(ART). A more detailed discussion of risk factors for PCP is found elsewhere.
(See "Clinical presentation and diagnosis of Pneumocystis pulmonary infection in HIV-
infected patients", section on 'Risk factors'.)

The most effective way to prevent PCP is by improving immune function through use of
antiretroviral therapy (ART). Antimicrobial agents should be administered for prophylaxis
while awaiting immune recovery. (See 'Initiating antiretroviral therapy' below
and 'Indications for antimicrobial prophylaxis' below and 'Regimens for prophylaxis' below.)
The risk of developing infection may also be reduced by avoiding exposure to P. jirovecii.
As an example, we avoid having hospitalized patients with PCP share rooms with other
immunocompromised patients since there are data to suggest that person-to-person
transmission of PCP can occur [56]. However, there is no clear evidence that isolating
patients with PCP will prevent transmission. A more detailed discussion on the
transmission of PCP is found elsewhere. (See "Clinical presentation and diagnosis of
Pneumocystis pulmonary infection in HIV-infected patients", section on 'Transmission'.)

Initiating antiretroviral therapy The most effective way to prevent PCP is by

improving the immune system through use of ART. Thus, antiretroviral therapy should be
initiated in all patients at risk of developing PCP. Immune recovery reduces the risk of
developing PCP and allows prophylaxis to be discontinued. (See 'Indications for
antimicrobial prophylaxis' below and 'Discontinuing prophylaxis' below.)

A detailed discussion on selecting an antiretroviral regimen is found elsewhere.

(See "Selecting antiretroviral regimens for the treatment-nave HIV-infected patient".)

Antimicrobial prophylaxis Antimicrobial prophylaxis reduces the risk of developing

PCP ninefold in patients who have a CD4 counts <200 cells/microL and are not on ART
[50]. Prophylaxis is also associated with decreased health care costs and decreased
mortality in those who develop infection [50,57,58]. The most common reasons for failure
of prophylaxis are nonadherence and/or a very low CD4 count (<50 cells/microL) [59].

Indications for antimicrobial prophylaxis We agree with guidelines that recommend

primary PCP prophylaxis for patients with any of the following [1]:

CD4 count <200 cells/microL

Oropharyngeal candidiasis
CD4 count percentage <14 percent
CD4 cell count between 200 and 250 cells/microL when frequent monitoring (eg,
every three months) of CD4 cell counts is not possible

We also administer PCP prophylaxis to individuals with a history of an AIDS-defining

illness if they have not initiated ART or are not virologically suppressed on an ART
regimen.

We would not initiate prophylaxis based on the CD4 count criteria above in patients who
meet criteria for discontinuation of prophylaxis (prolonged viral suppression and CD4 count
between 100 and 200 cells/microL) (see 'Discontinuing prophylaxis' below). This approach
is supported by an observational study of 12,412 patients receiving ART where 253 cases
of PCP occurred over approximately five years [60]. Antimicrobial prophylaxis significantly
reduced the risk of developing PCP in patients who had a CD4 count
<100 cells/microL (adjusted incidence rate ratio 0.41, 95% CI 0.27-0.60). However, among
patients with a CD4 count between 100 to 200 cells/microL and a viral load
<400 copies/mL, there was no significant difference in the incidence of PCP among those
who did or did not receive antimicrobial prophylaxis (2.1 versus 1.2 cases per 1000 person
years of follow-up).

Regimens for prophylaxis Several oral regimens are available for PCP prophylaxis.
Which regimen to use, and the recommended dose, are influenced by concurrent or prior
infection with toxoplasmosis.

There have been many trials comparing the efficacy of different regimens for PCP
prophylaxis [10,11,59,61-63]. Taken together, they suggest that TMP-SMX is the most
effective agent for prophylaxis in patients who can tolerate it. This was best illustrated in a
meta-analysis of 35 studies of PCP prophylaxis in 6583 patients [59]. TMP-SMX was
superior to dapsone or aerosolized pentamidine for the prevention of PCP. However, there
was no statistically significant survival advantage seen in those taking TMP-SMX
compared with alternative agents.

Patients without a sulfa allergy We recommend trimethoprim-

sulfamethoxazole (TMP-SMX) as the treatment of choice for primary PCP prophylaxis in
patients without a history of sulfa allergy. TMP-SMX also decreases this risk of
toxoplasmosis and bacterial infections (including many respiratory bacterial infections)
[59,64,65]. (See "Trimethoprim-sulfamethoxazole: An overview", section on 'Spectrum of
activity'.)

The dose of TMP-SMX depends upon the patients risk for developing toxoplasmosis.
Antimicrobial therapy to prevent toxoplasmosis is indicated for patients with a CD4 count
<100 cells/microL who are IgG-positive for Toxoplasma gondii. (See "Toxoplasmosis in
HIV-infected patients", section on 'Prevention'.)

We administer one double-strength (DS) tablet daily to patients who require

antimicrobial therapy to prevent toxoplasmosis.
We administer one single-strength (SS) tablet daily, or a DS tablet three times per
week, to patients who do not require preventive therapy for toxoplasmosis.

The lower doses of TMP-SMX are as effective as the higher doses in preventing PCP and
are better tolerated. As examples:

A randomized trial of 260 HIV-infected patients with a CD4 count

<200 cells/microL and no history of PCP compared daily treatment with TMP-SMX SS
and TMP-SMX DS [66]. Patients were followed for a median of 376 days, and no
patient in either group developed PCP. However, more adverse reactions requiring
treatment discontinuation were seen with the DS regimen (hazard ratio 1.4, 95% CI
0.95-2.02).
A randomized trial with a median follow-up of 22 months compared TMP-SMX DS
daily with TMP-SMX DS three times per week in 2625 HIV-infected patients with a
 CD4 cell count <200 cells/microL [67]. In an intention-to-treat analysis, the yearly rate
of PCP was similar in the two groups (3.5 versus 4.1 percent). However,
discontinuation due to adverse events was more common in the daily therapy group
(relative risk 2.14, 95% CI 1.73-2.66).

