Approach

Clinical presentation varies according to the degree of immune suppression. Diagnosis in known HIV-positive patients usually occurs earlier, whereas, in HIV-negative patients, there may be a delay in diagnosing Pneumocystis pneumonia (PCP), which may present in a more severe form. Diagnosis is confirmed by demonstration of the organism in bronchoalveolar lavage (BAL) fluid, induced sputum, or, less commonly, in lung tissue.

History

Clinicians should suspect PCP when caring for adult or adolescent patients who are HIV-positive, especially if they are nonadherent with combination antiretroviral therapy (ART) or PCP prophylaxis, have had a previous episode of PCP, and/or have a CD4 cell count <200 cells/microliter.[60]

HIV-positive children and HIV-indeterminate infants of HIV-infected mothers who present with respiratory symptoms should also be evaluated for PCP.

Other groups of patients in whom to suspect PCP are those who are immunocompromised with a history of:[31][47][48][49]

  • Hematologic malignancy

  • Hematopoietic cell transplantation

  • Other malignancies where chemotherapy regimen is associated with >3.5% risk of PCP

  • Solid-organ transplantation

  • Chronic use of corticosteroids with or without other immunosuppressive drugs

  • Certain primary immunodeficiencies (e.g., severe combined immunodeficiency)

In patients with atypical presentations of pneumonia, assessing for HIV risk factors and performing HIV testing can also help identify patients at risk of PCP.

In HIV-positive PCP, presentation is often an insidious progression of fatigue, fevers, chills, sweats, nonproductive cough, and dyspnea over several weeks. Other findings associated with PCP are a history of recurrent bacterial pneumonias, weight loss, and oral candidiaisis.[43]

In HIV-negative patients, the presentation is typically more rapid and more severe.[43] The onset of symptoms may occur while the usual dose of immunosuppressive agents is being decreased or discontinued.[61]

Rarely, infection causes extrapulmonary manifestations in those with advanced HIV; however, in patients with advanced AIDS or in HIV-positive patients who are not taking their prophylaxis, there may be systemic infection with visual symptoms, cognitive impairment owing to central nervous system involvement, and gastrointestinal symptoms, such as diarrhea.

Physical exam

The findings on physical examination are nonspecific and include fever, tachypnea, and tachycardia. Pulmonary examination is often normal but occasionally demonstrates mild crackles on auscultation. Children may present with cyanosis. Infection rarely causes extrapulmonary manifestations, but in patients with advanced AIDS there may be systemic infection.

Diminished breath sounds unilaterally may be a sign of pneumothorax. Pleuritic pain may be a sign of pneumothorax but is uncommon in PCP without a pneumothorax.

Investigations

If PCP is suspected based on clinical presentation, and the chest x-ray is compatible with PCP, the first step in diagnosis should be an induced sputum for visualization of Pneumocystis jirovecii.[62] Sputum that is spontaneously expectorated has low sensitivity for the diagnosis of PCP and should not be used. Sensitivity of induced sputum testing is 50% to 90% depending on the quality of the sample, the pathogen load, the staining method used, and the experience of the institution.[32][63][64][65][66]

If sputum induction is negative, bronchoscopic examination with BAL should be performed. The sensitivity for BAL is 90% to 99% in HIV-positive patients, so it is usually performed without transbronchial biopsy.[32] In general, if BAL is negative in an HIV-positive patient, then another etiology should be considered and treatment can be discontinued.

Transbronchial biopsies can be performed if initial BAL is negative but clinical suspicion of PCP is high or other diagnoses are considered likely. Sensitivity of transbronchial biopsies is 95% to 100%.[32] In HIV-negative patients, transbronchial biopsy is more often necessary to confirm a diagnosis because BAL is less sensitive. Transbronchial biopsy does have a higher risk of complications, such as bleeding and pneumothorax. Pneumothorax occurred in 9% of HIV-positive patients who had transbronchial biopsies in one series with 5% requiring insertion of a chest tube.[67]

If clinical suspicion for PCP remains high or prior testing does not reveal the etiology for the patient's illness, an open lung biopsy can be considered to confirm or rule out PCP as well as to determine if another pathology is present. The sensitivity of open lung biopsies is 95% to 100%.[32]

Elevated serum LDH (>220 international units/L) has both diagnostic and prognostic significance with a higher LDH level being associated with increased mortality.[68]

Arterial blood gas is used to determine severity:[32]

  • Mild-to-moderate PCP: arterial blood gas room air pO₂ ≥70 mmHg or an alveolar-arterial (A-a) gradient ≤35 mmHg

  • Moderate-to-severe PCP: arterial blood gas room air pO₂ <70 mmHg or an alveolar-arterial (A-a) gradient >35 mmHg

