Pneumocystis jirovecii pneumonia

• Pneumocystis jirovecii is a fungus that causes pneumonia only when the host's cellular immunity is badly impaired; it does not produce disease in a healthy adult, although colonisation can occur.
• The illness is a subacute, diffuse pneumonia: dry cough, steadily worsening breathlessness, fever and marked hypoxia on exertion, with bilateral interstitial or ground-glass shadowing on imaging.
• It is still one of the classic AIDS-defining illnesses, and it also affects transplant recipients, people on high-dose corticosteroids and other immunosuppressed patients.
• The diagnosis is made by finding the organism in a respiratory sample, usually induced sputum or bronchoalveolar lavage (BAL) fluid, by polymerase chain reaction (PCR) or by silver staining.
• First-line treatment is trimethoprim-sulfamethoxazole (TMP-SMX, also called co-trimoxazole) for 21 days, with adjunctive corticosteroids for moderate to severe disease, defined by a partial pressure of arterial oxygen (PaO2) under 70 mmHg on room air or an alveolar-arterial (A-a) oxygen gradient of 35 mmHg or more.
• Prophylaxis with TMP-SMX is highly effective and is given to all adults with HIV whose CD4 (helper T-cell) count is under 200 cells per mm3, and to many other at-risk groups.
• Where HIV is present, antiretroviral therapy (ART) should be started early, usually within two weeks of starting anti-Pneumocystis treatment, because this improves long-term outcomes without increasing harms.
• The disease remains common in settings with limited access to antiretroviral drugs and to prophylaxis, and it should be considered in any immunocompromised patient with unexplained hypoxic pneumonia.

By the end of this page you should be able to:

1. Name the patients at risk of Pneumocystis jirovecii pneumonia (PJP) and the immunological threshold that defines high risk in HIV.
2. Describe the typical clinical picture and explain why the physical signs are often few despite severe hypoxia.
3. Interpret the chest radiograph and the computed tomography (CT) findings, and state what serum lactate dehydrogenase (LDH) and beta-D-glucan add.
4. Choose the first-line diagnostic specimen and test, and recognise when bronchoscopy is needed.
5. Write the first-line regimen for PJP with dose, route and duration, and give the steroid taper used in moderate to severe disease.
6. List the alternative regimens and the monitoring each needs, including glucose-6-phosphate dehydrogenase (G6PD) deficiency.
7. Give the indications and drugs for PJP prophylaxis.
8. Adapt diagnosis, treatment and prevention to a low-resource setting.

The fungus responds poorly, or not at all, to the drugs used for most systemic mycoses: it has no ergosterol in its cell membrane and little chitin in its wall, so azoles and amphotericin B are not useful. ^[1] This is an important exam point, because PJP is one of the few "fungal" infections treated with an antibacterial, TMP-SMX, and not with an antifungal.

Two clinical forms are useful to separate:

• HIV-associated PJP usually evolves over two to four weeks, with well-preserved lung architecture until late.
• Non-HIV PJP (after transplantation, during cancer treatment, or on immunosuppressive drugs) tends to run a much faster course, with rapid deterioration over five to six days rather than over twenty-five to twenty-eight days. ^[1]

Both are the same infection; the difference reflects the host immune response rather than the fungus.

PJP was one of the defining illnesses of the early HIV epidemic and, before effective antiretroviral therapy, affected perhaps three-quarters of people with advanced HIV disease. ^[3] Routine prophylaxis and ART have reduced its incidence dramatically in people with HIV in well-resourced settings, while the rate has been rising among non-HIV immunocompromised patients receiving chemotherapy, biologics and high-dose steroids. ^[1]

In the United States, PJP still caused an estimated 10,590 hospitalisations in 2017, and in countries with limited access to ART and prophylaxis it remains one of the commonest AIDS-defining infections. ^[3]

P. jirovecii is acquired by the respiratory route. Transmission is from person to person, and healthy adults can carry the organism without symptoms. ^[3] Disease represents reactivation of latent infection or recent acquisition in a host unable to mount a CD4 T-cell response.

