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Abstract

Previous research has demonstrated that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gains cell entry through the angiotensin-converting enzyme 2 receptor, which is abundantly found throughout the gastrointestinal (GI) tract, resulting in a wide array of GI manifestations of coronavirus disease 2019 (COVID-19). By gaining entry into the intestinal epithelial and stromal cells, SARS-CoV-2 has been observed to cause intestinal inflammation and gut dysbiosis. Alterations in gut microbiota are known to be involved in the pathophysiology of Clostridioides difficile infection (CDI). During the initial stages of the COVID-19 pandemic, rates of CDI were similar to historical data despite the increased use of antibiotics. This may be due to increased emphasis on hygiene and protective equipment and reduced C. difficile testing as diarrhea was presumed to be COVID-19 related. Studies also demonstrated additional risk factors for CDI in COVID-19 patients, including length of hospitalization and new abdominal pain during admission. Although not associated with increased mortality, CDI was associated with increased length of hospital stay among patients admitted with COVID-19. Due to fecal viral shedding and concern of oral–fecal transmission of SARS-CoV-2, increased safety regulations were introduced to fecal microbiota transplantation (FMT) leading to reduced rates of this procedure during the COVID-19 pandemic. FMT for recurrent CDI during the COVID-19 pandemic remained highly effective without any reports of SARS-CoV-2 transmission. In addition, limited data show that FMT may be effective in treating COVID-19 and restoring healthy gut microbiota. The goal of this article is to review the impact that the COVID-19 pandemic has had on hospital-acquired CDI and the utilization of FMT.

Keywords

COVID-19 infectious diarrhea

Introduction

Clostridioides difficile infection (CDI) remains a healthcare epidemic, impacting approximately half of a million individuals in the United States annually with a mortality rate of approximately 6%.¹ CDI most commonly occurs in those recently treated with antibiotics, those with suppressed immunity, the elderly, and those with recent exposure to the healthcare system – though community-acquired CDI is becoming more common.¹ Primary CDI is treated with oral vancomycin or fidaxomicin, although recent Infectious Disease Society of America guidelines positioned fidaxomicin over vancomycin as the preferred treatment.² However, 15–30% of patients experience recurrent CDI (rCDI), defined as a recurrence of symptoms within 8 weeks following treatment for CDI.^3–5 For patients who have failed appropriate treatment for three or more episodes of CDI, fecal microbiota transplantation (FMT) is indicated for the prevention of subsequent recurrences. FMT consists of the infusion of healthy donor fecal microbiota into a recipient with the aim of restoring healthy microbial flora. FMT has been shown to be highly efficacious in rCDI.^6–9

The worldwide coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a significant impact on the healthcare system and healthcare delivery. In the early stages of the pandemic, there was a concern that SARS-CoV-2 infection would increase the risk of superimposed bacterial infections, which led to an increase in antibiotic utilization that could predispose individuals to CDI.¹⁰ However, due to concern regarding fecal–oral transmission of SARS-CoV-2, pandemic regulations limited the availability of FMT, which is an important treatment option for recurrent or fulminant CDI.¹¹ This review aims to explore the pathophysiologic relationship and healthcare impact of the COVID-19 pandemic on CDI and FMT.

Gastrointestinal pathophysiology of COVID-19

Similar to SARS-CoV-1, the angiotensin-converting enzyme 2 (ACE2) serves as the functional viral receptor required for SARS-CoV-2 entry into host cells.^12–16 ACE2 host expression is commonly seen in the epithelial cells of the upper and lower respiratory tract, leading to the commonly observed respiratory symptoms associated with SARS-CoV-2. However, ACE2 is heavily expressed in the stratified epithelium of the upper esophagus in addition to the epithelial and stromal cells of all parts of the small intestine and colon.^14,17–20 This high expression of ACE2 in the absorptive enterocytes of the small intestine and colon is most likely the cause of the gastrointestinal (GI) manifestations of SARS-CoV-2.

GI symptoms have been reported among COVID-19 patients, and a meta-analysis of 60 studies comprising 4243 patients demonstrated that 17.6% of COVID-19 patients experienced GI symptoms, with higher rates in patients with severe COVID-19.^21–28 This meta-analysis found that anorexia was the most common GI manifestation (26.8%), followed by diarrhea (12.5%), nausea/vomiting (10.2%), and abdominal discomfort (9.2%).²¹ In addition, patients presenting with GI symptoms typically present later than those with isolated respiratory symptoms; however, they have delayed viral clearance suggesting prolonged disease.^23,29 Notably, fecal shedding of viral RNA and nucleocapsid protein can be found up to weeks after nasopharyngeal PCR clearance.^{15,16,21,23,24,29–32} Fecal shedding also occurs in patients who do not present with GI symptoms.^27,32,33Interestingly, fecal calprotectin levels in COVID-19 patients have been shown to be elevated, regardless of presenting GI symptoms.^24,34,35 The combination of enterocyte viral replication and intestinal inflammation led to the release of microbial products and intestinal cytokines, promoting dysregulation of the intestinal barrier and dysbiosis of the gut microbiome.^23,24

Clostridioides difficile and COVID-19

Clostridioides difficile, formerly known as Clostridium difficile, is a spore-forming, toxin-producing bacteria. When pathogenic, CDI is clinically characterized by diarrhea which is mediated by release of toxin by the vegetative form.

