Visceral leishmaniasis in a type 1 diabetic patient with isolated pancreas transplant

Isolated pancreas transplant (IPT) is a treatment allowing for long-term normalization of carbohydrate metabolism in patients with type 1 diabetes mellitus (T1DM). It is currently indicted for patients with labile T1DM with frequent and severe acute metabolic complications and preserved kidney function.^1,2

We report below the case of a 31-year-old male patient with T1DM starting 16 years before who showed poor metabolic control, highly variable blood glucose levels, acute diabetic complications (repeated severe undetected hypoglycemic episodes and frequent episodes of ketosis and ketoacidosis), and chronic complications (proliferative retinopathy, established nephropathy with preserved glomerular filtration rate, peripheral and autonomic sensorimotor neuropathy: gastroparesis requiring jejunostomy for feeding and neurogenic bladder with daily self-catheterization and recurrent urinary tract infection). Patient attended the endocrinology department of another hospital and was referred to our center to be assessed for IPT. He was treated with rapid-acting insulin analogues and insulin glargine using a basal-bolus regimen, and had glycosylated hemoglobin (HbA_1c) levels ranging from 10% to 12%. Despite treatment optimization with an integrated system of continuous glucose monitoring and continuous subcutaneous insulin infusion, recurrent undetected hypoglycemia persisted, and IPT was therefore performed on November 2008. Patient had an uneventful postoperative course, and although insulin therapy could not be discontinued (insulin detemir at approximately 30 IU/day continued to be given), controls showed stable blood glucose levels, hypoglycemia did not recur, and tests showed HbA_1c values around 5.5% and C peptide levels of 1.5 ng/mL.

Four months after transplant, patient reported malaise, fever up to 40 °C with chills, irritative cough, watery diarrhea, and weight loss for the past 20 days. He was taking immunosuppressants (prednisone, mycophenolate mofetil, and tacrolimus), trimethoprim–sulfamethoxazole at prophylactic doses, insulin detemir, and antihypertensives (losartan, atenolol, manidipine, furosemide, and doxazosin). On admission, patient was conscious and oriented, with a moderately impaired general condition, tachycardia, fever, and mild skin and mucosal pallor. Small pustular lesions were seen in right nostril mucosa. Cardiorespiratory auscultation was normal. No changes were found in abdomen and limbs. Supplemental tests on admission showed the following results: hemoglobin 8.5 g/dL, hematocrit 27%, platelet count 62,000/L, WBC count 1800/L (absolute neutrophils 1300/L, absolute lymphocytes 290/L), and creatinine 2.9 mg/dL; results of all other biochemical tests, including liver profile, were normal.

Blood, urine, sputum, nasal exudate, and catheter tip cultures were all negative. Cytomegalovirus, Epstein–Barr virus, parvovirus B19, and herpesvirus 6 viral loads were all negative. An echocardiogram and a Doppler abdominal ultrasound of the graft were normal, and computed tomography (CT) of the chest only showed a mild pericardiac effusion. An abdominal CT revealed an enlarged spleen with infarction of 50% of its volume, no pancreatic graft changes, and no abdominal collections. Patient was initially treated with broad spectrum antibiotic therapy, with no response of fever. Bone marrow aspiration was performed because of the presence of pancytopenia and splenomegaly, showing amastigotes in monocytes consistent with visceral leishmaniasis.

Treatment was started with intravenous liposomal amphotericin B at 5 mg/kg for one week, followed by weekly booster doses of 3 mg/kg for one month in an outpatient setting. Gradual improvement occurred after the first week of treatment, with disappearance of fever and symptoms. A serologic test for Leishmania performed on a pre-transplant blood sample was negative. While serology of Leishmania in the donor is unknown, transmission of infection through the pancreas appears unlikely, because this organ has no phagocytic mononuclear system. Infection was probably acquired after transplant, because the patient leaves in an area where leishmaniasis is endemic (Murcia) and has a dog (which is a common host of the parasite).

Recurrence of leishmaniasis was not found during follow-up. Once leishmaniasis was cured, insulin was discontinued and patient remained stable for approximately two months. He subsequently experienced viral meningitis which required hospital admission and was probably associated to reduction of immunosuppression during the intercurrent infections, and finally experienced graft rejection which required graft removal eight months after transplant.

The term leishmaniasis encompasses several clinical syndrome caused by strict intracellular protozoa of the Leishmania genus. Leishmaniasis is endemic to Central and South America, the Mediterranean basin, Africa, India, and China.³ Its overall prevalence is estimated at some 12 million cases worldwide, with an incidence of two millions cases annually.⁴ Incidence is increasing mainly in South European countries due to immunosuppression associated with infection by the human immunodeficiency virus and to other situations such as immunosuppressive treatment in cancer and transplant patients.⁵

Visceral leishmaniasis is usually caused by microorganisms of the Leishmania donovani complex,³ which are transmitted by the bite of the sandfly (Phlebotomus or Lutzomyia genus), although transmission through blood transfusions, infection of a transplanted organ, or needles shared by intravenous drug users has also been reported.^6,7 In mammalian hosts, Leishmania spp. organisms are strict intracellular pathogens which infect hematopoietic cells of the monocyte/macrophage line.

Leishmaniasis is an uncommon disease in transplant patients and may occur in three ways: patient develops de novo infection after transplant, latent infection is reactivated in a patient infected before transplant, or patient becomes infected through the transplanted organ or blood transfusions.^6,8 In a literature review, in 2008 Antinori et al.⁶ found 81 cases of visceral leishmaniasis reported in transplant patients. Most of them had occurred in endemic areas with a high number of transplant patients (Spain, France, and Italy). A majority of cases were associated with kidney transplant (77%), and less commonly to liver transplant (9%), heart transplant (8%), lung transplant (8%), combined pancreas–kidney transplant (one patient), hematopoietic stem cell transplant (one patient), and bone marrow transplant (one patient). Torregrosa et al.⁹ reported visceral leishmaniasis in a patient undergoing kidney–pancreas transplant in Spain one year after surgery, and Aardema et al.¹⁰ reported in The Netherlands another case of visceral leishmaniasis in a patient undergoing kidney–pancreas transplant who had travelled to Greece 17 months before the condition occurred.

Clinical signs of visceral leishmaniasis in transplant patients are similar to those seen in immunocompetent subjects, and fever is the most common symptom. Diagnosis may be delayed for months because of the low suspicion index. Microscopic analysis of a bone marrow aspirate is considered to be the procedure of choice for documenting the disease. Leishmaniasis is fatal if left untreated, and its course depends on when diagnosis is made and treatment is started. Cure rates of 84% have been reported in transplant patients with visceral leishmaniasis. These rates are similar to those found in immunocompetent subjects. Liposomal amphotericin B is considered as the first-line drug to treat leishmaniasis.⁶

Visceral leishmaniasis should therefore be included in the differential diagnosis of transplant patients with fever and pancytopenia. This is the first case of visceral leishmaniasis reported in a patient with an isolated pancreas transplant in our environment.