Department of Medicine, Divisions of 1 Nephrology and 2 Infectious Diseases, Vanderbilt Transplant Center, Vanderbilt University, Medical Center, Nashville, TN, USA
Sir,
In the modern era of solid organ transplantation, vigorous efforts are aimed at reducing acute rejection rates with ever more potent immunosuppressive drugs. As a consequence, the physician often must deal with the adverse effects of excessive immunosuppression including opportunistic infections. Infections in the peri-engraftment period are commonly bacterial in origin, while, a few months later, the incidence of opportunistic fungal infections increases due to the defects in cell-mediated immunity [1]. We present a case of a kidneypancreas transplant recipient with an asymptomatic pleural effusion, which was caused by Cryptococcus neoformans. Isolated pleural involvement with Cryptococcus has not been reported previously in kidneypancreas or kidney transplant recipients.
Case.
A 49-year-old AfricanAmerican man was admitted to the hospital, for a massive pleural effusion incidentally diagnosed on routine chest X-ray. Twenty-one months prior to admission, he had received a simultaneous cadaveric kidneypancreas transplant for end-stage renal disease (ESRD) due to type 1 diabetes mellitus. He did not receive any anti-lymphocyte preparations. Maintenance immunosuppression included tacrolimus, mycophenolate mofetil and prednisone.
The patient described mild shortness of breath on exertion for 2 weeks prior to admission. He denied pleuritic chest pain, productive cough, fever, night sweats, weight loss, loss of appetite or orthopnea. There was no history of contact with tuberculosis. The patient was a heavy smoker with a 60-pack-years history. On physical examination, he was comfortable and afebrile. Pulmonary examination revealed dullness on percussion and diminished breath sounds at the left base. There was a tracheal shift to the right and a pleural rub was heard. No lymphadenopathy was noted. A chest X-ray showed a left-sided pleural effusion with mediastinal shift and a calcified hilar lymph node. Admission blood work revealed a white blood cell count of 9700/µl, haematocrit of 44% and serum creatinine of 2.4 mg/dl. Computed tomography (CT) scan of the chest showed a left-sided pleural effusion with compressive atelectasis of the left lower lobe, numerous tiny superior mediastinal lymph nodes and a large calcified right hilar lymph node.
Pleural fluid obtained by thoracentesis was an exudate. A Gram's stain, a stain for acid fast bacilli (AFB), a potassium hydroxide preparation for fungus and culture of the fluid were negative. Cell block preparation demonstrated benign mesothelial cells intermixed with lymphocytes and inflammatory cells, and was negative for malignancy. Bronchoscopy showed abnormal left lower lobe airways due to the extrinsic compression from pleural effusion. No endobronchial lesions were noted. A bronchial wash showed reactive squamous cells, bronchial cells, macrophages and fibrinous material. Gomori's methenamine silver (GMS) stain for fungus and pneumocystis carinii, and AFB stain were negative.
The patient underwent thoracoscopic visualization and biopsy of pleura. Multiple plaques and nodules were noted on the pleural surface. An aorto-pulmonary window lymph node biopsy showed sinus histiocytosis with anthracosis, but did not reveal tumour or granuloma. Necrotizing granulomatous inflammation with caseation was noted on biopsy of the pleural plaque. GMS and periodic acid schiff (PAS) stains showed numerous yeast forms, compatible with cryptococcal species. A culture of this tissue specimen grew C. neoformans. Serum cryptococcal antigen was positive at 1:32 dilution.
Except for mild elevation of cerebrospinal fluid (CSF) protein, lumbar puncture was unremarkable. He was started on fluconazole (400 mg/day for 1 month, then 200 mg/day for 5 months) and 5-flucytosine (5-FC) (1000 mg bid for 3 months). A chest X-ray obtained after the completion of therapy revealed no reaccumulation of the pleural fluid. The serum cryptococcal antigen decreased to <1:10 dilution, confirming an excellent response to the therapy.
Comment.
Isolated pleural involvement with Cryptococcus is rare in immunocompromised hosts, and to our knowledge has not been reported previously in a kidney or kidneypancreas transplant patient. A pleural effusion caused by Cryptococcus that preceded cryptococcal meningitis has been described previously in a patient with AIDS [2].
Cryptococcus neoformans is a yeast that has a large polysaccharide capsule seen in India ink preparations. These fungi are saphrophytes in nature and usually cause infection by inhalation into the lungs. From the initial focus in lungs, there may be haematogenous spread to distant sites. Patients with impaired cell-mediated immunity, such as those with AIDS, rheumatological conditions requiring chronic steroid therapy, organ transplantation and haematological malignancies, are more prone to disseminated crpytococcosis [3].
Patients usually present with fever, productive cough, dyspnoea, chest pain and haemoptysis. Interestingly, despite a large pleural effusion, our patient had only mild dyspnoea. Radiographic manifestations include poorly marginated masses, lobar or segmental parenchymal opacities, a diffuse scattered nodular or reticulonodular pattern, pleural effusions, cavitation and associated adenopathy [4]. In a transplant recipient, differential diagnosis of pleural effusion includes tuberculosis, malignancy, nocardiosis and other fungal infections.
Considering the associated mortality, early diagnosis and treatment is paramount. The cryptococcal antigen test is a specific and relatively sensitive indicator of cryptococcal infection. Serial determinations may be useful in assessing the response to treatment. Cryptococcus can be detected in cultures of CSF, bronchoalveolar lavage and pleural fluid. If cultures are negative, diagnosis can be confirmed by open biopsy, as illustrated in our patient.
Isolated pulmonary involvement carries a better prognosis than disseminated cryptococcosis. It has been reported previously that patients with AIDS who had localized pulmonary involvement had higher CD4+ lymphocyte counts, lower serum cryptococcal antigen titres and an overall better prognosis than patients with disseminated disease [5]. We think that since our patient had localized infection with a strong granulomatous response, this portends a good prognosis.
The immune status of the host and the anatomic sites of involvement determine the choice of antifungal therapy [6]. For immunocompetent hosts with isolated lung disease, careful observation may be all that is necessary. In the case of symptomatic pulmonary infection, the indicated treatment is fluconazole for 36 months. In each case, careful assessment of the CNS is required to rule out occult meningitis. The standard therapy for cryptococcal meningitis is amphotericin B in combination with 5-FC. Patients with AIDS generally require life-long maintenance therapy with fluconazole, but this may not be necessary in solid organ transplant recipients. The combination of fluconazole with 5-FC, as administered in our patient, has been used less often, but studies in animals and man suggest that it may be synergistic. Whenever azole antifungals and calcineurin inhibitors are used together, the levels of calcineurin inhibitors should be monitored carefully.
Our case illustrates the importance of having a high index of suspicion and employing a tissue diagnosis in an immunocompromised patient with an unusual illness that is difficult to diagnose. In the future, the development of more selective immunosuppression, and eventually the induction of tolerance, may free transplant recipients from the risk of opportunistic infections.
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