Initially, there was concern regarding the impact of the COVID-19 pandemic on CDI rates and severity. In the initial stages of the pandemic, while potential treatments were still being investigated, there was widespread use of antibiotics – increasing the risk of CDI, especially in hospitalized patients.^23,36–38 In addition, though overall emergency room utilization was decreased in the initial stages of the pandemic, studies demonstrated the rates of the emergency department visits that led to hospital admissions increased leading to crowded inpatient units which could contribute to CDI.^39,40 Conversely, the increased emphasis on personal protective equipment, enhanced cleaning protocols, and social distancing measures may serve as mitigating factors against nosocomial CDI.

Rates of CDI during the COVID-19 pandemic

Prior to the COVID-19 pandemic, the estimated global incidence of healthcare-associated CDI ranged from 2.8 to 15.8 cases per 10,000 patient-days.^41,42 Furthermore, incidence rates of CDI have been increasing over the last three decades.^42,43 In the COVID-19 era, the rate of healthcare-associated CDI has varied relative to historical data. In a multicenter, international systematic review of 11 studies that evaluated the rates of CDI during the pandemic, 4 studies showed a decrease in CDI incidence compared to their respective institutional historical data, 6 showed no statistically significant change, and only 1 study showed an increase in CDI incidence.^36,44–49 Though onset of diarrhea was uncommonly reported, Allegretti et al. reported that in all patients with confirmed CDI and COVID-19, none presented with diarrhea at the time of admission.⁴⁵ Similarly, Granata et al. found that 32 of 38 confirmed CDI in COVID-19 patients were hospital acquired.⁵⁰ The rate of CDI may be impacted by the rate of CDI testing during the initial stages of the pandemic, with multiple studies showing an initial trend toward decreased testing in the early stages.^47,49,51

Risk factors for CDI in confirmed COVID-19 patients

Risk factors for CDI, regardless of COVID-19 status, have been well established, including recent antibiosis, recent hospitalization, and increased age ⩾65 years. Additional studies have shown a correlation between CDI and proton pump inhibitors, chronic kidney disease, active immunosuppression, and diabetes.^52,53

During the COVID-19 pandemic, multiple studies observed increased antibiotic use, including antibiotic classes known to be high risk for CDI such as lincosamides, monobactams, and third-generation cephalosporins.^36,49,51,54 In the retrospective cohort study performed by Allegretti et al., the median number of distinct antibiotics for all COVID-19 patients during their hospitalization was 4, and all COVID-19 patient who developed CDI were exposed to at least two antibiotics prior to their CDI diagnosis.⁴⁵ However, no statistically significant difference in antibiotic exposures was observed between CDI and non-CDI COVID-19 patients in this study. In contrast, one case–control study showed that antibiosis prior to CDI was an independent risk factor for CDI in COVID-19 patients.

Regarding other CDI risk factors, two studies reported higher rates of proton pump inhibitor use in COVID-19 patients with CDI than those without CDI.^45,55 Multiple studies showed either a trend or statistical significance with immunosuppression or recent steroid administration and CDI.^50,55 Lewandowski et al. identified length of hospitalization, intensive care unit stay, and new abdominal pain during hospitalization as independent predictors of hospital-acquired CDI.⁴⁸

Morbidity and mortality of CDI in COVID-19 patients

The impact of CDI on COVID-19 severity is unknown. The mortality rate of COVID-19 patients with concurrent CDI ranged from 8% to 80%, with most studies showing no association between mortality and CDI.^{45,50,55–57} In addition, the cause of death was rarely attributed to CDI. CDI was not associated with subsequent intensive care unit stay or mechanical ventilation. However, patients with concurrent CDI and COVID-19 infections had increased length of admission compared to non-CDI COVID-19 patients.^36,50,51,55

FMT during the COVID-19 pandemic

FMT has been proven to be highly effective for the prevention of rCDI after a course of standard of care antibiotics and has shown promising results across multiple chronic conditions that have been linked with gut dysbiosis.^58–64 Furthermore, FMT is generally considered a safe and well-tolerated procedure, with a systematic review and meta-analysis showing no differences in adverse events in patients undergoing FMT compared to control groups.^65–67 Given the significant morbidity and mortality of CDI, FMT was recommended to be among non-delayable GI procedures during the COVID-19 pandemic.⁶⁸ However, given known fecal viral shedding of SARS-CoV-2, there was concern for transmission via FMT.

