|Year : 2021 | Volume
| Issue : 4 | Page : 139-142
Managing patients with inflammatory bowel disease during the COVID-19 pandemic
Balakrishnan S Ramakrishna
Institute of Gastroenterology, Hepatobiliary Science and Transplantation, SRM Institutes for Medical Science, Chennai, Tamil Nadu, India
|Date of Submission||01-Sep-2021|
|Date of Acceptance||04-Sep-2021|
|Date of Web Publication||24-Sep-2021|
Balakrishnan S Ramakrishna
Institute of Gastroenterology, Hepatobiliary Science and Transplantation, SRM Institutes for Medical Science, Vadapalani, Chennai - 600 026, Tamil Nadu
Source of Support: None, Conflict of Interest: None
The coronavirus disease 2019 pandemic has paralyzed the world now for 20 months. SARS-CoV-2 infection appears to result in a number of inflammatory, thrombogenic, and immune events in susceptible individuals. Patients with inflammatory bowel disease (IBD) are on chronic immunosuppressive medication. Furthermore, they have relapses of disease that requires intensification of their immunosuppressive treatment. Our understanding of the management of such patients during a viral pandemic has significantly improved due to the scientific exchanges that have taken place, through print publication and virtual sharing of experiences among IBD caregivers. This brief review provides an overview of the basic immunology of SARS-CoV-2 infection, how it impacts patients with IBD and current guidelines on managing therapy for IBD patients during a pandemic.
Keywords: Coronavirus disease 2019, Crohn's disease, pandemic, SARS-CoV-2, treatment, ulcerative colitis
|How to cite this article:|
Ramakrishna BS. Managing patients with inflammatory bowel disease during the COVID-19 pandemic. Gastroenterol Hepatol Endosc Pract 2021;1:139-42
| Introduction|| |
In November 2019, a cluster of viral pneumonias was detected in Wuhan, Hubei Province, China. This outbreak was reported to the World Health Organization on December 31, 2019. The causative agent was identified as a beta-coronavirus with high sequence homology to bat coronaviruses. It was determined that the virus entered cells using the angiotensin-converting enzyme 2 receptor on cell surfaces as the dominant mechanism of cell entry. The virus, initially called the Wuhan virus, was renamed as the severe acute respiratory distress syndrome Corona virus 2 (SARS-CoV-2) and the pneumonic illness that it caused was termed coronavirus disease 2019 (COVID-19). On March 11, 2020, the World Health Organization declared COVID-19 a pandemic. The COVID-19 pandemic has not yet subsided and has impacted the lives of many people, and the concern is that it would especially impact those individuals who are immunosuppressed due to disease or therapy.
| Immunology of SARS-CoV-2 Infection|| |
Overall responses of the immune system in SARS-CoV-2 infection
While a lot remains to be elucidated regarding the immunology of SARS-CoV-2, our understanding has been shaped by studies that have been carried out with respiratory viruses, especially coronavirus infections. [Figure 1] provides a broad (and oversimplified) overview of the immune response to SARS-CoV-2 infection in man. Viral replication in the body starts 2–3 days before the development of symptoms and is followed within a day by innate immune responses to the virus. Innate immunity is the first line of antiviral defense and is conserved across nature. Nonspecialized immune cells including epithelial cells, monocyte-macrophages, myeloid cells, lymphoid cells, and natural killer (NK) cells may all be involved in the innate immune response. These cells detect viral single-stranded or double-stranded RNA through pattern recognition receptors in the cytoplasm (RLR) or extracellular and endosomal toll-like receptors. Through the activation of nuclear factor kappa B and other transcription factors, this triggers release of cytokines – types I and III interferons, tumor necrosis factor α, interleukin-1, interleukin-6, and interleukin-18. Interferon-induced proteins have a biphasic effect in COVID illness. Early in the illness, they limit SARS-CoV-2 entry into cells and have a protective effect, whereas they cause tissue damage in later stages. The inhibition of interferon type I by SARS-CoV-2 plays a critical role in pathogenicity of the virus. Cellular immune responses and humoral immune responses start soon after the initiation of the innate immune response. Cellular immune responses tend to peak 10–12 days following onset of infection and wane in 6–8 weeks. Humoral responses, with the production of antibody, begin around day 5 of infection and continue for at least 3 months thereafter.