Dose modifications for renal impairment may be needed; detailed dosing

recommendations are available in the drug information monograph included within
UpToDate.

Severe adverse effects requiring discontinuation of prophylaxis have been reported in 25

to 50 percent of patients receiving TMP-SMX [10,62]. Approximately 40 percent of
reactions that require discontinuation of TMP-SMX occur in the first month of therapy [67].
More detailed discussions on adverse reactions to TMP-SMX are found elsewhere.
(See 'Adverse reactions' above and "Trimethoprim-sulfamethoxazole: An overview",
section on 'Adverse effects and precautions'.)

Patients with a sulfa allergy For patients unable to tolerate TMP-SMX, we

use dapsone over atovaquone since it is a less expensive alternative and has comparable
efficacy to atovaquone [68,69]. Aerosolized pentamidine (AP) is our last choice. Although
AP is better tolerated than the other regimens, it is less effective, requires special
equipment, and is associated with transmission of other respiratory pathogens [10,70]. In
addition, AP is only effective locally; if dispersal of the aerosol does not reach all portions
of the lungs, untreated areas remain at risk for PCP. Another option for TMP-SMX-allergic
patients is desensitization to TMP-SMX. This is discussed below. (See 'Desensitization for
patients with a sulfa allergy' below.)

The alternative regimens are dosed as follows:

Dapsone The usual regimens for dapsone when used for PCP prophylaxis are:
Dapsone 50 mg orally twice daily
Dapsone 100 mg orally once daily
(Dapsone 200 mg + pyrimethamine 75 mg + leucovorin 25 mg) orally once
weekly
If dapsone is going to be prescribed, patients should be screened for glucose-6-
phosphate dehydrogenase (G6PD) deficiency since patients with G6PD-deficiency
are at risk for developing hemolytic anemia with dapsone (see "Diagnosis and
management of glucose-6-phosphate dehydrogenase deficiency"). More detailed
discussions of dapsone are found above. (See 'Alternative regimens for mild to
moderate disease' above and 'Adverse reactions' above.)
Atovaquone The dose of atovaquone suspension for PCP prophylaxis is 1500 mg
daily given with food. There were concerns about absorption with early formulations
of atovaquone; however, absorption is improved with the use of the liquid formulation.
 More detailed discussions of atovaquone are found above. (See 'Alternative regimens
for mild to moderate disease' above and 'Adverse reactions' above.)
Aerosolized pentamidine We administer AP for PCP prophylaxis only when other
therapies cannot be used. The recommended dose of AP is 300 mg monthly via a
nebulizer. AP is generally administered with two puffs of albuterol to reduce cough
and bronchospasm.
Screening for active tuberculosis, including a baseline chest x-ray, should be
performed before AP is administered since there is a concern about transmission of
tuberculosis to health care workers and other patients through pentamidine-induced
bronchospasm [71,72]. In addition, AP should be administered in a negative pressure
room in order to contain both aerosolized particles of the drug and any microbes that
may be expectorated. When AP needs to be administered in an individual patient's
hospital room, a HEPA-filtered containment tent should be used and the airflow into
this room should be temporarily altered to negative pressure, if possible.
The major side effects of AP are cough and bronchospasm. The use of AP is also a
risk factor for developing a pneumothorax [73]. (See "Pneumothorax in HIV-infected
patients".)

Dapsone alone and aerosolized pentamidine do not provide sufficient protection to prevent
reactivation of T. gondii [74]. Thus, additional agents must be used for patients who
require treatment to prevent toxoplasmosis. A discussion on the prevention of
toxoplasmosis is found elsewhere. (See "Toxoplasmosis in HIV-infected patients", section
on 'Prevention'.)

Patients being treated for toxoplasmosis Patients who are receiving initial or
maintenance therapy for toxoplasmosis with pyrimethamine/sulfadiazine do not require
additional preventive therapy for PCP. (See "Toxoplasmosis in HIV-infected patients",
section on 'Preferred regimens'.)

Pregnant women A detailed discussion on the prevention of PCP in pregnant women

is found elsewhere. (See "Prenatal evaluation of the HIV-infected woman in resource-rich
settings", section on 'Chemoprophylaxis for opportunistic infections'.)

Discontinuing prophylaxis We discontinue primary PCP prophylaxis in patients

receiving ART if they have an undetectable viral load and have a rise in their CD4 count to
200 cells/microL for more than three months. Prophylaxis should be restarted if the CD4
cell count decreases to <200 cells/microL. These recommendations are consistent with
guidelines for the prevention and treatment of opportunistic infections in HIV-infected
adults and adolescents [1], and are supported by several studies [75-78]. As an example,
a meta-analysis evaluated 12 studies with 3035 subjects who discontinued primary PCP
prophylaxis [78]. Seven cases of PCP occurred with a cumulative incidence of 0.23
percent (95% CI, 0.090.48). All of the patients were receiving ART and had evidence of
immune recovery (typically a CD4 count >200 cells/microL).
We also stop primary prophylaxis in patients with a CD4 count between 100 and
200 cells/microL if they are receiving ART and have had an undetectable viral load for at
least twelve months. Although this has not yet been adopted by guideline panels, we feel
the risk of PCP is extremely low among such patients if virologic suppression is maintained
[60,79]. As an example, in a cohort study that followed approximately 5000 patients for a
median duration of 3.5 years, no cases of PCP occurred in patients who were virologically
suppressed and discontinued prophylaxis with a CD4 count between 100 and
200 cells/microL (95% CI 0.0-2.7 cases per 1000 PYFU) [60].

