Pneumocystis jirovecii (previously Pneumocystis carinii)1 is a fungus2 that is ubiquitous. It is unclear whether infection occurs as a primary event3 or as a result of colonisation with reactivation4,5, although antibodies against the organism are present in more than 85% of children under 3 years of age, suggesting that reactivation with immunosuppression occurs. P. jirovecii pneumonia (PJP), is still the most common AIDS defining condition, and is usually seen in people presenting late in the course of HIV infection6 or in people with poor adherence to PJP prophylaxis or combination antiretroviral therapy (cART). PJP occurs uncommonly in persons with a CD4 T-lymphocyte (CD4) cell count > 200 cells/μL, or proportion of CD4 cells that is > 14% of total lymphocytes, although cases have occasionally been reported in people with more preserved immune function.7
The major manifestation of P. jirovecii infection is that of PJP. The presentation of PJP is subacute with fever, a non-productive cough, chest tightness and dyspnoea. Symptoms may be present for 2 to 6 weeks or more before the diagnosis is made. Extrapulmonary manifestations are rare, and require tissue biopsy for diagnosis.8 The typical clinical scenario of a patient with PJP is an immunodeficient person (with a CD4 cell count < 200 cells/μL or a CD4 cell percentage < 14%), who has not achieved suppression of HIV replication, is not taking cotrimoxazole prophylaxis, and presents with fatigue and fevers. The patient may not necessarily have noticed cough or dyspnoea, yet a non-productive cough is commonly apparent during the clinical assessment. Respiratory examination may reveal no signs aside from tachypnoea and oxygen desaturation on exertion, although crackles may be present on auscultation of the chest. Pneumothoraces may complicate severe PJP.
Immune reconstitution inflammatory syndrome after commencing cART
Pneumonitis and organising pneumonia may be seen as manifestations of an immune reconstitution inflammatory syndrome (IRIS) after cART is commenced and occur in approximately 4% of cases. Distinguishing a pneumonitis secondary to an IRIS after commencement of cART from undiagnosed PJP may be difficult.
The initial diagnostic approach to PJP includes consideration of the clinical likelihood of disease. People with advanced immunodeficiency who present with fever, fatigue and a dry cough have a high likelihood of PJP if they are not taking PJP prophylaxis, although other infections may present in such a manner. Other pathogens may cause respiratory disease (e.g. Mycobacterium tuberculosis, Mycobacterium avium complex, Streptococcus pneumoniae, Rhodococcus spp., Nocardia spp. and Cryptococcus neoformans) and these need to be considered in the differential diagnosis of any pulmonary presentation. It is especially important to consider the possibility of tuberculosis, as infection control and public health issues need to be considered.
The initial recommended investigation is a chest radiograph, which may reveal peri-hilar interstitial infiltrates or diffuse alveolar shadowing (Image: Chest radiograph showing bilateral infiltrates Source). The chest radiograph may be normal in more than 10% of cases.9 Additional focal pathology is suggestive of an alternative diagnosis. PJP may be complicated by pneumothoraces and pleural effusions are very rare. If pleural effusions are detected, other diagnoses should be considered. Even in cases with a normal chest radiograph, high resolution computed tomography (CT) of the chest (Image: CT scan showing ground glass appearance consistent with Pneumocystis jirovecii pneumonia) may reveal the typical ‘ground glass’ changes seen in the alveolitis due to PJP.10 Changes other than ground glass may occur, but are less common.11
An expectorated sputum sample may be examined for P. jirovecii cysts by immunofluorescence (see below) but only has a sensitivity of approximately 55%.12 A more sensitive approach is the examination of an induced sputum specimen which is obtained by the induction of a deep cough after the inhalation of hypertonic saline.13,14 Pneumothorax should be excluded before sputum induction is undertaken. The procedure should be performed in an appropriately ventilated room, in case other pathogens are present. Induced sputum enables lower respiratory tract sampling, which is suitable for analysis for the presence of P. jirovecii cysts. An alternative to obtaining an induced sputum is bronchoscopy with bronchoalveolar lavage (BAL).
