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Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV

Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV
Authors:
Charles F Thomas, Jr, MD
Andrew H Limper, MD
Section Editor:
John W Baddley, MD, MSPH
Deputy Editor:
Milana Bogorodskaya, MD
Literature review current through: Dec 2022. | This topic last updated: Aug 02, 2022.

INTRODUCTION — Pneumocystis pneumonia (PCP) is a potentially life-threatening infection that occurs in immunocompromised individuals [1,2]. The nomenclature for the species of Pneumocystis that infects humans has been changed from Pneumocystis carinii to Pneumocystis jirovecii; this was done to distinguish it from the species that infects rats [3-7].

Patients with human immunodeficiency virus (HIV) and a low CD4 count are at the highest risk of PCP. Others at substantial risk include hematopoietic cell and solid organ transplant recipients, those with cancer (particularly hematologic malignancies), and those receiving glucocorticoids, chemotherapeutic agents, and other immunosuppressive medications. The incidence of PCP is increasing as the number of people receiving immunosuppressive medications continues to grow [8].

The epidemiology, clinical manifestations, and diagnosis of PCP in patients without HIV infection will be reviewed here. PCP in patients with HIV and the treatment, outcome, and prophylaxis of PCP in patients without HIV are discussed separately. (See "Clinical presentation and diagnosis of Pneumocystis pulmonary infection in patients with HIV" and "Treatment and prevention of Pneumocystis infection in patients with HIV" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)

TAXONOMY — The taxonomic classification of Pneumocystis as a genus of protozoan organisms was questioned for many years. Now these organisms are recognized as ascomycetous fungi based on ribosomal ribonucleic acid (RNA) and other gene sequence homologies, the composition of their cell walls, and the structure of key enzymes [9].

The nomenclature for the organism demonstrates the diversity of the Pneumocystis genus [3]. Several species have been described including P. carinii, which infects rats, and P. jirovecii, which infects humans [6]. P. carinii was formerly the species name attributed to infections in humans, but P. jirovecii has been designated as the species name used to describe human infections [6,10]. 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 amongst clinicians and maintains the accuracy of this abbreviation in older published papers.

EPIDEMIOLOGY — P. jirovecii was first appreciated as a cause of pneumonia among premature and malnourished infants in Europe following World War II [11,12]. In the 1960s and 1970s, it was diagnosed primarily among patients with hematologic malignancies [13,14]. The prevalence increased dramatically with the emergence of the HIV epidemic in the 1980s. Although the use of routine prophylaxis in patients with HIV led to reduced rates of PCP in that population, it remains a significant cause of pneumonia in patients with other types of immunodeficiencies [8]. (See "Clinical presentation and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Epidemiology'.)

Acquisition and transmission — Numerous animal and human studies suggest that Pneumocystis is transmitted by the airborne route. Acquisition of new infections in humans can most likely occur by person-to-person spread. Individuals with normal immune systems may have asymptomatic lung colonization and may serve as a reservoir for spread of Pneumocystis to immunocompromised hosts [15]. (See "Clinical presentation and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Transmission'.)

Risk factors — The most significant risk factors for PCP in patients without HIV infection are glucocorticoid use and defects in cell-mediated immunity [16-19]. Additional specific risk factors include other immunosuppressive medications, cancer (particularly hematologic malignancy), hematopoietic cell or solid organ transplantation, treatment for organ rejection, treatment for certain inflammatory conditions (particularly rheumatologic diseases), primary immunodeficiencies (eg, severe combined immunodeficiency), and severe malnutrition (table 1).

Several retrospective studies have evaluated the epidemiology of PCP in patients without HIV [16,17,20-25]. In a case series from the Mayo Clinic of 116 consecutive patients with a first episode of PCP, glucocorticoids had been administered within one month of diagnosis in 91 percent [16]. The median dose of prednisone equivalent in these patients was 30 mg/day, but some patients received as little as 16 mg/day. The median duration of glucocorticoid therapy before the development of PCP was 12 weeks, but 25 percent of patients had been receiving glucocorticoids for ≤8 weeks. Concurrent use of other immunosuppressive drugs was not reported. The following underlying diseases were present:

●Hematologic malignancy – 30 percent

●Organ transplantation – 25 percent

●Inflammatory conditions, such as granulomatosis with polyangiitis (GPA) and polymyositis/dermatomyositis – 22 percent

●Solid tumors – 13 percent

●Other miscellaneous conditions – 10 percent

In another study that included 293 cases of PCP from 1990 to 2010, 53 percent of patients did not have HIV [24]. The most common underlying conditions were hematologic malignancies (33 percent), solid tumors (18 percent), inflammatory diseases (15 percent), solid organ transplant (12 percent), and vasculitis (10 percent). Patients at highest risk (incidence rates >45 cases per 100,000 patient-years) included those with polyarteritis nodosa, GPA, polymyositis/dermatopolymyositis, acute leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. Patients at intermediate risk (25 to 45 cases per 100,000 patient-years) included those with Waldenstrom macroglobulinemia, multiple myeloma, and central nervous system cancer. Patients at low risk (<25 cases per 100,000 patient-years) included those with other solid tumors, inflammatory diseases, and Hodgkin lymphoma.

