AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Pneumocystis jiroveci, previously known as Pneumocystis carinii, is the organism responsible for Pneumocystis carinii pneumonia (PCP); the most common opportunistic infection in HIV-infected patients. As our understanding of the Pneumocystis genus has grown, the name was changed to specify Pneumocystis, which is isolated in humans. The abbreviation PCP is still used to designate Pneumocystis pneumonia. Pneumocystis is a genus of unicellular fungi found in the respiratory tracts of many mammals and humans. Distinct genomic variability exists between host-specific members of the genus. The organism was first described in 1909 by Chagas then a few years later by Delanöes who ultimately named the organism in honor of Dr Carini after isolating it from infected rats. Years later, Dr Otto Jirovec and his group isolated the organism from humans, and it is after him that the organism responsible for PCP pneumonia was renamed.

Pneumocystis first came to attention when it was found to cause interstitial pneumonia in Central and Eastern Europe during World War II in severely malnourished and premature infants. Prior to the 1980s, fewer than 100 cases of PCP occurred per year in the United States, occurring in immunosuppressed patients such as cancer patients treated with chemotherapy and solid organ transplant recipients on immunosuppressive agents. In 1981, the Centers for Disease Control and Prevention (CDC) reported the occurrence of PCP in 5 previously healthy homosexual males residing in the Los Angeles area. Pneumocystis jiroveci is now one of several organisms known to cause life-threatening opportunistic infections in patients with advanced HIV infection worldwide.

Microbiology

The taxonomic classification of the Pneumocystis genus was debated for some time. It was initially mistaken as a trypanosome then later as a protozoan. In the 1980s, biochemical analysis of the nucleic acid composition of Pneumocystis rRNA and mitochondrial DNA identified the organism as a unicellular fungus rather than a protozoa. Subsequent genomic sequence analysis of multiple genes including elongation factor 3, a component of fungi protein synthesis not found in protozoa, further supported this notion. The organism is found in 3 distinct morphologic stages. The trophozoite or trophic form, where it often exists in clusters; the sporozoite, which is a precystic form; and finally, the cyst, which contains several intracystic bodies also known as spores.

Pathophysiology

Pneumocystis is commonly found in the lungs of healthy individuals. Most children are believed to have been exposed to the organism by age 3 or 4 years, and its occurrence is worldwide.

Animal studies have suggested that Pneumocystis is communicable with airborne transmission reported. Human evidence of this is provided by molecular analysis of Pneumocystis isolates obtained from groups of patients involved in hospital outbreaks. Further evidence of human transmission is found in cases of recurrent pneumonia where the genotype of Pneumocystis in the same person was different in prior episodes.

Disease occurs when defects exist in both cellular immunity and humoral immunity. Once inhaled, the trophic form of the organism attaches to the alveoli. Multiple host immune defects allow for uncontrolled replication of the organism and development of illness including the following:

• Activated alveolar macrophages without CD4⁺ cells are unable to eradicate the organism
• Increased alveolar-capillary permeability documented on electron microscopy
• Physiologic changes that occur include the following:
  • Hypoxemia with an increased alveolar-arterial oxygen gradient
  • Respiratory alkalosis
  • Impaired diffusing capacity
  • Changes in total lung capacity, vital capacity

Frequency

United States

Prior to the widespread use of PCP prophylaxis, the frequency of infection in lung transplant patients alone was as high as 88%. Now with routine use of prophylaxis, PCP is very rare in solid organ transplant patients and has significantly decreased in HIV patients.

• Prior to highly active antiretroviral therapy (HAART), PCP occurred in 70-80% of HIV-infected patients.
• The frequency of PCP is decreasing with the use of PCP prophylaxis and HAART.
• PCP is still the most common opportunistic infection in HIV patients.
• HIV patients are more prone to recurrence than patients without HIV.

International

The prevalence of PCP was once thought to be much lower in developing regions of the world, but studies have shown that the lower incidence reported is likely a failure to accurately diagnose the condition. Accurate diagnosis requires access to modern medical care not available worldwide. Now, the frequency of documented infection is increasing in Africa, with Pneumocystis found in up to 80% of HIV-infected infants with pneumonia.