DESENSITIZATION FOR PATIENTS WITH A SULFA ALLERGY Trimethoprim-

sulfamethoxazole (TMP-SMX) can be reintroduced to certain individuals with a history of
an isolated cutaneous reaction to sulfa (ie, without systemic involvement). More detailed
discussions on the manifestations and management of sulfonamide allergies are found
elsewhere. (See "Sulfonamide allergy in HIV-uninfected patients" and "Trimethoprim-
sulfamethoxazole: An overview", section on 'Adverse effects and precautions'.)

For such patients, we attempt to "desensitize" the patient to TMP-SMX using a gradual
dose escalation. We administer the following desensitization protocol using TMP-SMX
pediatric suspension (TMP 8 mg/mL and SMX 40 mg/mL) [80]:

Day 1: 1.25 mL once

Day 2: 1.25 mL twice daily
Day 3: 1.25 mL three times daily
Day 4: 2.5 mL twice daily
Day 5: 2.5 mL three times daily
Day 6: one SS tablet

One SS tablet daily can be used for prophylaxis. For those who require full treatment
doses, the dose can then be gradually increased over several days (see 'Preferred
regimen' above).

For example, the protocol above can be continued as below:

Day 7: one SS tablet three times daily

Day 8: One DS tablet twice daily
Day 9: Two DS tablets twice daily
Day 10: Two DS tablets three times daily (for a target dose of approximately
15 mg/kg/day for a 60 kg person)

An alternative PCP regimen should be used until a patient is able to tolerate treatment
doses. (See 'Alternative regimens' above.)

Although a majority of patients may be able to tolerate TMP-SMX when rechallenged with
the full dose [80,81], dose escalation over one to two weeks reduces the risk of developing
an adverse reaction [80,82]. As an example, a randomized trial compared dose escalation
of TMP-SMX with immediate resumption of a SS tablet daily in 190 HIV-infected patients
who had previously discontinued TMP-SMX for an adverse reaction [80]. The trial was
stopped early by a monitoring board since more patients who received dose escalation
remained on TMP-SMX at six months (75 versus 57 percent).

Desensitization to TMP-SMX is reviewed in more detail separately. (See "Sulfonamide

allergy in HIV-uninfected patients", section on 'Protocols for past rash/fever'.)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education

materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Pneumocystis pneumonia (PCP) (The

Basics)")

