lNTRODUCTlON

Influenza is an infectious disease with a repetitive winter cycle.According to a report from the National Institute of Infectious Diseases,Japan,of a total population of 126 million in the country,an estimated 12 million individuals(population ratio,9.5%)were affected by influenza during the 2018-2019 season,and 7.28 million individuals were affected during the 2019-2020 season(population ratio: 5.7%)[1].In 2018,3325 deaths were reportedly due to influenza[1].In a meta-analysis of placebo-controlled clinical studies of oseltamivir in all adults,the oseltamivir group was observed to have a shortened duration of seasonal influenza and a reduced risk of hospitalization[2].Additionally,a decrease in the influenzaassociated mortality rate has been reported with the administration of neuraminidase inhibitors as the first-line of treatment[3].

Neuraminidase inhibitors approved in Japan include oral oseltamivir,inhaled zanamivir and laninamivir,and intravenous peramivir.Adverse reactions to neuraminidase inhibitors are usually mild;however,they can cause bronchospasm in patients with asthma or chronic obstructive pulmonary disease[4]and other relatively common adverse reactions such as nausea/vomiting and diarrhea.Similarly,rare occurrences of acute hemorrhagic colitis(hemorrhagic enterocolitis/ischemic enterocolitis)associated with neuraminidase inhibitors have been reported[5].

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Here,we report the case of a patient with ischemic enterocolitis that was considered to have been caused by laninamivir.

CASE PRESENTATlON

Chief complaints

Lower abdominal pain and bloody stools.

History of present illness

Although a clear mechanism underlying oseltamivir-associated hemorrhagic enteritis/ischemic enterocolitis has not been elucidated,simultaneous occurrence of the following two factors has been considered responsible for the condition:(1)Local angiospasm and vasculitis due to the effect of an allergic reaction to oseltamivir;and(2)Hypoperfusion in the intestinal tract due to the effect of dehydration caused by influenza[9,12].Laninamivir is considered to demonstrate the same mechanism as oseltamivir.Approximately three hours after inhalation,she reportedly experienced bloody stools and lower abdominal pain.In addition,she developed certain symptoms shortly after inhalation and a possible allergic reaction.Similarly,she was dehydrated based on physical findings.Therefore,the mechanism underlying oseltamivir-associated ischemic enterocolitis in this patient is considered related to these factors.

We present a case of ischemic enterocolitis that was considered to be caused by laninamivir.Although there have been a few reports of acute hemorrhagic colitis caused by neuraminidase inhibitors,to the best of our knowledge,this is the first reported case of acute hemorrhagic colitis caused by laninamivir.

Nothing in particular.

History of past illness

At the same institution,the patient was diagnosed with influenza type A using a rapid antigen kit(Quick Navi-Flu2 Influenza Diagnostic Kit,Otsuka Pharmaceutical Co.,Ltd.Tokushima,Japan),and she was administered a dose of 40 mg laninamivirinhalation.Approximately three hours after inhalation on the same day,the patient reportedly experienced bloody stools and lower abdominal pain while sleeping at night.On the third day of symptom onset,the patient visited our institution and was hospitalized due to persistent intermittent lower abdominal pain every 20 min and bloody stools at a frequency of ten times a day.No oral medication,including any anti-platelets/anticoagulants,was prescribed.

Personal and family history

Nothing in particular.

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Physical examination

Upon clinical examination,the patient appeared lucid.Her blood pressure was 125/67 mmHg,pulse rate was regular with 67 beats/min,body temperature was 36.7°C,respiratory rate was 16 breaths/min,and SpOwas 97% at room air.No pallor was observed on the palpebral conjunctiva.Heart sounds were regular,and there were no cardiac murmurs.Breath sounds were clear.The abdomen was flat and soft,with tenderness on the left flank.There was no rebound tenderness or muscle guarding.Bowel peristaltic sounds did not increase or decrease,and no palpable mass or hemorrhage was observed on rectal examination.There was no edema in the extremities,and no signs of cyanosis were observed.Her mouth was dry,and the capillary refilling time was four seconds,which suggested dehydration.

