Pneumocystis carinii pneumonia in a patient on etanercept for psoriatic arthritis
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- Lahiff, C., Khiaron, O.B., Nolan, N. et al. Ir J Med Sci (2007) 176: 309. doi:10.1007/s11845-007-0087-x
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Pneumocystis carinii pneumonia (PCP) is a rare form of pneumonia associated with immune-suppression. It is common in patients with AIDS and with a CD4 count of less than 200 cells/mm3. We report a case of PCP secondary to immune-suppression in a 41-year-old man with psoriatic arthritis being treated with the immune-modulatory agent etanercept.
Diagnosis of PCP was made histologically using tissue obtained via transbronchial biopsy.
There was a good response to standard treatment with high-dose co-trimoxazole.
This report highlights a recognised but previously unreported complication of etanercept.
KeywordsPneumocystis cariniiEtanerceptPsoriatic arthritisGrocott’s silver stainCo-trimoxazole
A 41-year-old male presented with a 2-day history of dyspnoea on exertion, fatigue and low-grade pyrexia. He had returned from a business trip to the United States 10 days previously and described a recent history of frequent long-haul flights related to his work as a computer programmer.
There was a 20-year history of psoriatic arthritis, currently treated with a combination of methotrexate (10 mg once weekly) and the immune-modulatory drug etanercept (25 mg twice weekly). The etanercept had been commenced 3 years previously and he had been on methotrexate for 10 years. He had not received a course of steroids since commencing etanercept and had achieved excellent control of his arthritis during this period. Both etanercept and methotrexate were stopped by his GP before referring on. He was a non-smoker and his medical history was otherwise unremarkable.
On examination temperature was 37.4°C, pulse 100 regular, respiratory rate 21 and oxygen saturation by transcutaneous oximetry 96%, falling to 88% on minimal exertion. Examination of the chest revealed reduced breath sounds and fine inspiratory crepitations in the right mid zone.
Full blood count on admission was as follows: Hb 15.9 × 109/l, WBC total 4.6 × 109/l (neutrophils 3.1, lymphocytes 0.8, monocytes 0.3).
The differential diagnosis included pulmonary embolus and pneumonia. In light of the patient’s drug history tuberculosis had to be ruled out.
Treatment was with high-dose intravenous co-trimoxazole with good response and the patient was discharged on oral therapy 10 days after admission and on review 14 days after initiation of treatment the chest radiograph and oxygen saturation were normal.
Corticosteroids have been shown improve outcome especially in patients with HIV  and where there is severe hypoxia . Our patient was not severely hypoxic and did not require steroids. He denied any high-risk behaviour with regard to HIV and was unwilling to undergo an HIV test.
Etanercept is a recombinant DNA-derived fusion protein which binds to soluble TNFα and prevents its interaction with cell surface receptors . It has been shown to improve symptoms in patients with inflammatory arthritis where they have not responded to methotrexate  and can be given with or without methotrexate as an adjunct. A wide range of infectious side effects has been reported in association with anti-TNF therapy  including PCP and miliary TB. Patients are routinely screened for latent TB before commencing anti-TNF therapy. Our patient underwent a Mantoux and chest X-ray before starting etanercept. He did not receive isoniazid prophylaxis.
Pneumocystis carinii pneumonia (PCP) is encountered with various immunosuppressant diseases and therapies. It is one of the commonest AIDS-defining illnesses and HIV positive patients with a CD4 count of <200 cells/mm3 are usually started on prophylaxis. PCP is also seen in other forms of immune-suppression including post-transplant and malignant disease. It has been reported in rheumatoid arthritis in the absence of immunosuppressive therapy and without HIV infection .
Pneumocystis carinii pneumonia has been shown to be present in up to 85% of asymptomatic children. It becomes reactivated when patients are immune-suppressed with a low CD4+ve T-cell count (such as in AIDS patients). The mode of transmission in non-AIDS PCP is postulated to be different. It can occur with a normal lymphocyte count. The normal immune response to PCP infection involves macrophage elucidation of TNFα and it is thought that the inhibition of this by drugs such as etanercept leaves patients susceptible to infection with the fungus .
Clinically, patients present with progressive dyspnoea (exacerbated by mild exertion), a low-grade fever and a non-productive cough. Chest examination is frequently normal and mild tachypnoea/tachycardia is often seen. Desaturation on exertion is a common feature.
Diagnosis is suspected where appropriate clinical features are present and high-resolution CT typically shows ground glass opacification starting centrally with areas of normal lung parenchyma and sparing of the peripheral tissue . As the infection progresses involvement of increasing amounts of tissue is seen with subsequent clinical deterioration.
Diagnosis may be confirmed on microscopy and culture of sputum and bronchial washings but this has low sensitivity in non-AIDS PCP where the pathogenic load is significantly less than in patients with AIDS . Transbronchial lung biopsy allows histological diagnosis (as in this case). Grocott’s silver stain is used to identify the organism. PCR analysis of both induced sputum and bronchial washings, targeting the mitochondrial rRNA of the pneumocystis organism, has been shown to be more sensitive for detection of PCP than cytology  but unfortunately was not available in this case.
Treatment is with high-dose co-trimoxazole (sulfamethoxazole and trimethoprim). Second line treatments include dapsone and aerosolised pentamidine. Steroids are indicated where there is severe hypoxia, as discussed above.
Resistance is an emerging problem, particularly in the third world where high rates of PCP infection lead to widespread use of co-trimoxazole. Several mutations in the DHRS gene of the pneumocystis organism have been identified but their significance is not clear . PCP was seen frequently in AIDS patients in first world countries before the widespread availability of anti-retroviral drugs.
Our patient was on both methotrexate and etanercept at the time of initial presentation. It is possible that the development of PCP was due to immune-suppression as a result of methotrexate therapy and not attributable to etanercept. However PCP in patients on methotrexate, where reported, has been associated with lymphopaenia/neutropaenia and concurrent corticosteroid treatment with or without renal impairment . Our patient was not on steroids, he had a normal neutrophil count at presentation and was only mildly lymphopaenic with normal renal function. It is therefore likely that etanercept contributed, at least in part, to the development of PCP in this patient.