SUMMARY AND RECOMMENDATIONS

Pneumocystis jirovecii pneumonia (formerly called Pneumocystis carinii pneumonia

or PCP) is the most common opportunistic respiratory infection in patients infected
with AIDS. It typically occurs in HIV-infected patients with a CD4 count
<200 cells/microL who are not receiving antiretroviral therapy or appropriate
prophylaxis. (See 'Introduction' above.)
Antimicrobial therapy directed against P. jirovecii is the mainstay of treatment for
PCP. In addition, some patients will require adjunctive corticosteroids. Antiretroviral
therapy (ART) should be initiated or resumed to restore cellular immunity.
(See 'Treatment' above.)
The approach to treatment (eg, the choice of agent, the mode of administration, and
the use of adjunctive corticosteroids) is based upon the severity of disease. Patients
are classified as having mild, moderate, or severe disease. (See 'Mild disease' above
and 'Moderate disease' above and 'Severe disease' above.)
For patients with severe disease, we recommend treatment with intravenous
(IV) trimethoprim-sulfamethoxazole (TMP-SMX) rather than IV pentamidine (Grade
1A). For individuals with mild to moderate disease, we suggest treatment with oral
trimethoprim-sulfamethoxazole rather than oral trimethoprim-dapsone (Grade 2B).
The standard dose of TMP-SMX is 15 to 20 mg/kg/day (based upon the TMP
component) in three or four divided doses. Therapy should be administered for 21
days. (See 'Preferred regimen' above.)
For individuals with mild to moderate disease who are unable to take TMP-SMX, we
suggest dapsone plus trimethoprim or clindamycin plus primaquine rather
than atovaquone (Grade 2B). Treatment with atovaquone for PCP should
preferentially be limited to patients with mild disease. (See 'Alternative
regimens' above.)
For patients with severe disease who are unable to take TMP-SMX, we suggest
IV pentamidine rather than clindamycin-primaquine (Grade 2B). Patients should be
switched to a less toxic regimen as soon as they can tolerate oral therapy.
(See 'Alternative regimens' above.)
For patients with moderate to severe disease (eg, a partial pressure of oxygen of
<70 mmHg on room air and/or an alveolar-arterial (A-a) oxygen gradient of 35
mmHg), we recommend corticosteroids be initiated (Grade 1A). We also administer
corticosteroids to patients with clear evidence of hypoxemia (eg, resting room air
oxygen saturation <92 percent). Corticosteroids should be administered concurrently
with anti-Pneumocystis therapy in this setting to decrease the incidence of mortality
and respiratory failure associated with PCP. (See 'Use of corticosteroids' above.)
TMP-SMX is the preferred therapy for PCP in pregnant women. If an alternative
therapy must be used, trimethoprim-dapsone can be administered since there is
clinical experience with this regimen in pregnancy. (See 'Pregnancy' above.)
Patients should be monitored for adverse events related to their treatment regimen.
Several of the antimicrobial regimens used to treat PCP are associated with
significant side effects. A change in regimen may be needed for patients who develop
severe adverse reactions (eg, Stevens-Johnson syndrome with TMP-SMX,
pancreatitis, or renal failure with pentamidine). (See 'Monitoring patients on
treatment' above and 'Adverse reactions' above.)
Patients who do not show any improvement (eg, tachypnea, hypoxemia) after four to
eight days of therapy are considered treatment failures. Treatment failure may be due
to the severity of disease at the time of diagnosis or to a concurrent infection that was
not previously identified. Although the impact of drug resistance on treatment
outcomes has not been established, we modify the treatment regimen for patients
failing therapy, especially those with severe disease and those who do not improve
after eight days. (See 'Treatment failure' above.)
For patients with PCP who are not receiving ART at the time of their diagnosis, we
recommend ART be initiated within two weeks of PCP treatment (Grade 1B). Early
ART (versus starting therapy after PCP treatment) can reduce the risk of AIDS
progression and death in patients presenting with PCP. (See 'Timing of ART
initiation' above.)
After completing their initial 21-day course of treatment, patients should continue to
receive antimicrobial therapy at a reduced dose to prevent recurrent infection (ie,
 secondary prophylaxis). Secondary prophylaxis can be discontinued in patients
receiving ART if they have an undetectable viral load and a rise in their CD4 count to
200 cells/microL for at least three months. (See 'Secondary prophylaxis' above.)
The most effective way to prevent PCP is by improving the immune system through
use of antiretroviral therapy. Antimicrobial therapy should be administered for
prophylaxis while awaiting immune recovery. (See 'Preventing initial infection' above.)
We administer PCP prophylaxis to patients with any of the following characteristics:
CD4 count <200 cells/microL; CD4 percentage <14 percent; oropharyngeal
candidiasis; or history of an AIDS-defining illness if they have not initiated ART or
are not virologically suppressed while receiving an ART regimen. Prophylaxis should
also be administered to those who have a CD4 count between 200 and
250 cells/microL when frequent monitoring of CD4 counts is not possible.
(See 'Indications for antimicrobial prophylaxis' above.)
For patients who meet criteria for PCP prophylaxis, we recommend TMP-SMX
rather than dapsone (Grade 1A). For individuals who cannot take TMP-SMX or
dapsone, atovaquone is preferred over aerosolized pentamidine. We discontinue
primary PCP prophylaxis in patients receiving ART if they have an undetectable viral
load and a rise in their CD4 count to 200 cells/microL for at least three months or
have prolonged viral suppression and a CD4 count between 100 and
200 cells/microL. (See 'Regimens for prophylaxis' above and 'Discontinuing
prophylaxis' above.)

Cryptococcus neoformans infection outside the central nervous system

Authors:
Gary M Cox, MD
John R Perfect, MD
Section Editors:
Carol A Kauffman, MD
Sheldon L Kaplan, MD
Deputy Editor:
Jennifer Mitty, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jan 2017. | This topic last updated: May 28, 2015.

INTRODUCTION Cryptococcus neoformans pneumonia and infection outside the

central nervous system in immunocompetent and immunocompromised patients will be
reviewed here.

The microbiology and epidemiology of C. neoformans infection are presented

separately. C. neoformans meningoencephalitis and Cryptococcus gattii infection are also
discussed elsewhere. (See "Microbiology and epidemiology of Cryptococcus neoformans
infection" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus
neoformans meningoencephalitis in HIV-infected patients" and "Clinical manifestations and
diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-seronegative
patients" and "Treatment of Cryptococcus neoformans meningoencephalitis in HIV-
infected patients" and "Treatment of Cryptococcus neoformans meningoencephalitis and
disseminated infection in HIV seronegative patients" and "Cryptococcus gattii infection:
Microbiology, epidemiology, and pathogenesis" and "Cryptococcus gattii infection: Clinical
features and diagnosis" and "Cryptococcus gattii infection: Treatment".)

PULMONARY INFECTION IN IMMUNOCOMPETENT ADULTS

Clinical manifestations Humans likely become infected with C. neoformans by

inhaling the basidiospore form of the fungus or small, poorly encapsulated yeasts.
Basidiospores are smaller than the yeast forms obtained from clinical samples and have
much smaller polysaccharide capsules, facilitating deposition in the alveoli and terminal
bronchioles after inhalation [1]. Following inhalation, C. neoformans likely cause a focal
pneumonitis that may or may not be symptomatic. The immune status is the most
important determinant of the subsequent course of the infection (eg, whether the
pneumonitis resolves or progresses to symptomatic dissemination) [2,3].

A large segment of the population has been exposed to C. neoformans [4]. Subclinical
primary infections are common and most are asymptomatic. Postmortem studies on
immunocompetent persons without antecedent respiratory complaints have demonstrated
small areas of granulomatous inflammation in the lung parenchyma and/or hilar lymph
nodes due to C. neoformans [5,6]. The foci are generally smaller than those seen in
tuberculosis and do not appear to calcify as frequently as seen with histoplasmosis.
Infection can persist in a latent state; if the host immune system becomes compromised,
organisms may be liberated from the granulomatous complexes and cause active
infection.

There are also descriptions of pulmonary cryptococcosis in apparently immunocompetent

patients [7,8]. In a review of approximately 90 immunocompetent hosts with pulmonary
cryptococcosis, 32 percent of the patients were asymptomatic, and pulmonary infection
was discovered as an incidental finding [7]. Asymptomatic patients with chest radiograph
findings suspicious for malignancy who undergo biopsy are occasionally found to have
cryptococcosis.