Availability and screening of FMT

Accessibility to FMT decreased during the COVID-19 pandemic. In the initial stages of the pandemic, the Food and Drug Administration recommended that stool samples obtained and prepared prior to 1 December 2019 be used until stool SARS-CoV-2 assays and protocols became established and readily available.⁶⁸ In addition, to decrease the risk of FMT transmission of SARS-CoV-2, expert consensus recommended that stool samples collected after this target date should be stored for 30 days before utilization. If the donor tested positive for COVID-19 in these 30 days, the stool sample was discarded and the donor was unable to supply samples for 8 weeks following infection.¹¹ In addition, it is recommended that all donors be screened for history of symptoms, known exposure to COVID-19, travel history, and prior confirmed infection within 30 days of stool sample donation.^11,68 If patients pass this screen, it is recommended that they undergo laboratory testing. Along with the standard recommended stool and serologic screening for donors, it is recommended to test for COVID-19 infection through combined nasopharyngeal swab and IgM serological testing.⁶⁸ Furthermore, as stool assays have become more validated and available, these tests can be used to detect fecal COVID-19 when accessible.⁶⁹ Positive nasopharyngeal PCR, stool assay, or IgM serological testing should be considered an absolute exclusion from stool donation until 8 weeks after positive laboratory testing.

Safety and efficacy of FMT during the COVID-19 pandemic

Pre-pandemic systematic meta-analyses have demonstrated that FMT is superior to oral vancomycin in treating relapsing and refractory CDI.⁷⁰ One meta-analysis comprising of 37 studies (7 randomized controlled trials and 30 case series) demonstrated a 92% positive response to FMT for the treatment of refractory and relapsing FMT, though with a moderate to high degree of heterogeneity.⁷⁰ In addition to being efficacious, FMT has been demonstrated to be highly safe in the treatment of CDI. Studies have shown that the pooled rate of adverse events following FMT ranges from 31% to 39%; however, these adverse events are mild in character.^71,72 Most commonly, patients experience abdominal pain (~6%), diarrhea (~5%), nausea (4.6%), and abdominal bloating (3.9%). Importantly, rates of significant adverse events ranged from 0% to 7%, with the most common significant adverse event being CDI. No deaths attributed to FMT have been reported. One study showed that younger patients, patients with history of irritable bowel syndrome, and preexisting inflammatory bowel disease were risk factors for GI symptoms following FMT.⁷²

Although no studies have directly compared the safety and efficacy of FMT during the pandemic to pre-pandemic data, available retrospective and prospective studies have demonstrated similar efficacy of FMT for CDI in patients with and without coinfection with COVID-19 during the pandemic compared to pre-pandemic literature. A retrospective cohort study by Khanna et al. demonstrated that in 57 patients undergoing FMT for rCDI during the COVID-19 pandemic, only three patients developed rCDI following FMT with one patient requiring repeat FMT. Only one patient developed respiratory symptoms following FMT, however tested negative for COVID-19.⁷³ No significant adverse events were reported in this study.

In a prospective study of 21 patients undergoing FMT for rCDI and refractory CDI during the COVID-19 pandemic, 18 patients completed 8-week follow-up. In these patients, there were no recurrences of CDI following FMT. In addition, two patients had concurrent COVID-19 pneumonia and CDI, both of which resolved following FMT.⁷⁴ Improved COVID-19 symptoms were also seen in a case series of two patients undergoing FMT for rCDI with concurrent COVID-19.⁷⁵ Furthermore, in one case series, FMT performed 1 month after resolved COVID-19 showed improved resolution of residual GI symptoms and restoration of normal gut microbiota.⁷⁶ Lastly, a retrospective study of 86 patients who had coinfection of CDI and COVID-19 demonstrated that in patients that received both antibiotics and FMT had decreased abdominal pain, decreased relapse rates of CDI, and decreased biomarkers of inflammation compared to those who only received antibiotics.⁷⁷ In the 46 patients who underwent FMT, no adverse events were reported. In these studies, the authors speculate that FMT may have contributed to modulation of the gut–lung axis which is implicated in the pathogenesis of COVID-19.^71,72

Conclusion

CDI remains a leading healthcare epidemic in the United States. Given the potential for life-threatening, fulminant colitis, time-sensitive management of CDI and rCDI remains paramount. During the COVID-19 pandemic, CDI rates have remained stable or may be paradoxically decreased compared to historical data—despite the widespread increased antibiotic administration. This is most likely due to increased emphasis on mitigating hygienic factors such as increased handwashing and the use of protective personal equipment. Though decreased CDI testing and inappropriate attribution of diarrhea to COVID-19 rather than CDI may have confounded these results.

During the COVID-19 pandemic, FMT remains a safe and effective therapeutic intervention in patients with rCDI. Increased safety regulations and stool viral assay testing have helped ease concern for fecal–oral transmission of COVID-19 via FMT. As the healthcare system returns to pre-COVID-19 capacities and behaviors, it is vital to continue hospital hygiene, antibiosis stewardship, and safe, time-sensitive treatment for CDI and rCDI.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Jessica R. Allegretti

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The impact of the COVID-19 pandemic on Clostridioides difficile infection and utilization of fecal microbiota transplantation

Abstract

Keywords

Introduction

Gastrointestinal pathophysiology of COVID-19

Clostridioides difficile and COVID-19

Rates of CDI during the COVID-19 pandemic

Risk factors for CDI in confirmed COVID-19 patients

Morbidity and mortality of CDI in COVID-19 patients

FMT during the COVID-19 pandemic

Availability and screening of FMT

Safety and efficacy of FMT during the COVID-19 pandemic

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References