Persistent symptoms are common after SARS-CoV-2 infection but correlation with objective measures is unclear.We invited all 3098 adults who tested SARS-CoV-2 positive in Iceland before October 2020 to the deCODE Health Study. We compared multiple symptoms and physical measures between 1706 Icelanders with confirmed prior infection (cases) who participated, and 619 contemporary and 13,779 historical controls. Cases participated in the study 5–18 months after infection.Here we report that 41 of 88 symptoms are associated with prior infection, most significantly disturbed smell and taste, memory disturbance, and dyspnea. Measured objectively, cases had poorer smell and taste results, less grip strength, and poorer memory recall. Differences in grip strength and memory recall were small. No other objective measure associated with prior infection including heart rate, blood pressure, postural orthostatic tachycardia, oxygen saturation, exercise tolerance, hearing, and traditional inflammatory, cardiac, liver, and kidney blood biomarkers. There was no evidence of more anxiety or depression among cases. We estimate the prevalence of long Covid to be 7% at a median of 8 months after infection.We confirm that diverse symptoms are common months after SARS-CoV-2 infection but find few differences between cases and controls in objective parameters measured. These discrepancies between symptoms and physical measures suggest a more complicated contribution to symptoms related to prior infection than is captured with conventional tests. Traditional clinical assessment is not expected to be particularly informative in relating symptoms to a past SARS-CoV-2 infection. Persistent symptoms are commonly reported after SARS-CoV-2 infection, and this is often described as long Covid. We compared different symptoms reported following SARS-CoV- 2 infection with the results obtained during various medical evaluations that are often used to assess health, such as blood tests, smell tests, taste tests, hearing tests, etc. We compared symptoms and test results between 1,706 Icelanders who had been infected previously with SARS-CoV-2 infection (cases) and 14,398 individuals who had not been infected (controls). Out of 88 assessed symptoms, 41 were more common in cases than controls. However, relatively few differences were seen in the results obtained from the various medical evaluations . The differences seen between symptoms and results of medical evaluations suggests that conventional clinical tests may not be informative in relating symptoms to a past SARS-CoV-2 infection. Holm, Ivarsdottir, Olafsdottir et al. compare symptoms and physical measures between Icelanders post SARS-CoV-2 infection with uninfected controls. From reported symptoms, they estimate the prevalence of long COVID as 7% at a median of 8 months after infection, while objective differences between cases and controls in the physical measures were few. As of January 2023, the pandemic has resulted in 664 million confirmed cases worldwide2 while the true number of infected persons is likely much higher3.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (Covid-19), emerged in December 20195. Several studies on the sequelae of Covid-19 in hospitalized patients found persistent symptoms and multiorgan abnormalities8, but good physical and functional recovery was reported for most severe Covid-19 survivors one year after the infection9. Evidence of various long-term effects of the SARS-CoV-2 infection on physical and mental health in those with milder disease, the majority of infected persons, is emerging. Protracted post-acute infection symptoms (long Covid)10, including fatigue, dyspnea, and brain fog have been described, with prevalence estimates ranging from 3% to 52%13 in non-hospitalized cohorts. However, a comprehensive comparison of post-Covid symptoms and objective measures in non-hospitalized persons is lacking.Covid-19 is an acute respiratory infection with the potential for widespread extrapulmonary complications14 or antibodies15 to the SARS-CoV-2 nucleocapsid (N) protein prior to October 2020 (cases), and a set of individuals who had been similarly tested but with negative results (contemporary controls), to participate in a modified deCODE Health Study (dHS)16, a prospective cohort study including questionnaires on symptoms and comprehensive physiological, cognitive and blood testing. History of prior infection was verified with measurement of anti-N antibodies15 at the time of the study visit (current vaccinations do not lead to the production of anti-N antibodies). Cases participated in the study 5–18 months after the acute infection. In addition to contemporary controls, our study includes a large control dataset of persons who participated in the dHS prior to the pandemic , facilitating assessment of time effects, importantly the pandemic itself, on measures. Furthermore, a subset of cases participated twice in the dHS, before and after the infection, allowing for the assessment of longitudinal measures. Similar longitudinal measures were available for a subset of controls. Our study is mostly of non-hospitalized persons as only 5% of cases required hospitalization during the acute infection as was typical for SARS-CoV-2 infection prior to the vaccination era.To investigate health outcomes after SARS-CoV-2 infection, we invited all Icelanders who had tested positive for the virus by qPCRIn our study, diverse symptoms were more commonly reported by those with prior SARS-CoV-2 infection than by controls, with 41 out of 88 assessed symptoms associating with past infection. However, few of the 150 objective physiological, cognitive, and blood parameters assessed differed between the two groups; cases had poorer smell and taste test results, less grip strength, and poorer memory recall than controls. Observed differences in grip strength and memory recall were small. We estimated the prevalence of long Covid to be 7%.17.This study was approved by the Icelandic National Bioethics Committee (VSN-15-214 with amendments). Written informed consent was obtained from all participants, in accordance with the Declaration of Helsinki. Personal identifiers were encrypted by a third-party system overseen by the Icelandic Data Protection Authority16 is a prospective cohort study in Iceland with extensive phenotypic and genotypic information produced and collected from the participants. More than 16,000 individuals participated in the study between its initiation in June 2016 and November 2021, aged between 18 and 97 years at recruitment. Participation in the study includes questionnaires about health and lifestyle, multiple physiological, cognitive, and blood tests, and authorization to access health-related information from registries and medical records, from where comprehensive information about comorbidities was obtained (The dHSobtained .18), Patient Health Questionnaire-9 (PHQ-919), Perceived Stress Scale (PSS20), Short Health Anxiety Inventory (SHAI21), and Symptom Impact Questionnaire (SIQR22), respectively, as well as the Satisfaction With Life Scale (SWLS23) and 36-Item Short Form Survey (36-SF24) to assess health-related quality of life. We added tests of taste and orthostatic intolerance and made other changes described in The dHS was paused in March 2020 due to the pandemic. To study the health consequences of SARS-CoV-2 infection, a modified dHS, termed the dHS Covid Study, was launched in September 2020. Added measures in the dHS Covid Study included the C19Q questionnaire on both the presence and frequency of symptoms during