Mortality/Morbidity

• In HIV patients
  • Mortality used to range from 20-40%, depending upon disease severity at presentation. Now, mortality rates of 10-20% are reported.
  • PCP is still a major cause of death in AIDS patients in the United States.
• Non-HIV patients
  • The outcome is worse in non-HIV patients without a significant change in 20 years.
  • Mortality rates of 30-50% have been documented in several large studies.
  • Higher incidence of mortality is likely a result of a delay in diagnosis and initiation of appropriate treatment.

CLINICAL

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History

The symptoms of PCP are very nonspecific. HIV-infected patients tend to have a more subacute indolent course and tend to present much later, often after several weeks of symptoms, when compared with other immunocompromised patients. Symptoms include the following:

• Progressive exertional dyspnea (95%)
• Fever (>80%)
• Nonproductive cough (95%)
• Chest discomfort
• Weight loss
• Chills
• Hemoptysis (rare)

Physical

Like the history, the physical examination findings of PCP are very nonspecific and include the following:

• Tachypnea
• Fever
• Tachycardia
• Pulmonary examination may reveal mild crackles and rhonchi but may be normal in up to half of patients.
• Additional findings in children with severe disease
• • Cyanosis
  • Nasal flaring
  • Intercostal retractions
• Extrapulmonary manifestations: While extrapulmonary manifestations are rare with Pneumocystis, they may be present in patients receiving aerosolized pentamidine for prophylaxis or in patients with advanced HIV infection who are not taking any prophylaxis. They may also occur in the absence of lung involvement. Pneumocystis may present in almost any organ system with the most well-documented findings, as follows:
• • Hepatomegaly
  • Skin lesions
  • Bone marrow (may have necrosis with resultant pancytopenia)
  • Lymphadenopathy
  • Eyes (may have retinal cotton-wool spots)
  • Thyroid (may present as a rapidly enlarging thyroid mass)
  • GI tract

Causes

P jiroveci causes PCP in the following patients:

• HIV patients when the CD4⁺ cells fall below 200/µL and not taking PCP prophylaxis; findings of other opportunistic infections such as oral thrush in an HIV patient increases the risk of PCP regardless of CD4⁺ count.
• In other patients with primary immune deficiencies including hypogammaglobulinemia and severe combined immunodeficiency (SCID).
• In patients on long-term immunosuppressive regimens for connective tissue disorders, vasculitides, and solid organ (eg, heart, lung, liver kidney) transplant recipients
• Patients with hematologic and nonhematologic malignancies including solid tumors and lymphomas
• Patients with severe malnutrition

DIFFERENTIALS

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Other Problems to be Considered

Legionellosis

WORKUP

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Lab Studies

• May obtain a lactic dehydrogenase (LDH) level as part of the initial workup
• • Levels are usually elevated >220 up to 550 in patients with PCP.
  • This study has a high sensitivity (78-100%).
  • LDH level is elevated in 90% of HIV-infected patients with PCP.
  • This study has a much lower specificity because an elevated LDH level can occur in other disease processes.
  • Levels appear to reflect the degree of lung injury.
  • Consistently elevated levels during treatment may indicate therapy failure and worse prognosis.
  • Levels should decline with successful treatment.

Imaging Studies

• Chest radiographs should be obtained in any immunocompromised patient with fever and/or respiratory signs or symptoms. Findings include the following:
• • Diffuse bilateral infiltrates extending from the perihilar region are seen in most patients.
  • Less common findings include patchy asymmetric infiltrates and pneumatoceles.
  • Pleural effusions and intrathoracic adenopathy are also rare.
  • The chest radiographic findings may be normal in patients with early mild disease.
  • Pneumothorax may occur in patients using aerosolized pentamidine.
  • Apical disease may also be found in patients using aerosolized pentamidine for prophylaxis.
• High-resolution CT scan of chest
• • High-resolution CT scan of chest (HRCT) is helpful when the CXR is equivocal.
  • Classic appearance is patchy areas of ground-glass attenuation with a background of interlobular septal thickening.
  • HRCT has a high sensitivity in HIV-infected patients with PCP.
  • A negative (normal or unchanged) CT scan alone does not rule out PCP.
• Gallium 67 scanning
• • Gallium 67 scan demonstrates an increased pulmonary uptake in PCP.
  • This study is highly sensitive (nearly 100%).
  • Specificity is low (some studies report as low as 20%).
  • The high cost and 2-day time delay in obtaining results have limited its use.
  • A gallium 67 scan is potentially more useful in patients with suspected relapse, as bronchoalveolar lavage (BAL) may be less diagnostic in such cases.

