key: cord-0981606-7god1s89
authors: Theodorou-Kanakari, Anna; Gkolfakis, Paraskevas; Tziatzios, Georgios; Lazaridis, Lazaros Dimitrios; Triantafyllou, Konstantinos
title: Impact of COVID-19 pandemic on the healthcare and psychosocial well-being of patients with inflammatory bowel disease
date: 2022-02-10
journal: Ann Gastroenterol
DOI: 10.20524/aog.2022.0686
sha: 09890c478b64b656ff7e505fb64193f7f2877dde
doc_id: 981606
cord_uid: 7god1s89

COVID-19 pandemic has resulted in unprecedented disruptions to several aspects of gastroenterology healthcare services worldwide. In particular, patients with inflammatory bowel disease (IBD) represent a sensitive population that must retain access to healthcare services to avoid potential disease exacerbation under the continuous threat of viral infection. Emerging evidence also highlights the severe impact on these patients’ mental well-being, leading to a constant cycle of stress/depression and disease activity relapse. In an effort to circumvent these healthcare challenges in a newly-shaped environment, physicians implemented telemedicine consultative care programs as a novel alternative follow-up method highly favored by the patients. The situation is still far from perfect, since a large proportion of patients are lost to follow up and/or lose adherence to their medication, especially when the exact timeframe or optimal strategy for the post-COVID era remains to be defined. Cancelation of elective endoscopic procedures has led to a significant decline of new IBD diagnoses. This review summarizes the data on the global impact of COVID-19 on IBD patients’ healthcare and their psychosocial status.

Starting from Wuhan city in Hubei province, China, the novel coronavirus SARS-CoV-2 rapidly spread all around the world, leading to a global health crisis, with millions of cases and deaths. During this period, 6242 patients with inflammatory bowel disease (IBD) have been entered into the SECURE-IBD database (until 8 June 2021), of whom 15% needed hospitalization and 2% lost their lives [1] . The IBD community worldwide had to face up to these unprecedented circumstances, while maintaining the quality of IBD care standards [2] . Telemedicine replaced face-to-face visits, elective endoscopy and surgical procedures were temporarily postponed, and strict hospital protocols were adopted in an effort to interrupt virus transmission [2, 3] .

There is unanimity among the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) [4] , the European Crohn's and Colitis Organization (ECCO) [2] , the American Gastroenterology Association (AGA) [5] and the Hellenic Study Group for Inflammatory Bowel Diseases (EOMIFNE) [6] that IBD patients are not facing a higher risk of SARS-CoV-2 infection compared to the general population. On the contrary, some might even develop less severe forms when infected [7] . Initially, evidence suggested a greater probability of hospitalization among patients receiving prednisolone, azathioprine, infliximab or adalimumab, compared to other IBD patients [6] . However, negative COVID-19 outcomes have only been associated with active IBD, older age, presence of comorbidities and high doses of corticosteroids, but not with other IBD treatments [8] . Therefore, patients should remain adherent to their medication to avoid an IBD flare that may require steroid therapy or hospitalization, both of which are related to a higher risk of an unfavorable COVID-19 outcome compared to the known risks of IBD therapies [5] .

All IBD patients are strongly recommended to get vaccinated against SARS-CoV-2 as soon as possible [9] . All available vaccines are considered equally safe and effective for IBD patients; however, vaccine efficacy may be decreased in those receiving systemic corticosteroids. As far as patients under biological treatment are concerned, the only recommendation is to avoid receiving the vaccine on the same day as an infusion/subcutaneous dose, to avoid misinterpretation in case an adverse event occurs [10] .

IBD is a chronic disease requiring tight control of activity, close monitoring of treatment, and a patient-oriented approach focusing on their physical and psychological well-being. Compared to non-IBD peers, they have a greater likelihood of developing depression and anxiety disorders [11] , especially in the case of active disease [12] . The COVID-19 pandemic has exacerbated the problem, since individuals in self-isolation or under quarantine measures are more likely to develop mental health problems such as depression and anxiety [13] . This review presents the available evidence about the impact of the COVID-19 pandemic on IBD patients' healthcare and their psychosocial well-being.

The Medline database was searched for eligible studies up to 12 OR (Crohn's Enteritis) OR (Ulcerative Colitis)). All types of studies published in the English language, referring to humans and providing numerical data, were considered eligible for inclusion, while studies in any other language, non-human, ex vivo or pilot studies, editorials, narrative or systematic reviews and case reports/series were excluded from this review. After the exclusion of duplicates and articles deemed irrelevant to the study's aim, 24 original studies are discussed . Their characteristics are summarized in Table 1 .