the previous four weeks, designed by us. We also added these questionnaires to assess symptoms of anxiety, depression, stress, health anxiety, and fatigue: General Anxiety Disorder-7 (GAD-714. Others (4%) were identified through antibody testing15. Of note, at this time, the presence of anti-N antibodies indicated prior infection, not vaccination, as the nucleocapsid protein was not targeted by any approved vaccine. Of the 3098 presumed cases invited, 1777 participated in the study between September 2020 and November 2021  by October 2020, the information provided by the Directorate of Health, to participate in the dHS Covid Study five or more months after the acute infection. The majority of those infected (96%) had either been identified through targeted qPCR testing aimed at those at high risk for infection , or through population screeningAs contemporary controls, we invited 1017 persons from a pool of Icelanders who had undergone PCR testing and/or anti-N antibody measurement with negative results, information available to us from the Directorate of Health , an online version of the C19Q, assessing symptoms in the previous four weeks, was sent to a subset of the historical controls who had undergone PCR testing and/or anti-N antibody measurement with negative results, 2000 persons, age and sex-matched to the cases, and 760 responded, resulting in a C19Q control group of 1379 persons  blood tests. The test procedures are described in In this study, we report the relationship between the history of SARS-CoV-2 infection and results from the following measures and tests: (a) health and symptom questionnaires including C19Q, GAD-7, PHQ-9, PSS, SHAI, SIQR, SWLS, and 36-SF; (b) physiological measurements of height, weight, BMI, blood pressure, heart rate, oxygen saturation, body composition by whole-body dual-energy X-ray absorptiometry (DXA) scan, grip strength, smell test, taste test, hearing test, spirometry, cardiopulmonary exercise test, ambulatory sleep test; (c) cognitive tests: Digit Coding33 of the Covid-19 outpatient clinic at Landspitali—the National University Hospital in Reykjavik, Iceland. We scaled the severity of the acute infection from 0 (least severe) to 8 (most severe) based on three factors: (1) intensity of treatment, (2) severity assessment by the TMS, and 3) self-assessment 34 or two months with an impact on daily function according to the World Health Organization (WHO) definition35. We assigned long Covid to cases who reported at least one of the following symptoms for five or more days per week: fatigue, lack of concentration, memory disturbance, dyspnea, or weakness, or at least one of the following for three or more days per week: malaise after physical exertion, chest pain, tachycardia in the four weeks prior to study visit, assessed with the C19Q, 5–18 months after infection. For comparison, we assessed how many of the controls fulfilled the same criteria.The term long Covid has been used to describe symptoms that develop during or following SARS-CoV-2 infection and last for more than four weeks per the National Institute for Health and Care Excellence guidelinesWith the C19Q we assessed both the presence and frequency of symptoms. For ease of interpretability, we treated the answers as binary traits for logistic regression , presenting ORs. As a robustness check, we also analyzed the answers as quantitative traits, yielding results similar to the results using logistic regression.We tested all measures for association with SARS-CoV-2 infection adjusting for age and sex. Adjustment for comorbidities  had minimal effect on associations and thus we report unadjusted results but show both in P values for all regression analyses were obtained with a likelihood ratio test. Individuals with missing data were not used in association analyses. To test for sensitivity of the results to comorbidity, we tested for association between phenotypes and SARS-CoV-2 as described above with indicator variables added for obesity, coronary artery disease, type II diabetes, asthma, hypertension, and cancer, restricting the data to non-missing observations in the comorbidity indicators. When comparing measurements for individuals that participated in the dHS both before and during the pandemic, we subtracted pre-pandemic measures from those taken during the pandemic for both cases and controls and regressed the difference against SARS-CoV-2 status, adjusting for age, sex, and time between measures using linear regression.When testing for association between SARS-CoV-2 infection and other phenotypes, logistic regression was performed for binary traits, and linear regression was performed for quantitative traits. The physiological traits were regressed against SARS-CoV-2 status , adjusting for age at time of measure and sex. The cognitive traits were similarly regressed against SARS-CoV-2 status, adjusting for age at time of measure, sex, and level of education obtained from the online questionnaire. Level of education was defined as a quantitative variable ranging from zero to six in the following manner: zero for no education, one for primary school, two for high school, three for other secondary education, four for an undergraduate university degree, five for Master’s degree and six for Doctorate degree. When testing for association between phenotypes and severity of the acute infection, the traits were regressed against the severity scale. For two of the cognitive traits, TMT-A and TMT-B, we log-transformed the test scores because of right-skewness in their distributions. Test scores for each of the 12 cognitive traits were then adjusted for age, gender, and education in a linear model prior to rank-based inverse normal transformation. The normalized and adjusted cognitive test scores were then used in association analyses to report effect estimates in SD units.We calculated the frequency of memory impairment, defined as z-score of less than or equal to −1.5, among cases and controls for logical memory measures, adjusting for age, gender, and educational level. Since cases and controls are not perfectly matched on those three covariates, we estimated parameters for those covariates using the control data as training set, applying the corresponding, measure-specific, parameters to create z-scores for cases and controls.P = 0.05/96 = 5 × 10−4 for health and symptom questionnaire data, P = 0.05/87 = 6 × 10−4 for physiological measures and cognitive tests, and P = 0.05/63 = 8 × 10−4 for blood tests, and (2) at least one of the following, as statistical power varies across measures: (i) consistent association results (same direction and non-heterogeneity in the effect estimates) with (1) when comparing cases with contemporary controls, (ii) consistent association results with (1) when comparing the subset of cases to the subset of controls with longitudinal measures. For symptoms and objective measures that associated with prior SARS-CoV-2 infection we required a P < 0.05 to establish a correlation with time from infection and the severity of the infection. For measures that did not associate with prior SARS-CoV-2 infection per se, we required the same multiple testing thresholds as listed above to establish an association with the severity of the infection. We used multiple linear or logistic regression for association testing. Analyses were performed in R, version 3.6.0.To establish association with SARS-CoV-2 infection, we required (1) association when comparing cases with all available controls using the following thresholds accounting for multiple testing: No patients