Other Tests

• Pulmonary function tests should be obtained as part of the initial noninvasive workup in patients with suspected PCP.
• • Results may demonstrate a decreased diffusion capacity of carbon monoxide (DLCO) of less than 75% predicted.
  • Decreased DLCO has a high sensitivity (89-100%) but poor specificity (53%).
  • PCP is unlikely if DLCO is normal.
  • When combined with a normal or unchanged HRCT, pulmonary function tests may be used to identify patients unlikely to have PCP who may be observed without treatment initiated.
• Pulse oximetry on room air should be measured in all patients. The oxygen saturation should be measured both at rest and with exertion. If any hypoxemia is found (O₂ saturation <90%), then an arterial blood gas (ABG) level should be obtained to evaluate the need for possible adjunctive corticosteroids (see Medications).

Procedures

• Obtain sputum sample by sputum-induction for histopathologic testing if PCP is strongly suspected. Pneumocystis is frequently found in sputum induced by inhalation of a hypertonic saline solution.
• • Expectorated sputum has a very low sensitivity and should not be submitted for diagnosis.
  • Sputum induction is the quickest and least invasive means by which to establish a definitive diagnosis of PCP.
  • Sensitivity varies widely (<50 to >90%) and is dependent on proficiency in using the technique and the experience of the laboratory.
  • Specificity is high (99-100%).
  • This study may be less sensitive in non-HIV patients, as the more severe immune defect in patients with HIV leads to a greater alveolar load of Pneumocystis organisms.
  • It also may be less sensitive in patients on aerosolized pentamidine for prophylaxis.
• Bronchoalveolar lavage (BAL) is the most common invasive procedure used to diagnose PCP.
• • BAL has a diagnostic yield >90% (may be increased if multiple lobes are sampled).
  • Obtain BAL if PCP is strongly suspected and induced sputum sample is negative.
  • BAL has a lower sensitivity in patients receiving aerosolized pentamidine, in which case a transbronchial biopsy may be performed in conjunction with BAL.
  • It may be used in situations where the patient is unable to cooperate with an induced sputum sample such as patients with altered mental status.
  • BAL may be less useful in cases of suspected PCP relapse (see Imaging Studies).
• Open lung biopsy is the most invasive procedure and has 100% sensitivity and specificity because it provides the greatest amount of tissue for diagnosis but is reserved for rare cases when bronchoscopy is nondiagnostic.

Histologic Findings

Because of its nonspecific clinical and radiologic findings and since Pneumocystis jiroveci cannot be grown in vitro, histopathologic demonstration is necessary before a definitive diagnosis is established. Multiple staining techniques for respiratory tract secretions are available:

• Cresyl violet, Giemsa, Diff-Quik, and Wright stain detect both the trophozoite and cyst forms but not the cyst wall (see Image 1).
• Methenamine silver, toluidine blue, and Gram-Weigert selectively stain the wall of Pneumocystis cysts (see Image 2).
• Papanicolaou smear may demonstrate a foamy-appearing eosinophilic material surrounding Pneumocystis (see Image 3).

Some facilities may prefer the use of direct immunofluorescence using monoclonal antibodies to detect Pneumocystis because it may be more sensitive than histologic staining.

TREATMENT

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Medical Care

Although officially classified as a fungus, PCP does not respond to antifungal treatment. Although a histopathologic demonstration of the organism is required for a definitive diagnosis, treatment should not be delayed. The organism persists in its host for anywhere from days to even weeks after therapy is started, allowing time for the appropriate workup to still be completed.

• Treatment depends upon classification of degree of illness at the time of diagnosis (see Medication below).
• Treatment is based upon the alveolar-arterial gradient, which may be mild (<35 mm Hg), moderate/severe (35-45 mm Hg), or severe (>45 mm Hg).
• Severe disease is also diagnosed by a room air pO₂ of less than 70 mm Hg.

Consultations

Consultation with a pulmonologist is required for BAL.

MEDICATION

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The recommended duration of treatment for PCP is 21 days in HIV patients and 14 days for all other patients. HIV patients tend to have a higher organism burden and respond to treatment slower than non-HIV patients and therefore require a longer duration of therapy.

