Stavudine induced acute necrotizing pancreatitis with tetany in a pediatric patient.

A nine year old female patient presented with complaints of severe colicky abdominal pain, vomiting, and tingling with numbness for 3 days. Acute necrotizing pancreatitis associated with tetany due to anti-retroviral therapy was diagnosed. Stavudine was the probable causal agent. Unfortunately, the patient died due to severity of the reaction. High index of suspicion and early withdrawal of the offending drug may prevent further harm in such cases.

Introduction

Drug-induced acute pancreatitis is a rare condition with an incidence that varies from 0.1 to 2.0%. Many frequently prescribed drugs are found to be associated with acute pancreatitis (AP). Among them, antiretroviral therapy (ART) is rarely associated with this complication with stavudine, didanosine and lamivudine being the most common causative agents.[12] Incidence of developing AP is higher in human immunodeficiency virus (HIV) patients than the general population.[3] Necrotizing pancreatitis (NP) is a severe form of acute pancreatitis which has a higher incidence of multi-organ failure. Initially, the necrotic tissue is sterile; however, it gets infected in 40-70% cases of NP with the natural course of the disease. Infected NP is the most important risk factor for the cause of death.[4] Few cases of stavudine induced pancreatitis have been reported from India.[12] Here, we report a rare case of acute necrotizing pancreatitis associated with tetany, which was probably due to stavudine.

Case Report

A nine year old female patient weighing 19 kg was admitted to the pediatric ward of our hospital, with complaints of severe colicky abdominal pain, vomiting, throat pain and tingling with numbness over both upper and lower limbs since 3 days. The patient had complained of weakness since last 1 month. Patient was conscious at the time of admission with normal pulse and respiratory rate. Blood pressure was 98/70 mmHg. On admission, there was the tonic posture of both the upper limbs. Extremities were cold. Patient was on antiretroviral therapy (ART) since 3 years and 8 months. She was taking zidovudine + lamovudine + nevirapine (ZLN) combination for the initial 3 years. Due to the development of anemia, zidovudine was replaced with stavudine 8 months prior and stavudine + lamovudine + nevirapine (SLN) regimen was started. Cluster of differentiation 4 (CD4) cells count was 247/7.5% (World Health Organization - WHO clinical stage 2) before 8 months. Patient was taking cotrimoxazole since last 8 months. A few days before the admission, patient's CD4 count was 179/10% (WHO clinical stage 3). There was no past history of similar complaints and no history of trauma, viral infections (mumps, viral hepatitis), ascariasis, choledochal cysts, hyperlipidaemia and hereditary pancreatitis. Provisional diagnosis of AP associated with tetany was suspected due to ART, and ART was discontinued.

Laboratory parameters like hemoglobin, differential leukocyte count, peripheral smear examination, platelet count, erythrocyte sedimentation rate (ESR), red blood cells (RBC) indices, Random blood sugar (RBS), serum billirubin, blood urea, serum potassium, serum protein, serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT) and serum widal were normal except high total white blood cells (WBC) count (19000/cumm: reference value: 4400 to 11000/cumm). The other tests conducted and their values were as follows: Serum amylase (1186 U/L; reference value: 28 to 100 U/L), serum lipase (5410 U/L; reference value: 25 to 160 U/L), serum ionized calcium (0.56 mmol/L; reference value: 1.16 to 1.32 mmol/L), serum sodium (129 mEq/L; reference value: 135 to 145 mEq/L) and serum alkaline phosphotase (378 IU/L; reference value: 98 to 279 IU/L). Ultrasound (USG) of abdomen showed moderate amount of free fluid in the peritoneal cavity. Diagnosis was confirmed with computed tomography (CT) scan abdomen showing signs of acute necrotizing pancreatitis with peripancreatic inflammatory changes.

The patient was treated with calcium gluconate (2 ml/kg, iv, 6 hourly for 8 days), Isolyte-P (340 ml iv, 6 hourly for 5 days), cefotaxime (50 mg/kg, iv, 12 hourly for 5 days), gentamycin (4 mg/kg, iv, 24 hourly for 2 days), and dopamine (5 mcg/kg/ min, iv, 24 hourly for 9 days; infusion rate adjusted according to blood pressure). Ciprofloxacin (10 mg/kg, iv, 12 hourly for 3 days) was started on the 3rd day. Amikacin (7.5 mg/kg, iv, 12 hourly for 6 days) and metronidazole (5 mg/kg, iv, 12 hourly for 6 days) were started on the 4th day. Levofloxacin (10 mg/kg, iv, 24 hourly for 4 days) and ceftriaxone (50 mg/kg, iv, 12 hourly for 4 days) were started on the 6th day.