The factors that determine whether an exposed person develops symptomatic infection
are uncertain but may include the inoculum of fungi (eg, burden of
exposure) and/or virulence factors of the infecting strain. Common symptoms include
cough, sputum production, hemoptysis, dyspnea, chest pain, fever, malaise, night sweats,
and weight loss [7,9-11]. Less common symptoms include rash and gastrointestinal
complaints. Rare manifestations include obstruction of the superior vena cava, Pancoast
syndrome due to granulomatous inflammation from the host response to C. neoformans,
eosinophilic pneumonia, and extension from the lung to the chest wall [12-15].

Diagnosis Diagnostic tools for pulmonary cryptococcosis include histology, fungal

culture, serum cryptococcal antigen, and radiography.

Culture and histology Visualization of encapsulated yeast forms in sputum,

bronchoalveolar lavage or tissue specimens is suggestive of cryptococcal pulmonary
infection. The diagnosis is established by culturing the organism from sputum or another
specimen. Biopsy specimens of asymptomatic nodules may have yeast on histopathologic
inspection but the culture may be negative.

Associated pleural effusions are usually exudative [16,17]. Yeast forms may be seen in the
pleural effusion, and cultures are usually positive.

Routine blood cultures are appropriate for patients who have extensive
infiltrates and/or systemic symptoms.

Cryptococcal antigen Serum cryptococcal antigen should be performed. Although

positive results are often found in immunocompromised hosts with C.
neoformans pneumonia, antigen detection is not a sensitive test for diagnosis of
pulmonary infection in immunocompetent patients. However, antigen testing may be more
useful for diagnosis of cryptococcal pneumonia due to C. gattii among immunocompetent
hosts in regions where C. gattii is endemic (eg, Australia) or has caused outbreaks of
disease (eg, the United States Pacific Northwest and British Columbia).
(See "Cryptococcus gattii infection: Clinical features and diagnosis", section on
'Cryptococcal antigen'.)

There is no role for monitoring serum cryptococcal antigen titers to determine duration of
therapy in either immunosuppressed or immunocompetent hosts.

Radiography Radiographic features of pulmonary cryptococcosis in immunocompetent

patients are variable. The most common findings are solitary or few well-defined,
noncalcified nodules that are often pleural based (image 1) [18-20]. Other radiographic
findings include lobar infiltrates, hilar and mediastinal adenopathy, and pleural effusions
[16,17,21-24]. In a case series of 12 immunocompetent hosts, 10 patients had nodules
and masses (eight were peripheral); three had cavitation [25].

Lumbar puncture Dissemination from the lungs to the central nervous system (CNS) in
immunocompetent patients is rare, and routine lumbar puncture to evaluate for
cryptococcal meningoencephalitis is generally not necessary [26]. Immunocompetent
hosts with no CNS symptoms and low serum cryptococcal antigen titer (<1:512) need not
undergo lumbar puncture. However, lumbar puncture is warranted for patients with
neurologic symptoms or an underlying condition that predisposes to dissemination.
Lumbar puncture is also appropriate for immunocompetent patients with a very high serum
cryptococcal antigen titer (>1:512); such patients appear to have a higher burden of
infection with risk for extrapulmonary spread and seeding of the central nervous system.

Treatment The goal of treatment is to control signs and symptoms of cryptococcal

pneumonia and minimize risk of dissemination to the central nervous system [27].
Literature for management of pulmonary cryptococcal infection consists of retrospective
reports; the approach is extrapolated from literature describing management of patients
with HIV infection and CNS disease [9,28-31].

Pleural effusions rarely require drainage [16,17]. Surgical excision of infected pulmonary
tissue is only indicated in cases of masses that impinge on adjacent structures [12,13].

The management of C. gattii infection is discussed separately. (See "Cryptococcus gattii

infection: Treatment".)

Antifungal therapy Patients with severe pulmonary disease (eg, diffuse pulmonary
infiltrates) or disseminated disease (eg, at least two noncontiguous sites) or a cryptococcal
antigen titer 1:512 (a known poor prognostic factor [32]) should be managed as outlined
separately. (See "Treatment of Cryptococcus neoformans meningoencephalitis and
disseminated infection in HIV seronegative patients".)

Based on extrapolation from literature describing management of patients with HIV

infection, treatment for immunocompetent patients with mild to moderate pulmonary
cryptococcosis in the absence of diffuse pulmonary infiltrates or disseminated infection
consists of fluconazole (400 mg [6 mg/kg] orally daily ) for 6 to 12 months (table 1) [27]. If
fluconazole is not available or is contraindicated, acceptable alternatives
include itraconazole (loading doses of 200 mg orally three times daily for three days, then
200 mg orally twice daily), voriconazole (loading doses of 6 mg/kg intravenously [IV] twice
daily or 400 mg orally twice daily on the first day, then 200 mg orally twice daily)
or posaconazole delayed-release tablets (loading doses of 300 mg orally twice daily on the
first day, then 300 mg orally once daily), although there are minimal data available
regarding the latter agents.

Asymptomatic patients who have cryptococcal infection diagnosed incidentally in the

setting of pulmonary nodule resection to rule out malignancy and who have negative
cultures and cryptococcal antigen titers may not require antifungal therapy. There are
reports of immunocompetent, asymptomatic patients with positive culture,
serology, and/or histopathology who improved radiographically with observation alone in
the absence of antifungal therapy [9,29,31].