|Figure 1: This figure is adapted from Subbarao and Mahanty 2020 (Ref. 2). Viral replication is observed 2 days before clinical disease and lasts into the first week of illness. Patients with mild disease recover within a week, and this is characterized by a self-limited waning of the innate immune response within the first week. The cellular immune response continues and wanes within about a month, while the humoral immune response continues even thereafter|
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Innate immune responses and genesis of inflammation in COVID
In individuals with minimal or no symptoms, the innate immune response and inflammatory cytokine output wane by about day 10 of infection, while humoral and cellular immune responses continue as described, leading to early recovery [Figure 1]. In a minority of individuals, the innate immune response and cytokine output continue unabated leading to severe disease, with consequent disability and, sometimes, death [Figure 2]. Myeloid and NK cells are the major innate immune cells that drive the hallmarks of severe COVID illness. These syndromes include acute respiratory distress syndrome, cytokine release syndrome (CRS), secondary hemophagocytic lymphohistiocytosis (sHLH), and lymphopenia. The major players in the cytokine storm in severe COVID illness include interleukin-1β, interleukin-6, and interleukin-18. Infected lung epithelial cells also play a part in pathogenesis by releasing interleukin-6, interleukin-1β, and interferon III, which in turn recruit monocytes, granulocytes, and lymphocytes to the sites of inflammation. Monocytes release interleukin-6 and tumor necrosis factor α leading to CRS and sHLH, which in turn leads to the generation of neutrophilic extracellular traps and microthrombosis. It is likely that innate lymphoid cells also play a role in the pathogenesis and this is an area that is under exploration.
|Figure 2: This extension of [Figure 1] shows that severe disease and death is essentially a consequence of a runaway innate immune response, one consequence of which is the cytokine release syndrome. The role of cellular immunity in these patients is not yet clear|
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Role of T cells in COVID
T cells include cluster of differentiation 4 positive (CD4+) T helper cells and cluster of differentiation 8 positive (CD8+) T cells. The CD4+T cells help B cells in antibody production and orchestrate the response of other immune cells. On the other hand, the CD8+T cells kill infected cells to reduce the viral burden. In severe COVID illness, lymphopenia with reduced CD4+and CD8+cells is characteristic. There is an increase in activated CD4+and CD8+T cells with an “exhausted” phenotype. An elevation of Th2 cytokines (interleukin-4, interleukin-5, and interleukin-10) correlates with lethal outcomes in the disease.
Role of B cells in COVID
In SARS-CoV-2 infection, antibody to spike protein (broadly correlating with neutralizing antibody) is detectable up to 60 days after symptom onset and decreases thereafter. A high titer of neutralizing antibody has been shown to correlate with mortality. It has been suggested that antibody-dependent enhancement contributes to pulmonary pathology. Studies from SARS-CoV-1 have shown that immunoglobulin G and neutralizing antibody responses diminish 2–3 years after infection. Long-lasting memory T cell responses have been shown. The role of memory B cells is not known.
| Treatment of Inflammatory Bowel Disease During the Pandemic|| |
The occurrence of the viral pandemic in 2020 placed a huge burden on caregivers of patients who were immunocompromised, including patients with chronic diseases, patients on immunosuppressive medication, and transplant recipients. It was not clear how these patients would respond if they were to be infected with SARS-CoV-2 with hypothetical beneficial or detrimental outcomes. Inflammatory bowel disease (IBD) posed a big challenge for gastroenterologists, but experience over the 20 months of this pandemic has left us with fairly clear guidelines on how to manage these patients.
Patients without SARS-CoV-2 infection
Here, the consensus is to continue immunomodulators, biologics, and JAK inhibitors. Corticosteroids should be reduced. Where possible, budesonide should be used in preference to prednisolone or methylprednisolone., [Table 1] lists the Asia Pacific Association of Gastroenterology guidelines and [Figure 3] shows the American Gastroenterological Association (AGA) guidelines for using medication in IBD patients who are not infected with SARS-CoV-2.
|Figure 3: Management algorithm proposed by the American Gastroenterological Association (Rubin et al, Ref. 4) for patients presenting with new onset IBD or flares of IBD|
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|Table 1: Medications that can be used in inflammatory bowel disease patients who are not infected with severe acute respiratory distress syndrome-coronavirus-2 (Asian Pacific Association of Gastroenterology guidelines)|
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Patients with mild COVID
Mild disease is defined as those patients who are not hospitalized, whose SpO2 is >94, and who have no pneumonia. In these patients, it is advisable to taper steroids to 20 mg per day or less of prednisolone, switch to budesonide, and to continue 5-ASA, rectal therapies, and enteral nutrition. Immunomodulators such as azathioprine and mercaptopurine and JAK inhibitors should be stopped. Biologics administration should be delayed for 2 weeks to see if the illness resolves or the patient develops convalescent titers to SARS-CoV-2. If not, biologics should continue to be withheld. In asymptomatic patients, the discontinued medication can be restarted 10–14 days after symptoms appearance. The guidelines of the AGA are summarized in [Figure 3].
