Background
Adverse drug reactions are common and often predictable based on a drug’s mechanism of action. However, 10%-15% are unpredictable reactions dependent on environmental and genetic susceptibilities, and often due to drug hypersensitivities [1,2]. Over 500 medications have been implicated in causing acute pancreatitis, with mesalazine and azathioprine being the most well-documented, while few biologics have ever been implicated [3,4]. Mepolizumab, a monoclonal antibody which inhibits interleukin-5, has been approved the by Food and Drug Administration for the treatment of severe eosinophilic asthma, with the most common adverse effects including headaches, nasopharyngitis, musculoskeletal and connective tissue disorders, and non-allergic infusion reactions [5-7]. Though scarce, pharyngeal swelling and hypersensitivity reactions have also been reported [7]. Here, we will describe a novel case of acute pancreatitis secondary to delayed-type hypersensitivity to mepolizumab.
Case Presentation
A 49-year-old female with severe persistent asthma, gastroesophageal reflux disease, diabetes mellitus, post-traumatic stress disorder, hypoadrenalism, and obesity presented to the emergency department with severe shortness of breath and abdominal discomfort. Pulmonology managed her asthma, prescribing oral prednisone 2.5 mg three times daily (based on asthma-specific dosing recommendations) for a recent exacerbation, and administering a second treatment with mepolizumab 2 weeks prior to admission. In the past, she visited rheumatology clinic for an extensive work-up of her restrictive pulmonary function tests, diffuse arthralgias, and wheezing, which was unrevealing. Medications included an albuterol nebulized inhaler, fluticasone/salmeterol inhaler, glipizide, loratadine, mepolizumab 100 mg every 4 weeks, montelukast, omeprazole, rosuvastatin, and a tiotropium inhaler. She had no known allergies and family history was not significant for any autoimmune disorders. The patient denied use of alcohol, tobacco, and recreational drugs.
On examination, the patient was tachycardic (maximum: 118 beats/minute), tachypneic (maximum: 25 breaths/minute), and hypertensive to 180/100 mm Hg. She appeared dyspneic and in distress, but lungs were clear to auscultation in all fields with mild end-expiratory wheezes. The abdomen was distended with diffuse tenderness and focal severe tenderness at the epigastrium. No shifting dullness could be appreciated. Bilateral lower extremities had pitting edema to the knee. Elevated laboratory values included glucose (305 mg/dl), alkaline phosphatase (186 U/l), aspartate transaminase (50 U/l), lipase (1,372 U/l), C-reactive protein (20.7 mg/l), erythrocyte sedimentation rate (52 mm/hour), lactate dehydrogenase (726 U/l), gamma-glutamyl transferase (189 IU/l), IgE (1,930 IU/ml), rheumatoid factor (41.7 IU/ml), aldolase (8.2 U/l), IgG-4 (90.6 mg/dl), and complement functional activity (>60 U/ ml). Serum triglycerides, antinuclear antibodies, antineutrophil cytoplasmic antibodies, and serum anti-cyclic citrullinated peptide were normal. Abdominal computerized tomography (CT) revealed an acutely edematous pancreatitis (Figure 1), conferring a diagnosis of acute pancreatitis.
Treatment included nebulized albuterol and ipratropium, aggressive intravenous (IV) lactated ringers (100 cc/hour), and morphine with hydromorphone for pain management. Without symptomatic improvement after 3 days of aggressive treatment with 9 l of IV fluids and in the setting of poor diuretic output, there were concerns for cardiovascular strain from this intravascular expansion and possible worsening of her condition. Concurrently, the patient developed a diffuse truncal urticaria. A repeat abdominal CT revealed worsening acute pancreatitis. Gastroenterology was consulted, who completed a thorough medication reconciliation, and attributed the patient’s presentation to a hypersensitivity-reaction to her second dose of mepolizumab, the only new medication within the past year. After 9 days of hospitalization, the patient’s abdominal pain resolved, and she returned to her baseline weight and room air oxygen requirement (Table 1).
Discussion
Drug-hypersensitivity reactions are relatively common, often presenting with cutaneous signs and symptoms [8]. However, drug eruptions can affect any organ system, and may cause acute pancreatitis [3,9]. Nonetheless, it remains unknown which genetic and environmental factors determine what organ systems are affected [8]. To the authors’ knowledge, this is the first report of acute pancreatitis secondary to a mepolizumab delayed-hypersensitivity reaction. Given lack of alcohol use and lack of gallbladder disease, it was presumed that this presentation was either autoimmune or drug mediated. However, our patient did not respond to the standard-of-care therapy after 72 hours, indicating that a separate process was occurring [10,11]. Following the development of diffuse truncal urticaria, concerns for a drug-related hypersensitivity reaction arose. It is possible that the patient had subclinical drug rash with eosinophilia and systemic symptoms (DRESS) presentation and/or delayed-type drug hypersensitivity due to concomitant inflammatory suppression from use of oral corticosteroids, which is the gold standard therapy for these hypersensitivity reactions [12].
| Week 0 | Administered first dose of mepolizumab |
| Week 4 | Administered second dose of mepolizumab |
| Week 6 | Patient admitted to hospital |
| Day 1 | Patient presents for severe dyspnea and abdominal pain |
| Day 2 | Patient diagnosed with acute pancreatitis; started IV fluids and pain management |
| Day 3 | Patient develops urticaria |
| Day 4 | Repeat CT scan shows worsening acute pancreatitis; Gastroenterology consulted |
| Day 5 | Gastroenterology attributed presentation to mepolizumab-associated hypersensitivity reaction |
| Day 7 | Patient dyspnea and abdominal pain starts to resolve |
| Day 9 | Patient discharged |
Recent large clinical studies utilizing mepolizumab demonstrated that the most common adverse events include headache and nasopharyngitis [12]. However, there are reports of decompensated heart failure and death secondary to acute pancreatitis, which were considered unrelated to mepolizumab [8]. Further studies are needed to discern which populations are at risk for developing hypersensitivity reactions to mepolizumab and the overall safety of long-term mepolizumab treatment for severe asthma.
Conclusion
We hope this case encourages physicians to consider drug hypersensitivity etiologies for common acute medical problems and highlights the need for strong clinical suspicion for hypersensitivity reactions in patients on biologic therapies.
What is new?
Biologic therapies are generally considered as safe and do not typically exhibit drug hypersensitivity reactions. Specifically, mepolizumab has not been shown to cause pancreatitis or drug hypersensitivity reactions. Here, the authors report a patient who presented with pancreatitis secondary to mepolizumab therapy, and possible subclinical DRESS.