During the COVID pandemic all IBD units had to remodel their everyday clinical practice, affecting the quality of healthcare services provided to their patients. Guidelines were immediately developed by ECCO [2] , BSG [3] , IOIBD [4] , AGA [5] and EOMIFNE [6] to provide actual guidance regarding the management of IBD patients during the COVID pandemic. However, findings from surveys around the world reveal significant diversity. Most of them were conducted via electronically distributed questionnaires, aiming to evaluate various outcomes such as disease activity, presence of symptoms, adherence to medication, psychological condition, possible worries of the patient, and familiarization with telemedicine.

For the purposes of this review, the impact of the COVID-19 pandemic on IBD patients' healthcare is presented in terms of direct and indirect outcomes. Direct outcomes include flareups, hospitalizations and emergent surgeries, while indirect outcomes include treatment discontinuation, delay in infusion of biological agents, and loss of patient follow up, namely outcomes that could lead to IBD exacerbation and need for intervention.

As presented in Table 2 , there is significant variance among the direct outcomes reported across different surveys. Flareup rates fluctuate between 0.5 and 56%, emergent surgeries between 0.2 and 17.9%, and hospitalization rates between 0.78 and 15.8%. That is also the case for indirect outcomes, where treatment discontinuation varies between 3.73 and 28%, and delay of infusions from 1.3-69.6%. The main reason for these outcomes is patients' choice to stop their treatment or delay their infusion due to fear of COVID-19 contamination, especially in healthcare settings. Moreover, 1 of 4 patients have been lost to follow up (range 4-38.7%).

An observational study performed in Spain aimed to evaluate the impact of COVID-19 on an IBD unit's activity, comparing data to those from the previous year [20] . Sixty-four (76.19%) of the elective endoscopies and all scheduled surgeries were suspended. This led 9.4% of patients to experience a flare of IBD symptoms in the first 2 months of lockdown, compared to 6.9% the previous year (2.5% increase, P=0.18). Loss of follow up increased from 3.6% to 5.1%, and adherence to medication decreased from 99.5% to 94.9% (P<0.05). In particular, the discontinuation of biological treatment was almost 8-fold (from 0.5% to 3.73%, P<0.05).

As expected, patients who discontinued medication on their own initiative faced an increased risk for adverse outcomes. In a study from China, where guidance through telemedicine was provided, 107/386 (28%) of the patients reported treatment discontinuation and 108/386 (28%) experienced a flare-up [15] . Among those stopping their treatment, 57% (61/107) eventually required hospitalization and 4.7% (5/107) needed surgical treatment. Hospitalization rates were clearly and significantly higher among patients who discontinued their medication (57% vs. 0.78-15.8%).

It is noteworthy that adherence to the different categories of medication may be variable. An online survey from the United Kingdom [21] showed that the most frequently discontinued medications were oral steroids (43.9%). Immunomodulators were discontinued by 11.2% of the patients, 1 of 3 against a physician's recommendation. Contrariwise, adherence to biological agents remained high, since 99% of them continued their use. Between March and August 2020, 36 half of them contacted neither their general practitioner nor the IBD helpline and self-managed their symptoms. A retrospective study conducted in the Netherlands used the nationwide registry of histo-and cytopathology researchers to compare the number of IBD-related procedures between 2020 and 2019 [38] . Overall, 14.2% fewer IBD-related procedures were performed between February and August 2020. More specifically, at the peak of the pandemic (April) the decline was almost 60%, while 125 fewer new diagnoses and 214 fewer lowgrade dysplasia diagnoses were established, corresponding to reductions of 6.5% and 25.5%, respectively, compared to the previous year. Notably, no decline in high grade dysplasia or colorectal cancer was recorded.

Apart from the direct and indirect outcomes mentioned above, all aspects of IBD patients' healthcare were also disrupted. A questionnaire survey conducted by phone in Brazil to estimate the impact of the pandemic on IBD follow up and on patients' well-being [37] showed that medical therapy was discontinued by 28.4% of the patients, with fear of infection being the main reason. In addition, 83% missed at least one medical appointment, 45.5% missed their laboratory test, while 17% did not have any access to medical prescriptions or skipped their endoscopy.