Cancer — Prior to the routine use of PCP prophylaxis, rates of PCP were substantial in patients with some types of cancer, particularly in those with hematologic malignancies. A retrospective study from the MD Anderson Cancer Center identified 80 cases of PCP in 79 cancer patients from 1990 to 2003 [20]. PCP occurred most commonly in patients with hematologic malignancies (66 percent), the majority of whom had either leukemia or lymphoma. In addition, 25 patients had solid tumors and 23 patients had undergone hematopoietic cell transplantation (HCT).

In a separate study of 180 children with acute lymphoblastic leukemia who were followed prospectively during the maintenance phase of treatment and who did not receive PCP prophylaxis, the risk of PCP was 16 percent [13]. The rates of PCP were highest in those receiving the most intense regimens (22 percent in those receiving four chemotherapeutic agents including cytarabine versus 2 to 5 percent in those receiving one to three agents not including cytarabine) and in those receiving mediastinal irradiation (6 of 14 patients).

Primary or secondary central nervous system (CNS) tumors confer a 1 percent overall risk of PCP [8,19]. The risk is substantially higher in patients receiving glucocorticoids, especially when they are being tapered [17,26-28]. In one series, for example, 90 percent of PCP cases were in patients with high-grade gliomas, all of whom had been treated with glucocorticoids for a median of 10 weeks [26].

The risk of PCP in patients receiving immunosuppressive drugs (including chemotherapeutic agents) is discussed in greater detail below. (See 'Immunosuppressive drugs' below.)

Hematopoietic cell transplantation — The risk of PCP following allogeneic HCT is approximately 5 to 15 percent in the absence of prophylaxis [8,19,29-31]. The rates are lower among autologous HCT recipients, although the incidence has not been determined [8].

The timing of PCP following HCT depends upon the use of prophylaxis. PCP usually occurs a median of nine weeks following allogeneic HCT in the absence of prophylaxis but later when prophylaxis is used (median 170 to 260 days after transplantation) [20,30,32]. (See "Overview of infections following hematopoietic cell transplantation", section on 'Pneumonia'.)

Solid organ transplantation — Approximately 5 to 15 percent of patients who undergo solid organ transplantation develop PCP in the absence of prophylaxis [8,19,33,34]. The rates are lowest in renal transplant recipients [33,34] and highest among lung and heart-lung transplant recipients [8,19,35,36].

The period of highest risk for PCP following solid organ transplantation is from one to six months postoperatively (if prophylaxis is not given). The risk is greatest in patients receiving the most intensive immunosuppressive regimens [34]. (See "Infection in the solid organ transplant recipient".)

Several clusters or outbreaks of PCP in solid organ transplant recipients (mostly renal transplant recipients) have been described [37-44]. Some examples of clusters or outbreaks include the following:

●A report from the Netherlands described a cluster of 22 cases of PCP among renal transplant recipients from 2005 to 2006 at one transplant center, a rate significantly higher than had been seen in previous years [37]. A single Pneumocystis genotype was identified in 12 of 16 successfully sequenced samples. Person-to-person transmission or a common environmental source of Pneumocystis both were hypothesized as the possible causes of the outbreak.

●Another study used restriction fragment length polymorphism analysis to compare Pneumocystis isolates from three outbreaks of PCP in renal transplant recipients in Germany, Switzerland, and Japan and from sporadic non-transplant-associated cases of PCP [38]. A single Pneumocystis strain was found to cause the outbreaks in Germany and Switzerland, and the strain was different from the strain that caused the outbreak in Japan and the strains that caused sporadic cases of non-transplant-associated PCP. A possible reason that a single strain caused outbreaks in two separate locations is that individuals within the same geographic region (the locations in Germany and Switzerland were only 300 km apart) could be colonized with the same strain [39]. Another hypothesis is that an index case transmitted Pneumocystis to secondary cases, but this could not be proven since a formal epidemiologic evaluation was not performed.

