On 12 March 2020, the World Health Organisation declared that the world was experiencing a pandemic due to human-to-human respiratory transmission of the new ®-coronavirus SARS-CoV-2. While many people with coronavirus disease 2019 (COVID-19) present with respiratory symptoms, a variable but significant percentage, ranging from 34% to 60% of patients with COVID-19 infection, present with gastrointestinal symptoms such as anorexia, vomiting, diarrhoea and abdominal pain1 that are not always associated with respiratory symptoms or symptoms. In fact, viruses have been found in the stool of patients with COVID-192 and diarrhoea has been reported in up to 34% of cases.3 The mechanism of diarrhoea in COVID-19 patients involves the interaction between the viral spike (S) protein with angiotensin-converting enzyme 2 (ACE2) and the TMPRSS2 protease. Both enzymes are not only present in the respiratory tract, but also, to a lesser extent, in the epithelium of the small intestine.4
Bismuth colloidal compounds such as bismuth subsalicylate are antidiarrhoeal drugs with a dual antisecretory and antimicrobial mechanism of action: on the one hand, it stimulates the absorption of fluids and electrolytes through the intestinal wall by inhibiting chloride secretion, and on the other hand, when hydrolysed to salicylic acid, it inhibits the synthesis of prostaglandins responsible for intestinal inflammation and hypermotility. They also have antimicrobial effects as they bind to the enterotoxins of some bacteria such as E. coli, through their conversion to bismuth oxychloride and bismuth hydroxide. Clinical guidelines specify that bismuth subsalicylate is indicated for the treatment of moderate diarrhoea and common digestive complaints such as heartburn and is now also indicated as an adjuvant in the treatment of Helicobacter pylori.
According to utilitarian ethics, in the context of the SARS-CoV-2 pandemic, a prioritisation of the use of health resources is established. This implies that frail, chronically ill elderly patients, who are also often institutionalised in social or residential care facilities with a high incidence of COVID-19, do not have access to mechanical ventilation and therefore have even higher mortality. Diarrhoea is a major problem in these patients, so we designed a prospective study in which the main objective was to determine the efficacy of treatment with bismuth subcitrate (the colloidal bismuth compound available in Spain) in frail patients who are not candidates for mechanical ventilation and admission to the ICU or referral to an acute hospital, with COVID-19 infection and acute diarrhoea as the main or relevant symptom.
To be included in the study, SARS-CoV-2 infection had to be diagnosed by RT-PCR and be a geriatric patient with frailty criteria. Patients with a formal contraindication for treatment with colloidal bismuth compounds, such as the presence of previous kidney failure, bleeding ulcers, hemophilia, or hypersensitivity to salicylates, were excluded.
In this prospective, open-label, single-arm study, all enrolled patients were treated with colloidal bismuth subcitrate (trade name in Spain: Gastrodenol®) from the day they had more than two clearly liquid stools or a total number of stools per day greater than 3 between liquid and pasty. The dosage administered was Gastrodenol® 240 mg (2 tablets) given every 12 h, half an hour before breakfast and dinner on an empty stomach. The study protocol called for treatment to be completed 48 h after cessation of diarrhoea. The endpoint of the study was the number of diarrhoeal stools per day and the number of days with diarrhoeal stools since the day of starting treatment. The study was approved by the CREC of the participating center and by the Spanish Agency for Medicines and Medical Devices in April 2020, under its COVID-19 study incentive programme.
A total of 21 patients (10 women) were included between April 2020 and July 2021, in different waves or peaks of the pandemic. The first 8 were included during the beginning of the pandemic, or what would later be known as the first wave, between March and May 2020. The median age was 78 years (62–92), with a median Charlson index of 4 (1–7). The median number of stools per day at inclusion was 4 stools, with a minimum of 2 and a maximum of 30 stools. Six patients (29%) had 6 or more stools/day. Eight patients (38%) had a fever of more than 38° C. From the date of initiation of bismuth subcitrate treatment until complete disappearance of diarrhoea (more than 24 h without diarrhoeal stools), a median of 4 days elapsed (1–16), with the 2 patients with the highest number of stools, 30 and 15 stools/day, showing resolution of diarrhoea in 2 and 5 days, respectively. Only in 5 patients (24%) the duration was longer than 6 days. A stool culture and Clostridium difficile toxin was requested in all cases, with negative results, thus ruling out a cause of diarrhoea other than COVID-19. In the last 2 cases included, corresponding to the fifth wave, the onset of diarrhoea was the prodrome of the clinical and respiratory worsening of the patient. The percentage of deaths during admission was 24%, with no relation to age (Mann-Whitney U test P = .60), duration of diarrhoea (P = .20) or Charlson index (P = .313). Patients who did not die had a higher mean number of stools than those who died, with a trend close to statistical significance (6.63 vs. 3.00; P = .075). The only side effect observed was the presence of black discolouration in the stool during treatment.
In conclusion, colloidal bismuth subcitrate treatment was effective in resolving diarrhoea in frail patients with COVID-19 infection, especially in those patients with a high amount of stools/day.
Ethical considerationsThe study has been approved by the CREC of the Institut d'Investigacions Sanitàries Pere Virgili (IISPV) in Tarragona and by the Spanish Medicines Agency (AEMPS). Patients verbally consented to inclusion in the study, and this was recorded in the medical records. The CREC granted the exemption from signed written consent, given the COVID-19 pandemic situation, as was customary at the time.
FundingThe study has not required funding.
Conflict of interestsThe authors declare that they have no conflicts of interest concerning this study.