Asymptomatic patients with detectable serum cryptococcal antigen probably have a very
low likelihood of symptomatic systemic dissemination. However, treatment
with fluconazole is appropriate since it is likely to be curative and the risk of adverse
effects is low [27].
There is no role for monitoring serum cryptococcal antigen titers to guide duration of
therapy.

Surgery Occasionally, localized cryptococcal infections of the lung not responding to

medical therapy may need surgical resection for cure [27].

PULMONARY INFECTION IN IMMUNOCOMPROMISED ADULTS Most cases of

pulmonary cryptococcosis in the immunocompromised host are likely due to reactivation of
latent infection. However, primary infection in a nave host or reinfection with a new strain
is also possible. Immunocompromised hosts with pulmonary cryptococcosis generally
have more symptoms than immunocompetent hosts and are more likely to present with
extrapulmonary disease.

Conditions that increase risk for pulmonary cryptococcosis include HIV infection,
malignancies, stem cell and solid organ transplantation, cirrhosis, renal failure, chronic
lung disease, diabetes, Cushing's syndrome, sarcoidosis, and treatment with
glucocorticoids or tumor necrosis factor-alpha antagonists [9,31,33-39]. Cryptococcal
pneumonia in a lung transplant patient due to asymptomatic C. neoformans carriage in the
donor lung has also been reported [40].

Clinical manifestations

HIV-negative patients Clinical manifestations due to pulmonary cryptococcosis range

from asymptomatic pneumonia to acute respiratory failure [9,28,31,41]. Among 34
immunocompromised patients with cryptococcal pneumonia, 28 developed
extrapulmonary disease [31]. The most common symptoms were fever (63 percent), chest
pain (44 percent), dyspnea (27 percent), cough (17 percent), and hemoptysis (7 percent).

Cryptococcal pneumonia and acute respiratory distress syndrome (ARDS) occur more
frequently among organ transplant recipients than other hosts [28,42,43]. In this setting,
ARDS is often associated with disseminated infection; mortality is high and urgent
treatment is required [28,41]. Such patients should be managed as outlined separately for
cryptococcal meningoencephalitis. (See "Treatment of Cryptococcus neoformans
meningoencephalitis and disseminated infection in HIV seronegative patients".)

HIV-positive patients The presentation of pulmonary cryptococcosis in patients with

HIV is more acute and severe than in other hosts. The severity of symptoms and extent of
dissemination are inversely proportional to the CD4 lymphocyte count; most symptomatic
cases occur in patients with CD4 counts less than 100/microL.

Clinical manifestations include fever (81 to 94 percent), cough (63 to 71 percent), dyspnea
(5 to 50 percent), and headache (41 percent) [37]. Some patients are hypoxic; some
present with ARDS. Dissemination from the lungs to the central nervous system occurs in
65 to 94 percent of cases of HIV-associated pulmonary cryptococcosis [30,37,44,45].
Other opportunistic infections with manifestations similar to pulmonary cryptococcosis
include those due to Pneumocystis jirovecii, Mycobacterium
avium complex, Mycobacterium tuberculosis, cytomegalovirus, and Histoplasma
capsulatum [37,45].

Diagnosis Diagnostic tools for pulmonary cryptococcosis include histology, fungal

culture, serum cryptococcal antigen, and radiography.

Evaluation of immunocompromised patients with pulmonary cryptococcosis should include

evaluation for disseminated infection; this includes blood and cerebrospinal fluid (CSF)
cultures as well as blood and CSF cryptococcal polysaccharide antigen testing [32].

Cryptococcal antigen The serum cryptococcal antigen is positive in virtually all

patients with HIV infection and pulmonary cryptococcosis and in 56 to 70 percent of
patients with other underlying immunocompromising conditions [9,30,35,36,46]. Therefore,
it is an excellent screening test in immunocompromised patients with respiratory
symptoms. False-positive serum cryptococcal antigen tests can occur in the setting of
infections due to the fungus Trichosporon asahii (formerly T. beigelii) or the bacterial
genera Stomatococcus or Capnocytophaga [47-49]. False-negative serum cryptococcal
antigen tests can occur with samples that contain a large amount of antigen (the prozone
phenomenon) if the laboratory is using a latex agglutination assay and doesn't pretreat the
sample with pronase [50].

In solid organ transplant recipients with pulmonary cryptococcosis, a positive serum

cryptococcal antigen test frequently reflects advanced lung
involvement and/or extrapulmonary disease, such as fungemia or central nervous system
infection [51]. In one series including solid organ transplant recipients, a positive serum
cryptococcal antigen titer was documented in 38 percent of patients with pulmonary
cryptococcosis [29]. In a prospective study of 60 solid organ transplant recipients with
pulmonary cryptococcosis, positive serum cryptococcal antigen results were observed in
84 percent of those with any pulmonary involvement; the test was positive in 73 percent of
those with disease limited to the lungs [51]. However, a negative cryptococcal antigen
result does not exclude the diagnosis of cryptococcosis.

Given the high rate of extrapulmonary disease among immunocompromised patients with
cryptococcal pneumonia, a positive serum cryptococcal antigen result should prompt
investigation for disseminated infection with blood culture, CSF cryptococcal antigen
assay, and CSF culture [32]. Positive results should prompt management as outlined
separately. (See "Treatment of Cryptococcus neoformans meningoencephalitis and
disseminated infection in HIV seronegative patients" and "Epidemiology, clinical
manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-
infected patients".)
Culture and histology Culture of expectorated sputum samples is often positive in
immunocompromised patients. C. neoformans in respiratory tract specimens from
transplant patients should be considered to represent a true pathogen. Bronchoscopy may
be indicated in patients with advanced HIV infection to rule out other opportunistic
infections [52].

