Pneumocystis jirovecii Pneumonia
Also known as: Pneumocystis Pneumonia, PJP, PCP, Pneumocystis carinii Pneumonia
Pneumocystis jirovecii is an atypical ascomycetous fungus that cannot be cultured and causes pneumonia in people with impaired cellular immunity. Pneumocystis pneumonia is a leading opportunistic infection in advanced HIV, and it has become more frequent in people without HIV who have cancer, transplant, inflammatory disease, and treatment with corticosteroids and biologic agents.
In people without HIV the disease is more fulminant, with a higher mortality (30 to 60 percent) than in HIV (10 to 20 percent). The organism is a taxonomic fungus without ergosterol in its membrane, so amphotericin B and azoles do not act on it, and treatment is with antifolate drugs.
| Feature | Description |
|---|---|
| Classification | A fungus of the class Pneumocystidomycetes (order Pneumocystidales), with host specific species: Pneumocystis jirovecii (humans), Pneumocystis carinii and Pneumocystis wakefieldiae (rats), Pneumocystis murina (mice), and others |
| Forms | Trophic forms (1 to 4 micrometres, the main form, attached to type I alveolar epithelium) and cysts (5 to 8 micrometres, thick walled, with up to 8 intracystic bodies); the wall contains beta 1,3 D glucan |
| Membrane | Cholesterol rather than ergosterol, so polyenes and azoles are inactive |
| Culture | No sustained culture system exists, and diagnosis rests on microscopy and molecular tests |
| Genome | A small genome, with dependence on the host for many nutrients; the dihydropteroate synthase gene (DHPS) is the target of sulfamethoxazole, and mutations occur with exposure to sulfonamides and dapsone, with unclear clinical effect |
| Transmission | Airborne person to person spread through the respiratory route (outbreaks in transplant units and in clinics); colonisation in healthy people and in those with chronic lung disease |
| Group | Notes |
|---|---|
| HIV | CD4 count below 200 cells per microlitre (usually below 100) or CD4 percentage below 14 percent, oral candidiasis, high viral load, and no prophylaxis or antiretroviral therapy; the leading AIDS defining illness in high income countries before antiretroviral therapy, with a high burden in low and middle income countries |
| Haematological malignancy | Acute lymphoblastic leukaemia, lymphoma, and chronic lymphocytic leukaemia, purine analogues (fludarabine), alemtuzumab, and allogeneic stem cell transplant |
| Solid organ transplant | The first 6 to 12 months, and more after rejection treatment (lung and heart transplant have a higher risk) |
| Corticosteroids | Prednisone 20 mg daily or more (or equivalent) for 4 weeks or more, especially with a second immunosuppressant or an underlying lymphopenia |
| Biologics and others | Rituximab with corticosteroids, cyclophosphamide, tumour necrosis factor inhibitors, Janus kinase inhibitors, and idelalisib |
| Rheumatological and inflammatory disease | Granulomatosis with polyangiitis, systemic lupus erythematosus, dermatomyositis, vasculitis, and inflammatory bowel disease |
| Primary immunodeficiency | Severe combined immunodeficiency, hyper IgM syndrome (CD40L deficiency), and others |
| Malnutrition and prematurity | Infantile pneumocystis pneumonia |
| Other | Cancer (solid tumours with chemotherapy and radiotherapy, brain tumours treated with temozolomide and corticosteroids) |
Organisms attach to type I alveolar cells, proliferate in the alveoli, and cause diffuse alveolar damage with an exudate of foamy proteinaceous material. CD4 T cells, alveolar macrophages, and cytokines clear the organisms. In HIV a high organism burden with a mild inflammatory response causes a subacute illness; in non HIV patients a low burden with a strong inflammatory response (neutrophils, with a rapid corticosteroid taper) causes acute respiratory failure. Lung injury also follows immune reconstitution after treatment.
| Feature | HIV | Non HIV |
|---|---|---|
| Onset | Subacute (weeks) | Acute (days), frequently after reduction of corticosteroids |
| Symptoms | Fever, dry cough, progressive exertional dyspnoea, chest tightness, and weight loss | Rapid dyspnoea, fever, cough, and respiratory failure |
| Signs | Tachypnoea, tachycardia, few chest signs, and oral candidiasis; exertional desaturation | Hypoxaemia at rest, with few chest signs |
| Hypoxaemia | Mild to severe | Severe |
| Organism burden | High | Low |
| Mortality | 10 to 20 percent (higher in respiratory failure) | 30 to 60 percent (up to 60 to 80 percent when mechanical ventilation is required) |
| Complications | Pneumothorax (in cystic disease), pneumatoceles | Acute respiratory distress syndrome, pneumothorax |
| Extrapulmonary | Rare in the era of prophylaxis: lymph nodes, spleen, liver, eye (choroiditis), and ear | Rare |
Laboratory features include a raised lactate dehydrogenase (above 500 units per litre, a sensitive but non specific marker), hypoxaemia with an increased alveolar to arterial oxygen gradient, and exertional desaturation.