Image: Chest radiograph showing bilateral infiltrates Source: Jeffrey J. Post, University of NSW, Sydney NSW. Used with permission:
Image: CT scan showing ground glass appearance consistent with Pneumocystis jirovecii pneumonia Source: Jeffrey J. Post, University of NSW, Sydney NSW. Used with permission:
The diagnosis of P. jirovecii infection is made by immunofluorescence staining of the sample using monoclonal antibodies,15 which typically takes 2 hours to process. Other stains, including silver stains, have a lower sensitivity. Investigation of induced sputum is not warranted in asymptomatic immunodeficient people.16
More recently, highly sensitive polymerase chain reaction (PCR) diagnostic assays have been developed, but their role in the diagnostic evaluation of P. jirovecii infection is yet to be fully defined. The assay results may be positive in people with colonisation of the airways by P. jirovecii and a threshold assessment is needed in the interpretation of the results, in conjunction with the clinical pre-test probability of disease. One older meta-analysis suggested that induced sputum with immunostaining is the preferred diagnostic approach in low-prevalence settings.17-23 A more recent meta-analysis which included studies with HIV and non-HIV associated PJP identified a sensitivity of 98.3% and a specificity of 91% for PCR testing of BAL specimens.24
In people with a high clinical likelihood of PJP, presumptive therapy is sometimes undertaken if the induced-sputum specimen is not diagnostic and other features are consistent with PJP, but bronchoscopy with BAL is generally indicated, as the differential diagnosis is broad.25 Bronchoscopy with BAL is also indicated in cases of presumptive PJP that do not respond to therapy. Bronchoscopy may be preferred where there is a high likelihood of other infectious agents such as M. tuberculosis.26 Open-lung biopsy is usually unnecessary as induced-sputum examination and bronchoscopy with bronchoalveolar lavage have a high sensitivity (approximately 97%). The pathology of PJP consists of an eosinophilic alveolar exudate with organisms present.27 Blood gas analysis should be undertaken to assess disease severity. Arterial blood hypoxaemia (while breathing room air), with a PaO2 < 70 mmHg, an alveolar-arterial (A-a) oxygen gradient of > 30 mmHg or oxygen saturation of < 94% indicates moderately severe or severe disease. Lesser impairment of gas exchange indicates mild disease. Therapeutic studies of mild-to-moderate disease have included those with a PaO2 > 50 mmHg.
Other investigations infrequently used in the diagnosis of PJP include the following:
- Rapid clearance of technetium in lung scans indicates altered alveolar permeability that is consistent with PJP28,29
- Pulmonary diffusing capacity for carbon monoxide is also typically impaired in persons with PJP30,31
- Although lactate dehydrogenase is often elevated in PJP, it is insufficiently specific to exclude other pathology or determine disease severity32
- More recently, there has been significant interest in serum markers of PJP, with low S-adenosylmethionine levels (a molecule that P. jirovecii must scavenge) seen in cases with PJP that recover in association with effective treatment33,34
- Other non-invasive markers such as serum beta-D-glucan have recently been of interest and have a reasonable sensitivity and specificity.35,36
The management of PJP depends on the degree of severity of disease.
People with severe disease should be managed in hospital, as ventilatory support may be required. Those who are not allergic to sulfa-containing drugs or hypersensitive to cotrimoxazole should receive high-dose intravenous cotrimoxazole (for adults trimethoprim+sulfamethoxazole 5+25 mg/kg intravenously every 6-8 hours) and should receive therapy for a total of 21 days (once improvement has occurred a switch to oral therapy may occur). People who are allergic to sulfa compounds, or unresponsive to cotrimoxazole, or who develop hypersensitivity during therapy should be treated with intravenous pentamidine (3-4 mg/kg/day for 21 days)37 or clindamycin (900 mg intravenously every 8 hours) with primaquine (30 mg orally daily; after assessing risk of glucose-6-phosphate dehydrogenase deficiency).38 Supplemental oxygen, non-invasive ventilation (e.g. continuous positive airways pressure or bilevel positive airways pressure),39 or intubation and ventilation may be required. It is not uncommon for patients to deteriorate during the first 48 hours after commencement of therapy. Patients with significant hypoxaemia (PaO2 < 70 mmHg) should receive corticosteroids prior to the commencement of antimicrobial therapy to reduce the risk of this complication and improve prognosis (prednisone 40 mg orally twice a day for 5 days, then 40 mg daily for 5 days, then 20 mg/day until completion of treatment).40-44 If oral corticosteroid therapy is not possible then hydrocortisone (100 mg intravenously every 6 hours) may be used. Corticosteroid therapy may be complicated by central nervous system toxicity (e.g. psychosis, mania), oral candidiasis and other opportunistic infections. Patients who respond well to initial intravenous therapy may complete the 21-day course with oral therapy (see below).
If disease severity is moderate (e.g. dyspnoea on minimal exertion, PaO2 50-70 mmHg) or adherence to or tolerance of an oral regimen is not likely, then initial inpatient management is recommended. Otherwise, oral regimens may be considered (see below). Patients with moderately severe PJP should also receive corticosteroids (if PaO2 < 70 mmHg).