●In a study that evaluated internal transcribed spacer types in Pneumocystis isolates from 18 renal transplant recipients evaluated during a cluster of PCP cases (12 patients with PCP, 6 colonized patients) and 91 other patients who were either colonized or infected with Pneumocystis, a single Pneumocystis strain was found to be most common, but its frequency was significantly higher in the renal transplant recipients than in the other patients [40]. Fourteen encounters were observed between renal transplant recipients who harbored an identical strain of Pneumocystis. Ten patients were considered as possible index patients, of whom three were colonized and seven had PCP.

The transmission of Pneumocystis is discussed in greater detail separately. (See "Clinical presentation and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Transmission'.)

Immunosuppressive drugs — Patients receiving immunosuppressive drugs are at risk for PCP. The risk is particularly high among patients receiving glucocorticoids in combination with cytotoxic agents (eg, cyclophosphamide) and in those receiving multiple chemotherapeutic agents, particularly during the period of leukopenia [13,33,34,45-48]. PCP may develop in the setting of an increase or, less commonly, a decrease in the dose of immunosuppressive drugs [1,17,49].

●Glucocorticoids – Glucocorticoid use in combination with other immunosuppressants is known to predispose to PCP [13,33,34,45-48]. However, glucocorticoid use in the absence of any other form of immunosuppression, such as in patients with asthma, is not sufficient to cause a substantial risk of PCP on a population-wide basis, although individual cases have been reported [50,51]. Glucocorticoids are thought to predispose to the development of PCP by suppressing cell-mediated immunity and altering lung surfactant [52,53]. (See "Glucocorticoid effects on the immune system", section on 'Infection risk'.)

●Chemotherapeutic drugs – Certain chemotherapeutic drugs, such as the purine analog fludarabine, which is associated with profound lymphopenia, are likely to predispose to PCP (see "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Fludarabine'). The oral alkylating agent, temozolomide, also causes lymphopenia and has been associated with PCP, particularly when used in combination with radiation [54,55].

●Mammalian target of rapamycin (mTOR) inhibitors – The risk of PCP in patients taking mTOR inhibitor agents is unclear. PCP has been reported in patients receiving mTOR inhibitors (eg, temsirolimus) and may be particularly likely in those receiving concomitant glucocorticoids or other immunosuppressive agents [56-59]. For example, in a meta-analysis of 15 studies that included over 37,000 solid organ transplant recipients, mTOR inhibitor use was associated with late-onset (>1 year post-transplant) PCP (OR 1.90, 95% CI 1.44-2.75) [58]. In contrast, in a case control study of 99 solid organ transplant recipients (33 with PCP), no difference in mTOR inhibitor use was seen between patients with and without PCP [60].

●Phosphatidylinositol 3-kinase or tyrosine kinase inhibitors – Cases of PCP have been reported in patients with chronic lymphocytic leukemia receiving idelalisib (a phosphatidylinositol 3-kinase inhibitor) or ibrutinib (a Bruton tyrosine kinase inhibitor). (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Idelalisib' and "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Ibrutinib'.)

●Biologic agents – Biologic agents, such as the anti-CD52 monoclonal antibody alemtuzumab [61] and the tumor necrosis factor-alpha inhibitor infliximab, have been associated with PCP. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Pneumocystis pneumonia'.)

●Anti-CD20 monoclonal antibodies – The extent of risk for PCP in patients taking anti-CD20 monoclonal antibodies is unknown. In one retrospective study of patients who received the anti-B cell monoclonal antibody rituximab between 1998 and 2011 at a single hospital, 30 patients developed PCP (90 percent had hematologic malignancy and 73 percent received glucocorticoids in addition to rituximab) [62]. Three patients developed PCP in the setting of rituximab therapy without concomitant chemotherapy or significant glucocorticoid exposure. In a subsequent study of patients with B cell lymphoma receiving rituximab as part of standard R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) chemotherapy, the cumulative incidence of PCP was only 1.51 percent [63].

Rheumatologic diseases — Approximately 1 to 2 percent of patients with rheumatologic diseases develop PCP, usually in the setting of immunosuppressive therapy, particularly combined therapy [8,46]. As an example, a retrospective study evaluated 180 patients with GPA, 11 of whom (6 percent) developed PCP during therapy with glucocorticoids and a second immunosuppressive agent (eg, cyclophosphamide) [45].