| Modality | Findings |
|---|---|
| Chest radiograph | Bilateral diffuse interstitial or alveolar infiltrates that begin in the perihilar region and spread; normal in 10 to 25 percent at presentation; pneumothorax and cysts; atypical forms are lobar infiltrates, nodules, cavities, and upper lobe disease (especially after aerosolised pentamidine) |
| Computed tomography | Diffuse ground glass opacities, often patchy and with subpleural sparing, thin walled cysts and pneumatoceles, septal thickening ("crazy paving"), and rarely pleural effusion; a normal high resolution computed tomography excludes the diagnosis with high negative predictive value |
| Others | Gallium or fluorodeoxyglucose scans are not specific |
| Condition | Points that separate it |
|---|---|
| Bacterial and viral pneumonia (including COVID-19 and influenza) | Cultures, polymerase chain reaction, and procalcitonin |
| Pulmonary oedema and heart failure | Echocardiography and natriuretic peptide |
| Tuberculosis and non tuberculous mycobacterial disease | Acid fast bacilli |
| Cytomegalovirus pneumonitis, and other opportunistic infections | Polymerase chain reaction on lavage |
| Drug induced pneumonitis (methotrexate, amiodarone, bleomycin) and radiation pneumonitis | History |
| Pulmonary alveolar proteinosis, lymphoma, and Kaposi sarcoma | Biopsy |
| Endemic mycoses, aspergillosis, and cryptococcosis | Antigen and culture |
| Acute interstitial pneumonia and acute respiratory distress syndrome of other causes | Exclusion by polymerase chain reaction and beta D glucan |
| Test | Details |
|---|---|
| Specimens | Induced sputum (sensitivity 50 to 90 percent in HIV, lower in non HIV), bronchoalveolar lavage (sensitivity above 90 percent), and rarely transbronchial or open lung biopsy; upper respiratory samples (oral wash, nasopharyngeal aspirate) for polymerase chain reaction |
| Microscopy | Immunofluorescence with monoclonal antibodies (the most sensitive stain) for cysts and trophic forms; Grocott Gomori methenamine silver, toluidine blue O, or calcofluor white for cysts; Giemsa or Diff Quik for trophic forms and intracystic bodies |
| Quantitative polymerase chain reaction | Highly sensitive in bronchoalveolar lavage, with a high negative predictive value; colonisation gives a low load, so thresholds are interpreted with the clinical picture |
| Serum beta D glucan | Above 80 picograms per mL has a sensitivity of 90 to 95 percent and a specificity of about 85 percent for pneumocystis pneumonia, with high negative predictive value; it is non specific for the species and false positives follow intravenous immunoglobulin, albumin, haemodialysis with cellulose membranes, gauze exposure, and some antibacterials |
| Lactate dehydrogenase | Raised, with low specificity |
| Arterial blood gas | Hypoxaemia and an alveolar to arterial gradient above 35 mm Hg |
| Others | HIV test and CD4 count, cytomegalovirus and other pathogens, and glucose 6 phosphate dehydrogenase test before dapsone and primaquine |
Treatment is started on clinical suspicion and does not wait for results, because organisms persist in the lung for days after treatment begins.
First line and alternatives
| Severity | Regimen |
|---|---|
| Mild to moderate (room air oxygen tension above 70 mm Hg, alveolar to arterial gradient below 35 mm Hg) | Trimethoprim sulfamethoxazole 15 to 20 mg per kg per day of trimethoprim in 3 divided doses orally (or two double strength tablets three times daily) for 21 days |
| Moderate to severe | Trimethoprim sulfamethoxazole 15 to 20 mg per kg per day of trimethoprim intravenously in 3 or 4 divided doses (5 mg per kg every 8 hours), with oral therapy when improved, for 21 days |
| Mild to moderate, sulfonamide intolerance | Atovaquone 750 mg orally twice daily with food (a fatty meal, for absorption) for 21 days; or dapsone 100 mg orally once daily with trimethoprim 15 mg per kg per day in 3 divided doses (glucose 6 phosphate dehydrogenase tested first); or primaquine 30 mg base orally once daily with clindamycin 300 to 450 mg orally every 6 to 8 hours |
| Moderate to severe, sulfonamide intolerance | Intravenous pentamidine 4 mg per kg once daily (infused over 60 to 90 minutes), or intravenous clindamycin 600 to 900 mg every 6 to 8 hours with oral primaquine 30 mg base daily |
| Salvage and limited evidence | Echinocandins (caspofungin 70 mg then 50 mg daily) with trimethoprim sulfamethoxazole in refractory disease, and a lower dose of trimethoprim sulfamethoxazole (10 mg per kg per day of trimethoprim, or 5 mg per kg per day in less severe disease) in some studies to reduce toxicity; high dose therapy remains the standard for severe disease |
| Duration | 21 days, with secondary prophylaxis afterwards; 14 days is used in non HIV disease in some practices |
Adjunctive corticosteroids
| Group | Regimen |
|---|---|
| HIV with oxygen tension below 70 mm Hg on room air or alveolar to arterial gradient of 35 mm Hg or higher | Prednisone 40 mg twice daily for 5 days, then 40 mg once daily for 5 days, then 20 mg once daily for 11 days (or intravenous methylprednisolone at 75 percent of the prednisone dose), started within 72 hours of the first antipneumocystis dose; reduces mortality and respiratory failure |
| Non HIV with moderate to severe hypoxaemia | Often used (methylprednisolone 1 mg per kg per day or prednisone 40 to 60 mg per day with a taper over 3 weeks), but evidence is limited and mixed, with no clear mortality benefit, and a risk of infection; individualised |
Supportive care
- Oxygen, high flow nasal oxygen, noninvasive ventilation, and mechanical ventilation with lung protective strategy; extracorporeal membrane oxygenation in selected patients.