There are many surveys featuring the negative impact of lockdown combined with the fear of SARS-CoV-2 infection on the psychosocial well-being of patients with IBD. For the purposes of this review, psychological outcomes have been divided into reported "negative mood", depression and anxiety (Table 3) . A point that deserves attention is the fact that, in the majority of the studies (n=5/6), establishment of a mood disorder was not achieved via implementation of a validated questionnaire, but based on a simple report by the patient evaluated through scales created by the authors themselves; thus, all results should be interpreted cautiously. Only the study by Trindale et al [36] used a validated instrument, the Hospital Anxiety and Depression Scale (HADS), specifically designed to address anxiety and depression as 2 separate subscales. Similarly, the validated Short Inflammatory Bowel Disease Questionnaire (SIBDQ) was used to assess the significant aspect of Health-Related Quality of Life (HRQoL) in the study by Yu et al [14] . As shown in Table 3 , reports about "negative mood" varied between 0.5 and 52.99%, while regarding depression and anxiety the respective percentages ranged from 52.4-58.2% and 2.98-80%. Stress and depression may lead to IBD exacerbation, while flares can be followed by depression and anxiety, leading to a self-perpetuating cycle [12] . This is corroborated by a survey from the UK, focusing on stress-related consequences of the pandemic in patients with Crohn's disease [22] . A total of 136 (56%) patients reported symptoms of disease activity. There was a 24% relative increase in active symptoms during the lockdown compared with the previous months. "Increased stress and/ or feeling of being overwhelmed" (118/236) was reported as the cardinal reason for the change. Among those reporting stress at the time of the survey, the relative increase in active symptoms was even more pronounced (42%). Despite the fact that IBD patients face no greater risk of SARS-CoV-2 infection [2] [3] [4] [5] , they seem to be more afraid than their non-IBD peers, since 38.2% of them admitted to leaving the house less frequently than their flat mates [23] . Findings from a similar survey [36] demonstrated that people in isolation had more symptoms of depression, but fewer symptoms of anxiety, because of the low fear of getting infected. According to the same survey, IBD patients reported that the pandemic had a negative or an extremely negative impact on their quality of life (42.8% and 10.2%, respectively). This impact was worse among younger adults. Almost half of the patients reported insomnia, reduced daily activity and productivity, as well as sexual dysfunction [37] .

Data comparing the psychosocial status of IBD patients between the pre-and during-COVID-19 periods remain scant and heterogeneous. Harris et al [21] documented a significant increase in overall stress between the 2 eras (mean stress score pre-lockdown 4.0 vs. 5.5 during lockdown). Moreover, a history of anxiety or depression correlated with greater stress scores pre-lockdown (P=0.0005), during lockdown (P=0.0005) and concerns about a "second wave" (P=0.008). In another study, the proportion of respondents feeling "stressed" of "very stressed" was significantly higher during the COVID-19 period compared to the pre-COVID-19 era (n=122/236, 52% vs. n=73/236, 31%) [22] . More importantly, not only were these higher stress levels identified as the reason for a change in symptoms from pre-to during COVID-19, but also the percentage increase in active symptoms was more pronounced among those reporting current stress (42%, n=122, P<0.0001).

The doctor-patient relationship has been always the cornerstone of IBD patient healthcare. Clinical visits were the most common manner of follow up. However, the urgent need for telemedicine during the COVID-19 pandemic probably introduced long-term changes in medical practice. Findings of a tertiary referral center for IBD in Italy, which has largely embraced telemedicine, especially video-consultations, suggested that 95% of their patients using telemedicine trusted this method of follow up [31] . Another survey revealed that, although 65.8% of patients preferred face-to-face visits during flares, 67.3% of them preferred telephone follow up at remission in the post-COVID era [21] . Regarding gastrointestinal physicians, the majority (72.0%) agree that telemedicine should partly replace clinic visits in the future [28] .

The healthcare environment of IBD patients has been greatly affected by the COVID-19 pandemic. Although telemedicine rapidly emerged to replace clinical visits, it cannot fully take their place. Many visits were postponed around the world without being replaced by virtual meetings, especially in the case of first visits, rather than follow ups. The greatest limitation of the studies conducted in this COVID-19 era is that a significant number of patients did not participate in the online surveys. It is possible that people who did not participate in the surveys might have had risky behavior, such as non-adherence to medications [39] . Hence, the actual impact of the pandemic may be even larger in the real world setting, and studies seem to underestimate it. To make things even more ambiguous, one should take into account that the pandemic is not over yet and the optimal strategy for restarting remains unknown. Thus, the consequences will not be fully understood until later. Another limitation is associated with the heterogeneity in methods, aims and patient cohorts among the aforementioned studies. As a result, the data are not easily comparable, warranting further and more detailed studies.