After dechallenge and treatment, serum amylase (186 U/L) and serum ionized calcium (1.18 mmol/L) were normal; however, the total WBC count remained to be high (20200/cumm). Symptoms of tetany disappeared on the 3rd day of admission; however, the patient's general condition was not improving. Patient was intubated due to respiratory distress, and she died on the 9th day of admission. Causality assessment with Naranjo's scale and WHO-UMC scale showed that the relationship between stavudine and acute necrotizing pancreatitis was probable. According to Modified Schumock and Thornton's criteria, this reaction was not preventable, and the Modified Hartwig and Siegel's scale showed that the reaction was severe (level 7).

Discussion

AP is one of the rare and life threatening complications of the ART (4% – 22%). The risk of AP in HIV-infected populations is 35 to 800 times higher than in the general population.[2] The risk increases with the progression of HIV infection and worsening of CD4 count. A retrospective cohort study of 10 years duration from United States of America observed that female gender, use of stavudine and aerosolized pentamidine, CD4 count less than 50 cells/cm3 are significantly associated with pancreatitis in HIV positive patients.[3] HIV patients are more susceptible to opportunistic infections at CD4 count less than 200 cells/cm3. Cytomegalovirus, varicella-zoster virus, Mycobacterium tuberculosis, Mycobacterium avium, toxoplasmosis, cryptococcosis and Pneumocystis jiroveci have all been associated with pancreatic involvement. The antiretroviral agents linked to AP include nucleoside reverse transcriptase inhibitors (NRTI) like didanosine, stavudine, lamivudine and protease inhibitors (PI). The exact mechanism for the pancreatitis due to ART is not clear. However, the clinical manifestations of NRTI - induced mitochondrial toxicity resemble those of inherited mitochondrial diseases (hepatic steatosis, lactic acidosis, myopathy, nephrotoxicity, peripheral neuropathy, and pancreatitis). Inhibition of Deoxyribonucleic acid (DNA) polymerase γ, adenylate kinase and the adenosine diphosphate/adenosine triphosphate translocator can gradually lead to mitochondrial dysfunction and cellular toxicity.[5]

Stavudine alone causing pancreatitis is rare. The incidence of pancreatitis is high, if it is used in combination with nucleoside analogs or cotrimoxazole. Pancreatitis usually develops 3 – 5 months after the therapy with stavudine is initiated.[6] In our case, patient was taking stavudine along with lamivudine and nevirapine since last 8 months. On development of AP, the combination was discontinued. Stavudine was added in place of zidovudine due to the development of anaemia 8 months prior. The other two drugs were continued. Thus, the temporal relationship between starting the stavudine therapy and development of pancreatitis suggests that stavudine was the offending agent. Although pancreatitis is likely to be caused by stavudine, this case is complicated by use of cotrimoxazole. Pancreatitis is also observed with cotrimoxazole. Occurrence of pancreatitis after the long term administration of cotrimoxazole is rare. Reported cases suggest the incubation period of pancreatitis to be from 2 days to 42 days, except in one case, where it occurred after the 20 years of use.[7] Probable mechanisms for the development of pancreatitis due to cotrimoxazole is either hypercalcemia due to stimulation of parathyroid hormone, or by hypersecretion of pancreatic enzymes.[8] In this case, the patient was receiving cotrimoxazole since 8 months and presented with hypocalcemia.

The tetany related symptoms were probably due to metabolic complications of pancreatitis. Tetany is a rare event in AP and is associated with poor prognosis. There is a higher prevalence of hypocalcemia in HIV patients due to vitamin D deficiency and lack of adequate secretion of parathyroid hormone. This may have exaggerated the hypocalcemia associated with pancreatitis resulting in tetany. There is no specific treatment of pancreatitis. Majority of the mild cases improve spontaneously. Early oxygen supplementation and adequate prompt fluid resuscitation is crucial in the prevention of complications and resolution of early organ failure.[9] In NP, early use of higher antibiotics prevent the infection of sterile necrosis, and lowers the mortality in the patients.[4] A serum calcium below 2.0 mmol/l and leucocytosis more than 16000/ mm3 are the Ranson's early signs which correlate with severe illness in pancreatitis. Both signs were positive in the present case.[10] Death in this case is possibly related with the severity of reaction or delay in starting the rescue treatment. Fine needle aspiration with Gram's stain and bacteriological culture should be carried out in NP to determine status of infection. Surgical treatment is preferable over non-surgical treatment in infected necrosis.[4] This case highlights the rare complication of ART which require a high index of suspicion, early intervention along with withdrawal of offending drug and appropriate management to prevent mortality and morbidity in the patient.