eMedicine Specialties > Infectious Diseases > Fungal Infections

Pneumocystis (carinii) jiroveci Pneumonia

Nicholas John Bennett, MB, BCh, PhD, Fellow in Pediatric Infectious Disease, Department of Pediatrics, State University of New York Upstate Medical University
Shelley A Gilroy, MD, Clinical Professor of Medicine, State University of New York Upstate; Medical Director, Infection Control, University Hospital and Crouse Hospital, Syracuse; Frederick Burton Rose, MD, FACP, Professor, Department of Medicine, University Hospital Epidemiologist, State University of New York Upstate Medical University; Joseph C McLean, MD, Staff Physician, Department of Internal Medicine, William Beaumont Army Medical Center; Clinton Murray, MD, Program Director, Infectious Disease Fellowship, San Antonio Uniformed Services Health Education Consortium; Tanya S Schreibman, MD, Consulting Staff, Department of Internal Medicine, Bach and Godofsky; Michael Rigsby, MD, Director of HIV Care Program, VA Connecticut Healthcare System, West Haven Campus; Associate Professor, Department of Internal Medicine, Yale University School of Medicine

Updated: Nov 20, 2009

Introduction

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 with HIV infection.

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

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

There have been reports of PCP occurring as part of the immune reconstitution syndrome.^3,4

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,⁵ 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.⁶

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 infection⁷ ; 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

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

Differential Diagnoses

Acute Respiratory Distress Syndrome
Cytomegalovirus
Lymphocytic Interstitial Pneumonia
Mycoplasma Infections
Pneumonia, Viral
Pulmonary Embolism

Other Problems to Be Considered

Legionellosis
Tuberculosis
Mycobacterium avium complex (MAC) infection

Workup

Laboratory 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.
  • 
    

    

    Chest radiograph demonstrating diffuse bilateral infiltrates in a patient with Pneumocystis carinii pneumonia.

    
    
• 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.
  • 
    

    

    CT scan of chest, with classic patchy areas of ground-glass attenuation.

    
    
• 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.⁸
  • 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).⁹
  • 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.¹⁰
  • 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).
• 
  

  

  Diff-Quik stain demonstrating Pneumocystis jiroveci.

  
  
• Methenamine silver, toluidine blue, and Gram-Weigert selectively stain the wall of Pneumocystis cysts (see Image 2).
• 
  

  

  Silver Gram stain showing Pneumocystis jiroveci.

  
  
• Papanicolaou smear may demonstrate a foamy-appearing eosinophilic material surrounding Pneumocystis organisms (see Image 3).
• 
  

  

  Papanicolaou smear of Pneumocystis jiroveci.

  
  

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

Treatment

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

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.

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.¹¹ 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.^12,13

One study has reported that a lower dose of TMP-SMX (10 mg/kg/d) is effective and carries fewer side effects,¹⁴ but this should not yet be taken as a recommendation. Recent guidelines have been published.¹⁵

Primaquine phosphate

A member of the 8-aminoquinoline group. Binds to parasite DNA and causes a major disruption in the metabolic process of the parasite.

Dosing

Adult

Moderate-to-severe disease: 15-30 mg PO qd for 21 d and clindamycin 900 mg IV q8h
Mild-to-moderate disease: 15-30mg PO qd for 21 d and clindamycin 600 mg IV q8h (or 300-450 mg PO q8h)

Pediatric

Not established

Interactions

May reduce thyroxine efficacy; coadministration with quinacrine may increase toxicity

Contraindications

Documented hypersensitivity; G-6-PD deficiency (may cause fatal hemolysis); NADH methemoglobin reductase deficiency (may cause methemoglobinemia)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in G-6-PD deficiency and those with tendency to develop granulocytopenia; caution in systemic lupus erythematosus or rheumatoid arthritis

Trimetrexate (Neutrexin) and leucovorin (Wellcovorin)

A lipid soluble derivative of methotrexate. One study showed it to be less effective but better tolerated than TMP-SMX in hospitalized patients with severe PCP. Inhibits dihydrofolate reductase, inhibiting bacterial growth. Given with leucovorin to attenuate bone marrow suppression.