• Treatment of extrapulmonary manifestations is the same as that for pneumonia.
• In mild-to-moderate disease, failure to respond to antibiotic treatment because of lack of drug efficacy may occur in up to 10% of patients.
• In non-HIV patients, response to treatment should begin in 4-5 days.
• In HIV patients, typically a response to treatment takes longer but a response should occur by 8 days.
• If no response occurs within the expected time, then the patient's current regimen should be stopped and changed to an appropriate alternative regimen.
• Adding additional PCP medications to a current regimen only increases the risk of adverse drug reactions without improved outcome.

Drug Category: Antibiotic

Primary recommended treatment for mild, moderate, or severe disease. TMP-SMX has been shown to be as effective as intravenous pentamidine and more effective than other alternative treatment regimens. The parenteral route may be considered in patients who present seriously ill or in those with gastrointestinal side effects. TMP-SMX is the preferred initial therapy during pregnancy according to consensus guidelines. The patient's neonatologist should be informed if the medication is used near delivery because of potential for hyperbilirubinemia and kernicterus.

Drug Category: Corticosteroid

Adjunctive initial therapy only in HIV patients with severe PCP as defined by a room air arterial oxygen pressure <70 mm Hg or arterial-alveolar O₂ gradient >35 mm Hg. Adjunctive steroids are not recommended in non-HIV patients. Microbial degradation and clearance may trigger further inflammation, which can provoke a severe inflammatory response in the lungs that often worsens after therapy is begun. Adjunctive corticosteroid therapy can blunt this inflammatory response and reduce deterioration of oxygenation and reduce the incidence of respiratory failure.

FOLLOW-UP

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Further Inpatient Care

• All patients requiring corticosteroids should be admitted because of the potential to develop progressive respiratory compromise.
• Treatment may be initiated before workup is complete in severely ill high-risk patients.
• Appropriate histopathologic testing may still be used to confirm the diagnosis after treatment is initiated.
• Endotracheal tube aspirates from severely ill patients on mechanical ventilation may be submitted for diagnosis.
• Because of increasing evidence of possible human transmission (see Pathophysiology), the CDC Hospital Infection Control Practice Advisory Committee has recommended that patients with PCP not have direct contact with other immunocompromised patients.

Further Outpatient Care

• Arranging close medical follow-up with a primary care provider upon hospital discharge is essential to follow resolution of disease and to initiate prophylactic medication.

In/Out Patient Meds

• Oral therapy with TMP-SMX has been shown to be very effective in the outpatient setting. However, oral therapy should only be considered in patients with mild-to-moderate disease who have reliable outpatient follow-up care.

