Pneumocystis (carinii) jiroveci Pneumonia Overview of PCP

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 with HIV infection.

Pneumocystis first came to attention as a cause of interstitial pneumonia in severely malnourished and premature infants during World War II in Central and Eastern Europe. Before the 1980s, fewer than 100 cases of PCP were reported annually in the United States, occurring in patients who were immunosuppressed (eg, cancer patients receiving chemotherapy and solid-organ transplant recipients receiving immunosuppressants). In 1981, the Centers for Disease Control and Prevention reported PCP in 5 previously healthy homosexual men 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.

While officially classified as a fungal pneumonia, PCP does not respond to antifungal treatment. Although a histopathologic demonstration of the organism is required for a definitive diagnosis (see Histologic Findings), treatment should not be delayed.^[1] Treatment of PCP may be initiated before the workup is complete in severely ill high-risk patients. Treatment of PCP depends on the degree of illness at diagnosis, determined on the basis of the alveolar-arterial gradient.

Antibiotics are primarily recommended for treatment of 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.^[2] Corticosteroids are used as adjunctive initial therapy only in patients with HIV infection who have severe PCP. Preventive measures (eg, smoking cessation and chemoprophylaxis) can play an important role in disease management.

For other discussions on pneumonia,^[3] see the following:

• Mycoplasma Pneumonia
• Bacterial Pneumonia
• Viral Pneumonia
• Imaging Pneumocystis Carinii Pneumonia
• Community-Acquired Pneumonia
• Nosocomial Pneumonia
• Ventilator-Associated Pneumonia
• Aspiration Pneumonia
• Fungal Pneumonia
• Pneumonia, Immunocompromised
• Nursing Home Acquired Pneumonia
• Chlamydial Pneumonias
• Lymphocytic Interstitial Pneumonia
• Imaging Typical Bacterial Pneumonia
• Imaging Atypical Bacterial Pneumonia
• Imaging Viral Pneumonia

For patient education resources, see the Procedures Center, as well as Bronchoscopy.

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.^{[4, 5]}

The taxonomic classification of the Pneumocystis genus was debated for some time. It was initially mistaken for a trypanosome and then later for 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 protozoan. 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)

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.^[6]

Transmission of Pneumocystis

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.^{[7, 8]}

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. Despite this, barrier precautions are not required for patients hospitalized with P carinii pneumonia (PCP) except to protect other patients with depressed immunity.

Development of PCP

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. 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

There have been reports of PCP occurring as part of the immune reconstitution syndrome.^{[9, 10]}

Risk factors for PCP

PCP is caused by infection with P jiroveci. The following groups are at risk for PCP^{[11, 12, 13]} :

• 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.)^{[14, 15]}
• 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)^[16]
• Persons with hematologic and nonhematologic malignancies, including solid tumors and lymphomas^[17]
• Persons with severe malnutrition

Before the widespread use of prophylaxis for P carinii pneumonia (PCP), 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.

In developing regions of the world, the prevalence of PCP was once thought to be much lower,^[18] 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, which is 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.^[19]

In patients with HIV infection, 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 persons without HIV infection, PCP carries a worse prognosis^[20] ; this has not changed significantly in the past 20 years. Mortality rates of 30-50% have been documented in several large studies.

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. The higher mortality rate is likely a result of delayed diagnoses and delayed initiation of appropriate treatment.

Patient 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.^[21] Symptoms of PCP include the following:

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

Physical examination

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 include cyanosis, nasal flaring, and intercostal retractions.

Extrapulmonary manifestations

Although Pneumocystis infection rarely causes extrapulmonary manifestations, such findings 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.

On the basis of most well-documented findings, Pneumocystis infection may present in almost any organ system, as follows:

• Central nervous system
• 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)
• Gastrointestinal tract

Complications

A pathophysiologic process similar to acute respiratory distress syndrome (ARDS) may occur in patients with severe PCP.^[22] These patients may require intubation. This greatly diminishes the prognosis.

The differential diagnosis of P carinii pneumonia (PCP) includes the following conditions^[23] :

• Acute Respiratory Distress Syndrome
• Cytomegalovirus
• Lymphocytic Interstitial Pneumonia
• Mycoplasma Infections
• Viral Pneumonia
• Pulmonary Embolism
• Legionellosis
• Tuberculosis
• Mycobacterium avium Complex (MAC) Infection

A lactic dehydrogenase (LDH) study is performed as part of the initial workup.^[24] LDH levels are usually elevated (>220 U/L) in patients with P carinii pneumonia (PCP). They are elevated in 90% of patients with PCP who are infected with HIV. The study has a high sensitivity (78-100%); its specificity is much lower because other disease processes can result in an elevated LDH level.