or members of the public were involved in the conceptualization or design of this study nor in the interpretation of the results.Further information on research design is available in the The study design is shown in Fig. 36 (Supplementary Data The severity of the acute SARS-CoV-2 infection ranged from no/mild illness 41%) to severe illness requiring hospitalization 5%)  associating with prior SARS-CoV-2 infection (P < 0.05); smell and taste improving but others including malaise after physical exertion worsening : 0.37–0.68, Supplementary Figure r = 0.78) and considerably less with other symptoms (r < 0.26), but highest with memory disturbance .We noted a large cluster of correlated symptoms including dyspnea, fatigue, weakness, malaise after physical exertion, memory disturbance, and lack of concentration (Pearson correlation coefficient (20) among cases than controls (P < 5 × 10−4). Longitudinal measures demonstrated less symptoms of stress among both cases and controls during the pandemic than before it, but the reduction in symptoms of stress was larger in cases than controls (Table 18), health anxiety (SHAI21), depression (PHQ-719), fatigue (SIQR22), satisfaction of life (SWLS23), or health-related quality of life (36-SF24) in these data , were smell, taste, and grip strength , selective anosmia (loss of smell for one or more odors), and selective ageusia  and the prevalence of impairment in immediate memory recall was 9.8% for cases and 8.7% for controls, respectively . Restricting the analysis to cases with symptoms of memory disturbance at least five times per week yielded a prevalence of impairment of 15.2% for delayed recall and 14.0% for immediate recall.We calculated the prevalence of memory impairment, defined as a z-score of less than or equal to −1.5, among cases and controls, adjusting for age, gender, and educational levelP < 8 × 10−4, Supplementary Data We compared multiple blood tests between cases and contemporary controls and none associated with prior infection, including C-reactive protein, white blood cell count, and conventional cardiac, kidney, liver, and thyroid function tests, accounting for multiple testing  with malaise after physical exertion, dyspnea, and correlating symptoms associating most significantly (Supplementary Data P < 0.05), anxiety (GAD-7), health anxiety (SHAI), depression (PHQ-7), and fatigue (SIQR), as well as less satisfaction of life (SWLS) and poorer health-related quality of life (36-SF) associated with more severe acute illness  correlated also with severity of the acute infection ( of life 6-SF assoP < 0.05) (Supplementary Data P < 6 × 10−4). The WMS Logical Memory tests of immediate and delayed recall did not associate with severity (P > 0.05)   and 16% of controls met our long Covid symptom criteria. Cases were 2.1  times more likely to fulfill the criteria than controls. Adjustment for comorbidities increased the odds ratio to 2.9 . Of cases fulfilling the criteria, 54% had to reduce their regular hours for work, school, household, or other, due to persistent symptoms or complications from their SARS-CoV-2 infection, compared to 23% of cases overall. This translates to a long Covid prevalence of 7% according to the WHO case definitionWe explored the association of long Covid with physiological, cognitive, and blood traits in cases and controls separately  have been explained.We performed a detailed assessment of 1706 persons with a confirmed SARS-CoV-2 infection 5–18 months prior and compared to 14,398 controls. A wide variety of symptoms associated with prior infection and for objective measures associations were observed for smell, taste, grip strength, and memory recall.38. It follows that our study population consists mainly of persons who did not require hospitalization during acute illness. The comorbidities that predisposed to severe acute infection in our sample were the same as others have reported36, suggesting that our sample is representative of those infected with SARS-CoV-2. Based on self-report, 15% had not recovered and 1% still suffered severe symptoms 13 months after the infection.Our case population represents the severity spectrum of the acute SARS-CoV-2 infection, ranging from no or very mild symptoms to severe illness with 5% hospitalized in the acute phase39 and reports suggest full recovery in most at six months41. We found both subjective and objective measures of smell and taste impairment to be more common among cases than controls in our study, with the slow improvement of symptoms with time. Some test results of smell and taste improved with time, with hyposmia normalizing at nine to 10 months after infection, but selective anosmia and selective ageusia did not improve.Deficits in smell and taste are common symptoms of the acute SARS-CoV-2 infection42. Here, cases noted worsening of hearing from before the pandemic four times more often than controls, with half of them linking the noted change to the infection. However, hearing test results did not associate with a history of SARS-CoV-2. Thus, we do not have objective evidence of SARS-CoV-2 causing hearing loss among our mostly non-hospitalized patients.Sensorineural hearing loss is a recognized complication of viral infections and there are multiple reports of hearing loss in persons with a history of SARS-CoV-2, with most studies based on self-reported questionnaires or medical reports without conclusive hearing tests43, and indeed incident cardiovascular outcomes appear to be more common in survivors of acute Covid-19 than controls44. It should be noted that although significant, the difference in grip strength between cases and controls was small. We did not observe association between prior infection and exercise capacity as measured with a cardiopulmonary exercise test.We observed lower grip strength in persons with prior SARS-CoV-2 infection, possibly due to deconditioning. Grip strength, a measure of muscle strength, is a strong predictor of cardiovascular disease and mortality47. One case-control study, assessing 443 individuals after SARS-CoV-2 infection, reported a small reduction in left ventricular ejection fraction and higher concentration of hs-TNT and NT-proBNP after infection compared to controls47. Complicating the interpretation of that study is the lack of contemporary controls, as the control data were derived from persons assessed prior to the pandemic, precluding exploration of time trends in measures as well as any effect of the pandemic itself. The lack of association of the cardiac biomarkers hs-TNT and NT-proBNP with history of SARS-CoV-2 infection in our study of 1706 cases, argues against persistent myocardial involvement as a common complication of milder infections. Similarly, we found no evidence of persistent systemic inflammation, hematologic abnormalities, kidney, or liver dysfunction using conventional blood biomarkers.It has been suggested that chronic myocardial inflammation is a common complication of SARS-CoV-2 infection, irrespective of both pre-existing conditions and severity of the acute infection48. In our study, we measured heart rate variability during sleep and found no association with either history of infection  or long Covid . The discrepancy between the two studies could be explained by different selection of cases or different heart rate variability measurement or both.There have been several reports of dysautonomia after SARS-CoV-2 infection, in particular orthostatic intolerance. We assessed several measures of dysautonomia in our study, including heart rate variability, orthostatic