AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Pneumocystis carinii pneumonia (PCP), as the condition is commonly termed (although the causative organism has been renamed Pneumocystis jiroveci [pronounced "yee-row-vet-zee"]), is the most common opportunistic infection in persons infected with HIV.

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 and 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 the organism responsible for PCP was renamed after him.

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 per year were reported in the United States, occurring in immunosuppressed patients such as patients with cancer treated with chemotherapy and solid-organ transplant recipients receiving immunosuppressive agents. In 1981, the Centers for Disease Control and Prevention (CDC) reported PCP in 5 previously healthy homosexual males residing in the Los Angeles area.

P jiroveci is now one of several organisms known to cause life-threatening opportunistic infections in patients with advanced HIV infection worldwide. Well over 100,000 cases of PCP were reported in the first decade of the HIV epidemic in the United States in people with no other cause for immunosuppression.

Microbiology

The taxonomic classification of the Pneumocystis genus was debated for some time. It was initially mistaken as a trypanosome and 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, as follows:

• The trophozoite (trophic form), in which it often exists in clusters
• The sporozoite (precystic form)
• The cyst, which contains several intracystic bodies (spores)

Pathophysiology

Pneumocystis organisms are 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 organisms are communicable; airborne transmission has been reported. Human evidence of this is provided by molecular analysis of Pneumocystis isolates obtained from groups of patients involved in hospital outbreaks.^{1, 2} Further evidence of human transmission has been found in cases of recurrent pneumonia in which the genotype of Pneumocystis organisms in the same person differed in prior episodes.

Disease occurs when both cellular immunity and humoral immunity are defective. Once inhaled, the trophic form of Pneumocystis organisms attach to the alveoli. Multiple host immune defects allow for uncontrolled replication of Pneumocystis organisms and development of illness, including the following:

• Activated alveolar macrophages without CD4⁺ cells are unable to eradicate Pneumocystis organisms.
• Increased alveolar-capillary permeability is visible on electron microscopy.
• Physiologic changes include the following:
• • Hypoxemia with an increased alveolar-arterial oxygen gradient
  • Respiratory alkalosis
  • Impaired diffusing capacity
  • Changes in total lung capacity and vital capacity

Frequency

United States

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

• Prior to the widespread use of highly active antiretroviral therapy (HAART), PCP occurred in 70-80% of patients with HIV infection.
• The frequency of PCP is decreasing with the use of PCP prophylaxis and HAART.
• PCP is still the most common opportunistic infection in patients with HIV infection.
• Patients with HIV infection are more prone to PCP recurrence than patients not infected with HIV.

International

The prevalence of PCP was once thought to be much lower in developing regions of the world,³ but studies have shown that the lower reported incidence is likely a failure to accurately diagnose PCP. An accurate diagnosis requires access to modern medical care not available worldwide. Currently, the frequency of documented Pneumocystis infection is increasing in Africa, with Pneumocystis organisms found in up to 80% of infants with pneumonia who have HIV infection. In sub-Saharan Africa, tuberculosis is a common co-infection in persons with PCP.⁴

Mortality/Morbidity

• In patients with HIV infection
• • In this population, PCP once carried a mortality rate of 20-40%, depending on disease severity at presentation. Currently, mortality rates of 10-20% are reported.
  • PCP is still a major cause of death in patients with AIDS in the United States.
• In patients without HIV infection
• • PCP carries a worse prognosis in persons without HIV infection; this has not changed significantly in the past 20 years.
  • Mortality rates of 30-50% have been documented in several large studies.
  • The higher mortality rate is likely a result of delayed diagnoses and initiation of appropriate treatment.

CLINICAL

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History

The symptoms of P carinii pneumonia (PCP) are nonspecific. PCP in patients with HIV infection tends to run a more subacute indolent course and tends to present much later, often after several weeks of symptoms, compared with PCP associated with other immunocompromising conditions. Symptoms of PCP include the following:

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

Physical

The physical examination findings of PCP are nonspecific and include the following:

• Tachypnea
• Fever
• Tachycardia
• Pulmonary symptoms: Pulmonary examination may reveal mild crackles and rhonchi but may yield normal findings in up to half of patients.
• Additional findings in children with severe disease
• • Cyanosis
  • Nasal flaring
  • Intercostal retractions
• Extrapulmonary manifestations: Although Pneumocystis infection rarely causes extrapulmonary manifestations, 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. Based on most well-documented findings, Pneumocystis infection may present in almost any organ system, as follows:
• • CNS
  • 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

PCP is caused by infection with P jiroveci. The following groups are at risk for PCP:

