Vomiting and Diarrhea: Side Effect or Allergic Reaction?

Case Report

A 6-year-old girl was under the care of a pulmonologist for recurrent wheezing episodes. During the outpatient follow-up, mother reported multiple reactions after the ingestion of amoxicillin (AMX) with or without clavulanic acid. A few days after the first administration of oral suspension of amoxicillin with clavulanic acid (AMX/CL), due to otitis media, she developed abdominal pain followed by vomiting, diarrhea, and flatulence at 2½ years of age. Considering the symptoms, it was assumed that acute viral gastroenteritis coincided with otitis media, and she was treated with AMX/CL for 10 days. The next 2 administrations of AMX were with oral suspensions at 4 and 5 years of age. At the age of 4, she was treated with AMX for an upper respiratory tract infection. Three hours after the first dose, she began vomiting and suffered abdominal cramps, and through the evening and the next day, she developed diarrhea. Therapy was discontinued after 3 days. Seven days after the first dose of AMX, she developed a maculo-papular erythematous rash without pruritus. She took 1 dose of desloratadine, and the rash disappeared the next day. At age 5, the first dose of AMX was followed by a brief period of drowsiness, abdominal pain, repeated vomiting, and severe diarrhea 1 to 2 hours after ingesting the drug, and therapy was immediately discontinued. During the last response, the parents called an ambulance because of drowsiness and poor general condition after severe vomiting and diarrhea, and the girl was treated shortly thereafter with an intravenous infusion of normal saline solution. Symptoms resolved within 12 hours.

The next time she needed an antibiotic for an acute febrile respiratory infection, she was prescribed cefalexin and azithromycin, and no adverse effects occurred.

After these anamnestic findings, we performed an allergy study and confirmed negative specific IgE antibody to amoxicillin in the blood (<0.35 kU/L; ImmunoCAP, Phadia, Uppsala, Sweden), ¹ as well as the basophil activation test for amoxicillin and clavulanate.

Therefore, we performed an open 3-step graded supervised drug provocation test (DPT) in the hospital setting with written informed consent from the parents for both doing the test and publishing their child’s case.

The competent Ethics Committee approved the conduct of the research.

Discussion

Hospital Course

On admission to the hospital, she was afebrile, weighed 25 kg, and physical examination was normal. After admission to the Pediatric Department, we performed an open 3-step graded oral provocation test with AMX according to the published guidelines. ² Considering the severity of the previous reaction, when she was parenterally rehydrated, we used a lower initial dose (1/100-1/10-full single therapeutic dose) and adjusted the time interval between doses to 2 hours. A single therapeutic dose was calculated as 1/3 of a daily dose.

Approximately 3 hours after receiving the first dose (5 mg) and 1 hour after the second dose (50 mg), the girl developed severe abdominal pain, nausea, and repeated vomiting, and an hour later she became pale and developed severe diarrhea. During the reaction, she had no cutaneous or respiratory symptoms, and she remained hemodynamically stable (blood pressure 105/60 mm Hg, heart rate 95/min). Because of persistent vomiting, she was parenterally hydrated, and her vital signs were continuously monitored. She did not receive antiemetics, corticosteroids, or adrenaline.

The third scheduled dose was not administered, and the DPT was considered positive. Approximately 5 to 6 hours after the onset of symptoms, she showed progressive improvement to complete recovery. A blood test performed 1 hour after the onset of the reaction showed a normal complete blood cell count. No tryptase or blood gas test was performed. She was discharged the same day in good condition with a recommendation to avoid amoxicillin.