hypotension, and postural orthostatic tachycardia, and found no association with prior infection. Marques et al compared 155 select individuals with long Covid to 94 controls and found they had reduced heart rate variability37 for non-hospitalized persons. However, we did not find significant differences between cases and controls in other cognitive tests, unlike Becker and colleagues who reported high prevalence of cognitive impairment of many domains in their smaller study of 740 persons evaluated after Covid-19 in a clinical setting.We performed extensive cognitive testing and observed that poorer delayed and immediate memory recall associated with prior SARS-CoV-2 infection, but the effects were small. We calculated the prevalence of impairment in delayed memory recall as 12.5% for cases and 7.4% for controls providing an objective measure of the memory disturbance commonly reported after infection. The prevalence of memory recall impairment in our study is comparable to the 12% reported by Becker et al51. The subjective cognitive impairments that are some of the more debilitating symptoms of ME/CFS52 have been captured by objective measures53 but discrepancies between symptoms and test results are common, possibly due to inability of cognitive tests to capture mild impairment and deficits affecting real-life tasks54. The WMS Logical Memory test may be a relatively sensitive measure of cognitive deficits following SARS-CoV-2 infection, as it has previously been used to detect subtle changes in memory55. Furthermore, the pathogenesis of these symptoms is unclear. A study leveraging longitudinal brain imaging data from the UK Biobank reported changes in brain structure associated with prior infection with SARS-CoV-2 but changes in areas related to memory did not associate with cognitive tests results56. It is also notable that while symptoms of neurocognitive disturbance associated with severity of the acute infection in our study, measured deficits in memory recall do not.The protracted symptoms of fatigue and neurocognitive disturbance after SARS-CoV-2 infection are reminiscent of other post-infective fatigue syndromes and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)57, and thus the observed association likely reflects the predisposition, rather than being a consequence of more severe infection. We replicate the association of more anxiety and depression with more severe infection47 but given the lack of association between these phenotypes and prior infection, the causal nature of this relationship is not clear.Higher BMI, higher triglycerides, and lower HDL-C levels associated with the severity of the acute infection but not with prior SARS-CoV-2 infection per se. These are all risk factors for more severe acute infection58 in self-reported symptoms following SARS-CoV-2 infection and a more complicated biological or biopsychosocial contribution to the persistent symptoms59 that are not well captured by conventional tests. These are important considerations for both research and clinical assessment of post-Covid conditions. Conventional clinical assessment would thus not be expected to be particularly informative in relating reported symptoms to a past SARS-CoV-2 infection.The high prevalence of symptoms among cases compared to controls contrasts notably with the small difference observed in test measures between the two groups, as well as with discrepancies between some symptoms and related test measures. For example, tachycardia was a prominent symptom after infection but there was no significant difference in measured heart rate between the two groups. Cases reported gaining weight since before the pandemic more often than controls, but there was no difference in BMI between cases and controls, or in longitudinal measures for cases. Similar observations for hearing are described above. Measured memory impairment was 1.78-fold more common in cases than controls while self-reported memory disturbance was described 3.5-fold more commonly by the cases. These observations support an element of response bias60.There are extensive research efforts ongoing worldwide aiming to increase our understanding of the pathophysiology of illness following infection with the SARS-CoV-2 virus and several mechanisms have been identified as potential mediators or culprits, including immune dysregulation, viral persistence, and endothelial dysfunction. Hopefully, this research will lead to improved diagnostics and effective treatments of this heterogenous condition13. The approach by the Coronavirus (COVID-19) Infection Survey in the UK was similar to ours and reported a 3% prevalence of continuous symptoms after infection compared to 0.5% of controls11.Our attempt to estimate the prevalence of long Covid, using data for both cases and controls, highlights not only how common the symptoms of long Covid are in the general population but also the importance of control data for comparison. The excess of cases meeting our criteria for long Covid was 13% with half of those reporting impact on everyday function, translating to a long Covid prevalence of 7% at a median of 8 months after infection. These estimates do not account for potential biases in self-reported symptoms. The lack of a universal and uniform definition of long Covid is problematic for both research and health care and complicates comparison between studies and populations. Indeed, prevalence estimates for long Covid in non-hospitalized cohorts have a wide range, up to at least 52% when the presence of one persisting symptom is sufficient for the diagnosisThis study has limitations. First, although more than half of Icelanders diagnosed with SARS-CoV-2 infection before October 2020 participated in the study, participation bias cannot be excluded and it is plausible that cases with more pronounced symptoms were more likely to participate, although demographics and comorbidities were similar among those who participated and those who did not. Second, while the study represents adults of all ages, it does not include children. Third, while the availability of measures before and after the infection with similar longitudinal measures for controls is a particular strength of the study, this sample set was relatively small. Fourth, this is a study of Icelanders, a North European ethnic group, in Iceland, a wealthy country with universal access to health care. The study results may not apply to persons of other origins and/or in different circumstances. Fifth, the study includes cases infected with SARS-CoV-2 before vaccinations started. Last, with regard to the objective traits assessed in our study, we can only assess what we measure.We believe that the inclusion of both historical and contemporary controls is a major strength of our study, allowing for consideration of possible time effects, i.e., general consequences of the pandemic itself  in addition to direct effects of the SARS-CoV-2 infection .In conclusion, in our comprehensive case-control study of mostly non-hospitalized Icelanders, multiple and diverse symptoms were more common among cases than controls 5–18 months after SARS-CoV-2 infection. However, objective differences between cases and controls in the parameters we measured were few. Cases performed worse than controls in tests of smell and taste with improvement in some of these measures over time. Cases also performed worse in tests of grip strength and immediate and delayed memory recall, but here differences between cases and controls were small. We show that many symptoms associated with prior SARS-CoV-2 infection are common in the general population and, accounting for that, estimate the prevalence of long Covid to be ~7%. Discrepancies between symptoms and objective measures suggest an element of response bias in self-reported symptoms and a more complicated contribution to symptoms related to prior infection than is captured by conventional tests.Description of Additional Supplementary FilesSupplementary InformationSupplementary Data 1Supplementary Data 2Supplementary Data 3Supplementary Data 4Supplementary Data 5Supplementary Data 6Supplementary Data 7Reporting Summary


