Pneumocystis Jirovecii (Carinii) Pneumonia

Synonyms: Pneumocystis jirovecii, pneumocystosis

Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality among immunocompromised people. It remains a leading AIDS-defining opportunistic infection in HIV-infected individuals.¹ Pneumocystis is primarily a pulmonary pathogen but extrapulmonary disease occurs in about 1% of cases.

Pneumocystis organisms from different host species have very different DNA sequences, indicating multiple species. Because of the genetic and functional distinctness, the organism that causes human PCP (formerly known as Pneumocystis carinii) is now named Pneumocystis jirovecii.²

P. jirovecii is a unicellular eukaryote which shares characteristics with both protozoa and fungi.

• The background rate of infection in the general population is extremely low at less than 1 case per million population per year.
• When HIV was first characterised, PCP affected up to 75% of HIV-infected individuals. Current rates of infection in the HIV-positive population in the developed world are about 10–20%.
• The incidence of PCP in HIV-positive patients has been significantly reduced by prophylactic medication and highly active antiretroviral therapy (HAART).³
• In the developing world, rates of PCP are lower, possibly due to poor survival with HIV, underdiagnosis and prior pulmonary infection with TB and other organisms.

Risk factors

• PCP tends to affect HIV positive patients who have a CD4 count below 200 cells/mm³
• HIV patients with oral thrush or fever, or AIDS-defining diagnosis
• Patients taking steroids or other immunosuppressants
• Patients with haematological malignancy
• Organ-transplant recipients
• Congenital immune deficiency, e.g. thymic aplasia, severe combined immune deficiency (SCID), hypogammaglobulinaemia
• Severe malnutrition (poor nutrition in HIV-positive individuals increases risk)

• Cough is usually non-productive but productive cough may occur in up to a third of patients
• Exertional dyspnoea
• Fever
• Tachypnoea
• Chest pain
• There may be signs of AIDS such as thrush, oral hairy leucoplakia or Kaposi's sarcoma
• Respiratory examination is highly variable and often normal. Scattered crackles and wheeze may be present, or rarely signs of focal consolidation
• Pulse oximetry may show low SaO₂ at rest
• Extrapulmonary disease may manifest as hepatosplenomegaly, lymphadenopathy or ocular disease

• Bacterial or viral pneumonia
• Mycobacterium avium-intracellulare complex infection
• Atypical pneumonia
• Pulmonary Kaposi's sarcoma
• Tuberculosis
• Influenza
• Cytomegalovirus infection
• Aspergillosis
• Measles
• Varicella (chickenpox) pneumonitis
• Coxiella burnetii (Q fever)
• Thoracic actinomycosis
• Pulmonary nocardiosis
• Lymphocytic interstitial pneumonia (associated with autoimmune disease)
• Pulmonary embolism

• Bloods:
  • Elevated lactate dehydrogenase is indicative of the diagnosis but not highly specific or sensitive.
  • Arterial blood gases may show hypoxia and hypocarbia due to hyperventilation.
  • The alveolar-arterial oxygen tension gradient may be increased.
  • The use of serum (1-->3) beta-D-glucan levels (high in PCP) is currently being investigated as a diagnostic test.⁴
• Radiology:
  • Chest X-ray can be normal or show perihilar fluffy shadows or pneumothorax.
  • CT imaging shows ground glass infiltrates but has low sensitivity and specificity.
  • Gallium scanning is highly sensitive but with low and variable specificity.
• Microbiology:
  • The organism cannot be routinely cultured and is detected by staining of the cyst wall or trophozoite in sputum samples, usually with silver-based stains. Repeated samples may need to be taken to confirm the diagnosis.
  • Sputum may be collected following inhalation of nebulised saline and/or chest physiotherapy and should also be sent for routine and mycobacterial culture.
  • If sputum is negative but PCP is still suspected, then bronchoscopy with bronchoalveolar lavage or transbronchial biopsy may detect the organism.
  • Open lung biopsy may occasionally be employed.
• Pulmonary function tests:
  • May show a modest reduction in the vital capacity (VC) and the total lung capacity (TLC).
  • Most consistent abnormality is a decrease in the single-breath diffusing capacity for carbon monoxide (DLCO), which has a sensitivity of 89%.