A third limitation concerns the number of deaths due to disease exacerbation, which were excluded from the strict/ direct outcomes, since the studies were conducted mostly via questionnaires and not using hospital medical files. Moreover, reported flare-ups were mostly based on patients' symptoms and were not confirmed by either endoscopy or laboratory findings. Notably, symptoms like diarrhea, even increased fecal calprotectin (FC) levels, have been associated not only with IBD flare but also with COVID-19 disease [40] .

Indeed, diarrhea represents a common symptom of COVID-19 infection, and for almost 10% of non-IBD patients can be the only symptom, without respiratory involvement [41] . These patients are at risk for a severe COVID-19 disease outcome, probably because of the delay in diagnosis. This percentage is even higher among IBD patients, according to a recent systematic review [42] .

FC, a stool marker extremely useful in the differential diagnosis of an IBD flare-up, has been suggested as a homebased test for remote monitoring during the pandemic. However, there are indications that FC can be elevated in COVID-19 positive patients, especially among those with symptoms of diarrhea [40] . This is in line with the findings of a systematic review, according to which more than half of SARS-CoV-2 positive patients with gastrointestinal symptoms had elevated FC [43] . This means that the use of FC as a tool during the follow up of IBD patients is problematic during the pandemic, especially in the discrimination between COVID-19 infection and an IBD flare.

Another important issue is postponed endoscopies. Endoscopic procedures are an integral part of IBD surveillance, especially in monitoring therapy efficacy and screening for dysplasia or cancer [44] . Long waiting lists in the postpandemic era will bring the need for specific prioritization. Experts recommend [45] that, during the first 3-6 months after lockdown, priority should be given to mild or moderate flares, subacute bowel obstruction, new IBD diagnosis with abnormal biochemical test, and surveillance for colorectal cancer and postoperative recurrences. All patients should be tested for COVID before the procedure. Capsule endoscopy (CE) could find a breeding ground in the post COVID era [46] . CE could play an important role in Crohn's disease activity monitoring before and after the escalation of treatment, as it provides an alternative evaluation method that will offload the pressure from endoscopy departments. Fear of SARS-CoV-2 infection in healthcare settings is one of the main reasons for non-adherence to medication during the pandemic. However, adherence to biological treatment was already a major issue even before the pandemic. A systematic review in 2013 reported that pooled adherence to anti-tumor necrosis factor (TNF) was 82.6% (83% for adalimumab and 71% for infliximab) [47] . As a result of anti-TNF discontinuation, 55% of patients with Crohn's disease or ulcerative colitis relapse after 32 and 18 months, respectively [48] . Hence, the effects of treatment discontinuation on patient health during the COVID era will be best evaluated in the near future. On the other hand, delays in the management of IBD patients due to limited access to the healthcare system will also have a huge impact on their overall well-being. A recent study estimated that a 3-month delay in cancer surgery, due to focusing on COVID-19 care, reduces the benefit in life-years gained of all COVID-19 care by 19% [49] .

Hence, in light of the community's uncertainty-despite the vaccination-about when we will fully return to normality, there are some issues that needed to be directly addressed. Firstly, IBD units should actively ensure that patients will not delay their infusions. Phone calls 1 or 2 days earlier than the infusion could play a key role in patient adherence. Moreover, medical staff should be familiar with telemedicine. Home care nurses could play a crucial role in this direction by roughly assessing IBD patients well-being, carrying out blood tests and collecting FC samples. Lastly, effective and frequent communication between doctor and patient is the steppingstone for patients to express their worries or practical problems. Of course, they should be strongly advised to remain adherent to their medication, get vaccinated and apply hygiene measures, but at the same time to exercise, keep up with their hobbies and close friends if possible, so they can preserve their physical and mental well-being. From the clinician's point of view, all appropriate measures that should be implemented to optimize IBD patients' management (assessment according to severity of IBD and concurrent underlying COVID-19 infection, as well as prevention of infection transmission and management of non-COVID IBD patients) are thoroughly summarized within currently available guidelines [4, 5] . Rather than focusing on efforts to address this topic, our review adds to the existing literature by identifying gaps in current knowledge, discussing important flaws of study design, and contextualizing the benefit of existing studies for everyday clinical practice.

The COVID-19 pandemic has negatively affected the quality of healthcare of IBD patients. Despite the widespread use of telemedicine, a large proportion of patients have been lost to follow up, while others failed to remain adherent to their medication. A pronounced decline in new IBD diagnoses has also been reported. Moreover, the pandemic has had a detrimental psychological impact on IBD patients, leading to a self-perpetuating cycle of stress/depression and disease activity. Telemedicine has been gaining ground as a possible alternative follow-up method in IBD remission, accepted both by patients and physicians.

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