Pneumocystis jirovecii pneumonia

Synonym: pneumocystosis

What is pneumocystis jirovecii pneumonia?

Pneumocystis jirovecii is a ubiquitous fungus, which causes pneumonia in humans.¹ Extrapulmonary disease occurs occasionally.

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.² However, about half of patients with PCP do not have HIV infection.³

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.⁴ P. jirovecii is a unicellular eukaryote which shares characteristics with both protozoa and fungi.

How common is pneumocystis jirovecii pneumonia? (Epidemiology)

• DNA studies suggest that P. jirovecii is frequently found in healthy adults in the normal community. It can cause a transient infection in an immunocompetent host.

• A UK study of reported cases in England between 2000-2010 showed an increase of laboratory-confirmed cases of 7% per year. These were principally non-HIV infected cases, mainly in immunocompromised transplant recipients or patients with haematological malignancy.⁵

• The rates of PCP are increasing in the HIV-negative susceptible population, which includes transplant recipients.⁶

• The introduction of antiretroviral therapy (ART) dramatically reduced the incidence of PCP in HIV-positive individuals.⁷

• In the developing world, rates of PCP are lower, possibly due to poor survival with HIV, underdiagnosis and prior pulmonary infection with tuberculosis and other organisms.⁸

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.

• Connective tissue diseases such as rheumatoid arthritis.

• Congenital immune deficiency - eg, thymic aplasia, severe combined immune deficiency (SCID), hypogammaglobulinaemia.

• Severe malnutrition (poor nutrition in HIV-positive individuals increases risk).

• Pre-existing lung disease.

Symptoms of pneumocystis jirovecii pneumonia (presentation)³⁹

• 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 leukoplakia 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.

Differential diagnosis

• 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.

Diagnosing pneumocystis jirovecii pneumonia (investigations)³⁹

Blood tests

• Elevated lactate dehydrogenase is indicative of the diagnosis but not highly specific or sensitive. Multivariable regression identifies lactate dehydrogenase (LDH) as predictor of in-hospital mortality (adjusted OR 1.17 (95% CI 1.09-1.27), p < 0.0001). Mortality in LDH quartiles increases from 8% to 49%, and a cutoff value of 495 U/L predicts mortality with sensitivity and specificity of 70%.³

• 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 being investigated as a diagnostic test.¹⁰

• Molecular methods of detection such as polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), and antibody-antigen assays have been developed.¹¹¹²

Radiology

• CXR can be normal or show perihilar fluffy shadows or pneumothorax.

• Standard CT imaging shows ground glass infiltrates but has low sensitivity and specificity.

• High-resolution CT, however, has a sensitivity of 100% and a specificity of 89%.¹³

• 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).

• The most consistent abnormality is a decrease in the single-breath diffusing capacity for carbon monoxide (DLCO), which has a sensitivity of 89%.

Grading of severity⁶

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%.

• CXR: 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%.

• CXR: 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%.

• CXR: extensive interstitial shadowing, with or without alveolar shadowing.

Management of pneumocystis jirovecii pneumonia¹⁴¹⁵

• Early diagnosis greatly aids successful therapy.

• It is important to consider the diagnosis in patients who are HIV-negative but have other risk factors.¹⁶

• 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.

• A favourable response to treatment may take seven days or more.
  

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 and hypersensitivity reactions are common in such patients and include fever and maculopapular rash. Co-trimoxazole is usually well tolerated in immunocompetent patients but should be avoided in those with severe hepatic or renal dysfunction and porphyria. It is also best avoided during pregnancy and breastfeeding. Side-effects are numerous and include nausea, vomiting, skin reactions, neutropenia, thrombocytopenia, hepatitis and cholestatic jaundice.

• Alternatives if the patient is unable to tolerate co-trimoxazole are:

  • Atovaquone suspension - 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.

  • Dapsone with trimethoprim - dapsone is given intravenously or occasionally in nebulised form in the treatment of PCP.

  • Clindamycin with primaquine (unlicensed use in the UK) - clindamycin is associated with the development of antibiotic-associated colitis and treatment must be immediately discontinued if diarrhoea develops.

  • Aerosolised pentamidine isetionate is no longer recommended because it is associated with increased frequency of relapse.¹⁷

Severe disease

• Intravenous or oral 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.

Drug resistance

Prior to the HIV epidemic, co-trimoxazole was rarely used in high-income 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 dapsone for the treatment and long-term prophylaxis of PCP and toxoplasmosis, increased levels of resistance have been detected.¹⁸

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 sulfonamides and dapsone.¹⁹

The impact of highly active antiretroviral therapy

Before the introduction of ART, the two-year probability of developing PCP in HIV-positive patients was 40%. ART has reduced the rate of opportunistic infections and so the absolute benefit of prophylactic treatment in those taking ART is less significant.

Recent studies have suggested that in HIV patients taking ART 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/mm³.¹⁷ For more information see the separate Antiretroviral agents article.

Prophylaxis¹⁵¹⁷

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

• 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.

• Prophylaxis should continue until immunity recovers sufficiently.

• Co-trimoxazole by mouth is the drug of choice for prophylaxis against pneumocystis pneumonia. It is given daily or on alternate days (3 times a week). The dose may be reduced to improve tolerance.

• Inhaled pentamidine isetionate is better tolerated than parenteral pentamidine isetionate. Intermittent inhalation of pentamidine isetionate is used for prophylaxis against pneumocystis pneumonia in patients unable to tolerate co-trimoxazole. It is effective but patients may be prone to extrapulmonary infection.

• Dapsone and atovaquone have also been used for prophylaxis.

• Patients (particularly children) who start ART and attain low HIV viral load and improved CD4 counts may have prophylactic therapy safely discontinued.

Complications of pneumocystis jirovecii pneumonia

• Respiratory failure.

• Acute respiratory distress syndrome.

• Worsening of condition after starting therapy.

• Pulmonary cyst formation.

• Pneumothorax.

• Haematogenous spread.

• Extrapulmonary infection (typically affecting the bone marrow, liver, spleen, lymph nodes, gut and eyes).

Prognosis

The use of ART has made significant changes to the prognosis of HIV-related pulmonary infections. Currently, the most common HIV-related pulmonary infection diagnosed in high-income countries is bacterial pneumonia, and in developing countries, tuberculosis.¹³

In-hospital mortality rates are very high: 15% for HIV-infected patients and 50% in some HIV-uninfected patients.²⁰ In a 2018 17-year retrospective study overall in-hospital mortality was 25.4%, increasing to 58% if ICU admission was required.³