Deterrence/Prevention

• Smoking cessation is strongly recommended in patients with HIV, as studies have shown that in addition to the common deleterious effects of tobacco use, smokers have a higher likelihood to develop PCP and have a more complicated treatment course.
• An expert panel overseen by the US Public Health Service and Infectious Disease Society of America has published guidelines on PCP prophylaxis in adult and pediatric HIV patients. Chemoprophylaxis is recommended for the following groups:
• • Adults, adolescents, and pregnant patients with a CD4 count less than 200/µL, oropharyngeal candidiasis, unexplained fever >100°F (37.7° C) for >2 weeks, and a prior episode of PCP regardless of CD4 count should receive prophylaxis.
  • Children born to HIV-infected mothers should receive prophylaxis with TMP-SMX beginning at 4-6 weeks of life. The drug should be discontinued if they are subsequently determined not to be infected with HIV.
  • Children who are determined to be HIV positive through the first year of life, then as determined by age-specific CD4 levels, should receive prophylaxis.
• Two types of outpatient chemoprophylactic therapies exist:
• • Primary prophylaxis is for immunocompromised patients without a history of PCP.
  • Secondary prophylaxis is aimed at patients with a prior bout of PCP.
• Prophylaxis may be discontinued in HIV patients when the CD4 count is greater than 200/µL for 3 consecutive months while on HAART. Prophylaxis should be restarted if the CD4 count decreases to less than 200/µL. Prophylaxis should be continued for life in patients who developed an episode of PCP while their CD4 level was greater than 200/µL.
• Unlike HIV patients, no specific guidelines exist for which non-HIV immunocompromised patients should receive prophylaxis. In general, chemoprophylaxis should be considered in any patient, as follows:
• • Patients with an underlying primary immune deficiency such as severe combined immunodeficiency or hypogammaglobulinemia
  • Patients with a persistent CD4 count less than 200/µL
  • Solid organ transplant recipients
  • Hematopoietic stem cell transplant (HSCT) recipients beginning after engraftment until 6 months or >6 months after HSCT in patients who are still receiving immunosuppressive therapy (eg, prednisone, cyclosporine) or have chronic graft versus host disease
  • Patients receiving daily systemic corticosteroid therapy (at least 20 mg daily for at least 1 mo)
  • Patients with cancer, vasculitides, collagen vascular disorders, and others receiving cytotoxic or immunosuppressive treatments such as cyclosporine or the purine analogs fludarabine or cladribine
• TMP-SMX is the agent of choice for PCP prophylaxis unless a contraindication is identified. In patients who cannot tolerate TMP-SMX, other options include dapsone, dapsone combined with pyrimethamine, atovaquone, and aerosolized pentamidine.
• Prophylactic regimens are briefly reviewed here (see Medication for complete details on individual agents).
• • Trimethoprim-sulfamethoxazole
  • • Dose is one double-strength tablet (160 mg TMP to 800 mg SMX) daily.
    • One single-strength tablet (80 mg TMP to 400 mg SMX) daily is also effective.
    • Another alternative is one double-strength tablet 3 times per week.
    • Daily-dosing regimen provides an additional benefit of cross protection against Toxoplasma gondii and other bacterial infections.
  • Dapsone: Dose is 100 mg by mouth daily if administered alone.
  • Dapsone with pyrimethamine (plus leucovorin)
  • • Dose is 50 mg of dapsone by mouth daily with 50 mg of pyrimethamine weekly and 25 mg of leucovorin weekly.
    • Dapsone with pyrimethamine (plus leucovorin) provides protection against T gondii but not other bacterial infections.
  • Atovaquone
  • • Dose is 1500 mg by mouth once daily given with food.
    • Atovaquone is an alternative if the patient cannot tolerate TMP-SMX or dapsone.
    • Atovaquone has a low toxicity profile.
    • This is a very expensive regimen.
  • Aerosolized pentamidine
  • • Dose is 300 mg in 6 mL sterile water via Respirgard nebulizer every 4 weeks.
    • Aerosolized pentamidine is better tolerated than dapsone or TMP-SMX.
    • Side effects include cough and bronchospasm.
    • This treatment is much more expensive and less effective than other prophylactic regimens.
    • The potential for extrapulmonary Pneumocystis manifestations and apical lung disease exists.
    • This treatment may lead to diminished diagnostic sensitivity of sputum induction/BAL.

Complications

• Hypoxemia and respiratory failure
• • A pathophysiologic process similar to ARDS occurs in patients with severe PCP.
  • These patients may need intubation and have a significantly worse prognosis.

Prognosis

• The prognosis is worse in patients who present with concurrent pulmonary disease, in patients who develop a pneumothorax, and in patients requiring mechanical ventilation.
• Other factors affecting prognosis include a delay in diagnosis leading to delayed treatment.

Patient Education

• For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article Bronchoscopy.

MISCELLANEOUS

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Medical/Legal Pitfalls

• The diagnosis of PCP may lead to the need for HIV testing.
• If HIV testing is performed, appropriate pretest and posttest counseling guidelines must be followed.

MULTIMEDIA

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Media file 1:  Diff-Quik stain demonstrating Pneumocystis jiroveci.
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Media file 2:  Silver Gram stain showing Pneumocystis jiroveci.
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Media file 3:  Papanicolaou smear of Pneumocystis jiroveci.
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Media file 4:  Chest radiograph demonstrating diffuse bilateral infiltrates in a patient with Pneumocystis carinii pneumonia.
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Media type:  X-RAY

Media file 5:  CT scan of chest, with classic patchy areas of ground-glass attenuation.
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Media type:  CT

REFERENCES

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• Huang L, Hecht FM, Stansell JD. Suspected Pneumocystis carinii pneumonia with a negative induced sputum examination. Is early bronchoscopy useful?. Am J Respir Crit Care Med. Jun 1995;151(6):1866-71. [Medline].
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Article Last Updated: May 8, 2007