Rare case of pancrelipase therapy-induced neutropaenia

Abstract

A 61-year-old man was transferred to our facility from an outside hospital due to refractory neutropaenia of unknown aetiology. The patient presented to the referring hospital with a 5-day history of worsening diarrhoea and abdominal pain. Initial lab results at presentation showed severe neutropaenia with an absolute neutrophil count of 0. Investigations included a bone marrow biopsy which showed slightly hypocellular marrow with near absence of granulocytic precursors. A CT without contrast showed evidence of chronic pancreatitis and acute colitis. The patient’s neutropaenia persisted despite granulocyte colony-stimulating factor therapy. The patient was, thus, transferred to our facility for a higher level of care. At our facility, the patient had rapid correction of neutropaenia after discontinuation of pancrelipase therapy. The patient’s abdominal pain and diarrhoea also improved while off pancrelipase. Neutropaenia has completely resolved 6 weeks after discharge without any further therapy.

Background

White blood cells (WBCs) are key to the body’s defence mechanism against infections. WBCs are composed of granulocytes and agranulocytes. Granulocytes or polymorphonuclear cells are composed of neutrophils, basophils, eosinophils and bands to form the bulk of white cell counts (WCC). WCC ranges from 4 to 11 x10⁹/L in a healthy adult and about 60% are neutrophils. Neutrophil levels below certain defined thresholds increase the risk of infection and the human body’s ability to fend off infection. Absolute neutrophil count (ANC) is the product of WCC and percentage of neutrophils and bands observed on differential analysis of the complete blood count (CBC). An ANC less than 1.5 x10⁹/L is defined as neutropaenia. Severe neutropaenia is when ANC is below 0.5 x10⁹/L. Agranulocytosis is defined as an ANC of 0, although it is commonly used to indicate a high severity of neutropaenia, such as ANC less than 0.1x10⁹/L.

Neutropaenia can be induced by a number of causes including but not limited to myelodysplastic syndromes, chemotherapy, metabolic disorders, mineral deficiencies, infections: viral, bacterial, fungal and parasitic, sepsis, autoimmune causes and drugs.¹ Ascertaining the cause of neutropaenia can prove to be very challenging. Drug-induced neutropaenia, although rare, is an important cause that must be considered. Identifying the culprit drug from often long lists of medications can also be difficult. Idiosyncratic drug-induced neutropaenia (IDIN) cases are caused by several well-known agents; chemotherapy agents form the bulk of cases. Others include clozapine, carbamazepine, several antibiotics including but not limited to amoxicillin, cefotaxime, vancomycin, cefepime, sulfasalazine and thionamides such as methimazole and mesalamine.^1–3

The incidence of IDIN varies significantly per report. It is approximately 2–15 cases/million population per year. IDIN reportedly is the cause of nearly two-thirds of severe neutropaenia and should be highly suspected by clinicians.^{1 4–6} Pancrelipase delayed-release capsules (CREON, Abbott, Marietta, Georgia, USA) are used as pancreatic replacement therapy in chronic pancreatitis. The safety of pancrelipase has been demonstrated in clinical trials.⁷ To our knowledge, there has never been an IDIN related towards pancrelipase.

We present to you a rare case of neutropaenia in a patient at our tertiary care centre.

Case presentation

A 61-year-old man was transferred to our tertiary care centre for a higher level of care due to neutropaenia of unknown aetiology associated with fevers. His medical history was significant for chronic pancreatitis, hypertension and recently diagnosed inflammatory bowel disease (IBD) by colonoscopy 3 months before presentation, for which he was started on mesalamine, which was stopped a month prior to this admission due to worsening diarrhoea. He initially presented to an outside hospital with a 5-day history of abdominal pain and watery diarrhoea. Workup at the outside hospital was revealing for an acute kidney injury with creatinine of 1.8 mg/dL, leucopenia with WCC 1.4 x10⁹/L and neutropaenia with ANC of 0 x10⁹/L (lymphocytes 87%, monocytes 2%, atypical lymphocytes 8%). His last CBC was normal 3 months prior to admission. His hospital course at that facility was complicated by relapsing fevers of up to 38.9°C, persistent abdominal pain associated with non-bloody, greasy diarrhoea, refractory electrolyte abnormalities: hypokalaemia, hypocalcaemia and hypomagnesaemia. For the possibility of infection, he was pan-cultured and empirically given vancomycin, cefepime and metronidazole. Urine cultures were positive for Candida spp and thus, fluconazole was added. The patient was transferred to our facility for a higher level of care due to persistent neutropaenia and fever.

Investigations

Referring hospital

The patient underwent an extensive workup for neutropaenia at the outside hospital. Peripheral blood smear confirmed neutropaenia without significant abnormality in morphology of cells. Flow cytometry revealed myeloid hypoplasia with no discrete atypical immunophenotypic findings.