Pericarditis is the inflammation of the pericardial layers. Myopericarditis is diagnosed when this inflammation involves the myocardium, which is marked by elevated serum cardiac enzymes. With these two pathologies sharing overlaps in etiology, we present a case of a young patient with a recent history of COVID-19 infection who presented with pleuritic and positional chest pain with troponin I elevation and serial ECG changes attributed to myopericarditis as a post-viral sequela of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection. This case demonstrates the importance of identifying and managing the potential cardiac complications in coronavirus disease 2019 (COVID-19) patients, regardless of age or symptom onset. Pericarditis is referred to as the inflammation of the layers of the pericardium . Based oPericarditis and myopericarditis overlap in etiology, with cardiotropic viruses being one of the primary inciting causes ,6. The eWe present a case of a young patient diagnosed with myopericarditis after the resolution of a recently confirmed COVID-19 infection.History of presentationA 30-year-old male presented with chest pain for one day at rest. He described the pain as a squeezing sensation, exacerbated with breathing and by leaning forward. The pain interrupted his sleep, as he usually sleeps prone. The patient stated he tried aspirin 81 mg with no relief. Notably, the patient contracted COVID-19 three weeks prior with mild symptoms, confirmed positive via over-the-counter antigen testing. At that time, he used over-the-counter medications for symptom management without requiring subsequent hospitalization. On presentation to the internal medicine team, the patient was afebrile and normotensive. Heart and respiratory rates were within normal limits, and the situation of peripheral oxygen (SpO2) was >95% in room air. His physical exam was significant for pleuritic and positional chest pain. The rest of his cardiac exam was otherwise normal, without murmurs, rubs, gallops, or reproducible chest pain on palpation. Lungs were clear to auscultation bilaterally with no crackles or wheezing. Troponin I level was elevated to 241.13 pg/L (reference range: <36 pg/L) and a normal B-type natriuretic peptide (BNP) of 68 pg/mL (reference range: <100 pg/mL) [Past medical historyIn addition to the recent COVID-19 infection, this patient’s medical history includes anxiety and post-traumatic stress disorder. He received two doses of Pfizer-BioNTech vaccines months before his most recent infection, although he was unable to provide the exact date. Also, the patient was diagnosed with asthma after a burn pit exposure one year before this admission. The patient stated that he used albuterol before exercise. He had been prescribed amlodipine for bronchodilator-induced hypertension, though he remained normotensive without daily use. He denied any prior surgical history, and his family history was unremarkable. Differential diagnosisWith primary pertinent presenting information of chest pain, elevated troponin level, and this patient’s history, the differential diagnosis included inflammatory cardiac conditions , acute coronary syndrome ,10, and InvestigationsThe patient’s initial laboratory results were notable for within normal range complete blood count, complete metabolic panel, and erythrocyte sedimentation rate, with elevated C-reactive protein at 75. Initial troponin level was elevated at 241 pg/L, with repeat troponin levels obtained approximately every four hours. Troponin elevation peaked at the 24-hour mark from presentation to the emergency department, with a troponin level of 30,158 pg/L. Subsequent values trended down afterward. Viral PCR obtained via nasopharyngeal swab for COVID-19, influenza A and B, and respiratory syncytial virus (RSV) were negative. ECG on admission demonstrated normal sinus rhythm with nonspecific T-wave abnormalities  was not available at our institution; therefore, diagnosis was made by echocardiography on the day of admission. The patient was continued on colchicine 0.6 mg once daily and ibuprofen 600 mg three times daily on subsequent days, with oxycodone 10 mg as needed for severe pain. The patient reported improved chest pain on hospital day 2, requiring fewer opioid medications for pain management. The patient was discharged on hospital day 3 with continued improvement of chest pain and was advised to taper his ibuprofen weekly after discharge with close follow-up with cardiology. He was advised to continue colchicine 0.6 mg at the same dose on discharge for three months and was counseled to abstain from strenuous activity until outpatient follow-up with cardiology.Follow-upThe patient followed up with his primary care physician one month after discharge. The patient reported the resolution of his chest pain and had completed his ibuprofen taper before his appointment. At that time, he noted mild shortness of breath on exertion, though he had improved overall. Due to the long waitlist for a cardiology appointment, the cardiologist saw the patient 2.5 months later. The patient reported complete resolution of symptoms at that time.This patient was diagnosed with myopericarditis given the presence of pleuritic and positional chest pain, non-focal and evolving ECG changes, elevated troponin levels, and preserved ejection fraction with minimal pericardial effusion demonstrated on echocardiography, likely secondary to his previous COVID-19 infection. This patient’s clinical course appeared to be mild overall. Diagnosis of pericarditis and myopericarditis in patients with active or recent COVID-19 is the same as in other populations, but careful attention must be observed to prevent transmission of the infection . The TTEAlthough the exact prevalence of cardiovascular involvement in COVID-19 patients remains unknown, a recent study has demonstrated the increased risk of cardiac injury in unvaccinated individuals . AlthougA systematic review performed by Sawalha et al. identified 14 cases, primarily males with a median age of 50.4 years, of myocarditis/myopericarditis suspected to be associated with COVID-19 infection, with 50% noted to have no comorbid conditions . All patCases of myopericarditis associated with mRNA COVID-19 vaccines have been reported, though the presentation usually occurs within days of immunization ,17. On tTreatment of myopericarditis warrants a higher level of evidence due to the limited clinical trials available . A systeFindings of COVID-19-associated myopericarditis appear similar to those caused by more well-known etiologies. Although COVID-19-induced myopericarditis typically presents in older individuals with active disease, we highlight the importance of considering myopericarditis in young patients with a recent history of SARS-CoV-2 infection presenting with chest pain, cardiac enzyme elevation, and ECG changes. The lack of data regarding COVID-19-induced myopericarditis pathophysiology, diagnostic protocol, and medical management warrants further research.