• Mild:
  • Breathlessness on mild exercise, which may be associated with cough and sweats
  • Arterial blood gases and oxygen saturation at rest, on air: PaO₂ >11 kPa; SaO₂ >96%
  • Chest X-ray: normal or minor perihilar infiltrates
• Moderate:
  • Breathlessness on minimal exercise, fever (with or without sweats)
  • Arterial blood gases and oxygen saturation at rest, on air: PaO₂ 8–11 kPa; SaO₂ 91-96%
  • Chest X-ray: diffuse interstitial shadowing
• Severe:
  • Breathlessness at rest, persistent fever and cough
  • Arterial blood gases and oxygen saturation at rest, on air: PaO₂ <8 kPa; SaO₂ <91%
  • Chest X-Ray: extensive interstitial shadowing, with or without alveolar shadowing

• Early diagnosis greatly aids successful therapy.
• Mild cases may be treated with oral medication as outpatients. Moderate to severe cases usually require hospitalisation and intravenous therapy.
• Treating empirically without confirmation of the diagnosis may be necessary but is best avoided if possible, due to the danger of missing other causes for the symptoms.
• Patients often deteriorate 3–5 days after starting treatment. This is thought to be due to inflammation caused by dead pneumocystis organisms.
• Treatment is usually given for 2–3 weeks.

Mild-to-moderate disease

• High-dose co-trimoxazole (trimethoprim-sulfamethoxazole) is the drug of choice. Concomitant host disease influences susceptibility to adverse drug reactions. HIV increases the risk of toxicity with many drugs including co-trimoxazole. Adverse effects occur in up to 65% of those receiving the drug and 50% will discontinue treatment. Hypersensitivity reactions are most common in such patients and include fever and maculopapular rash. Co-trimoxazole is usually well tolerated in immunocompetent patients⁶ but should be avoided in those with severe hepatic or renal dysfunction and porphyria. It is also best avoided during pregnancy and breast-feeding. Side-effects are numerous and include nausea, vomiting, skin reactions, neutropenia, thrombocytopenia, hepatitis and cholestatic jaundice.⁷
  
  
• Alternatives if the patient is unable to tolerate co-trimoxazole are:
  • Atovaquone - this has similar efficacy as pentamidine and is better tolerated than parenteral pentamidine, co-trimoxazole or dapsone. However, oral atovaquone has limited and unpredictable bioavailability.⁸
  • Dapsone with trimethoprim - dapsone is given intravenously or occasionally in nebulised form in the treatment of PCP.
  • Clindamycin with primaquine - clindamycin is associated with the development of antibiotic-associated colitis and treatment must be immediately discontinued if diarrhoea develops.
  • Inhaled pentamidine isetionate - this is restricted to specialist care, under careful patient observation and with laboratory monitoring.

Severe disease

• Intravenous high-dose co-trimoxazole is first-line treatment but toxic effects mean it may not be tolerated.
• Pentamidine isetionate:
  • Given by intravenous infusion, is used for patients who either cannot tolerate co-trimoxazole or who have not responded to it.
  • Can cause severe hypotension during or immediately after infusion; blood pressure and glucose should be carefully monitored.
• Oral prednisolone or parenteral hydrocortisone:
  • Steroids are an important adjunctive therapy for patients with moderate-to-severe infections associated with HIV infection.
  • Steroids are usually given in high dosage for 5-7 days and then the dose is reduced and continued for a further two weeks.
  • Steroid treatment should be started at the same time as the antimicrobial therapy and withdrawn before antimicrobial treatment is complete.