• Persons with HIV infection whose CD4⁺ cells fall below 200/µL and who are not receiving PCP prophylaxis (In addition, in patients with HIV infection, findings of other opportunistic infections [eg, oral thrush] increases the risk of PCP, regardless of CD4⁺ count.)
• Persons with primary immune deficiencies, including hypogammaglobulinemia and severe combined immunodeficiency (SCID).
• Persons receiving long-term immunosuppressive regimens for connective-tissue disorders, vasculitides, or solid-organ transplantation (eg, heart, lung, liver, kidney)
• Persons with hematologic and nonhematologic malignancies, including solid tumors and lymphomas
• Persons with severe malnutrition

DIFFERENTIALS

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Other Problems to be Considered

Legionellosis
Tuberculosis
Mycobacterium avium complex (MAC) infection

WORKUP

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Lab Studies

• Lactic dehydrogenase study as part of the initial workup
• • Lactic dehydrogenase (LDH) levels are usually elevated (>220 U/L) in patients with P carinii pneumonia (PCP).
  • This study has a high sensitivity (78-100%).
  • The LDH level is elevated in 90% of patients with PCP who are infected with HIV.
  • This study has a much lower specificity because other disease processes result in an elevated LDH level.
  • LDH levels appear to reflect the degree of lung injury.
  • Consistently elevated LDH levels during treatment may indicate therapy failure and a worse prognosis.
  • LDH levels should decline with successful treatment.

Imaging Studies

• Chest radiography should be obtained in any immunocompromised patient with fever and/or respiratory signs or symptoms. Findings include the following:
• • The chest radiographic findings may be normal in patients with early mild disease.
  • Diffuse bilateral infiltrates extending from the perihilar region are visible in most patients with PCP.
  • Less-common findings include patchy asymmetric infiltrates and pneumatoceles.
  • Pleural effusions and intrathoracic adenopathy are rare.
  • Pneumothorax may develop in patients using aerosolized pentamidine.
  • Apical disease may also be found in patients using aerosolized pentamidine for prophylaxis.
• High-resolution CT scanning of the chest
• • High-resolution CT scanning of chest (HRCT) is helpful when the chest radiography findings are equivocal.
  • The typical appearance is patchy areas of ground-glass attenuation with a background of interlobular septal thickening.
  • HRCT yields a high sensitivity for PCP in patients with HIV infection.
  • Negative (normal or unchanged) CT scan findings alone do not rule out PCP.
• Gallium 67 scanning
• • Gallium 67 scan demonstrates an increased diffuse symmetrical pulmonary uptake in patients with PCP.
  • This study is highly sensitive (nearly 100%).
  • The 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; see Procedures) 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 normal or unchanged HRCT findings, pulmonary function tests may be used to identify patients unlikely to have PCP; such patients may be managed with observation alone.
• 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 organisms are 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 method for definitively diagnosing PCP.⁵
  • Sensitivity varies widely (<50% to >90%) and depends on proficiency in using the technique and the experience of the laboratory.
  • Specificity is high (99-100%).
  • This study may be less sensitive in patients without HIV infection, as the immunodeficiency caused by HIV infection typically leads to a greater alveolar load of Pneumocystis organisms.
  • It may also be less sensitive in patients receiving aerosolized pentamidine for prophylaxis.
• BAL is the most common invasive procedure used to diagnose PCP.
• • BAL has a diagnostic yield that exceeds 90% (may be increased if multiple lobes are sampled).⁶
  • Obtain BAL if PCP is strongly suspected and the induced sputum sample findings are negative.
  • BAL yields a lower sensitivity in patients receiving aerosolized pentamidine, in which case a transbronchial biopsy may be performed in conjunction with BAL.⁷
  • BAL may be used in patients who are unable to cooperate with an induced sputum sample (eg, because of 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 yields 100% sensitivity and specificity because it provides the greatest amount of tissue for diagnosis. However, this procedure is reserved for rare cases when bronchoscopy findings are nondiagnostic.

Histologic Findings

Because clinical and radiologic findings are not specific for PCP and because P jiroveci cannot be grown in vitro, histopathologic demonstration is necessary before a definitive diagnosis is established. The following are the staining techniques available for respiratory tract secretions:

• Cresyl violet, Giemsa, Diff-Quik, and Wright stain are used to 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 organisms (see Image 3).

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

TREATMENT

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Medical Care

While officially classified as a fungal pneumonia, P carinii pneumonia (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. Pneumocystis organisms persist in the host for days to weeks after therapy is started, allowing time for completion of the appropriate workup.

• Treatment depends on the degree of illness at diagnosis (see Medication).
• Treatment is based on 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 indicated 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 P carinii pneumonia (PCP) is 21 days in patients with HIV infection and 14 days for all other patients. Patients infected with HIV tend to have a higher organism burden and respond to treatment slower than patients without HIV infection and therefore require a longer duration of therapy.