Risk is governed by cellular immunity:

• HIV. A CD4 count under 200 cells per mm3 is the classic threshold at which PJP prophylaxis is started and at which disease risk rises sharply; a high HIV viral load, weight loss, recurrent bacterial pneumonia and a prior episode of PJP add risk. ^[1]
• Transplantation. Solid organ and haematopoietic stem cell transplant recipients are at high risk, particularly in the first six months, or where T-cell-mediated rejection has been treated and immunosuppression intensified. ^[1]
• Malignancy and chemotherapy. Haematological malignancies (especially lymphoma and chronic lymphocytic leukaemia), solid tumours receiving radiotherapy or concurrent chemoradiotherapy, and the lymphopenia they produce are settings in which PJP is increasingly recognised. ^[1][4]
• Immunosuppressive drugs. High-dose corticosteroids (studies in rheumatic disease have implicated doses above 40 mg per day), calcineurin inhibitors, cyclophosphamide, rituximab, alemtuzumab and tumour necrosis factor inhibitors all predispose; systemic lupus erythematosus and dermatomyositis are over-represented. ^[1]
• Other immune defects. Severe combined immunodeficiency, hyper-IgM syndromes, Good's syndrome (thymoma with hypogammaglobulinaemia) and primary antibody deficiency can present with PJP. ^[1]
• Chronic lung disease and chronic corticosteroid use for non-malignant disease are additional risk factors noted in population studies. ^[3]

After inhalation the organism attaches to type I pneumocytes in the alveolus and proliferates, filling alveolar spaces with a foamy, protein-rich exudate. ^[1] Alveolar macrophages normally clear it. When CD4 T-cell help fails, the organism is not eliminated, yet the inflammatory response, dominated by CD8 T cells, damages tissue and impairs gas exchange. ^[1]

The result is a pneumonia that is more physiological than anatomical: the lungs are diffusely involved but not consolidated, so gas transfer across the alveolar-capillary membrane fails and hypoxia precedes most physical signs. A surface antigen, the major surface glycoprotein (MSG), also alters surfactant handling and worsens oxygenation. ^[1]

Histology shows eosinophilic amorphous material in alveoli with a honeycomb appearance plus interstitial lymphocytic infiltration, which explains the reticulonodular pattern seen on imaging. ^[1]

PJP has a fairly stereotyped presentation, although the pace varies with the host. ^[1]

• Dry cough in around ninety-five per cent of HIV-infected patients.
• Progressive dyspnoea in around ninety-five per cent.
• Low-grade fever in around eighty per cent.
• Exertional (or resting) hypoxia that is out of proportion to the findings on auscultation.
• Chest pain and pneumothorax in about two to four per cent. ^[1]

In HIV infection the illness usually builds over two to four weeks: a gradually worsening dry cough, then breathlessness on stairs, then on the flat, then at rest. In non-HIV immunocompromised patients the same syndrome can reach respiratory failure in five to six days. ^[1]

Constitutional upset (fatigue, weight loss) often accompanies the pulmonary symptoms, and co-infection with cytomegalovirus (CMV) is common in advanced HIV disease and adds to the severity.

The striking finding is how normal the chest sounds despite significant disease. Breath sounds are usually clear or show only fine basal crepitations; the severity is revealed by pulse oximetry and arterial blood gas rather than by auscultation. Look for:

• tachypnoea at rest,
• intercostal recession and accessory muscle use,
• cyanosis,
• fever,
• diffuse crepitations in the more advanced cases.

Because the disease is diffuse and alveolar, lobar signs are absent, which is one of the features that separates PJP from routine bacterial pneumonia.

PJP is a diagnosis of probability and then of proof. The common mimics are listed because missing them in a hypoxic immunocompromised patient is common. ^[1]

A sudden pneumothorax in a patient with known PJP should raise suspicion of cystic change and cavitation rather than a labelled "spontaneous" pneumothorax.