Biopsy is necessary only if malignancy is suspected. Histology can help to establish the
diagnosis by demonstrating encapsulated yeast forms (picture 1).

Routine blood cultures are appropriate for patients with severe immunosuppression,
extensive infiltrates, and/or systemic symptoms.

Radiography Radiographic findings are usually more severe than those seen in
apparently immunocompetent patients. (See 'Radiography' above.)

In patients with HIV, alveolar infiltrates, lymphadenopathy, mass lesions, and small pleural
effusions have been described [37]. Interstitial infiltrates may mimic the radiographic
presentation of P. jirovecii pneumonia [37,53]. (See "Clinical presentation and diagnosis of
Pneumocystis pulmonary infection in HIV-infected patients".)

Lumbar puncture Lumbar puncture to evaluate for cryptococcal meningoencephalitis

is warranted for patients with neurologic symptoms or an underlying condition that
predisposes to dissemination. In a study of HIV-seronegative patients with pulmonary
cryptococcal disease, those with disseminated disease were more likely to have cirrhosis,
headache, weight loss, fever, altered mental status, and/or to be receiving high-dose
glucocorticoids [26].

Although the definition of the immunocompromised state is imprecise, a lumbar puncture

to rule out central nervous system disease should be performed in those with pulmonary
cryptococcosis who are considered to be immunosuppressed even in the absence of
neurologic signs or symptoms. Such patients appear to have a higher burden of infection
with risk for extrapulmonary spread and seeding of the central nervous system.
(See "Clinical manifestations and diagnosis of Cryptococcus neoformans
meningoencephalitis in HIV-seronegative patients".)

Treatment

Antifungal therapy Patients with severe pulmonary disease (eg, diffuse pulmonary
infiltrates) or disseminated disease (eg, at least two noncontiguous sites) or a serum
cryptococcal antigen titer 1:512 (a known poor prognostic factor [32]) should be managed
as outlined separately. (See "Treatment of Cryptococcus neoformans meningoencephalitis
and disseminated infection in HIV seronegative patients".)

The optimal treatment of cryptococcal pneumonia is uncertain; management is

extrapolated from literature describing management of patients with HIV infection and
central nervous system disease [9,29,30]. In general, treatment for immunocompromised
patients with mild to moderate pulmonary cryptococcosis in the absence of diffuse
pulmonary infiltrates or disseminated infection consists of fluconazole (400 mg
[6 mg/kg] orally daily) for 6 to 12 months (table 1) [27]. If fluconazole is not available or
contraindicated, acceptable alternatives include itraconazole (loading doses of 200 mg
orally three times daily for three days, then 200 mg orally twice
daily), voriconazole (loading doses of 6 mg/kg intravenously twice daily or 400 mg orally
twice daily on the first day, then 200 mg orally twice daily), and posaconazole delayed-
release tables (loading doses of 300 mg orally twice daily on the first day, then 300 mg
orally once daily) [54,55], although there are minimal data for the latter agents.

The efficacy of this approach was illustrated in a study of 39 solid organ transplant
recipients with extraneural cryptococcosis who received fluconazole or a regimen
containing amphotericin B; the mortality was comparable (10 to 11 percent) [56]. Among
109 HIV-negative immunocompromised patients with pulmonary cryptococcosis treated
with fluconazole, the 12-month survival was 95 percent [9]. In a retrospective review of 14
solid organ transplant recipients with extraneural cryptococcosis who received fluconazole
as primary therapy for a median of 60 days, no therapeutic failures were observed [56].

HIV-infected patients should continue chronic suppressive therapy with 200 mg per day
of fluconazole. In patients with HIV who are receiving highly active antiretroviral therapy
and have CD4 count >100 cells/microL, suppressed viral load, and a cryptococcal antigen
titer 1:512 that is not increasing, it may be reasonable to discontinue maintenance
fluconazole after one year of treatment [57].

Patients who have responded to therapy for pulmonary cryptococcosis and subsequently
must undergo chemotherapy or intensive therapy for graft rejection within two years of the
diagnosis should be treated with fluconazole while receiving such therapy to prevent
recurrent cryptococcal infection.

There is no role for monitoring serum cryptococcal antigen titers to determine duration of
therapy.

Surgery Occasionally, localized cryptococcal infections of the lung not responding to

medical therapy may need surgical resection for cure [27].

PULMONARY INFECTION IN PREGNANT WOMEN There have been cases of

cryptococcal pneumonia described in pregnancy, although there are insufficient
epidemiologic data to implicate pregnancy as a predisposing condition [58].

Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or disseminated
disease (eg, at least two noncontiguous sites or cryptococcal antigen titer 1:512) should
be managed as outlined separately.
Pregnant women with stable pulmonary cryptococcosis should be followed closely, and
therapy with fluconazole can begin following delivery [27]. Immune reconstitution
inflammatory syndrome can occur in the postpartum period [59-61]. Indeed, nearly half of
the Cryptococcus cases reported in pregnancy presented with symptomatic disease in the
third trimester or postpartum period [58]. (See "Immune reconstitution inflammatory
syndrome".)

PULMONARY INFECTION IN CHILDREN Cryptococcus has been reported in children

with primary immunodeficiencies such as hyperimmunoglobulin M syndrome and severe
combined immunodeficiency syndrome, as well as children with HIV, connective tissue
diseases, and solid organ transplant recipients. Cryptococcosis has also been described in
children with no recognized immunodeficiency.

Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or disseminated
disease (eg, at least two noncontiguous sites or serum cryptococcal antigen titer 1:512)
should be managed as outlined separately.

