Infection caused by Leishmania species has been increasingly reported in solid-organ transplant recipients since the first case report in 1979. Visceral leishmaniasis is endemic in central and eastern regions of India. Clinical features may simulate a variety of other infections, and a high index of suspicion is required for the diagnosis. Early diagnosis of this endemic infection is likely to result in improved outcome. We describe an unusual presentation of leishmaniasis in a kidney allograft recipient with organomegaly and pancytopenia sans fever detected by isolation of amastigotes in duodenal biopsy. To the best of our knowledge, this is the first case report of this kind in a kidney transplant recipient.
Key words : Duodenal biopsy, Hepatosplenomegaly, Pancytopenia, Protozoal infections
Infections remain the second most common cause of death and the most common cause of hospitalization in solid-organ transplant recipients.1 The incidence and fatality of infectious diseases after kidney transplant are affected by the potent immunosup-pression drugs given to these patients.2 Visceral leishmaniasis (VL), also known as kala-azar, is endemic in many countries, including several parts of eastern India.3 Clinical features of VL may simulate a variety of other infections, and a high index of suspicion is required for the diagnosis; on the other hand, it can be potentially fatal if unrecognized and untreated. We report a case of VL in a renal allograft recipient with an unusual presentation and very unlikely mode of diagnosis from an endemic area in India. To the best of our knowledge, this is the first case report of this kind in a renal transplant recipient.
A 40-year-old hypertensive man from Varanasi, Uttar Pradesh, India, was diagnosed with chronic kidney disease (CKD) in September 2015. He underwent living donor kidney transplant in November 2015 with his 62-year-old mother as donor. He received antithymocyte globulin (thymoglobulin; dose of 3 mg/kg) as induction immunosuppression and continued treatment with a maintenance regimen comprising tacrolimus, mycophenolate mofetil (MMF), and steroids. His baseline serum creatinine level was 1.8 mg/dL posttransplant, and it remained the same for the next 4 years with no intervening episode of rejection or major infection. He presented 4 years posttransplant with complaints of left-sided abdominal pain (dragging sensation) and weight loss of 7 kg in the preceding 4 months. He denied history of fever, night sweats, dyspnea, or diarrhea. Evaluation in the outpatient department revealed pancytopenia and graft dysfunction, and he was admitted for further evaluation and management.
Physical examination revealed a pale, anicteric, afebrile patient with no significant lymphadenopathy. Systemic examination revealed hepatosplenomegaly (liver palpable 1 cm below the right costal margin and spleen palpable 6 cm below the left costal margin), and laboratory evaluation showed pancytopenia (hemoglobin level of 6.2 g/dL, total leucocyte count [TLC] of 3.3 × 109/L, and platelet count of 90 000/μL) and a raised serum creatinine level (2.7 mg/dL). He had hypergammaglobulinemia (gamma-globulin level of 5.8 g/dL) with normal bilirubin and transaminase levels (aspartate aminotransferase, 36 U/L; alanine aminotransferase, 24 U/L) (Table 1). A peripheral smear revealed predominantly normocytic, normochromic blood cells, leukopenia with an absolute neutrophil count (ANC) of 1310/μL, reduced platelets, and no schistocytes or hemoparasites. Serology results for hepatitis B virus, hepatitis C virus, human immunodeficiency virus (HIV), cytomegalovirus, parvovirus B19, and BK virus were all negative. A chest radiography showed no abnormalities, and ultrasonography of the abdomen revealed massive hepatosplenomegaly (liver, 14.5 cm; spleen, 17 cm) with unremarkable transplanted kidney. Treatment with MMF was stopped because of the pancytopenia.
A differential diagnosis of chronic malaria, chronic liver disease, tuberculosis, and VL was generated given the patient was from an endemic region. His malaria antigen test was found to be negative; meanwhile, his pancytopenia worsened, and his hemoglobin level decreased to 5.4g/L with a TLC of 1300/μL (ANC 650/μL) and a platelet count of 61 000/μL. He was transfused 2 units of packed red blood cells and received a single dose of granulocyte colony-stimulating factor. He then underwent bone marrow aspiration and biopsy, which revealed mildly increased cellularity with normal marrow elements and no evidence of granuloma, infiltration, parasitic or viral infection, or dyspoiesis. He remained afebrile, and his pancytopenia improved mildly (hemoglobin level of 8.4 g/dL, TLC of 2.06 × 109/L, platelet count of 100 000/μL). He took discharge against medical advice on the fifth day of admission at a serum creatinine level of 2.1 mg/dL.
He presented 2 weeks later with severe fatigue and lassitude. Laboratory evaluation revealed worsening pancytopenia (hemoglobin level of 6.1 g/dL, TLC of 1590/μL, ANC of 470/μL, platelet count of 120 000/μL) and a serum creatinine level of 2.5 mg/dL. He underwent renal biopsy after receiving 1 unit of packed red blood cells, which showed changes of diffuse acute tubular injury but no indication of tacrolimus toxicity; staining tests for BK virus and cytomegalovirus were negative. This time, an enzyme-linked immunosorbent assay for anti-recombinant K39 antigen antibody was performed, which was found to be positive. Splenic aspiration was planned to confirm the diagnosis; however, before that was scheduled, he underwent gastroduodenoscopy to rule out chronic liver disease (hypersplenism) as a differential for splenomegaly, since he did not have any fever.