It is not clear if there is a specific propensity to develop PCP in certain rheumatic diseases. Some rheumatologists feel that the risk may be greater in polymyositis/dermatomyositis and lower in systemic lupus erythematosus (SLE) at the same intensity of immunosuppression [64]. Support for this hypothesis comes from a study of 75 patients treated with ≥40 mg/day of prednisolone for SLE or polymyositis/dermatomyositis [65]. The incidence of PCP was much higher in patients with polymyositis/dermatomyositis (6 of 16 versus 1 of 59 [38 versus 2 percent]). The seven patients who developed PCP were much more likely to have interstitial pulmonary fibrosis (100 versus 9 percent) and had a significantly lower peripheral blood lymphocyte count.

Primary immunodeficiencies — Certain primary immunodeficiencies, particularly those that involve defects in T cell immunity (eg, severe combined immunodeficiency, idiopathic CD4 T-lymphocytopenia), are associated with an increased risk of PCP [14,66-73]. Severe combined immunodeficiency appears to be the most common underlying disease [14,66]. (See "Severe combined immunodeficiency (SCID): An overview".)

Immunocompetent patients — PCP rarely occurs in patients without apparent immunodeficiency [67,74].

CLINICAL MANIFESTATIONS — Traditionally, patients without HIV infection who had PCP were described to typically present with fulminant respiratory failure associated with fever and dry cough [1,16,17,75,76]. This may occur in the setting of an increase or, less commonly, a decrease in the dose of immunosuppressive drugs [1,17,49]. However, as the clinical awareness of PCP in patients without HIV has increased and the laboratory diagnosis of PCP has improved, it is now common to see mild to moderate PCP presenting in patients without HIV with more indolent and less severe dyspnea and cough. However, some patients still present with more severe infection with accompanying respiratory compromise. Nearly all patients with PCP will have either hypoxemia at rest or with exertion or an increase in the alveolar-arterial oxygen tension gradient.

LABORATORY FINDINGS — An elevated lactate dehydrogenase (LDH) is often used as a clinical indicator of possible PCP in individuals with HIV. However, in immunocompromised patients without HIV infection, LDH has little utility as it can be elevated from underlying hematologic malignancy. It can also be elevated from causes of acute lung injury other than PCP. Nonetheless, an elevated LDH in the setting of pulmonary infiltrates without another apparent cause should raise suspicion for PCP.

Beta-D-glucan is a cell wall component of most fungi, including Pneumocystis. Although the serum beta-D-glucan assay can be elevated in the setting of a number of other fungal infections, when it is elevated, it also raises suspicion for PCP. When the beta-D-glucan assay is elevated in a patient with risk factors and clinical findings suggestive of PCP, a specific microbiologic or molecular diagnosis should be pursued. (See 'Approach to diagnosis' below.)

RADIOGRAPHIC FINDINGS — The typical radiographic features of PCP in patients without HIV are diffuse, bilateral, interstitial infiltrates (image 1 and image 2 and image 3) [76,77]. Unusual radiographic patterns include lobar infiltrates; solitary or multiple nodules (image 4), which may become cavitary; pneumatoceles (image 5); pneumothorax; and, in patients receiving aerosolized pentamidine, upper lobe infiltrates due to reduced deposition of pentamidine in the upper lobes. When chest radiograph findings are normal, high-resolution computed tomography scanning may demonstrate extensive ground-glass opacities or cystic lesions [77-81]. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

DIAGNOSIS

Approach to diagnosis — The diagnosis of PCP should be considered in patients with risk factors for PCP who present with pneumonia and suggestive radiographic findings. Prompt evaluation is particularly warranted in patients who have immunocompromising conditions or are being treated with combined immunosuppressive therapy (eg, glucocorticoids with cyclophosphamide) and have not been receiving PCP prophylaxis. (See 'Risk factors' above.)

Our approach to diagnosis includes microbiologic identification of the organism when possible (ie, when a sample such as an induced sputum or bronchoalveolar lavage [BAL] fluid can be obtained safely). In situations in which a respiratory specimen cannot be obtained safely, treatment can be initiated based upon the patient's risk, clinical presentation, and use of serum diagnostic assays such as beta-D-glucan testing as the basis for presumptive diagnosis.

Definitive diagnosis — The definitive diagnosis of PCP requires identification of the organism either by tinctorial (dye-based) staining, fluorescent antibody staining, or polymerase chain reaction (PCR)-based assays of respiratory specimens. This is particularly true of the diagnosis of PCP in patients without HIV infection, since the number of organisms is significantly lower than in patients with HIV [82].

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 these 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 risk factors for PCP. Increasingly, elevated serum levels of beta-D-glucan are used to help support this diagnosis.