Rotavirus, a vaccine preventable disease, causes significant morbidity and mortality in children < 5 years of age. Globally, the COVID-19 pandemic reduced the rates of pediatric vaccinations, and the Military Health System (MHS) was no different . This gap in immunizations left many children vulnerable to preventable illnesses, including rotavirus. We hypothesized that the reduction in rotavirus vaccine administration during the pandemic would lead to an increase in rotavirus related hospitalizations within the MHS.A repeated monthly cross-sectional study was performed using inpatient data from the MHS to observe differences in rotavirus rates and risk factors before and during the COVID-19 pandemic. Data from March 2018 to February 2020 was considered pre-pandemic, while the following two years (until February 2022), were divided into COVID Year 1 and Year 2. Children included in the study were between 0-59 months of age and those with rotavirus were identified using ICD-10 codes. Poisson regression calculated rate ratios of rotavirus, adjusting for several demographic variables and time period at diagnosis. Monthly counts and rates of rotavirus were also documented.Across the cohort of 1.14 million MHS beneficiaries, there were 3,503 unique cases of rotavirus infections in hospitalized children < 5 years old (Table 1). During both Years 1 and 2 of COVID-19, there was a significant decrease in rotavirus related hospitalizations compared to the pre-pandemic period . Younger age was associated with increased risk. Patient sex, parent military rank, and region were not statistically significant (Table 2).Despite the reduction in routine immunization administration to children in the MHS after the COVID-19 pandemic started, there was not an increase in rotavirus related hospitalizations. In the two years following the start of the pandemic, there was a statistically significant decrease in hospitalizations related to rotavirus in our cohort. Social distancing to include daycare closures, increased hygiene measures, and catch-up immunizations may explain this finding. Continued research into this topic will help determine if rotavirus related hospitalizations return to pre-pandemic levels.All Authors: No reported disclosures


After COVID-19 infection, individuals can experience a variety of symptoms that mightrequire further treatment. Early data showed the value of adapted pulmonaryrehabilitation programmes and technology-based interventions. To develop appropriateservices, it is important to understand the symptom burden and the preferred mode ofrehabilitation delivery.Post-hospital discharge (H) and post-community-managed (C) individuals received afollow-up call. A survey was completed to assess the most burdensome symptoms for whichthe patients would require support and their preference for the mode of rehabilitationdelivery.Overall, 160 individuals who received a follow-up call completed the survey  and 126 (78.8%) were post-hospital, while 34 (21.3%)had community-managed infections. A total of 101 (63.1%) reported that COVID-19-relatedsymptoms were affecting their daily activities, and 106 (66.3%) reported their desire tobe more active. The most common symptoms identified as needing support were fatigue andshortness of breath. Both groups expressed a preference for a face-to-face groupprogramme , while (38.7%) of post-community-managed individuals and(40.3%) post-hospital patients preferred a supported digital rehabilitation programme.Few opted a non-digital home-based programme .The survey responses indicated a significant symptom burden that may benefit from anintervention such as rehabilitation. Preferences for rehabilitation indicated that aface-to-face intervention was preferred by the majority, with a large proportionpreferring digital intervention. Individuals infected with SARS-CoV-2 might experience a variety of ongoing symptomssuch as fatigue, cough, shortness of breath, dizziness, palpitations, increased levels ofanxiety, and depression.3 TheNational Institute for Health and Care Excellence (NICE) guidelines classified the signs andsymptoms of COVID-19 that lasted more than 12 weeks after the initial onset of an infectionas “long COVID” or “post-COVID-19 syndrome”.5 It became obvious that a recoveryintervention would be required to improve physical and psychological functions and enableCOVID-19 patients to continue with their lives as normal. A clinical task force published by the European Respiratory Society suggested theneed for a comprehensive rehabilitation programme after recovery. It has been reported that a pulmonary rehabilitation programme (PR) could be adaptedto meet the needs of individuals with COVID-19. A PR programme is a complex intervention that involves education, assessment,physical training, and psychological support to improve the quality of daily life ofindividuals with chronic respiratory conditions. Symptoms presented in those recovering from COVID-19 such as dyspnoea, fatigue,cough, reduced exercise capacity, and increased levels of anxiety are similar to those withchronic respiratory diseases who benefit from rehabilitation. Rehabilitation programmes have been developed and tailored to accommodate individualsfollowing an infection of SARS-CoV-2, and have reported improvements in respiratorysymptoms, fatigue, and exercise capacity in both technology-based and traditionalface-to-face programmes.12Moreover, an improvement in quality of life, anxiety, and depression scores was reported bythose who were discharged from hospital, and the programme was acceptable to participantswith a high retention rate, and no adverse events were reported during enrolment.Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome(SARS-CoV-2), was declared as a worldwide pandemic by the World Health Organisation (WHO).In this study, we aimed to understand the most bothersome symptoms individuals requiredsupport with and their preference for the mode of delivery following COVID-19 infection. Tohelp develop an appropriate service, it is important to assess individuals’ symptoms andtheir preferred rehabilitation services. This survey consisted of ten closed questions and free text for additional comments,and was completed between February and October 2021. (Supplement1).This cross-sectional survey for individuals with post-COVID-19 symptoms was conducted atthe Biomedical Research Centre (BRC), University Hospitals of Leicester; and gained anethical approval from the National Health Service Research Ethics Committee (Reference17/EM/0156). Approximately 3 months after discharge, those who were discharged (H) fromGlenfield Hospital, Leicester were automatically followed up, and individuals withcommunity-managed (C) infections who were referred to the hospital for reported symptomsonly received a follow-up call. Individuals