Discussion of Case and Literature

Drug-induced enterocolitis syndrome (DIES) is described as a rare, non-IgE-mediated hypersensitivity reaction with a potentially severe outcome. Despite its potential severity, awareness of DIES is still very low. We performed a comprehensive literature search and found 7 cases of DIES to amoxicillin ± clavulanic acid reported in children,^3-7 1 in a young male patient that persisted over time, ⁸ and 1 in an adult patient who developed a severe reaction with shock. ⁹ Bouvette et al ¹⁰ described the case of an adult with DIES to pantoprazole, and recently Pascal et al ¹¹ published a case report of DIES with paracetamol (acetaminophen) in a 12-month-old boy. All previous publications emphasize the lack of diagnostic criteria for DIES and emphasize its clinical resemblance to food protein-induced enterocolitis syndrome (FPIES), which is much better recognized by clinicians.^3,5,7 FPIES is considered a non-IgE-mediated gastrointestinal food allergy characterized by vomiting and diarrhea after ingestion of certain food proteins and typically occurs in infancy. The main difference between FPIES and DIES is in the type of allergen, food, and drugs. Furthermore, beside acute FPIES, there is also a chronic FPIES that develops on repeated ingestion of the triggering food, presenting with intermittent vomiting, diarrhea and failure to thrive. Diagnose of FPIES is based on a clinical history and improvement after withdrawal of the suspected trigger food. Oral food challenge for diagnosing FPIES is not always necessary, but it is still a gold standard to confirm the diagnosis, same as a DPT in DIES. ¹² Accordingly, some of the authors have proposed diagnostic criteria for DIES based on the most recent published criteria for FPIES. The primary criterion is repeated vomiting within a 1- to 4-hour period after ingestion of the suspected drug with the absence of classic IgE-mediated skin or respiratory symptoms. Three or more secondary criteria are also required for diagnosis, including a second episode of repeated vomiting after ingestion of the same drug or after ingestion of another drug, extreme lethargy, pallor, need for an emergency department visit, intravenous fluid support, diarrhea within 24 hours of ingestion of the drug, hypotension, and hypothermia. ⁵ Laboratory findings such as leukocytosis, neutrophilia, thrombocytosis, metabolic acidosis, and methemoglobinemia may be present in DIES but they are not specific. To confirm the diagnosis, a monitored diagnostic drug provocation test (DPT) should be performed in the hospital setting. In most of the cases described, symptoms resolved spontaneously, although some of the patients received antiemetics, corticosteroids, adrenaline, and intravenous fluids due to severe reactions and shock.^3,5,7,9-11 The prognosis of DIES is unknown, whereas the majority of children with FPIES outgrow it over time, depending on the allergen. ¹²

One of the recent publications described the case of an 18-year-old man with positive DPT to amoxicillin-clavulanic acid, 9 years after the first reaction. ⁸ There is also a case of a 60-year-old male patient with a severe reaction with shock and gastrointestinal symptoms after amoxicillin-clavulanic acid, who had tolerated the drug on several occasions before the first reaction. ⁹ In the case of DIES to pantoprazole in a 69-year-old man, the data on past tolerance of the drug are unknown. ¹⁰ However, the parents of a 12-month-old boy (DIES with paracetamol) recalled that their child had gastrointestinal symptoms every time he was treated with paracetamol since birth. ¹¹ In 2 recent papers, patients with DIES for amoxicillin ± clavulanic acid tested negative for penicillin V and G, phenoxymethylpenicillin, and cefpodoxime on DPT.^6,8 Although data on the pathogenesis of DIES are scarce in the literature, these results may suggest that the beta-lactam ring is not involved in the pathogenesis of DIES and may lead us to the conclusion that there is no cross-reactivity with cephalosporins. The study published by Mori et al ¹³ shows that a drug-specific T-cell-mediated response may be involved in the pathogenesis. Once the diagnosis is established, the culprit drug should be contraindicated. ⁸ When comparing FPIES and DIES, there are some similarities and differences and, more importantly, unanswered questions about pathophysiology, phenotypes, the natural history of the disease, triggers, and outcomes.^7,14 Both FPIES and DIES can be considered potentially related syndromes, and clinicians must be trained to recognize them and make appropriate recommendations to patients.

Final Diagnosis

Considering previous reactions, laboratory findings, and results of the oral challenge test, we believe our patient meets the criteria for DIES due to amoxicillin. She was previously treated with AMX and developed a characteristic reaction; she had a positive DPT with typically repeated vomiting approximately 3 hours after AMX ingestion, followed by marked pallor and severe diarrhea several hours later, without classic IgE-mediated skin or respiratory symptoms and with the need for intravenous fluids. The major and 4 minor diagnostic criteria (a second episode of repeated vomiting after the ingestion of the same drug, marked pallor, need for intravenous fluid administration, diarrhea within 24 hours of drug ingestion) were met, and she recovered completely, ruling out other differential diagnoses such as septic shock, metabolic disease, or surgical emergency.

Conclusion and Lessons Learned

In the case of acute gastrointestinal symptoms that resemble FPIES after taking amoxicillin ± clavulanic acid, we should keep DIES in mind as a differential diagnosis. Clinical awareness of DIES and its potential severity should be improved, and it is important to distinguish it from a side effect of the drug. Because of the risk of severe reactions and shock, DPT with AMX should be performed under medical supervision in the hospital if necessary. A positive DPT confirms the diagnosis, and AMX should be contraindicated. To our knowledge, all cases of DIES involved aminopenicillins (except 1 case involving pantoprazole and 1 case involving paracetamol). Although no cases of DIES to other antibiotics have been reported, it would be wise to assess the tolerability of other types of penicillin and cephalosporins before prescribing them to patients with DIES to AMX.

Author Contributions

SI: Contributed to conception; contributed to acquisition; literature search; drafted manuscript; approved the final manuscript as submitted. MSI: contributed to conception; contributed to interpretation; critically revised manuscript; approved the final manuscript as submitted. VR: contributed to conception and design; contributed to acquisition, analysis, and interpretation; literature search; provided mentorship; reviewed and edited all drafts; approved the final manuscript as submitted.