Patients with moderate to severe COVID
Moderate COVID-19 is where a patient is hospitalized with SpO2 <94, and the computed tomography scan shows pneumonia. Severe COVID is defined when a patient develops organ failure or is intubated. In these patients, it is essential to taper prednisolone and to switch to budesonide, to continue 5-ASA, rectal therapies and enteral nutrition, and to hold azathioprine, methotrexate, and JAK inhibitors. Biologics are withheld just as in mild COVID. The focus in these patients is on the support and treatment of COVID-19 with anti-inflammatory, anticytokine, and antiviral therapies [Figure 3]. In patients with severe COVID illness, the treatment may be withheld until the nasopharyngeal swab polymerase chain reaction (PCR) for SARS-CoV-2 becomes negative.
| Outcomes of SARS-COV-2 Infection in Inflammatory Bowel Disease Patients|| |
Are inflammatory bowel disease patients on immunosuppressants more likely to contract COVID?
In general, it is believed that the incidence of COVID-19 is not increased in patients with IBD. In a systematic review that analyzed 10 studies with 249,095 patients, 309 patients tested positive for the virus. Of 5098 patients receiving biologics, 4 tested positive for SARS-CoV-2. The pooled incidence among all IBD patients was 1.93 (95% confidence interval [CI]: 0.48–7.77) per 1000 IBD patients. The incidence among IBD on biologics was 0.68 (95% CI: 0.26–1.82) per 1000. In studies using only reverse transcription PCR, the incidence was 4.2 per 1000 for all IBDs and 1.14 per 1000 for IBD patients on biologics.
Are inflammatory bowel disease patients more likely to develop severe illness if they contract SARS-CoV-2 infection?
Data from the surveillance epidemiology of coronavirus under research exclusion–IBD (SECURE-IBD) registry initially suggested that IBD patients may be at increased risk of adverse outcomes if they contracted SARS-CoV-2 infection, with a sex-standardized mortality ratio of 1.4. However, a propensity-matched study showed no increased hospitalization or mortality. In the latter study, it was shown that patients with more than one risk factor were likely to need hospitalization while those with two or more comorbidities had a 3-fold risk of requiring intensive care unit (ICU) care, ventilation, or death. Of 6176 patients with IBD who had COVID-19 illness, 83% were managed as outpatients, 15% were hospitalized and recovered (3% required ICU care), and 2% died (SECURE-IBD registry data accessed on May 26, 2021). When the influence of different medications on COVID-19 outcome in IBD patients is considered, data from the SECURE-IBD registry indicate that steroid use confers the greatest risk of mortality, while the use of antitumor necrosis factor α agents is associated with least risk of mortality [Figure 4].
|Figure 4: Data from the SECURE-IBD registry (Ref. 6) showing the breakdown of IBD patients with symptomatic COVID according to the medication being consumed (bars indicate numbers of patients on each type of medication, plotted on the left Y axis). Also shown are the percentage o f deaths in patients on each type of medication (line, plotted on the right Y-axis). Deaths were least in patients on biologics and highest in those on steroids|
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| Prevention of COVID Illness in inflammatory bowel disease Patients|| |
During the very first wave of SARS-CoV-2 infection, none of 318 IBD patients living in Wuhan contracted symptomatic SARS-CoV-2 infection, despite living in the epicenter of COVID-19. They were all contacted in advance and counseled to stay at home and follow masking and strict social distancing. All patients with IBD are advised to get immunized against SARS-CoV-2. The international organization for IBD has made consensus recommendations regarding vaccination in patients with IBD. In summary, these recommendations are as follows. Patients with IBD should be vaccinated against SARS-CoV-2 at the earliest opportunity. The vaccines that may safely be used include messenger RNA vaccines, replication-incompetent vector vaccines, inactivated vaccines, and recombinant vaccines. Immunization need not be deferred if the patient is receiving immune-modifying therapies. For patients receiving biologics, there is no specific recommended time when the vaccine can be administered; immediately after an infusion or midway between two doses is all acceptable. Vaccine efficacy may be decreased when receiving systemic corticosteroids and this needs to be discussed with the patient.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]