People with mild disease may be treated with oral cotrimoxazole (two double-strength tablets three times daily –one double-strength tablet contains trimethoprim 160 mg and sulfamethoxazole 800 mg) for 21 days. Oral therapy should only be considered where adherence is likely. Adjunctive antiemetic therapy is commonly prescribed. Alternative regimens in cases of non-severe disease include clindamycin (450 mg orally four times daily) with primaquine (15 mg orally daily; after assessing risk of glucose-6-phosphate dehydrogenase deficiency); dapsone (100 mg orally daily) with trimethoprim (300 mg orally every 8 hours; 15 mg/kg/day),45 or atovaquone (750 mg orally twice daily).46
Salvage therapy of PJP with caspofungin has been reported in the non-HIV setting although the role of this agent in the initial treatment of PJP has not been studied and there are case reports of failure of this agent in the HIV setting in people thought to have multiple infective pathologies.47,48 Further data are needed before caspofungin can be recommended.
The most common toxicity of cotrimoxazole is a hypersensitivity reaction. This typically manifests as a maculopapular rash with recrudescence of fever after initial resolution of fever due to PJP. There may be associated haematological and liver function abnormalities. The hypersensitivity reaction may progress to a life-threatening systemic reaction if the drug is not ceased. Secondary PJP prophylaxis with cotrimoxazole following a hypersensitivity reaction may be considered if desensitisation is successful. PJP therapy should be completed and the hypersensitivity reaction fully resolved before cotrimoxazole desensitisation is undertaken.49-51 A rapid oral desensitisation protocol can be found in the most recent version of the Australian Therapeutic Guidelines: Antibiotic.52 If immune reconstitution is unlikely to occur with cART, or is likely to be delayed (e.g. very low nadir CD4 cell count or unlikely adherence to cART), then desensitisation should be undertaken, as PJP prophylaxis will be needed for this period.
Early in the HIV epidemic, patients with PJP had a poor prognosis; with better management of respiratory failure and the introduction of cART, prognosis has improved, with recent data suggesting a 10% mortality rate overall.53 The prognosis of people with severe PJP requiring ventilation has improved, with one study reporting a 47% overall survival rate.54 Factors associated with a poor prognosis include the degree of hypoxaemia, neutrophilia, high numbers of organisms in bronchoalveolar lavage fluid and severe radiological abnormalities. Point mutations in the dihydropteroate synthase gene which confers resistance against sulfa drugs have been suggested to worsen the prognosis.55,56
Prophylaxis against PJP is recommended in patients with a CD4 cell count < 200 cells/μL or CD4 cell proportion < 14% of lymphocytes, or oral candidiasis or unexplained fever of more than 2 weeks duration. The institution of prophylaxis (without cART) reduces the risk of PJP in susceptible populations by nine fold.30 Mutations in dihydrofolate reductase may be associated with failure of prophylaxis.57
The optimal regimen is cotrimoxazole: one double-strength tablet orally once per day, although half a tablet daily is efficacious and may have a lower rate of toxicity. The risk of acquiring PJP while taking cotrimoxazole prophylaxis is extremely low. Cotrimoxazole is also active against toxoplasmosis and some bacterial pathogens. The most common toxicity is a cotrimoxazole hypersensitivity reaction (see above). Alternative regimens include double-strength cotrimoxazole (orally twice daily on 2 or 3 days per week), nebulised pentamidine (300 mg once per month, with salbutamol retreatment to reduce bronchospasm), dapsone (100 mg orally daily) or atovaquone (750 mg orally twice daily) (Table 13).58,59
|Atovaquone||Hypersensitivity Gastrointestinal Biochemical hepatitis|
|Clindamycin||Hypersensitivity Diarrhoea Pseudomembranous colitis Haematological|
|Cotrimoxazole||Hypersensitivity – typically fever and maculopapular rash; dose related; may develop into Stevens-Johnson syndrome Nausea, vomiting Bone marrow toxicity – neutropenia, thrombocytopenia Biochemical hepatitis|
|Dapsone||Hypersensitivity Haemolysis in G6PDH-deficient people|
|Pentamidine||Renal tubule dysfunction – renal impairment, hyperkalaemia Pancreatic toxicity – hypoglycaemia, hyperglycaemia Arrhythmias Hypotension|
G6PDH = glucose 6-phosphate dehydrogenase
Secondary prophylaxis after an episode of PJP is recommended to prevent relapse or recurrence until immune reconstitution has occurred.
Cohort studies have demonstrated the safety of discontinuing both primary and secondary PJP prophylaxis after the CD4 cell count has risen above 200 cells/μL or the proportion of CD4 cells is > 14% of total lymphocytes for longer than 3 months, in the setting of viral suppression with cART.60-66 More recent data suggest that the risk of PJP is as low with even earlier discontinuation of prophylaxis when the CD4 cell count is > 100 cells/μL, in the setting of viral suppression.67-69
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