Trimethoprim and dapsone may be used in combination for mild-to-moderate PCP, although unlicensed.⁷ An alternative regimen should be used in patients with G6PD deficiency.⁷

Prior to the HIV epidemic, co-trimoxazole was rarely used in developed countries due to concerns regarding toxicity. Resistance to co-trimoxazole in such countries was therefore very low. However since the use of co-trimoxazole and dapsone⁹ for the treatment and long-term prophylaxis of PCP and toxoplasmosis, increased levels of resistance have been detected.¹⁰

A number of single base polymorphisms have been demonstrated in the P. jirovecii nucleotide sequence that codes for dihydropteroate synthetase. These mutations may affect substrate binding and be associated with the emergence of resistance to sulphonamides and dapsone.¹¹ Mutations in the cytochrome b gene have been demonstrated in atovaquone-resistant P. jirovecii isolates, which are likely to represent mechanisms of resistance.⁸

Findings linking mortality rates to the acquisition of the mutated P. jirovecii organism are inconsistent, which is not surprising, since survival in HIV-positive patients depends on many other factors. However, it does make assessment of the impact of drug resistance in such patients difficult and more research is required to develop strategies to prevent the emergence of further resistance strains.^1,9

Before the introduction of HAART, the two-year probability of developing PCP in HIV-positive patients was 40%. HAART has reduced the rate of opportunistic infections and so the absolute benefit of prophylactic treatment in those taking HAART is less significant. Recent studies have suggested that in HIV patients taking HAART with CD4 T-cell counts above 200 cells/mm³, discontinuation of prophylaxis does not increase the incidence of PCP. Current guidelines recommend that persons who meet these criteria can discontinue PCP prophylaxis and remain off prophylaxis as long as the CD4 T-cell count remains above 200 cells/mm³.¹ For more information see separate article Antiretroviral Agents.

New drugs against P. jirovecii are in development. Sordarin derivatives are a novel class of antifungal compounds that inhibit protein synthesis. Animal models of infection have shown promising activity against PCP with limited toxicity. Echinocandins and pneumocandins, which inhibit beta-glucan synthesis are also being investigated.^12,13 The promise of future new targets is expected with the annotation of the pneumocystis genome.¹⁴

Drug prophylaxis reduces the incidence of PCP and lengthens the disease-free intervals between episodes.¹⁵

• It should be considered for:
  • All patients with a history of the pneumocystis infection.
  • Severely immunocompromised patients.
  • All HIV-positive individuals once their CD4 T-cell count falls below 200 cells/mm³.⁷
• Prophylaxis should continue until immunity recovers sufficiently.
• Oral co-trimoxazole by mouth is the drug of choice.
• Intermittent inhalation of pentamidine isetionate is used for patients unable to tolerate co-trimoxazole but it doesn't suppress extrapulmonary pneumocystosis.
• Dapsone and atovaquone have also been used for prophylaxis.
• Patients (particularly children) who start HAART and attain low HIV viral load and improved CD4 counts may have prophylactic therapy safely discontinued.^16,17

• Respiratory failure
• Acute respiratory distress syndrome
• Worsening of condition after starting therapy
• Pulmonary cyst formation
• Pneumothorax
• Haematogenous spread
• Extrapulmonary infection (typically affects bone marrow, liver, spleen, lymph nodes, gut and eyes)

The use of HAART has made significant changes to the prognosis of HIV-related pulmonary infections. Mortality is about 10–20% in mild-to-moderate cases,¹⁸ rising to 40–50% in patients who require artificial ventilation. Due to restricted access to optimal medical care, PCP remains a common AIDS-defining illness in developed nations and is associated with significant morbidity and mortality.¹⁹

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16. Esposito S, Bojanin J, Porta A, et al; Discontinuation of secondary prophylaxis for Pneumocystis pneumonia in human immunodeficiency virus-infected children treated with highly active antiretroviral therapy. Pediatr Infect Dis J. 2005 Dec;24(12):1117-20. [abstract]
17. Urschel S, Ramos J, Mellado M, et al; Withdrawal of Pneumocystis jirovecii prophylaxis in HIV-infected children under highly active antiretroviral therapy. AIDS. 2005 Dec 2;19(18):2103-8. [abstract]
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