- Early antiretroviral therapy in HIV: within 2 weeks of the start of therapy (the immune reconstitution inflammatory syndrome can follow; corticosteroids are used for it).
- Reduction of immunosuppression in non HIV patients, with corticosteroids tapered slowly.
- Care for pneumothorax with chest drainage; surgical or pleurodesis for persistent air leak.
Adverse effects and monitoring
| Drug | Adverse effects and monitoring |
|---|---|
| Trimethoprim sulfamethoxazole | Rash (including Stevens Johnson syndrome and toxic epidermal necrolysis), fever, hyperkalaemia, creatinine rise (trimethoprim blocks tubular secretion), cytopenias, hepatitis, hyponatraemia, aseptic meningitis, and nausea; potassium, creatinine, blood counts, and liver tests twice weekly; hyperkalaemia is highest at high doses with renal impairment or with angiotensin converting enzyme inhibitors; dose adjustment for renal function; folinic acid is not given as it is associated with treatment failure |
| Pentamidine | Hypoglycaemia and hyperglycaemia, pancreatitis, nephrotoxicity, hypotension, arrhythmia (QT prolongation), leucopenia, and hypocalcaemia; monitor glucose, creatinine, and electrolytes |
| Primaquine | Methaemoglobinaemia and haemolysis (glucose 6 phosphate dehydrogenase deficiency); check methaemoglobin |
| Dapsone | Haemolysis and methaemoglobinaemia (test for glucose 6 phosphate dehydrogenase), rash, and hepatitis |
| Atovaquone | Rash, gastrointestinal upset, and variable absorption; lower efficacy in severe disease |
| Clindamycin | Diarrhoea and Clostridioides difficile infection |
Clinical failure is defined as no improvement after 4 to 8 days (early worsening in the first few days is common and is due to inflammation from dying organisms). Then other causes (cytomegalovirus, bacteria, heart failure) are looked for, and the regimen is changed only after a prolonged trial of first line therapy.
| Group | Mortality |
|---|---|
| HIV, mild to moderate disease | Under 5 to 10 percent |
| HIV, mechanical ventilation | 50 to 70 percent |
| Non HIV | 30 to 60 percent (older age, high lactate dehydrogenase, low albumin, bone marrow transplant, and ventilation increase the risk) |
| Recurrent disease | Common without prophylaxis |
| Indication | Regimen and duration |
|---|---|
| HIV with CD4 below 200 cells per microlitre (or below 14 percent, or oral candidiasis) | Trimethoprim sulfamethoxazole one double strength tablet daily (preferred, with protection against toxoplasmosis and some bacterial infections), or one single strength tablet daily (lower toxicity), or one double strength tablet three times weekly; stop when the CD4 count is above 200 cells per microlitre for more than 3 months on antiretroviral therapy (or above 100 with an undetectable viral load for 3 to 6 months) |
| Alternatives | Dapsone 100 mg daily (or 50 mg twice daily), atovaquone 1500 mg once daily with food, aerosolised pentamidine 300 mg every 4 weeks by a Respirgard II nebuliser (no protection outside the lung, and a risk of upper lobe and extrapulmonary disease), or intravenous pentamidine 4 mg per kg every 3 to 4 weeks |
| Infants exposed to HIV | Trimethoprim sulfamethoxazole from 4 to 6 weeks of age until HIV is excluded (trimethoprim 150 mg per square metre per day, in two divided doses on 3 consecutive days weekly, or 5 mg per kg per day) |
| Solid organ transplant | Trimethoprim sulfamethoxazole for 6 to 12 months after kidney, liver, and pancreas transplant (longer or lifelong after lung and heart transplant, and after rejection treatment) |
| Haematological malignancy and stem cell transplant | Acute lymphoblastic leukaemia (throughout treatment), allogeneic stem cell transplant (at least 6 months, and during immunosuppression or graft versus host disease), and alemtuzumab or purine analogues (for at least 2 to 6 months after therapy) |
| Corticosteroids | Prednisone 20 mg daily or more for 4 weeks or more in people with a second cause of immunosuppression, or with a primary disease (granulomatosis with polyangiitis, lymphoma) |
| Rituximab and other biologics | With corticosteroids or cyclophosphamide, for at least 6 months after the last dose, depending on the regimen |
| Secondary prophylaxis | After any episode, until the immune defect has resolved |
Immunosuppressed patients are separated from patients with active pneumocystis pneumonia in transplant and haematology units. Standard precautions are used for the patient, and prophylaxis protects contacts in outbreak settings.