Figure 1PCP CAP CXR

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Long description

PA chest radiograph of a patient with Pneumocystis jiroveci pneumonia showing reticular interstitial markings in all lung fields.

The classic picture is bilateral, diffuse, symmetrical interstitial shadowing: a finely granular, reticular or ground-glass pattern, often perihilar and spreading outward. ^[1] The radiograph can be normal early in the illness, especially in non-HIV patients, and may show cysts, nodules or pneumothorax later.

When the radiograph is inconclusive but the clinical picture fits, high-resolution CT of the chest is the most sensitive imaging test. ^[1] The hallmark is ground-glass opacification, often with a mosaic or diffuse distribution and a perihilar predominance. Cystic change is more common in HIV infection, and nodular or solitary-lesion presentations are reported but rare. ^[1]

The absence of ground-glass opacities on CT makes PJP unlikely, although atypical infiltrates occur. ^[1]

• Lactate dehydrogenase (LDH). An elevated level is common and is a marker of disease severity rather than a diagnostic test in its own right; a high value supports the diagnosis of PJP and a very high value correlates with poor outcome, but a normal value does not exclude the disease. ^[1]
• Beta-D-glucan. A serum biomarker of fungal cell-wall components; it is elevated in PJP and can be used when an invasive procedure is not possible. ^[1] It is not specific, because it is also raised in invasive aspergillosis, candidaemia and several other conditions, and it is falsely elevated by some wound dressings, haemodialysis membranes and certain antibiotics. ^[1]
• HIV testing and CD4 count, where the risk group or HIV status is unknown.

Figure 2Pneumocystis carinii 01

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Long description

Methenamine silver stain of Pneumocystis jiroveci cysts in tissue from an AIDS patient, showing thick-walled Pneumocystis jirovecii organisms including characteristic cup-shaped forms and dot-like cysts.

Routine culture does not grow P. jirovecii; definitive diagnosis requires molecular or direct visualisation methods on a respiratory specimen. ^[1]

• Induced sputum is the non-invasive first step: the patient inhales hypertonic saline after nebulisation and produces a deep cough specimen.
• Bronchoalveolar lavage has a better diagnostic yield and is used when induced sputum is negative or cannot be obtained; bronchoscopic washings or biopsy are occasionally needed.
• PCR on induced sputum or BAL fluid is highly sensitive (97 to 100 per cent in many series in HIV-infected patients), although it may be less useful in non-HIV immunocompromised patients, where specificity falls and the test can detect colonisation as well as disease. ^[1]
• Silver staining (Grocott-Gomori methenamine silver) and immunofluorescence (direct or indirect fluorescent antibody) demonstrate the cysts on stained preparations of induced sputum or BAL fluid. ^[1]

Clinical practice therefore requires correlating respiratory symptoms, imaging and laboratory results; a positive PCR in an immunocompetent, asymptomatic person may represent colonisation rather than pneumonia. ^[1]

There are no universally accepted diagnostic criteria for PJP beyond a compatible clinical picture plus microbiological or histological evidence. ^[1] Severity is best judged clinically.

Moderate to severe disease is defined for treatment decisions (mainly for steroids) as either:

• PaO2 under 70 mmHg on room air, or
• an A-a oxygen gradient of 35 mmHg or more. ^[1]

Non-HIV PJP is graded more sharply than ordinary pneumonia; standard pneumonia scores such as CURB-65 underestimate the risk, so the Miller severity system, which incorporates oxygen saturation, respiratory rate, age and comorbidity, is preferred in this group. ^[1]

Management is best delivered by a multidisciplinary team: infectious diseases, respiratory medicine, intensive care, pharmacy, nursing and respiratory therapy. ^[1]

• Oxygen therapy to keep the saturation adequate; early non-invasive or invasive ventilation when the disease is severe.
• Fluids and nutrition, and treatment of precipitating illnesses.
• Search for co-infection (CMV, tuberculosis, bacterial pneumonia), especially in HIV with a very low CD4 count.

