Fatal acute pancreatitis in a patient with visceral leishmaniasis during miltefosine treatmentK Pandey1, D Singh2, CS Lal3, VNR Das1, P Das2
1 Department of Clinical Medicine, Rajendra Memorial Research Institute of Medical Sciences, Indian Council of Medical Research, Agamkuan, Patna, Bihar, India
2 Department of Molecular Biology, Rajendra Memorial Research Institute of Medical Sciences, Indian Council of Medical Research, Agamkuan, Patna, Bihar, India
3 Department of Clinical Biochemistry, Rajendra Memorial Research Institute of Medical Sciences, Indian Council of Medical Research, Agamkuan, Patna, Bihar, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.123161
Source of Support: None, Conflict of Interest: None
Pancreatitis is a known side effect of the once commonly used drug, sodium stibogluconate, for treatment of visceral leishmaniasis (VL). In India, miltefosine has recently been introduced as the first-line drug. Its side effects include loose motions, vomiting, and teratogenicity. We report here a case of a 41-year-old parasitologically confirmed male case of VL, who developed acute pancreatitis during treatment with miltefosine. On the 13 th day of treatment, he presented with abdominal pain and vomiting. The biochemical, hematological, and radiological features were suggestive of acute pancreatitis. The patient was put on conservative treatment for pancreatitis at the specialized center but succumbed to renal failure and septicaemia.
Keywords: Acute pancreatitis, miltefosine, visceral leishmaniasis
Visceral leishmaniasis (VL) or kala-azar is quite common in the Indian subcontinent, Brazil and Sudan. The prevalence and incidence of the disease are 2.5 million and 0.5 million worldwide, respectively.  About 80% of the cases reported from India are from Bihar state alone.
Pancreatitis has been reported as one of the side effects of sodium stibogluconate (SAG), the medicine which has almost been discarded for VL treatment due to increasing resistance. , In the recent years, miltefosine, the first ever oral drug, has been introduced in VL elimination program in the Indian subcontinent as first-line drug, as it is easy to use as domiciliary treatment. The common side effect of miltefosine is limited to gastrointestinal toxicity like nausea, vomiting, and loose motion. Association of acute pancreatitis with miltefosine has not been reported previously. This case report of acute pancreatitis in miltefosine-treated VL case warrants further study as to whether miltefosine can aggravate the pathology of pancreatitis.
In April 2009, a 41-year-old male consulted the outpatient department of Rajendra Memorial Research Institute of Medical Sciences, Patna, India with a year-long duration of fever that was worse in the last 2 weeks. The patient was a farmer hailing from an endemic area of VL. Besides fever (38°C) on the day of visit, he looked pale and had hepatosplenomegaly (liver 5 cm below right costal and spleen about 8 cm below the left costal margin). His weight was 45 kg and height 165 cm. The hematological examination revealed haemoglobin 7 g/dL, total leukocyte count (TLC) 3000/cubic mm with neutropenia and platelet count of 1,00,000 per cubic mm. The liver and renal function tests were normal. The prothrombin time was within 4 s of control value. The rK39 strip test for leishmaniasis (InBios, International, Seattle, USA) with both serum and blood sample was found positive. After confirmatory diagnosis by demonstration of Leishmania donovani bodies (2 + as per WHO criteria), treatment with miltefosine capsules (50 mg twice daily for 28 days) was started in domiciliary mode with an advice to report every week.
On the 13 th day of treatment, he presented with pale appearance of the body, diffuse abdominal pain (more marked in the epigastrium radiating to the back), and vomiting (3-4 times per day) since last 2 days with slight hematemesis and melaena. The patient had abdominal tenderness, rebound tenderness, rigidity, guarding with absent bowel sounds. Pulse was 120/min, blood pressure (systolic/diastolic) 100/60 mm Hg in the left upper limb in supine posture, liver 4 cm below the right costal margin and spleen about 4 cm below the left costal margin. Considering the clinical features, he was diagnosed clinically as a case of acute pancreatitis concurrent with VL. Consequently, the patient was referred to a higher center for further management.
Blood tests showed TLC 15000 per cubic mm (normal 4-11000 per cubic mm), eosinophils 0%, neutrophils 75%, lymphocytes 25%, basophils 0%, monocyte 0%, hemoglobin 8 g/100 ml (normal 12-14 g/dL), serum lipase 346 U/L (normal 7-58 U/L), serum amylase 780 U/L (normal 70-200 U/L), aspartate transaminase (AST) 250 U/L (normal 5-40 U/L), lactate dehydrogenase (LDH) 350 U/L (normal 105-300 U/L), alanine transaminase (ALT) 200 U/L (normal 7-56 U/L), blood urea nitrogen 100 mg/dL (normal 7-20 mg/dL), serum creatinine 2.5 mg/dL (normal 0.7-1.2 mg/dL), blood sugar (random) 200 mg/dL, and serum calcium 8.2 mg/dL (normal 9-11 mg/dL).