Some clinicians may choose to forego obtaining a definitive diagnosis if beta-D-glucan levels are markedly elevated and the clinical presentation and radiographic findings are highly consistent with PCP. However, such testing can yield positive results in patients with a number of other fungal infections and some bacterial infections (eg, Pseudomonas) or exposure to materials contaminated with reactive components (eg, gauze packing, intravenous immunoglobulin). Given the lack of specificity of beta-D-glucan testing for PCP, the possibility of other fungal infections should be kept in mind. (See 'Beta-D-glucan assay' below.)

As noted above, we favor obtaining a definitive diagnosis when it can be obtained safely. Using the beta-D-glucan assay for making a presumptive diagnosis potentially exposes patients unnecessarily to antibiotics, which may have toxicities. In addition, this approach may result in failure to diagnose the causative pathogen, which may require treatment with different antimicrobial therapies.

Diagnostic tests

Microscopy with staining — Detection of the organism in respiratory specimens is most commonly achieved by microscopy with staining of an induced sputum specimen or BAL fluid (image 3). Staining is necessary because Pneumocystis cannot be cultured. Direct fluorescent antibody staining using a fluorescein-conjugated monoclonal antibody can visualize both trophic forms and cysts and is the most common technique used. Trophic forms can also be seen with tinctorial stains such as Gram-Weigert, Wright-Giemsa, or modified Papanicolaou stains. The cell wall of the cysts can be visualized with calcofluor white, cresyl echt violet, Gomori methenamine silver, or toluidine blue.

Type of respiratory specimen — The most rapid and least invasive method of diagnosing PCP is by analysis of sputum induced by the inhalation of hypertonic saline [1]. If PCP is not identified by this modality, then bronchoscopy with BAL should be performed. Lung biopsy with tissue stains and PCR has excellent sensitivity for diagnosing PCP but is rarely required (image 6). Lung biopsy for diagnosis is generally reserved for patients in whom there is a high suspicion of PCP and in whom BAL testing has been negative or in those who have another reason to proceed to lung biopsy for diagnosis of a pulmonary process.

The diagnostic yield of microscopy with staining of induced sputum is 50 to 90 percent in patients with HIV and PCP but is thought to be lower in patients without HIV due to a decreased organism burden [23,82-85]. A similar difference has been noted with BAL. The diagnostic yield is over 90 percent in patients with HIV but may be lower in patients without HIV [85]. However, in one report, BAL was positive for PCP in 47 of 48 patients [23].

Polymerase chain reaction — A number of PCR assays have been developed for the detection of Pneumocystis in induced sputum or BAL fluid, blood, or nasopharyngeal aspirates. These assays may be of particular use in patients without HIV, in whom the sensitivity of microscopy with staining is substantially lower than in patients with HIV. (See "Clinical presentation and diagnosis of Pneumocystis pulmonary infection in patients with HIV", section on 'Definitive diagnosis'.)

Nested PCR strategies identify both colonization and infection [86]. In contrast, single-copy real-time PCR assays rapidly identify patients with infection rather than colonization and hence are more useful in clinical settings [87]. Overall, PCR-based detection of PCP adds roughly 7 percent yield over stains alone when applied to BAL specimens [87].

The utility of PCR for the diagnosis of PCP in immunocompromised patients without HIV was evaluated in a prospective study of 448 such patients with pulmonary infiltrates, the majority of whom had a hematologic malignancy [88]. The study compared conventional staining (Giemsa staining and indirect immunofluorescence) with PCR for P. jirovecii. The following findings were noted:

●Thirty-nine patients (8.7 percent) were diagnosed with PCP by conventional staining of BAL fluid or induced sputum. Of these, 34 (87 percent) had a positive PCR result.

●PCR was also positive in 32 patients who had a negative PCP stain. Complete follow-up was available in 21 of these patients, 14 of whom were diagnosed with probable or definite PCP.

Thus, PCR of BAL fluid or induced sputum can increase the diagnostic yield over conventional staining alone in immunocompromised patients without HIV.

Beta-D-glucan assay — Beta-D-glucan is a cell wall component of all fungi, including Pneumocystis. A serum assay for beta-D-glucan is available and can be used to screen for a variety of invasive fungal infections. Although this test has been best studied for Candida and Aspergillus spp, it may also have utility for diagnosing PCP [89-93]. (See "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay'.)

The serum beta-D-glucan assay can be used as an adjunct to the diagnosis of PCP. Generally, the test has good sensitivity in patients with HIV and PCP [94] and a high negative predictive value, making it unlikely that a patient with a negative beta-D-glucan result has PCP [95]. However, cut-offs have not been well defined and the sensitivity of the assay may be reduced, particularly when the burden of fungal disease is low or in patients without HIV [96]. The cut-off for a positive result for the currently available assay in the United States (>80 pg/mL) was established to predict candidemia in neutropenic patients and thus may not be generalized to PCP [97]. Given this caveat, investigators have assessed performance for diagnosing PCP at different quantitative cut-offs.

