key: cord-0810287-74i5rpsw
authors: Maslennikov, R.; Ivashkin, V.; Ufimtseva, A.; Poluektova, E.
title: Two consecutive attacks of diarrhea in 15 COVID-19 patients: An antibiotic-associated one following the viral one
date: 2021-12-03
journal: Rev Gastroenterol Mex (Engl Ed)
DOI: 10.1016/j.rgmxen.2021.06.008
sha: 68a0726b25a0f1415813474642c11d93ddfe55cd
doc_id: 810287
cord_uid: 74i5rpsw

Of the 971 patients admitted to our Clinic with suspected COVID-19, 15 (1.5%) presented with two consecutive attacks of diarrhea. One of those patients (a 47-year-old woman) required admission to the intensive care unit and mechanical ventilation. She died on the 11th day of hospitalization (18th day of illness). The first attack of diarrhea in those patients occurred on the 6 th (4th-7th) day of disease and lasted 3 (3-5) days. The second attack of diarrhea developed 11 (8-12) days after the initial onset of diarrhea. Despite the existing trend, the difference in the duration of the diarrhea and the maximum number of bowel movements per day between the first and second attacks was not statistically significant (p = 0.130; p = 0.328). There was no significant difference between the patients with a double attack of diarrhea and those with no diarrhea, regarding the results of the complete blood count, biochemical blood tests, and inflammation biomarkers.

De los 971 pacientes admitidos en nuestra clínica por sospecha de COVID-19, 15

(1.5%) presentaron dos ataques de diarrea consecutivos. Uno de dichos pacientes (una mujer de 47 años) requirió admisión a la unidad de cuidados intensivos y ventilación mecánica. Murió el 11º día de hospitalización (18 días de enfermedad).

El primer ataque de diarrea en dichos pacientes ocurrió el 6º (4º-7º) día de enfermedad con una duración de 3 (3) (4) (5) días. El segundo ataque de diarrea se desarrolló 11 (8-12) días después del comienzo inicial de diarrea. A pesar de la tendencia existente, la diferencia en la duración de la diarrea y el número máximo de movimientos intestinales por día entre el primer y el segundo ataque no fue estadísticamente significativa (p = 0.130; p = 0.328). Tampoco existió diferencia

The novel coronavirus infection (COVID-19) has become a new challenge of our time, 1 but not only as a disease of the respiratory system. Approximately 10% of COVID-19 patients present with diarrhea. [2] [3] In addition, heavy use of antibiotics can lead to the development of antibiotic-associated diarrhea. 4 Our wish was to bring to your attention 15 cases of COVID-19 patients that presented with two consecutive attacks of diarrhea: antibiotic-associated diarrhea following coronavirus-induced diarrhea.

A retrospective single-center study was conducted and included all the patients admitted to the Internal Diseases, Gastroenterology, and Hepatology Clinic of the Sechenov University, with suspected COVID-19, according to the World Health Organization guidelines, 5 from April to July 2020.

Diarrhea was defined as the presence of loose or watery stools, occurring more than 3 times a day. A second attack of diarrhea was defined as loose or watery stools occurring after at least 2 days of bowel movement normalization.

The data were presented as median values (interquartile range) and group comparisons were carried out using the Mann-Whitney U test.

Of the 971 patients with suspected COVID-19 that were admitted to the Clinic, 5 235 presented with diarrhea. Fifteen of those patients had two consecutive attacks of diarrhea. All patients received antibiotics. In addition, they received anticoagulants, glucocorticoids, hydroxychloroquine, and anticytokine drugs, according to indications and contraindications.

There were two-times more women than men (10/5), body mass index was 29.8 kg/m 2 (26.0-33.9), age was 64 years (49-69), and body temperature upon admission was 37.7 (37.2-38.3).

One of the patients that presented with a double diarrhea attack had been previously hospitalized 3 months earlier.

Another of those patients (a 47-year-old woman) was admitted to the intensive care unit and required mechanical ventilation. She died on the 11th day of hospitalization (18th day of illness).

The patients with the two attacks of diarrhea were in hospital for 15 days (13-20) and the total duration of the disease was 25 days (20-29).

The first attack of diarrhea developed before taking antibiotics, and the second one developed after antibiotic use, in all 15 patients (p < 0.001).