The patient underwent a CT-contrast of thorax, abdomen and pelvis, which showed small pleural effusions and bibasilar atelectasis, oesophagitis, atrophic pancreas with dystrophic pancreatic calcifications suggestive of chronic pancreatitis, diffuse colonic thickening consistent with colitis, numerous small mediastinal lymph nodes read as likely reactive. An ultrasound of the abdomen showed diffuse hepatic steatosis, cholelithiasis without evidence of acute cholecystitis, homogeneous and normal size spleen. He eventually underwent bone marrow biopsy due to persistent neutropaenia that showed slightly hypocellular marrow with near absence of granulocytic precursors but erythrocytic precursors and megakaryocytes were present with adequate iron stores.

Extensive infectious workup included: stool analysis for ova and parasites, giardia antigens, Clostridium difficile antigens, blood cultures, fungal workup: fungitell, aspergillus galactomannan antigens, acid fast bacilli, Beta-D glucan assays, viral workup; HIV, herpes simplex virus, Epstein-Barr virus (EBV) and rickettsia antigens.

Our tertiary hospital

Given the concern for febrile illness in a patient with severe neutropaenia, the above infectious workup was repeated at our facility and also expanded to include EBV, cytomegalovirus, typhus fever, parvovirus, SARS-CoV-2, hepatitis B and C, histoplasma antigens, anaplasma antigens, blood cultures and stool cultures.

Almost all infectious workup was negative at both the referring hospital and our hospital. He did grow Candida spp on urine cultures, but the patient was asymptomatic. EBV immunoglobulin G was positive at our facility but immunoglobulin M was negative. Workup for autoimmune causes was checked with antinuclear antibodies (ANA), rheumatoid factor and antineutrophil cytoplasmic antibodies, which were essentially negative. Nutritional deficiency was also considered with copper, folate and vitamin B₁₂ levels found to be within normal limits as well.

Differential diagnosis

Infectious enterocolitis causing neutropaenia versus idiosyncratic drug reaction.

Treatment

Given the bone marrow biopsy results, drug-induced agranulocytosis was likely the aetiology. On admission, the patient’s home medications included the following: aspirin, atorvastatin, pancrelipase, enalapril, fluoxetine, fluticasone furoate/vilanterol, hydrochlorothiazide. He had been on both mesalamine and pantoprazole recently, but both had been discontinued, the mesalamine about 1 month ago and the pantoprazole 4 days before admission to outside hospital.

Mesalamine is a commonly known medication to cause neutropaenia but was less likely given the timeline of events. The patient was started on mesalamine 4.8 g per day in July 2020 after new diagnosis of IBD. However, mesalamine was stopped a month later due to worsening diarrhoea. Proton pump inhibitors (PPIs) are also a well-known culprit of neutropaenia but same were discontinued without improvement with the WCCs. At the outside hospital, patient was started on 480 µg filgrastim for 6 days following the bone marrow biopsy results. However, there was lack of response to the same (figure 1). The patient was, thus, transferred to our facility for further management.

Figure 1.

Daily white cell count (WCC) throughout hospital admission. The patient was trialled on filgrastim from days 3–9 without improvement. PPIs were discontinued days 5 and 9. WCC began to trend upwards after discontinuation of pancrelipase therapy on day 16. PPIs, proton pump inhibitors.

On transfer to our tertiary care centre, WCC was 0.81 x10⁹/L with ANC of 0.02 x10⁹/L. The patient was afebrile. He had persistent steatorrhoea despite pancrelipase 5000 total units daily. He was also requiring several potassium and calcium repletion daily. The clinical team suspected electrolyte abnormalities were secondary to gastrointestinal losses. Infectious workup was sent as described above. No evidence of bacterial infection was found and eventually the vancomycin, cefepime, fluconazole and metronidazole were discontinued. A repeat bone marrow biopsy was being planned for day 18 overall of admission. As of day 16, a decision was made to discontinue pancrelipase given no improvement with steatorrhoea while on same. The patient was placed on a strict fat-free diet as a result. On the discontinuation of pancrelipase, patients WCC the following day improved to 1.77 x10⁹/L with an ANC of 0.08 x10⁹/L. The improvement in WCCs continued over the next few days without any other active interventions or new medications (figure 2). Concomitantly, the patient’s steatorrhoea also began to improve. His diarrhoea reduced from about 6–8 times daily to 3–4 times daily. He was then started on Imodium afterwards to help further manage the diarrhoea. On the day of the planned procedure, haematology colleagues decided against repeating another bone marrow biopsy given marked improvement in WCC. The impression was now of suspected drug-induced agranulocytosis.

Figure 2.

Daily absolute neutrophil counts (ANC) throughout hospital admission. The patient was trialled on filgrastim from day 3–9 without improvement in ANC. ANC began to trend upwards after discontinuation of pancrelipase therapy on day 16.

Furthermore, all infectious workup for both the blood and the diarrhoea were negative.

The patient was safely discharged to a skilled nursing facility for rehabilitation on day 23. WCC was up to 3.47 x10⁹/L and ANC of 1.49 x10⁹/L on day of discharge.

Outcome and Follow-up

The patient initially spent several weeks at a rehabilitation facility for physical therapy. He was eventually discharged home. The patient continued to report improved diarrhoea symptoms while off pancrelipase. About 6 weeks after discharge, his WCC was now normalised at 5.31 x10⁹/L.