were approached consecutively, and the surveywas administered by a highly specialised physiotherapist (ED). All study participants wereaged ≥18 years. Those unable to communicate fluently in English were excluded. The surveywas designed based on a previous survey formulated by the National Institute for HealthResearch (NIHR) Global RECHARGE Group.The first part of the questionnaire focused on the participants’ basic demographicinformation, including age, gender, their current activity level, and if they like to beactive. They were also asked about the most bothersome symptoms that they need assistancewith, and if they were interested in participating in a COVID-19 rehabilitation programme.In addition, they were asked about their preferences for the delivery of the rehabilitationprogramme, and they had to choose one option. The approximate time to complete the surveywas 5–10 min. The results of the survey would be used to assist in the design of a flexibleapproach to rehabilitation interventions. Simple descriptive statistical analysis was used, and the data were presented asfrequency, percentages and mean standard deviation as appropriate.After completing the survey, the data were then transferred to the statistical package forthe social science (SPSS) V.25 for further analysis.Overall, 160 individuals who were approached, completed the survey ; 126 (78.8%) were patients who had been discharged from hospital, while34 (21.3%) had community-managed infections. At the time of this study, the predominantCOVID-19 strain in the UK was Delta variant.A total of 101 (63.1%) reported that COVID-19-related symptoms were affecting their dailyactivities, and 106 (66.3%) reported their desire to be more active.The most common symptoms reported among participants from each group were fatigue  and shortness of breath . Higher anxiety levels werereported by half of the community-managed participants compared to very few in the hospitaldischarge group . Other important symptoms were brain fog , cough , and pain . Chest tightness  and palpitations  were less frequently reported as troublesomesymptoms .Figure 1The majority of community-managed participants  and  post-hospitalreported their willingness to participate in a programme that would help to reduce theirpost COVID symptoms and improve their physical performance and quality of life. Of these,the dominant symptoms were fatigue  and shortness of breath .The preferred mode of programme delivery was also assessed, and both groups expressed apreference for a face-to-face supervised group programme , while 38.7%of participants who had had a community-managed infection and 40.3% of participants who hadbeen discharged from hospital preferred a digital rehabilitation programme supported by ahealthcare professionals. Only a few expressed a desire for a non-digital home-basedprogramme . A small number of individuals who had had a community-managedinfection expressed a preference for a programme based in a leisure centre (C: 3.2%) .Figure 2In this study, we investigated the ongoing and important symptoms of COVID-19  in individuals who had been dischargedfrom hospital and those who had community-managed infections. Based on our results,shortness of breath and fatigue appeared to be the most bothersome symptoms in both groups.In addition, anxiety and brain fog were reported more frequently by community-managedparticipants than those who were discharged from hospital. Other symptoms such as coughingand pain were reported equally by both groups, while fewer participants reported signs ofchest tightness and palpitations.16 Furthermore, our study is consistent witha previous review conducted by Aiyegbusi et al., who investigated the most prevalentsymptoms reported by individuals post-COVID-19. They found that fatigue (47%) and shortnessof breath (32%) were the most prevalent symptoms in individuals who had been hospitalised. These symptoms were also reported by those who were not hospitalised.We observed a higher percentage of reported symptoms in the community-managed group. Itshould be noted that we only surveyed those who presented with symptoms and were referred tothe management services from the community, while we surveyed all those who were dischargedfrom hospital. The symptoms reported in our study were similar to those reported in previousstudies that have identified fatigue, shortness of breath, and generalised pain as the mostprevalent symptoms documented in individuals post-COVID-19.19 In our study, we found that the majorityof participants in both groups were enthusiastic about participating in a programme thatwould help them to manage their symptoms and improve their physical activity levels andquality of life. In the development of any rehabilitation intervention as our data indicatedthat shortness of breath, fatigue and anxiety were the most burdensome symptoms andhealthcare professionals need to be equipped with knowledge and skills to offer support tothe post COVID-19 community. Staff delivering PR have a considerable experience in managingdyspnea and anxiety, but may be familiar with fatigue management, and the impact of postexertional symptoms exacerbation.Importantly, our survey assessed the most bothersome symptoms rather than the mostprevalent symptoms in post-hospital discharge and community-managed settings, andspecifically sought to confirm the most important symptoms to inform service development. Weare aware of the symptoms reported in the literature, but as healthcare professionals, weneed to gauge the most troublesome symptoms to develop rehabilitation services that canaddress multiple symptoms at any one time. A few reports have highlighted the need for arehabilitation programme and identified that pulmonary rehabilitation (PR) could be adaptedto accommodate those with long COVID symptoms.Due to the burden of long COVID, we anticipated that there would be a significant demandfor rehabilitation services. Therefore, it would be logical to devise flexible ways ofdelivering the rehabilitation services, and an option for face-to-face and digitalinterventions may help meet the demand and offer patients a choice of interventions, asindicated in this data. This study assessed individuals’ preferences for rehabilitationprogramme delivery when it comes to the management of post-COVID-19 symptoms. They had achoice between a face-to-face programme in a group supervised by a team of healthcareprofessionals or a programme manual to be used at home with support from healthcareprofessionals. The delivery options included an online-based comprehensive programme and aleisure centre scheme. The majority of participants in both groups preferred a supervisedface-to-face rehabilitation programme followed by an online-based programme. A small numberof participants opted for the home-based