Gastroduodenoscopy revealed no gross abnor-malities. Random duodenal biopsies were taken, which to our surprise showed sheets of macrophages loaded with amastigote forms of organisms resembling Leishmania donovani (LD) bodies that were Giemsa stain positive, along with a few trophozoites of Giardia (Figure 1). Grocott methenamine silver and periodic acid-Schiff stains for fungus (Histoplasma and Cryptococcus) were negative. The patient received 7 doses (3 mg/kg) of liposomal amphotericin B on alternate days (cumulative dose of 21 mg/kg). Subsequently, all his parameters improved, including the pancytopenia, and treatment with MMF was reintroduced after 4 weeks. He had regression of spleen size from 17 cm to 13 cm on ultrasonographic scan. Currently, he is doing well on triple immuno-suppression therapy, with a serum creatinine level of 2.1 mg/dL on last follow-up.
Despite the high prevalence of parasitic diseases worldwide, parasitic infections remain the most understudied of all infections related to organ transplantation. Growing mobility with migration and travel to and from areas endemic to such infections are bringing new challenges to the management of transplant infections, such as leishmaniasis, which were previously less commonly seen. Visceral leishmaniasis on the Indian subcontinent is a disease caused by the parasite L. donovani and transmitted to humans by female Phlebotomus argentipes sand flies. The symptomatic form of the disease is also known as kala-azar.3
The clinical signs and symptoms are not pathognomonic of VL and may be confused with other similar conditions. The main clinical manifestation are fever (94%), enlargement of spleen (75%), and pancytopenia (85%).4 The untreated disease has a case fatality rate of over 95%; however, more effective treatments have reduced the case fatality rate to 10% in recent reports.5 Derangement of cellular immune mechanisms, such as those seen with corticosteroid use, is a risk factor for occurrence of symptomatic and severe infections with increased mortality.6 Among organ transplant recipients, renal transplant patients are more commonly affected than others.7
Most reports of VL in renal transplant have included fever as a common presenting complaint.8-10 Presentation of VL without fever is very unusual. We found reports in 1 renal transplant recipient11 and 1 pediatric non-solid-organ transplant recipient with such atypical presentation.12 Our patient had no fever, albeit presenting with hepatosplenomegaly and pancytopenia, and hence leishmaniasis was kept a lower probability in the differential diagnosis in our workup.
The test utilizing recombinant K39 antigen to detect antibodies is reported to be 100% sensitive and 100% specific in the diagnosis of VL and post-kala-azar dermal leishmaniasis by enzyme-linked immunosorbent assay.13 This test was positive in our patient. In regions where VL is endemic, positive antibody tests may be observed in individuals with subclinical infections or in those recovering from past infections; hence, it should be interpretated with caution.
Definitive diagnosis of VL requires demonstration of the parasite. Histopathological diagnosis rests on visualization of amastigotes, which are spherical, or ovoid bodies measuring 1 to 5 μm. Spleen aspirate is more sensitive (96%) than bone marrow (70%) or lymph node (58%) aspirates for showing LD bodies. The high sensitivity for Leishmania yield in splenic aspirate comes with its share of risk of bleeding and other complications; hence; it is usually not done at first. In our case, bone marrow aspirate and biopsy failed to show LD bodies.
Gastrointestinal involvement in leishmaniasis is not uncommon and is mostly reported in immuno-compromised HIV hosts.14 Common presentations of such patients include odynophagia, diarrhea, epigastric pain, or features of malabsorption. Our patient did not have any gastrointestinal complaints, and gastroduodenoscopy incidentally picked up LD bodies on random biopsies. There was no gross mucosal abnormality. We did an extensive literature research on PubMed and found no reported case of leishmaniasis involving the gastrointestinal tract or use of duodenal biopsy to diagnose leishmaniasis in a renal transplant recipient. This puts emphasis on aspects peculiar to immunocompromised renal transplant recipients (ie, atypical presentation of infections and the need for tissue diagnosis in these cases).
Agents used for treatment of VL include amphotericin B, pentavalent antimonial drugs, paromomycin, and miltefosine. There is a widespread resistance to antimonial drugs in India. Liposomal amphotericin B has the highest therapeutic efficacy with the least adverse effects.15 The recommended cumulative dose of liposomal amphotericin B ranges from 10 to 20 mg/kg/day given over the course of 7 to 10 days. Our patient received 3 mg/kg on alternate days and a total cumulative dose of 21 mg/kg liposomal amphotericin B with improvement in pancytopenia and regression of splenomegaly (Table 1). Spleen size is a sensitive marker for predicting response to treatment as well as for relapses.4
Immunosuppression was temporarily reduced in our patient; on improvement of pancytopenia, treatment with MMF was restarted with considerable improvement in graft function over the course of time. Data on secondary prophylaxis to avoid recurrence of disease are inconclusive. No specific study on prevention strategy in transplant candidates with a history of exposure or leishmaniasis has been conducted. Absence of fever on presentation, bone marrow aspirate negative for LD bodies, and finding the amastigote form of Leishmania on random duodenal biopsy make this case unique and highlight the need for broad differentials and the need for tissue diagnosis in posttransplant infections.
Visceral leishmaniasis should be kept as a differential diagnosis in all renal transplant recipients from endemic areas presenting with hepatosplenomegaly and hematological abnormalities, even if they are afebrile. Patients with infections in the posttransplant period may not present with classical features. Tissue diagnosis is needed for all suspected infections after renal transplant. A high index of suspicion is required for diagnosing and treating endemic infections early to reduce mortality and morbidity.
Volume : 20
Issue : 3
Pages : 311 - 315
DOI : 10.6002/ect.2021.0160
From the 1Department of Nephrology and Renal Transplant Medicine and the 2Department of Pathology and Laboratory Medicine, Medanta, The Medicity, Gurugram, India
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Shyam B. Bansal, Department of Nephrology and Renal Transplant Medicine, Medanta, The Medicity, Sector 38, Gurguram, Haryana 122001, India
Table 1. Summary of Laboratory Analysis
Figure 1. Duodenal Villi With Lamina Propria Showing Sheets of Macrophages Loaded With Amastigote Forms of Leishmania Donovani