In one retrospective case-control study of 295 patients with suspected PCP who had microscopy of BAL fluid for PCP and serum testing with beta-D-glucan, the beta-D-glucan assay had a sensitivity of 92 percent and a specificity of 86 percent for detecting PCP when using a cut-off 31.1 pg/mL [89]. In another study evaluating >400 immunocompromised patients with lower respiratory tract disease, the sensitivity and specificity correlated with the height of the beta-D-glucan value [98]. Using a cut-off of 80 pg/mL, the assay had a sensitivity and specificity of 70 and 81 percent, respectively. The specificity of the assay rose to 100 percent when a >200 pg/mL cut-off was used. As expected, the predictive value of the beta-glucan assay rose when combined with PCP PCR.

As noted above, the assay reacts with beta-glucans released from other fungal organisms, reducing specificity, and diagnostic efforts to exclude other fungal infections are often necessary [94,96]. There are also several causes of a false-positive result, including some bacterial infections (eg, Pseudomonas) or exposure to reactive compounds (eg, gauze packing, intravenous immunoglobulin). Although the beta-D-glucan assay is not specific for PCP, it is useful while awaiting an induced sputum or BAL specimen for microscopy with staining for PCP or in situations in which respiratory sampling such as BAL cannot be performed safely.

Possible causes of a false-positive beta-D-glucan are discussed separately. (See "Diagnosis of invasive aspergillosis", section on 'Caveats'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pneumocystis pneumonia in patients without HIV".)

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 email 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 (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Risk factors − Pneumocystis pneumonia (PCP) is a potentially life-threatening infection that occurs in immunocompromised individuals, such as hematopoietic cell and solid organ transplant recipients, individuals with HIV or cancer (particularly hematologic malignancies), and those receiving glucocorticoids, chemotherapeutic agents, and other immunosuppressive medications. The most significant risk factors for PCP in patients without HIV are receipt of glucocorticoids combined with other immunosuppressive therapies (eg, cyclophosphamide) or presence of defects in cell-mediated immunity. (See 'Risk factors' above.)

●Clinical manifestations − In patients without HIV, PCP typically presents as fulminant respiratory failure associated with fever and dry cough. This is in contrast with PCP in patients with HIV, in whom the infection is usually indolent. (See 'Clinical manifestations' above.)

●Radiographic findings − The typical radiographic features of PCP in patients without HIV are diffuse, bilateral, interstitial infiltrates, but other patterns may be seen. (See 'Radiographic findings' above.)

●Diagnosis

•Approach to diagnosis − The diagnosis of PCP should be considered in patients with risk factors for PCP who present with pneumonia. The definitive diagnosis of PCP requires identification of the organism either by tinctorial (dye-based) staining, fluorescent antibody staining, or polymerase chain reaction-based assays of respiratory specimens. Our approach to diagnosis includes microbiologic identification of the organism when possible. (See 'Approach to diagnosis' above.)

•Type of respiratory specimen − An induced sputum sample is usually the initial procedure for the diagnosis of PCP. If PCP is not identified by this modality, then bronchoscopy with bronchoalveolar lavage should be performed. (See 'Type of respiratory specimen' above.)

•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 these 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 risk factors for PCP. Increasingly, elevated levels of beta-D-glucan are used to help support this diagnosis. (See 'Presumptive diagnosis' above.)

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Topic 1406 Version 51.0

References

1 : Pneumocystis pneumonia.

2 : Current insights into the biology and pathogenesis of Pneumocystis pneumonia.

3 : A new name (Pneumocystis jiroveci) for Pneumocystis from humans.

4 : Pneumocystis nomenclature.

5 : Pneumocystis carinii nomenclature: response to Cushion and Stringer.

6 : Has the name really been changed? It has for most researchers.

7 : Pneumocystis and Trypanosoma cruzi: nomenclature and typifications.

8 : Opportunistic infections in patients with and patients without Acquired Immunodeficiency Syndrome.

9 : Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the fungi.

10 : Pneumocystis carinii: has the name really been changed?

11 : [Parasitic pneumonia. Interstitial plasma cell pneumonia of premature, caused by pneumocystis Carinii].

12 : Pathogenese und aetiologie der interstitiellen plasmacellulaeren Saeuglingspneumonie

13 : Intensity of immunosuppressive therapy and the incidence of Pneumocystis carinii pneumonitis.