Dosing

Adult

45 mg/m² IV (over 60-90 min) qd for 21 d and leucovorin (folinic acid) 20 mg/m² IV or PO for 24 d (continue for 3 d after trimetrexate)

Pediatric

Not established

Interactions

Increases toxicity of yellow fever vaccine; decreases effect of pneumococcal vaccine; erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole may alter serum trimetrexate levels; cimetidine can decrease trimetrexate metabolism and cause an increase in trimetrexate levels; acetaminophen may compete for sulfate metabolites, causing changes in concentration of trimetrexate metabolites; clotrimazole, ketoconazole, and miconazole may increase trimetrexate plasma levels

Contraindications

Documented hypersensitivity; severe myelosuppression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

To avoid potentially life-threatening toxicities, administer concurrently with leucovorin; caution in renal or hepatic dysfunction and mild myelosuppression

Trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim, Septra, Co-trimoxazole)

Inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid. This results in inhibition of bacterial growth.
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.

Dosing

Adult

Intravenous: (TMP) 20 mg/kg/d, (SMX) 75-100 mg/kg/d IV divided tid/qid
Oral: 2 double-strength tab tid

Pediatric

<2 months: Do not administer
>2 months: 15-20 mg/kg/d PO tid/qid based on TMP

Interactions

May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly persons; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine

Contraindications

Documented hypersensitivity; megaloblastic anemia due to folate deficiency; age <2 mo

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Discontinue at first appearance of skin rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, give 5-15 mg/d leucovorin); caution in folate deficiency (eg, chronic alcoholics, elderly, those receiving anticonvulsant therapy, or those with malabsorption syndrome); hemolysis may occur in G-6-PD deficient individuals; AIDS patients may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation

Pentamidine (Pentam-300)

Inhibits growth of protozoa by blocking oxidative phosphorylation and inhibiting incorporation of nucleic acids into RNA and DNA, causing inhibition of protein and phospholipid synthesis.

Dosing

Adult

4 mg/kg/d IV/IM for 14-21 d; dilute in 50-250 mL of 5% dextrose solution and infused over at least 1 h

Pediatric

150 mg/m²/d IV for 5 d, followed by 100 mg/m²/d IV for 16 d

Interactions

Coadministration with cidofovir increases risk of nephrotoxicity; concomitant use of foscarnet may decrease serum calcium level; risk of pancreatitis with zalcitabine may be additive; coadministration with other drugs that prolong QT interval (eg, dofetilide) increases risk

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adverse reactions in up to 70-80% of patients include nausea, cardiac arrhythmias, hyperkalemia, and nephrotoxicity; caution in diabetes mellitus (hypoglycemia and hyperglycemia), hypertension or hypotension, hepatic dysfunction, hypoglycemia, leukopenia, and thrombocytopenia

Atovaquone (Mepron)

A hydroxynaphthoquinone that inhibits mitochondrial electron transport chain by competing with ubiquinone at ubiquinone-cytochrome-c-reductase region (complex III). Inhibition of electron transport by atovaquone results in inhibition of nucleic acid and ATP synthesis in parasites and microorganisms.

Dosing

Adult

750 mg PO bid ac

Pediatric

Treatment or prevention:
<13 years: Not established
>13 years: Administer as in adults

Interactions

May increase zidovudine serum levels; coadministration with rifampin or rifabutin may decrease atovaquone levels; atovaquone may decrease levels of TMP-SMX

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in elderly persons and in those with hepatic and renal impairment; may cause skin rash, fever, and abnormal liver function test results

Clindamycin (Cleocin HCl)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Widely distributes in the body without penetration of CNS. Protein bound and excreted by the liver and kidneys. Alternative therapy for mild, moderate, or severe disease. Given with primaquine.

Dosing

Adult

Moderate-to-severe disease: 900 mg IV q8h and primaquine 15-30 mg PO qd for 21 d
Mild-to-moderate disease: 600 mg IV q8h (or 300-450 mg PO q8h) and primaquine 15-30mg PO qd for 21 d

Pediatric

Not established

Interactions

Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin

Contraindications

Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficile

Dapsone (Avlosulfon)

Given with trimethoprim. Mechanism of action is similar to that of sulfonamides where competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth.

Dosing

Adult

100 mg PO qd and trimethoprim 5 mg/kg PO tid

Pediatric

Not established

Interactions

May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists, eg, pyrimethamine (monitor for agranulocytosis during the second and third months of therapy); probenecid increases dapsone toxicity; trimethoprim with dapsone may increase toxicity of both drugs; due to increased renal clearance, dapsone levels may significantly decrease when administered concurrently with rifampin; DDI (dideoxyinosine) may reduce antipneumocystic activity of dapsone