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Laboratory examinations

Blood test results revealed the following: white blood cell count,7810/μL;hemoglobin,12.9 g/dL;platelet count,20.7 × 10/μL;L-dimer,1.0 μg/mL;blood urea nitrogen,17.7 mg/dL;creatinine,0.47 mg/dL;creatinine kinase,75 U/L;aspartate aminotransferase,17 U/L;alanine aminotransferase,13 U/L;lactate dehydrogenase,155 U/L;alkaline phosphatase,210 U/L;C-reactive protein,3.08 mg/dL;and glycated hemoglobin A1c,5.9%.She had no abnormalities,such as diabetes mellitus or liver dysfunction,which could manifest in ischemic episodes.Stool culture tests were performed for normal intestinal flora alone,andgrowth was not observed.Polymerase chain reaction was not performed to detect bacteria in stools,and the stool was negative fortoxin A and B.

Imaging examinations

Abdominal contrast-enhanced computed tomography showed edema-like changes that extended from the descending colon to the sigmoid colon(Figure 1).

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FlNAL DlAGNOSlS

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TREATMENT

Fluid replacement was administered for bowel rest,and food and drink intake was withheld.For influenza type A,laninamivir had been administeredinhalation two days ago,and the patient was kept in a private room and followed up with symptomatic treatment.On the second day of hospitalization,fresh blood in the stool disappeared,and abdominal pain improved.On the third day of hospitalization,the patient started eating again,which did not worsen the symptoms.The patient was discharged on the fifth day of hospitalization.

OUTCOME AND FOLLOW-UP

Our patient was a middle-aged female individual without any risk factors;however,she developed ischemic enterocolitis within half a day after the administration of laninamivirinhalation.Consistent with the previously reported patient who experienced hemorrhagic enteritis/ischemic enterocolitis after the oral administration of oseltamivir[5,7],this patient was diagnosed with ischemic enterocolitis induced by laninamivir,which is a neuraminidase inhibitor similar to oseltamivir.

DlSCUSSlON

Her blood pressure was 115/60 mmHg,and her pulse rate was regular with 77 beats/min.

In total,13 reports of acute hemorrhagic colitis associated with neuraminidase inhibitors,which were published between 2005 and 2020,are shown in Table 1[5,7-14].All previous cases have been attributed to oseltamivir.The age of onset ranged from 12 to 61 years,and there have been no reports of onset among the elderly.Among the 13 patients,nine were female individuals.The time of onset was fourdays following oral administration of oseltamivir in one patient;however,in the remaining patients,acute onset was observed immediately-to-within two days following the oral administration of oseltamivir.The descending colon was the most common site of onset.The outcome was favorable after discontinuation of the drug and conservative treatment;however,in patient 13,the hemoglobin level decreased to 3.8 mg/dL,which necessitated red blood cell transfusions.

Lower gastrointestinal endoscopy performed following hospital discharge(8 d after admission)showed a longitudinal ulcer extending from the descending colon to the sigmoid colon and circumferential edema-like changes(Figure 2).Histopathological examination of the same region(Figure 3)revealed stromal edema,hemorrhage,and inflammatory cell infiltration,with a prominent tendency for detachment of the superficial epithelium.These findings were consistent with those observed in ischemic enterocolitis.She had a score of seven points on the Naranjo algorithm for the adverse drug reaction causality assessment scale[6].Therefore,the patient was diagnosed with laninamivir-induced ischemic enterocolitis.No recurrence of ischemic enterocolitis has been observed in the last five years since the patient presented to us.

During winter,a 54-year-old female patient with no significant medical history presented with general malaise and a fever of 39.2°C.The next day(the second day of symptom onset),the patient visited a nearby medical institution.

During treatment for influenza,attention should be paid not only to respiratory tract symptoms such as pyrexia,cough,and sputum but also to abdominal symptoms.

CONCLUSlON

In conclusion,we treated a patient with ischemic enterocolitis that was considered to be caused by laninamivir.The onset of ischemic enterocolitis,although rare,has been reported following the administration of oseltamivir.Similarly,laninamivir may cause similar abdominal symptoms through the same mechanism;thus,caution should be exercised during the administration of this medication.

FOOTNOTES

Suzuki C managed the case and redaction and correction of the manuscript;Kenzaka T assisted with redaction,correction,and reconstruction of the manuscript;All authors read and approved the final manuscript.

Written informed consent was obtained from the patient for publication of this case report and accompanying images.A copy of the written consent is available for review by the Editor of this journal.

The authors declare that they have no competing interests.

Based on the patient’s clinical symptoms and imaging,her condition was diagnosed as ischemic enterocolitis.

The authors have read the CARE Checklist statement,and the manuscript was prepared and revised according to the CARE Checklist statement.

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Japan

Chihiro Suzuki 0000-0002-2011-6006;Tsuneaki Kenzaka 0000-0002-3120-6605.

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