14 : Pneumocystis carinii pneumonia in the United States. Epidemiologic, diagnostic, and clinical features.

15 : Pneumocystis colonization is highly prevalent in the autopsied lungs of the general population.

16 : Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy.

17 : Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital.

18 : Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients.

19 : Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome. More patients, same risk.

20 : Influence of type of cancer and hematopoietic stem cell transplantation on clinical presentation of Pneumocystis jiroveci pneumonia in cancer patients.

21 : Pneumocystis jiroveci pneumonia (PCP) in HIV-1-negative patients: a retrospective study 2002-2004.

22 : Analysis of underlying diseases and prognosis factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients.

23 : Pneumocystis carinii pneumonia in patients with malignant haematological diseases: 10 years' experience of infection in GIMEMA centres.

24 : Incidence of Pneumocystis jiroveci pneumonia among groups at risk in HIV-negative patients.

25 : Pneumocystis jirovecii pneumonia in patients with or without AIDS, France.

26 : Pneumocystis carinii pneumonia in patients with primary brain tumors.

27 : Pneumocystis carinii pneumonia during steroid taper in patients with primary brain tumors.

28 : Pneumocystis pneumonia in brain tumor patients: risk factors and clinical features.

29 : Nonbacterial pneumonia after allogeneic marrow transplantation: a review of ten years' experience.

30 : Infectious complications and outcomes after allogeneic hematopoietic stem cell transplantation in Korea.

31 : Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study.

32 : Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study.

33 : Pneumocystis carinii pneumonia in HIV-negative immunocompromised adults.

34 : Risk factors for Pneumocystis carinii pneumonia in kidney transplant recipients: a case-control study.

35 : Infections in heart-lung transplant recipients.

36 : Unexpectedly high incidence of Pneumocystis carinii infection after lung-heart transplantation. Implications for lung defense and allograft survival.

37 : An outbreak of Pneumocystis jiroveci pneumonia with 1 predominant genotype among renal transplant recipients: interhuman transmission or a common environmental source?

38 : Outbreaks of Pneumocystis pneumonia in 2 renal transplant centers linked to a single strain of Pneumocystis: implications for transmission and virulence.

39 : Linking Pneumocystis epidemiology, transmission, and virulence.

40 : A cluster of Pneumocystis infections among renal transplant recipients: molecular evidence of colonized patients as potential infectious sources of Pneumocystis jirovecii.

41 : Molecular epidemiology linking multihospital clusters of opportunistic Pneumocystis jirovecii pneumonia.

42 : Epidemiological Outbreaks of Pneumocystis jirovecii Pneumonia Are Not Limited to Kidney Transplant Recipients: Genotyping Confirms Common Source of Transmission in a Liver Transplantation Unit.

43 : Outbreak of Pneumocystis jirovecii Infection Among Heart Transplant Recipients: Molecular Investigation and Management of an Interhuman Transmission.

44 : Pneumocystis Infection Outbreaks in Organ Transplantation Units in France: A Nation-Wide Survey.

45 : Pneumocystis carinii pneumonia: a major complication of immunosuppressive therapy in patients with Wegener's granulomatosis.

46 : Pneumocystis carinii pneumonia in the course of connective tissue disease: report of 34 cases.

47 : Pneumocystis carinii pneumonia in patients with connective tissue disease.

48 : Pneumocystis carinii pneumonia in patients receiving chemotherapy for breast cancer.

49 : The unmasking of Pneumocystis jiroveci pneumonia during reversal of immunosuppression: case reports and literature review.

50 : Pneumocystis carinii pneumonia associated with inhaled corticosteroids in an immunocompetent child with asthma.

51 : Legionella and Pneumocystis pneumonias in asthmatic children on high doses of systemic steroids.

52 : Primary brain tumors treated with steroids and radiotherapy: low CD4 counts and risk of infection.

53 : Regulation of surfactant phosphatidylcholine secretion from alveolar type II cells during Pneumocystis carinii pneumonia in the rat.

54 : Selective lymphopenia and opportunistic infections in neuroendocrine tumor patients receiving temozolomide.

55 : Selective lymphopenia and opportunistic infections in neuroendocrine tumor patients receiving temozolomide.

56 : Selective lymphopenia and opportunistic infections in neuroendocrine tumor patients receiving temozolomide.

57 : Identification of Predictive Markers and Outcomes of Late-onset Pneumocystis jirovecii Pneumonia in Kidney Transplant Recipients.

58 : m-TOR inhibitors and risk of Pneumocystis pneumonia after solid organ transplantation: a systematic review and meta-analysis.