LDH levels appear to reflect the degree of lung injury. They should decline with successful treatment. Consistently elevated LDH levels during treatment may indicate therapy failure and a worse prognosis.

Quantitative PCR for pneumocystis may become useful in distinguishing between colonization and active infection, but these assays are not yet available for routine clinical use.^[25]

In one study, patients with positive quantitative PCR but negative immunofluorescence for pneumocystis had a higher 1-year mortality but only in the context of systemic inflammatory conditions. There was no significant difference for patients with solid-organ or hematologic malignancy.^[26]

β-D-Glucan (BDG) is a cell-wall component of many fungi, including candida, aspergillus, and pneumocystis (but not the zygomycetes). It has been shown to be a sensitive test to detect PCP in a meta-analysis of 12 studies assessing the sensitivity, specificity and overall accuracy of the test.^[27]

Chest radiography should be obtained in any immunocompromised patient with fever and/or respiratory signs or symptoms.^[28] 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 P carinii pneumonia (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, as shown in the image below.

Go to Imaging Pneumocystis Carinii Pneumonia for complete information on this topic.

High-resolution computed tomography (HRCT) scanning of chest is helpful when the chest radiography findings are equivocal. HRCT yields a high sensitivity for P carinii pneumonia (PCP) in patients with HIV infection.

The typical appearance is patchy areas of ground-glass attenuation with a background of interlobular septal thickening. Negative (normal or unchanged) CT scan findings alone do not rule out PCP (see the image below).

Go to Imaging Pneumocystis Carinii Pneumonia for complete information on this topic.

Gallium 67 scanning demonstrates an increased diffuse symmetrical pulmonary uptake in patients with P carinii pneumonia (PCP). Its sensitivity is high (nearly 100%).^[29] However, its 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 (see Invasive Procedures) may be less diagnostic in such cases.

Go to Imaging Pneumocystis Carinii Pneumonia for complete information on this topic.

Pulmonary function tests

Pulmonary function tests should be obtained as part of the initial noninvasive workup in patients with suspected P carinii pneumonia (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 high-resolution computed tomography (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

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.

HIV testing

The diagnosis of PCP should prompt consideration for HIV testing. If HIV testing is performed, appropriate pretest and posttest counseling guidelines must be followed.

If P carinii pneumonia (PCP) is strongly suspected, obtain a sputum sample by sputum induction for histopathologic testing. Pneumocystis organisms are frequently found in sputum induced by inhalation of a hypertonic saline solution. Sputum induction is the quickest and least-invasive method for definitively diagnosing PCP.^[30] Expectorated sputum has a very low sensitivity and should not be submitted for diagnosis.

The sensitivity of sputum induction 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.

Bronchoalveolar lavage

Bronchoalveolar lavage (BAL) is the most common invasive procedure used to diagnose P carinii pneumonia (PCP). It has a diagnostic yield that exceeds 90% (and may be higher if multiple lobes are sampled).^[31] BAL yields a lower sensitivity in patients receiving aerosolized pentamidine, in which case a transbronchial biopsy may be performed in conjunction with BAL.^[32]

Obtain BAL if PCP is strongly suspected and the induced sputum sample findings are negative. 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. Consultation with a pulmonologist is required for BAL.

Lung biopsy

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.

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. Diff-Quik stain demonstrating P jiroveci is seen in the image below.

Methenamine silver, toluidine blue, and Gram-Weigert selectively stain the wall of Pneumocystis cysts. Silver Gram stain showing Pneumocystis jiroveci is seen in the image below .

Papanicolaou smear may demonstrate a foamy-appearing eosinophilic material surrounding Pneumocystis organisms (as seen in the image below).

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

While officially classified as a fungal pneumonia, P carinii pneumonia (PCP) does not respond to antifungal treatment. However, there are a few reports of successful caspofungin administration in PCP. Echinocandins such as caspofungin may be active against pneumocystis based on their activity against the inclusion of (1-3)beta-D glucan into the fungal cell wall, but clinical data is lacking. Case reports suggest it may be worthy of consideration as a treatment option in non-responsive cases, and further research is clearly warranted.^[33]

Although a histopathologic demonstration of the organism is required for a definitive diagnosis (see Histologic Findings), treatment should not be delayed. Treatment of 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. Pneumocystis organisms persist in the host for days to weeks after therapy is started, allowing time for completion of the appropriate workup.