Ultrasonography (USG) of whole abdomen was performed to find out the etiology for diffuse abdominal pain and it revealed features of acute pancreatitis; however, no gallstone was observed. Computerized tomography (CT) scan of abdomen showed features of acute necrotising pancreatitis [Figure 1]. The observed hematemesis and melaena could have been due to decreased platelet count as in VL as well as due to acute pancreatitis. The patient was put on conservative treatment with antibiotics, intravenous (I.V.) fluids, proton pump inhibitors, and I.V. octreotide at the higher specialized center, but he died after 3 days most probably because of renal failure and septicaemia. As per the Naranjo Causality score, the development of acute pancreatitis seems to have probable relationship with miltefosine treatment. The World Health Organization- Uppsala Monitoring Centre (WHO-UMC) causality scale also suggests that the relationship of miltefosine to development of this fatal acute pancreatitis could be probable/likely or possible.
Acute pancreatitis usually occurs in adult males and is associated with gallstones, other biliary diseases, and excess use of alcohol. Viral infection (mumps, coxsackie B, mycoplasma pneumoniae, and campylobacter), hereditary conditions, traumatic injury, pancreatic, or common bile duct surgical procedures and certain medications (especially estrogens, corticosteroids, thiazide diuretics, and azathioprine) are other causative factors for idiopathic pancreatitis. The exact cause of acute pancreatitis may differ from patient to patient; but in general it is not well-understood.  As per the Ranson's criteria, three or more of the following factors predict a severe course of acute pancreatitis: Age >55 years, TLC (white blood cell) >16000/mm 3 , serum glucose >200 mg/dL, serum LDH >350 U/L, AST >250 U/L, serum calcium <8 mg/dL, base deficit >4 meq/L.  The diagnosis is mainly based on the clinical features and raised serum amylase and lipase along with imaging technique like X-ray, USG, and/or CT abdomen. Upper gastrointestinal endoscopy may reveal features of upper gastrointestinal bleed. If there is a gall stone, then endoscopic retrograde cholangiopancreatography is indicated. These days magnetic resonance cholangiopancreatography is another safe investigation but requires trained personnel and is costly.  In the case presented here, acute pancreatitis was diagnosed on the basis of clinical presentation and CT abdomen.
Intravascular volume depletion is the most important complication of acute pancreatitis. There are chances of developing septicemia which need cover of proper antibiotics. Multiorgan failure is an immediate cause of death mainly because of hepatic and renal failure.
The once common previously used drug for VL treatment, SAG had been shown to cause pancreatitis. , But this drug has gone out of use due to increased resistance of more than 50% in some of the endemic areas of Bihar.  Miltefosine is an antineoplastic agent previously used as a topical application for the skin metastasis of breast cancer. Based on high efficacy against L. donovani during in vitro and preclinical animal studies, phase-wise clinical trials of this drug were conducted in VL patients. The final cure rate observed in indoor as well outdoor set up during phase III and IV trial, respectively was about 94%. Presently, miltefosine has been launched as the first-line oral drug under VL elimination program in the Indian subcontinent. The standard dose of miltefosine is 2.5 mg/kg body weight in patients <12 years. For patients >12 years and <25 kg, the dose is 50 mg once daily and for the patients ≥25 kg the recommended dose is 50 mg twice daily for 28 days. Half-life of this drug is about 7 days. Being an oral drug, it has various advantages, as it can be easily administered as domiciliary treatment and does not require cold chain for storage. Some of its adverse effects include gastrointestinal toxicity like diarrhea and vomiting, raised ALT/AST, renal toxicity, and possible teratogenicity in pregnant females.  It is not to be given in children <2 years, lactating mothers, and women of child-bearing age not willing for contraception.
VL and acute pancreatitis have already been reported in VL-human immunodeficiency virus coinfected patients treated with SAG.  However, this case report is one in which pancreatitis developed in an immunocompetent VL patient during treatment with miltefosine. Acute renal failure and multiorgan failure in acute pancreatitis indicate a bad prognosis with a very high mortality. Diabetes mellitus and exocrine pancreatic insufficiency can occur in patients who survive after the acute episode. This patient died because of renal failure which occurred as a complication of acute necrotizing pancreatitis.
This study points to further explore pancreatitis as one of the possible adverse drug reaction of miltefosine. Second, whether the drug miltefosine can aggravate the already existing pathology may be a matter of speculation, as this has not been studied extensively and needs further evaluation. It would be better if hematological and biochemical markers for pancreatitis are considered as safety evaluation of miltefosine treatment.
The authors wish to acknowledge efforts of Mr. Naresh Kumar Sinha, Technical Assistant, RMRIMS, Patna for his help in compiling the patient's information and Mr. Rakesh Bihari Verma, Technical officer, RMRIMS, Patna for manuscript preparation. (This report will be submitted to the National Pharmacovigilance program of India).