59 : m-TOR inhibitors and risk of Pneumocystis pneumonia after solid organ transplantation: a systematic review and meta-analysis.

60 : Risk factors of Pneumocystis pneumonia in solid organ recipients in the era of the common use of posttransplantation prophylaxis.

61 : Risk factors of Pneumocystis pneumonia in solid organ recipients in the era of the common use of posttransplantation prophylaxis.

62 : Pneumocystis pneumonia in patients treated with rituximab.

63 : Low incidence of pneumocystis pneumonia utilizing PCR-based diagnosis in patients with B-cell lymphoma receiving rituximab-containing combination chemotherapy.

64 : When is it safe to stop Pneumocystis jiroveci pneumonia prophylaxis? Insights from three cases complicating autoimmune diseases.

65 : Risk factors for Pneumocystis carinii pneumonia in patients with polymyositis/dermatomyositis or systemic lupus erythematosus.

66 : Prevalence of Pneumocystis carinii pneumonitis in severe combined immunodeficiency.

67 : A cluster of Pneumocystis carinii pneumonia in adults without predisposing illnesses.

68 : Unexplained opportunistic infections and CD4+ T-lymphocytopenia without HIV infection. An investigation of cases in the United States. The Centers for Disease Control Idiopathic CD4+ T-lymphocytopenia Task Force.

69 : Pneumocystis carinii pneumonia as a presenting feature of X-linked hyper-IgM syndrome.

70 : The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.

71 : Pneumocystis jiroveci infection in patients with hyper-immunoglobulin E syndrome.

72 : Pneumocystis carinii pneumonia in an infant with transient hypogammaglobulinaemia of infancy.

73 : Pneumocystis carinii pneumonia in an infant with X-linked agammaglobulinemia.

74 : Pneumocystis carinii pneumonia in patients without predisposing illnesses. Acute episode and follow-up of five cases.

75 : Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies.

76 : Clinical picture of Pneumocystis jiroveci pneumonia in cancer patients.

77 : Imaging features of Pneumocystis carinii pneumonia.

78 : Accuracy of high-resolution CT in distinguishing between Pneumocystis carinii pneumonia and non- Pneumocystis carinii pneumonia in AIDS patients.

79 : Atypical roentgenographic manifestations of Pneumocystis carinii pneumonia.

80 : Atypical presentations of Pneumocystis carinii pneumonia in patients receiving inhaled pentamidine prophylaxis.

81 : Case report: Pneumocystis carinii pneumonia presenting as a solitary cavitating lung lesion in non-HIV immunosuppressed patients.

82 : Pneumocystis carinii pneumonia. Differences in lung parasite number and inflammation in patients with and without AIDS.

83 : Bronchoalveolar lavage fluid cytology in patients with Pneumocystis carinii pneumonia.

84 : Pneumocystis pneumonia: clinical presentation and diagnosis in patients with and without acquired immune deficiency syndrome.

85 : The laboratory evaluation of opportunistic pulmonary infections.

86 : Prevalence and clinical predictors of Pneumocystis colonization among HIV-infected men.

87 : Pneumocystis jirovecii testing by real-time polymerase chain reaction and direct examination among immunocompetent and immunosuppressed patient groups and correlation to disease specificity.

88 : Polymerase chain reaction for diagnosing pneumocystis pneumonia in non-HIV immunocompromised patients with pulmonary infiltrates.

89 : Serum indicators for the diagnosis of pneumocystis pneumonia.

90 : (1->3)beta-D-glucan assay positivity in patients with Pneumocystis (carinii) jiroveci pneumonia.

91 : Serum (1-3)-beta-D-glucan as a tool for diagnosis of Pneumocystis jirovecii pneumonia in patients with human immunodeficiency virus infection or hematological malignancy.

92 : Serum (1-->3) beta-D-glucan as a noninvasive adjunct marker for the diagnosis of Pneumocystis pneumonia in patients with AIDS.

93 : Accuracy ofβ-D-glucan for the diagnosis of Pneumocystis jirovecii pneumonia: a meta-analysis.

94 : Diagnostic accuracy of serum 1,3-β-D-glucan for pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis.

95 : ECIL guidelines for the diagnosis of Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients.

96 : Detection of (1, 3)-β-D-glucan in bronchoalveolar lavage and serum samples collected from immunocompromised hosts.

97 : Detection of (1, 3)-β-D-glucan in bronchoalveolar lavage and serum samples collected from immunocompromised hosts.

98 : Clinical Performance of (1,3) Beta-D Glucan for the Diagnosis of Pneumocystis Pneumonia (PCP) in Cancer Patients Tested With PCP Polymerase Chain Reaction.