Discussion

IDIN is rare but a fatal cause of neutropaenia. IDIN is most associated with severe neutropaenia and thus should be suspected in those instances. The Berlin Case-Control Surveillance Study, a large 10-year study, conducted in Berlin indicated that most of confirmed neutropaenia cases are likely drug induced.³ Identifying IDIN can be challenging and requires a multidisciplinary effort. As seen in our case, it took a multidisciplinary team of internal medicine, haematology, infectious disease and gastroenterology.

Mesalamine contains 5-aminosalicyclic, the active moiety of sulfasalazine. As an anti-inflammatory drug, it is one of the mainstay agent used to treat ulcerative colitis.⁸ Mesalamine was initially suspected as the culprit drug for this patient’s neutropaenia. Agranulocytosis is a well-established adverse effect associated with mesalamine.^9–11 Mesalamine-induced neutropaenia usually occurs within the first 2 months of therapy.¹² Mesalamine was initially ruled out as the cause of our patient’s neutropaenia for a number of reasons. First, the patient’s neutropaenia was found a month after mesalamine discontinuation. Furthermore, there was lack of response to filgrastim at the outside hospital. Likewise, PPIs are known to rarely cause neutropaenia.¹³ Thus, these agents were initially suspected and withdrawn appropriately (see figures 1–3).

Figure 3.

Daily relative neutrophil percentage throughout hospital admission.

The mechanisms of IDIN are hypothesised to be due destruction of circulating granulocytes by drug-induced antibodies or direct/indirect toxic effects on granulocyte precursors by a drug or its metabolites. Immune-mediated neutropaenia usually presents days to weeks after initiating the offending drug. On the other hand, the presentation can be delayed for months when a drug or its metabolites toxicity induce neutropaenia. Metabolites of said drug trigger an immune cascade leading to the death of neutrophils.⁶ IDIN occurs within the first 6 months of initiating the drug. Severe IDIN can present with or without associated fever. Oral ulceration is also a common presenting feature clinically.¹⁴ The timeline of resolution of neutropaenia after withdrawing the offending drugs varies between patients. It can take as little as several days up to weeks for recovery after cessation of the drug.^{12 15 16}

Granulocyte colony-stimulating (G-CSF) factors such as filgrastim have been shown in multiple non-randomised studies to be efficacious in reducing the recovery time in drug-induced neutropaenia. Recovery time also largely depends on concurrent bone marrow reserve. In the absence of bone marrow suppression and adequate granulocyte marrow storage pool, recovery can be as rapid as few hours.¹⁷

Pancrelipase is frequently used in the management of chronic pancreatitis. The safety and efficacy of pancrelipase in chronic pancreatitis patients has been well demonstrated by many randomised and/or placebo-controlled trials.^{7 18 19} Common adverse effects like headaches, constipation, heartburn, flatulence, hyperglycaemic, hypoglycaemic, abdominal pain, among others have been reported.²⁰ Rarely pancrelipase can cause worsening diarrhoea which we believe we saw in this patient. The patient’s steatorrhoea frequency and abdominal pains paradoxically improved while off pancrelipase. Serious adverse effects like fibrosing colonopathy and viral transmission, especially hepatitis E virus infection, have been associated with pancrelipase.^{7 20} However, there has been no report of pancrelipase-induced agranulocytosis to the best of our knowledge. Reviewing the clinical trial data published by the United States’ Food and Drug Administration (FDA) revealed a report of transient neutropaenia in one of the subjects. This occurred in one of the studies; a randomised, double-blind, placebo-controlled, cross-over study of 32 cystic fibrosis patients. Transient neutropaenia without any significant sequelae was reported in one of the patients that received pancrelipase and a macrolide antibiotic.²⁰ It was reported as an observed abnormal finding without clinical significance. Therefore, if held true, our case would be the first-reported pancrelipase-induced neutropaenia with significant clinical sequalae.

We decided to discontinue the pancrelipase in our patient mainly because his abdominal pain and steatorrhoea were still persistent while on the pancreatic enzyme replacement therapy. Consequently, while off pancrelipase, the patient rapidly improved clinically. His ANC quadrupled and the up-trend persisted while off pancrelipase (see figure 4). There were no new stimulating agents such as G-CSF used. A repeat bone marrow biopsy was planned, but this was deferred given the rapid improvement in leucopenia/neutropaenia. It is to be noted that, neutropaenia can occur several months even after discontinuing the offending drug and recovery may also take several weeks. While we cannot definitely say that neutropaenia in this was due to pancrelipase, the recovery time after the discontinuation is striking.

Figure 4.

Absolute neutrophil count trend after discontinuation of pancrelipase on day 16.

IDINs are rare but can be fatal. IDIN are mostly underreported. It takes a multidisciplinary effort to successfully identify idiosyncratic drug reactions. Clinicians should always suspect IDIN in all cases of severe neutropaenia.

Learning points.

• Drug-induced neutropaenia should be suspected in all cases of severe neutropaenia.

• It may take several weeks to months for neutropaenia to occur after discontinuation of the offending drug.

• Recovery may be as rapid as few hours or take several days to weeks despite granulocyte colony-stimulating factor therapy.

• Pancrelipase may be associated with neutropaenia.