TMP-SMX is first-line for PJP whatever the underlying condition. ^[1]

• Moderate to severe disease: TMP 15 to 20 mg per kg per day plus SMX 75 to 100 mg per kg per day, intravenously in three or four divided doses, converting to oral once the patient improves.
• Mild to moderate disease: the same total dose by mouth, or double-strength tablets (160 mg TMP with 800 mg SMX) two to three times daily. ^[1]

Most units treat for 21 days, although at least fourteen days are used for mild to moderate disease and longer courses are given when improvement is slow. ^[1]

In moderate to severe HIV-associated PJP (PaO2 under 70 mmHg on room air or A-a gradient of 35 mmHg or more), adjunctive corticosteroids halves the risk of death and is started within 72 hours of anti-Pneumocystis therapy. ^[1]

Standard taper: ^[1]

• Days 1 to 5: prednisone 40 mg by mouth twice daily.
• Days 6 to 10: prednisone 40 mg once daily.
• Days 11 to 21: prednisone 20 mg once daily.

Intravenous methylprednisolone is an acceptable alternative where oral therapy is not possible. ^[1]

In non-HIV PJP the role of steroids is contested. Some retrospective studies report shorter intensive care unit stays and ventilator times, but a meta-analysis found no clear survival benefit, and several cohort studies found no effect on mortality or ventilation. ^[1][4] In solid organ transplant recipients, some guidelines recommend prednisone 40 to 60 mg twice daily for five to seven days started within 72 hours for moderate to severe disease, tapered over the following one to two weeks. ^[1] Steroids are never a substitute for effective anti-Pneumocystis treatment.

These are used when TMP-SMX is contraindicated, not tolerated or fails. ^[1]

TMP-SMX remains the most effective agent; second-line drugs are clearly inferior in most comparisons and should not be chosen lightly. ^[1]

• Common TMP-SMX effects: rash, fever, nausea and marrow suppression. ^[3][1] Hypersensitivity reactions and bone-marrow suppression are particularly common in children on chronic therapy. ^[1]
• Sulphonamide-specific problems: hyperkalaemia (TMP is potassium-sparing), renal impairment and crystal deposition in concentrated urine; maintain good hydration, take renal impairment into account and reduce the dose in renal failure.
• G6PD deficiency: test for it before primaquine or dapsone, and choose another alternative if the patient is deficient.
• Pentamidine: pancreatic, renal and cardiac toxicity; monitor glucose, renal function and blood pressure.
• Atovaquone: variable absorption with food; take with fatty meals.

Response is assessed clinically (oxygen requirements, fever) and radiologically. If there is no improvement after about eight days, repeat investigations including CT and bronchoscopy to look for co-infection. ^[1] Persistent PCR positivity in a repeat BAL sample does not indicate treatment failure. ^[1]

PJP in a patient not on ART is an emergency in both directions: treat the pneumonia and start ART. Early initiation of ART, within two weeks of anti-Pneumocystis treatment, produced no increase in mortality, AIDS-defining events, immune reconstitution inflammatory syndrome (IRIS) or adverse events compared with deferring, and many early deaths occurred in patients who never reached ART at all. ^[2] This supports starting ART within two weeks of treatment, tailored to the patient's ability to absorb oral medication and to the clinical course. ^[2]

A transient worsening can occur when ART is started, sometimes with a new systemic inflammatory response (IRIS). This is rare in PJP, is treated with continued therapy and targeted supportive care, and does not usually mean treatment failure.