Contraindications

Documented hypersensitivity; known G-6-PD deficiency (may cause hemolysis in these patients)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adverse effects include fever, rash, methemoglobinemia, hemolytic anemia, nausea, vomiting, hepatitis, headache, neuropathy, insomnia, aplastic anemia, and erythema multiforme; perform weekly WBC counts (first month), then monthly (6 mo), then semiannually (discontinue if significant reduction in platelets, leukocytes, or hematopoiesis observed)
Caution in methemoglobin reductase deficiency, G-6-PD deficiency (patients receiving >200 mg/d), or hemoglobin M because of high risk for hemolysis and Heinz body formation; caution in patients exposed to other agents or conditions capable of producing hemolysis (eg, infection, diabetic ketosis); phototoxicity may occur when exposed to UV light

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.^16,17

Prednisone (Sterapred)

Consensus guidelines recommend beginning corticosteroids as early as possible in HIV patients with severe disease.
Adjunctive corticosteroids may be used with the same indications as in nonpregnant adults. The maternal fasting and postprandial serum glucose levels should be monitored if used in the third trimester because of increased risk of glucose intolerance.
Methylprednisolone may be substituted at 75% of dose below if parental administration preferred.

Dosing

Adult

40 mg PO bid for 5 d, then 40 mg/d for 5 d, then 20 mg qd for 11 d (administer 30 min before TMP-SMX)

Pediatric

4-5 mg/m²/d or 1-2 mg/kg PO qd; taper over 2 wk as symptoms resolve

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral, connective tissue, fungal, or tubercular skin infections; peptic ulcer disease; hepatic dysfunction; GI bleeding or ulceration; not recommended for treatment of non-HIV patients with severe PCP

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Follow-up

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.

Inpatient & Outpatient Medications

• 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

Medicolegal 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

Media file 1: Diff-Quik stain demonstrating Pneumocystis jiroveci.

Media file 2: Silver Gram stain showing Pneumocystis jiroveci.

Media file 3: Papanicolaou smear of Pneumocystis jiroveci.

Media file 4: Chest radiograph demonstrating diffuse bilateral infiltrates in a patient with Pneumocystis carinii pneumonia.

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

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Keywords

Pneumocystis carinii pneumonia, PCP, P carinii pneumonia, Pneumocystis jiroveci pneumonia, P jiroveci pneumonia, Pneumocystis pneumonia, PCP prophylaxis, PCP prevention, opportunistic respiratory infection, opportunistic pneumonia, HIV, AIDS

Contributor Information and Disclosures

Author

Nicholas John Bennett, MB, BCh, PhD, Fellow in Pediatric Infectious Disease, Department of Pediatrics, State University of New York Upstate Medical University
Nicholas John Bennett, MB, BCh, PhD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Pediatrics
Disclosure: Nothing to disclose.

Coauthor(s)

Shelley A Gilroy, MD, Clinical Professor of Medicine, State University of New York Upstate; Medical Director, Infection Control, University Hospital and Crouse Hospital, Syracuse
Shelley A Gilroy, MD is a member of the following medical societies: American College of Physicians, American Medical Association, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Frederick Burton Rose, MD, FACP, Professor, Department of Medicine, University Hospital Epidemiologist, State University of New York Upstate Medical University
Frederick Burton Rose, MD, FACP is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Joseph C McLean, MD, Staff Physician, Department of Internal Medicine, William Beaumont Army Medical Center
Joseph C McLean, MD is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Clinton Murray, MD, Program Director, Infectious Disease Fellowship, San Antonio Uniformed Services Health Education Consortium
Clinton Murray, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Association of Military Surgeons of the US, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Tanya S Schreibman, MD, Consulting Staff, Department of Internal Medicine, Bach and Godofsky
Disclosure: Nothing to disclose.

Michael Rigsby, MD, Director of HIV Care Program, VA Connecticut Healthcare System, West Haven Campus; Associate Professor, Department of Internal Medicine, Yale University School of Medicine
Disclosure: Nothing to disclose.

Medical Editor

Klaus-Dieter Lessnau, MD, FCCP, Clinical Associate Professor of Medicine, New York University School of Medicine; Medical Director, Pulmonary Physiology Laboratory; Director of Research in Pulmonary Medicine, Department of Medicine, Section of Pulmonary Medicine, Lenox Hill Hospital
Klaus-Dieter Lessnau, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Medical Association, American Society for Artificial Internal Organs, American Thoracic Society, Physicians for Social Responsibility, and Society of Critical Care Medicine
Disclosure: sepracor Ownership interest None

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Harold L Manning, MD, Associate Professor, Departments of Medicine, Anesthesiology and Physiology, Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School
Harold L Manning, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society
Disclosure: Nothing to disclose.

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

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