Treatment of PCP depends on the degree of illness at diagnosis. Degree of illness is determined on the basis of the alveolar-arterial gradient: mild (< 35 mm Hg), moderate/severe (35-45 mm Hg), or severe (>45 mm Hg). Severe disease is also indicated by a room air partial pressure of oxygen lower than 70 mm Hg. Treatment of extrapulmonary manifestations of PCP is the same as that for other pneumonias.

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. Up to 10% of mild-to-moderate PCP cases fail to respond to antibiotic treatment because of lack of drug efficacy.

All patients who require corticosteroids should be admitted to the hospital because of the risk of progressive respiratory compromise.

Because of increasing evidence of possible human transmission (see Pathophysiology and Etiology of PCP),^[34] the CDC Hospital Infection Control Practice Advisory Committee has recommended that patients with PCP not have direct contact with other immunocompromised patients.

Antibiotics are primarily recommended for treatment of mild, moderate, or severe P carinii pneumonia (PCP). Trimethoprim-sulfamethoxazole (TMP-SMX) has been shown to be as effective as intravenous pentamidine and more effective than other alternative treatment regimens.^{[2, 35]} The parenteral route may be considered in patients who present with serious illness or in those with gastrointestinal side effects.

Thomas et al have reported that a lower dose of TMP-SMX (10 mg/kg/d) is effective for PCP associated with HIV infection and carries fewer side effects,^[36] but this should not yet be taken as a recommendation. Recent guidelines have been published.^[37]

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. For the treatment of infections that are resistant to TMP-SMX, the combination of clindamycin and primaquine is likely to be more effective than intravenous pentamidine.^{[38, 39]}

The recommended duration of treatment for 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.

Corticosteroids are used as adjunctive initial therapy only in patients with HIV infection who have severe P carinii pneumonia (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.^{[40, 41]}

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 (see Prevention of PCP).

Oral therapy with trimethoprim-sulfamethoxazole (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 P carinii pneumonia (PCP) who have reliable outpatient follow-up care.

Smoking cessation

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 P carinii pneumonia (PCP) and have a more complicated treatment course.^[42]

Chemoprophylaxis in patients with HIV Infection

Two types of outpatient chemoprophylactic therapies exist. Primary prophylaxis is used in immunocompromised patients without a history of PCP. Secondary prophylaxis is used in patients with a prior bout of PCP.

An expert panel overseen by the US Public Health Service and Infectious Disease Society of America has published guidelines on prophylaxis against P carinii pneumonia (PCP) 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 trimethoprim-sulfamethoxazole (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.

Prophylaxis may be discontinued in patients with HIV infection whose CD4 count exceeds 200/µL for 3 consecutive months while on highly active antiretroviral therapy (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.

One study suggests that discontinuation of prophylaxis may be safe in patients with HIV and CD4 counts of 101-200 cells/μL and suppressed viral load.^[43]

Chemoprophylaxis in patients without HIV infection

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, 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, 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 month)
• 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

Chemoprophylactic regimens

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. Commonly used prophylactic regimens are as follows.

For TMP-SMX, the normal dosage 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. However, a daily-dosing regimen provides an additional benefit of cross protection against Toxoplasma gondii infection and other bacterial infections.

The use of TMP-SMX for long-term PCP prophylaxis does not seem to affect the rates of infection by drug-resistant organisms such as pneumococcus or Staphylococcus aureus. TMP-SMX resistance has been reported among some isolates of Pneumocystis.^[44]

For dapsone, the dosage is 100 mg daily by mouth if it is administered alone. If dapsone is given with pyrimethamine (plus leucovorin), the dosage is 50 mg of dapsone daily by mouth 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.

For atovaquone, the dosage is 1500 mg by mouth once daily given with food. This agent has a low toxicity profile and is an alternative if the patient cannot tolerate TMP-SMX or dapsone. However, atovaquone is very expensive.

For aerosolized pentamidine, the normal dosage is 300 mg in 6 mL sterile water via Respirgard nebulizer every 4 weeks. This agent is better tolerated than dapsone or TMP-SMX. However, it is much more expensive and less effective than other prophylactic agents. Side effects include cough and bronchospasm. The potential for extrapulmonary Pneumocystis manifestations and apical lung disease exists. In addition, aerosolized pentamidine may diminish the diagnostic sensitivity of sputum induction and bronchoalveolar lavage.