• Respiratory failure and need for mechanical ventilation, with higher failure rates of non-invasive ventilation in non-HIV PJP. ^[1]
• Pneumothorax from cystic change, which can occur spontaneously or with ventilation.
• Disseminated infection is not typical; extrapulmonary PJP is rare.
• Drug toxicity (see above) may force a change of regimen.
• Co-infection with CMV, bacterial pneumonia and tuberculosis, particularly in late HIV.
• Treatment failure with resistant (DHPS mutant) organisms is reported but has not changed first-line empirical practice. ^[1]

Outcomes differ markedly by host. Mortality is around ten to twenty per cent in HIV-associated PJP and thirty to sixty per cent in non-HIV PJP, largely because the latter group presents later and with more respiratory failure. ^[1] Need for intensive care, mechanical ventilation, pneumothorax, a high LDH and a low CD4 count predict poor outcomes; the degree of hypoxaemia (the A-a gradient) tracks response to treatment in HIV-associated disease. ^[1] In HIV, early anti-Pneumocystis treatment and early ART substantially improve survival.

• HIV: adults and adolescents with a CD4 count under 200 cells per mm3; HIV-infected children according to age-based CD4 thresholds (under 500 cells per mm3 at one to five years, under 200 cells per mm3 at six to twelve years) also require prophylaxis. ^[1]
• Non-HIV patients at high risk: prolonged high-dose corticosteroids (more than 20 mg prednisone equivalent for three weeks or more in lung cancer, for example), combined immunosuppression, absolute lymphopenia, transplant recipients (especially the first six months and after rejection treatment), autoimmune disease on cyclophosphamide or rituximab, and haematological malignancy. ^[1]
• Secondary prophylaxis is given after an episode of PJP until the underlying immunosuppression resolves.

TMP-SMX is the agent of choice for both primary and secondary prophylaxis. ^[1]

TMP-SMX is markedly more effective than the alternatives and should be used wherever it is tolerated. ^[1][3] Where a patient has a history of a mild sulphonamide rash, desensitisation or re-challenge is often attempted under specialist guidance.

Pregnant patients need specialist obstetric and infectious disease input, because drug choices for treatment and prophylaxis, especially in the first trimester, differ from those for other adults. Follow local guidance.

The clinical picture, complications and radiology are close to those in adults. The treatment of choice is TMP-SMX, 15 to 20 mg of the TMP component per kg per day with 75 to 100 mg per kg per day of SMX, intravenously or by mouth in three to four divided doses for 21 days. ^[1] Pentamidine and atovaquone are the main alternatives; caspofungin added to TMP-SMX has shown good results in immunocompromised children. ^[1] Hypersensitivity reactions and bone-marrow suppression are common with prolonged therapy. ^[1]

There is no change in recommended regimen, but drug toxicity and renal impairment need particular attention; dose adjustment in renal failure is standard.

• The disease is common where ART and routine prophylaxis are not universally available, and it should be considered in every immunocompromised patient with an unexplained hypoxic pneumonia. ^[3]
• Induced sputum and PCR, bronchoscopy, CT and serum beta-D-glucan are frequently unavailable. In that situation the diagnosis is made clinically from risk factors, presentation and the plain chest radiograph, and treatment is started empirically.
• Cotrimoxazole (TMP-SMX) is cheap, widely available and effective by mouth; intravenous therapy is reserved for severe disease or inability to take oral medication. The same oral regimen used for treatment can be completed as an outpatient once the patient is stable.
• Adjunctive corticosteroids require clinical oxygen assessment (room-air saturation or arterial blood gas), not imaging alone, to identify moderate to severe disease.
• HIV testing must be offered, because PJP is often the presenting illness of undiagnosed HIV; linking the patient to HIV services and starting ART promptly is central.
• Local tuberculosis prevalence means TB should be actively excluded in every patient, since the two can coexist and TB can mimic PJP.
• Prophylaxis with TMP-SMX is one of the cheapest, most effective interventions available; health systems should ensure it reaches all adults with HIV whose CD4 is under 200 and anyone starting potent immunosuppression.

Pneumocystis jirovecii pneumonia intersects with HIV infection (risk threshold, ART and prophylaxis), transplant immunosuppression, haematological malignancy, interstitial lung disease and corticosteroid use. Readers should also revise acute respiratory failure, pneumothorax, hypoxaemia and opportunistic infections in immunocompromised hosts.