Treatment of children with mild to moderate pulmonary cryptococcosis consists

of fluconazole (6 to 12 mg/kg per day orally) for 6 to 12 months [27].

NONMENINGEAL, NONPULMONARY CRYPTOCOCCOSIS

Clinical manifestations Nonmeningeal, nonpulmonary cryptococcosis generally

reflects disseminated infection, even if clinical manifestations are confined to a single
anatomic site (such as skin, soft tissue, or osteoarticular infection).

Cryptococcal skin lesions are seen in up to 15 percent of patients with disseminated

infection; they manifest as papules (picture 2), plaques, purpura, ulcers, cellulitis,
superficial plaques, abscesses, and sinus tracts [62,63]. Patients with advanced HIV
infection may have umbilicated papules resembling molluscum contagiosum; in transplant
patients, cellulitis may occur without evidence of dissemination. Although the majority of
cryptococcal skin lesions result from disseminated infection, primary cryptococcal skin
infections by direct inoculation may occur [64].

Cryptococcal lesions of the skeletal system occur in <10 percent of patients with
disseminated disease [65]. The vertebrae are the most common site of osteoarticular
infection. Radiography typically demonstrates a well-circumscribed osteolytic lesion
resembling malignancy. Septic arthritis is rare.

Cryptococcal infection can involve any body site or structure following dissemination,
including the liver, lymph nodes, peritoneum, urogenital tract, adrenal glands, and eyes.
Involvement of the eyes frequently reflects central nervous system (CNS) infection, which
should be sought in all cases [66]. The prostate may serve as a reservoir of infection [67].
(See "Clinical manifestations and diagnosis of Cryptococcus neoformans
meningoencephalitis in HIV-seronegative patients".)
Among 175 solid organ transplant recipients with cryptococcosis, nine patients (5 percent)
presented very early following transplantation (defined as 30 days post transplant; mean
5.7 days post transplant) [68]. Patients who presented very early were more likely to have
disease at unusual locations, including in the transplanted allograft or in the surgical fossa.
These locations suggest that the infections were donor derived. Five of the nine patients
(56 percent) with very earlyonset disease were liver transplant recipients compared with
43 of 166 patients (26 percent) with disease occurring >30 days post transplant [68],
suggesting that some of these patients may have had unrecognized infection prior to
transplantation as a result of the impaired host defenses that accompany cirrhosis [69].

Treatment Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or
disseminated disease (eg, at least two noncontiguous sites or cryptococcal antigen titer
1:512) should be managed as outlined separately. (See "Treatment of Cryptococcus
neoformans meningoencephalitis and disseminated infection in HIV seronegative
patients".)

There are no studies evaluating treatment of cryptococcal infection involving sites other
than lungs and CNS. In general, infection at a single site in the absence of CNS disease,
fungemia or risk factors for immunosuppression may be managed with fluconazole (400
mg [6 mg/kg] orally once daily) for 6 to 12 months [27,70,71].

Management of ocular infections must be managed in consultation with ophthalmologic

expertise and tailored to individual circumstances depending on the extent of eye structure
involvement and whether CNS involvement has been documented. Therapeutic
possibilities include systemic therapy with high penetration into the eye such
as fluconazole or flucytosine and/or adjunctive intravitreal amphotericin B deoxycholate.

SUMMARY AND RECOMMENDATIONS

A large segment of the population has been exposed to Cryptococcus neoformans.

Subclinical primary infections are common, and most are asymptomatic. Infection can
persist in a latent state; if the host immune system becomes compromised, organisms
may be liberated from the granulomatous complexes and cause active infection.
Symptomatic pulmonary cryptococcosis can also occur in apparently
immunocompetent patients. (See 'Pulmonary infection in immunocompetent
adults' above and 'Pulmonary infection in immunocompromised adults' above.)
Clinical manifestations due to cryptococcal pneumonia range from asymptomatic
pneumonia to acute respiratory failure. The presentation of pulmonary cryptococcosis
in patients with HIV is more acute and severe than in other hosts. Most symptomatic
cases occur in patients with CD4 counts less than 100 cells/microL. (See 'HIV-
positive patients' above.)
The diagnosis of cryptococcal pneumonia in immunocompetent hosts is established
by culturing the organism from sputum or another specimen. Visualization of
encapsulated yeast forms in sputum, bronchoalveolar lavage, or tissue specimens is
suggestive of cryptococcal pulmonary infection. The most common radiographic
findings are solitary or few well-defined, noncalcified nodules. Lumbar puncture is
warranted for patients with neurologic symptoms and for patients with serum
cryptococcal antigen titer >1:512. (See 'Diagnosis' above.)
The serum cryptococcal antigen titer is often positive in immunocompromised
patients with cryptococcal pneumonia. Culture of respiratory specimens is also a
useful tool. A lumbar puncture to rule out central nervous system disease should be
performed in those with pulmonary cryptococcosis who are considered to be
immunosuppressed even in the absence of neurologic signs or
symptoms.(See 'Diagnosis' above.)
We suggest that patients with mild to moderate pulmonary cryptococcosis in the
absence of diffuse pulmonary infiltrates or disseminated infection be treated
with fluconazole (Grade 2B). Dosing is fluconazole 400 mg (6 mg/kg) orally once
daily for 6 to 12 months (table 1). (See 'Antifungal therapy' above.)
Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or
disseminated disease (eg, at least two noncontiguous sites or cryptococcal antigen
titer 1:512) should be managed as outlined separately. (See "Treatment of
Cryptococcus neoformans meningoencephalitis and disseminated infection in HIV
seronegative patients".)