Patients with a clinical presentation suggestive of PCP, but a normal or unchanged chest x-ray, should undergo either a high-resolution computed tomography (HRCT) scan of the chest or pulmonary function tests with measurement of diffusing capacity for carbon monoxide (DLCO). If the HRCT scan shows ground glass opacities or the DLCO is decreased, then the patient should undergo sputum induction followed by BAL (if sputum induction is negative), as the presence of ground glass opacities or decreased DLCO are sensitive, but not specific, tests for PCP.[69][70][71] If both tests are negative, then another etiology should be considered and appropriate diagnostic workup performed. If all diagnostic samples for Pneumocystis jirovecii are negative, then the patient is very unlikely to have PCP and the patient should be observed and other etiologies considered. Further testing may be necessary depending on the clinical situation.

A diagnosis of PCP does not rule out the possibility of a second, concurrent process. Although it is preferable to confirm the diagnosis of PCP microscopically because many conditions can have similar presentations, empiric treatment of patients with a clinical presentation suggestive of PCP may be undertaken, particularly in places where there are limited resources for performing induced sputum or BAL.

The identification of Pneumocystis jirovecii in sputum or BAL fluid has typically been performed with stains, such as toluidine blue, Geimsa, Diff-Quik, and methenamine silver. Immunofluorescent assays (direct fluorescent-antigen testing) may also be used, which have a higher sensitivity.[72] Transbronchial biopsies along with BAL can increase the diagnostic yield.[73]

Other assays, such as polymerase chain reaction (PCR), real-time PCR, and reverse transcriptase PCR, can detect low levels of Pneumocystis jirovecii DNA. These assays, along with plasma levels of S-adenosylmethionine, may increase sensitivity of diagnosing PCP but are often not clinically available. PCR techniques have a higher false-positive rate than histochemical staining.[74][75][76][77][78][79][80]

There has also been interest in measuring serum (1,3)-beta-D-glucan, an element of the fungal wall, for the diagnosis of PCP.[81][82][83][84][85] These studies show (1,3)-beta-D-glucan to be significantly elevated in patients with PCP, although less so in HIV-negative patients with PCP, and the levels did not correlate with severity or response to therapy.[86] One 2012 meta-analysis of studies on (1,3)-beta-D-glucan in the diagnosis of PCP in various populations (HIV-infected and HIV-uninfected) showed that the pooled sensitivity and specificity were 96% and 84%, respectively.[87] One more recent 2015 meta-analysis demonstrated similar sensitivity (92%) and specificity (78%) for HIV-infected patients; however, in HIV-uninfected patients, sensitivity and specificity were lower, at 85% and 73%, respectively.[88] In one of the largest studies of HIV-infected participants (n=282) with 69% having PCP, the sensitivity and specificity were 92% and 65%, respectively.[89] In a study of 159 AIDS patients with at least one respiratory symptom, 139 of whom had PCP, the sensitivity and specificity of (1,3)-beta-D-glucan were 92.8% and 75.0%, respectively.[90] While the sensitivity may be helpful in ruling out PCP in settings where more sensitive tests are not available, the decreased specificity is due to detection of (1,3)-beta-D-glucan during other fungal infections, since (1,3)-beta-D-glucan is not a Pneumocystis-specific protein and may be less reliable in HIV-uninfected people.[Figure caption and citation for the preceding image starts]: Posteroanterior chest x-ray showing mild, reticular, bilateral pulmonary interstitial infiltratesFrom the collection of Matthew Gingo, UPMC [Citation ends].com.bmj.content.model.Caption@46e30327[Figure caption and citation for the preceding image starts]: Posteroanterior chest x-ray showing severe, bilateral pulmonary interstitial infiltrates with pneumatocelesFrom the collection of Matthew Gingo, UPMC [Citation ends].com.bmj.content.model.Caption@1da6d2d7[Figure caption and citation for the preceding image starts]: Computed tomography scan of the thorax showing bilateral pulmonary interstitial infiltrates and pneumatoceles (cysts), which are typical of Pneumocystis pneumonia (PCP)From the collection of Matthew Gingo, UPMC [Citation ends].com.bmj.content.model.Caption@378b7d02[Figure caption and citation for the preceding image starts]: Photomicrograph of bronchoalveolar lavage (BAL) fluid showing Pneumocystis cysts, stained black with Grocott-Gomori methenamine-silver stain (methyl green counterstain)From the collection of Matthew Gingo, UPMC [Citation ends].com.bmj.content.model.Caption@721cf361

[Figure caption and citation for the preceding image starts]: Algorithm for the diagnosis of Pneumocystis pneumonia; bronchoalveolar lavage (BAL)Matthew Gingo, adapted from Singh, HIV Clinical Manual, 2003 [Citation ends].com.bmj.content.model.Caption@793fcc81

Use of this content is subject to our disclaimer