• Treatment of extrapulmonary manifestations is the same as that for other pneumonias.
• Up to 10% of mild-to-moderate PCP cases fail to respond to antibiotic treatment because of lack of drug efficacy.
• In patients without HIV infection, response to treatment should begin in 4-5 days.
• In patients infected with HIV, the treatment response typically takes longer but should occur within the first 8 days.
• If no response occurs within the expected time, an appropriate alternative regimen should be used.
• Adding additional PCP medications to a current regimen only increases the risk of adverse drug reactions without improving the likelihood of a good outcome.

Drug Category: Antibiotic

Antibiotics are primarily recommended for treatment for mild, moderate, or severe PCP. Trimethoprim-sulfamethoxazole (TMP-SMX) has been shown to be as effective as intravenous pentamidine and more effective than other alternative treatment regimens.⁸ The parenteral route may be considered in patients who present with serious illness 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.

The combination of clindamycin and primaquine is likely to be more effective than intravenous pentamidine in the treatment of infections that are resistant to TMP-SMX.^{9, 10}

Drug Category: Corticosteroid

These agents are used as adjunctive initial therapy only in patients with HIV infection who have severe PCP as defined by a room air arterial oxygen pressure of less than 70 mm Hg or an arterial-alveolar O₂ gradient that exceeds 35 mm Hg. Adjunctive steroids are not recommended in patients without HIV infection. 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, reduce deterioration of oxygenation, and reduce the incidence of respiratory failure.^{11, 12}

FOLLOW-UP

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Further Inpatient Care

• All patients who require corticosteroids should be admitted to the hospital because of the risk of progressive respiratory compromise.
• Treatment of P carinii pneumonia (PCP) may be initiated before the workup is complete in severely ill high-risk patients.
• Appropriate histopathologic testing may still be used to confirm a diagnosis of PCP 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 monitor 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 be considered only in patients with mild-to-moderate PCP who have reliable outpatient follow-up care.

Deterrence/Prevention

• Smoking cessation is strongly recommended in patients with HIV infection, as studies have shown that, in addition to the common deleterious effects of tobacco use, smokers are at an increased risk of 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 patients with HIV infection. Chemoprophylaxis is recommended for the following groups:
• • Adults, adolescents, and pregnant patients with a CD4 count of less than 200/µL, oropharyngeal candidiasis, unexplained fever exceeding 100°F (37.7° C) for more than 2 weeks, and a prior episode of PCP regardless of CD4 count should receive prophylaxis.
  • Children born to mothers with HIV infection should receive prophylaxis with TMP-SMX beginning at age 4-6 weeks. 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, as follows:
• • Primary prophylaxis is used in immunocompromised patients without a history of PCP.
  • Secondary prophylaxis is used in patients with a prior bout of PCP.
• Prophylaxis may be discontinued in patients with HIV infection whose CD4 count exceeds 200/µL for 3 consecutive months while on HAART. Prophylaxis should be restarted if the CD4 count drops below 200/µL. Prophylaxis should be continued for life in patients who developed PCP while their CD4 level exceeded 200/µL.
• Unlike in patients with HIV infection, no specific PCP prophylaxis guidelines exist for immunocompromised patients without HIV infection. In general, chemoprophylaxis should be considered in any of the following patients:
• • Patients with an underlying primary immune deficiency (eg, SCID or hypogammaglobulinemia)
  • Patients with a persistent CD4 count less than 200/µL
  • Solid organ transplant recipients
  • Hematopoietic stem cell transplant (HSCT) recipients, with prophylaxis administered (1) for 6 months after engraftment months or (2) for more than 6 months after HSCT in those who are still receiving immunosuppressive therapy (eg, prednisone, cyclosporine) or who 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, or 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 in the absence of a contraindication. In patients who cannot tolerate TMP-SMX, other options include dapsone, dapsone plus pyrimethamine, atovaquone, and aerosolized pentamidine.
• Prophylactic regimens include the following (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 infection 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 infection 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 diminish the diagnostic sensitivity of sputum induction/BAL.
• For an excellent discussion of PCP prophylaxis, see the eMedicine article Prevention of Opportunistic Infections in Patients Infected With HIV.

Complications

• Hypoxemia and respiratory failure
• • A pathophysiologic process similar to acute respiratory distress syndrome (ARDS) may occur in patients with severe PCP.
  • These patients may require intubation.
  • This greatly diminishes the prognosis.

Prognosis

• The prognosis of PCP is worse in patients who present with concurrent pulmonary disease, in patients who develop pneumothorax, and in patients who require mechanical ventilation.
• Other factors that affect prognosis include a delay in diagnosis that leads to 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 P carinii pneumonia (PCP) should prompt consideration 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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19. Cincinnati Children's Hospital Medical Center. Evidence based clinical practice guideline for Pneumocystis carinii pneumonia prophylaxis following solid organ or blood and marrow transplants. Cincinnati, OH: Cincinnati Children's Hospital Medical Center; 2001.
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Article Last Updated: Oct 10, 2008