The first attack of diarrhea occurred on the 6th day (4th-7th) of disease and lasted 3 days (3) (4) (5) . The maximum number of bowel movements was 3.5 per day (2-4.5).

The initial diarrhea was self-limiting and did not require special treatment in most cases.

The second attack of diarrhea developed 11 days (8-12) from the onset of the first one (i.e., 5 days [4] [5] [6] [7] [8] [9] [10] [11] after the end of the initial attack). It occurred on the 15th day (12th-19th) of disease and lasted 5 days The chronic diseases present in the patients that developed two consecutive attacks of diarrhea were: cardiovascular disease (n = 9), respiratory disease (n = 2), liver disease (n = 1), and kidney disease (n = 3). Three of the patients presented with obesity, one patient presented with cancer, and 4 had diabetes. Five of the 15 patients with a double attack of diarrhea did not have chronic diseases.

There was no significant difference between the patients with a double attack and the patients with no diarrhea, regarding the results of the complete blood count, biochemical blood tests, and inflammation biomarkers.

The mortality of patients with a double attack of diarrhea (6.7%) did not differ significantly from the mortality of patients without diarrhea (3.8%; p = 0.596) or from the patients with one attack of diarrhea (4.5%; p = 0.707).

The patients with a double attack of diarrhea had no history of inflammatory bowel disease or irritable bowel syndrome and had no diarrhea after hospital discharge, during the 6 months of follow-up.

can also be a complication of antibiotic treatment for mixed viral-bacterial pneumonia. Separating those types of diarrhea remains challenging. Diarrhea in COVID-19 can be divided into early diarrhea (which develops before hospitalization) and late diarrhea (which appears during hospitalization). [6] [7] Moreover, in a study by Lin et al., late diarrhea developed almost exclusively in patients that were given antibiotics. 6 The incidence of late diarrhea was approximately 25% in the patients that received antibiotics and about 5% in those that did not. Therefore, we believe that in most cases, early (pre-hospitalization) diarrhea has a viral origin, whereas late (during hospitalization) diarrhea is antibiotic-associated. In our cases, late diarrhea developed after antibiotic use in all the cases, and C. difficile toxins were detected in all of the four patients tested.

The differential diagnosis of late diarrhea also included other infectious diarrheas, inflammatory bowel disease, and irritable bowel syndrome. The development of another type of infectious diarrhea during hospitalization at our clinic is extremely unlikely due to the existing high sanitary standards. Inflammatory bowel disease J o u r n a l P r e -p r o o f and irritable bowel syndrome are manifested by chronic diarrhea, but in our cases, the diarrhea was acute. There was also no history of those bowel diseases, nor were there any new attacks of diarrhea during the 6 months of follow-up, making inflammatory bowel disease and irritable bowel syndrome unlikely causes of diarrhea in our patients.

We present herein a case series of COVID-19 patients that had a double attack of diarrhea, in which the first attack developed before the patients received antibiotics, and the second attack developed after the patients started receiving antibiotics. Our observations provide evidence of the heterogeneity of diarrhea in COVID-19: the first attack can be interpreted as viral diarrhea, and the second as antibiotic-associated diarrhea.

The strength of our manuscript lies in the fact that it is the first to describe a case series on COVID-19 patients with a double attack of diarrhea. A limitation of our study is its small number of cases, as well as the low number of patients tested for the presence of C. difficile toxins. Further studies with a large number of such cases and C. difficile testing at each attack in all patients are needed, to confirm our study conclusions.

All procedures involving human participants were performed in accordance with the ethical standards of the institutional research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent was obtained from all individual participants included in the study.

The study was approved by the ethics committee of the Sechenov University.

COVID-19: a review

Patients With Gastrointestinal Symptoms: A Systematic Review and Metaanalysis

Diarrhoea in adults with coronavirus disease-beyond incidence and mortality: a systematic review and meta-analysis. Infectious diseases (Lond)

Clostridium difficile infection and antibioticassociated diarrhoea

Clinical management of COVID-19. WHO/2019-nCoV/clinical/2020.5 Clinical management of COVID-19: interim guidance

Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection

Diarrhea and altered inflammatory cytokine pattern in severe coronavirus disease 2019: Impact on disease course and inhospital mortality