programme manual, while a couple ofcommunity-managed participants preferred the leisure centre option. The COPD survey didn’t evaluate digital competency, but the average age of our studypopulation was about 20 years younger than COPD population surveyed. Another limitation thatpatients’ comorbidities and length of hospital stay were not recorded. However, the studysought to gain an initial insight about the symptoms burden and thoughts about enrollinginto rehabilitation programme.The study has several limitations. Firstly, the study was not asked individuals about theirdigital competency. However, the appetite for technology based programmes was much higherthan what we have observed in COPD population.This study demonstrated the need for flexible rehabilitation options to alleviate thepersistent symptoms of COVID-19 infection in those who have been discharged from hospital orthose whose infections have been community managed. This will require the delivery of arange of options to meet patients’ preferences and demands.The survey responses indicated a significant symptom burden that may benefit from anintervention such as rehabilitation. Preferences for rehabilitation indicated that aface-to-face intervention was preferred by the majority, with a large proportion preferringdigital intervention.Click here for additional data file.Supplemental Material for The formal rationality of artificial intelligence-basedalgorithms and the problem of bias by Munyra Alhotye, Enya Daynes, Charlotte Gerlis andSally J Singh in Chronic Respiratory Disease


Progressive fibrosing interstitial lung disease (ILD) is a relatively new clinical concept describing a variety of ILDs characterized by progressive pulmonary fibrosis with associated lung function decline and worsening chest imaging. Little is known about health care resource utilization (HCRU) and costs associated with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF). This study analyzed the adjusted HCRU and cost burden among patients with incident non-IPF progressive fibrosing ILD vs matched patients with incident fibrosing ILD that had not yet progressed.This was a retrospective study of insured US adults newly diagnosed with non-IPF fibrosing ILD from October 2016 to June 2019, conducted using administrative claims data from the Optum Research Database. Progressive disease was identified using claims-based proxies comprising health care utilization associated with management of progressive fibrosing ILD. Patients in the progressive population were 1:1 propensity score matched to not-yet-progressed patients on the basis of baseline demographic and clinical characteristics. All-cause HCRU and health care costs were presented as weighted per-patient-per-month (PPPM) measures to account for variable follow-up. Differences in study outcomes between matched cohorts were evaluated using Z-tests for continuous measures and Rao-Scott tests for binary measures.P < 0.001 for all). Among patients with an IP stay, those with progressive disease had more inpatient days than those with not-yet-progressed disease . Mean weighted PPPM (SD) all-cause health care costs were also significantly higher for progressive vs not-yet-progressed patients, including total costs , medical costs , and pharmacy costs . The difference in medical costs between cohorts was driven primarily by higher inpatient costs for progressive vs not-yet-progressed patients .The postmatch cohorts comprised 11,025 patients with evidence of progression matched to 11,025 patients with not-yet-progressed fibrosing ILD. Mean (SD) weighted PPPM counts of follow-up health care encounters were significantly higher for the progressive vs not-yet-progressed cohort: ambulatory visits, 4.2 (3.6) vs 3.1 (3.3); emergency department visits, 0.3 (0.5) vs 0.1 (0.3); and inpatient (IP) stays, 0.1 (0.2) vs 0.0 (0.1)  other than idiopathic pulmonary fibrosis (IPF). We found that health care use and costs for patients with a new non-IPF fibrosing ILD diagnosis were higher if they had progressive disease than if their disease had not yet progressed. Higher costs for progressive patients were due mostly to longer and more frequent hospital stays. Implications for managed care pharmacyNon-IPF progressive fibrosing ILD carries substantial health care and economic costs, which are driven primarily by hospitalizations. Awareness of this burden and implementation of disease management approaches that reduce hospitalization risk are critical to minimizing the impact of progressive fibrosing ILD on patients and health care systems.2 The clinical course of these disorders follows a similar path independent of the underlying cause of disease, as the development of self-sustaining progressive fibrosis appears to be mediated by a shared underlying pathophysiology.3 It is thought that approximately 1 in 4 patients with fibrosing ILD will develop a progressive phenotype.4 These patients not only have persistent and worsening symptoms such as cough, dyspnea, and fatigue as well as impaired quality of life but also face early mortality, with median survival times as low as 3-5 years after diagnosis.8 The prevalence of progressive fibrosing ILD has been difficult to determine because the disorders it comprises are numerous and diagnostically complex, but it was recently estimated to range from 0.89 per 10,000 to 2.36 per 10,000 for commercially insured patients and from 12.14 per 10,000 to 29.05 per 10,000 for Medicare beneficiaries in the United States.9Chronic fibrosing interstitial lung disease (ILD) with a progressive phenotype comprises a variety of interstitial lung diseases characterized by progressive fibrosis, with associated lung function decline and increasing chest imaging abnormalities.13 However, little is known about health care resource utilization (HCRU) and costs associated with other forms of progressive fibrosing ILD. Administrative claims provide a rich source of real-world clinical and economic data, but the use of claims for analyzing progressive fibrotic ILD presents some challenges. There was no specific diagnosis code for this disease behavior until October 2020, as it is a relatively new clinical concept. Moreover, administrative claims do not include information about patient symptoms or results from chest imaging and pulmonary function tests, which are necessary to identify the hallmark features of the progressive phenotype. Recent descriptive claims studies have found that patients with progressive fibrotic ILD have higher HCRU and costs than those without progressive disease, but these analyses were not conducted on matched populations or adjusted for potential confounders, such as comorbidities.15Idiopathic pulmonary fibrosis (IPF) is the most common and well-defined progressive fibrosing ILD; accordingly, the health and economic burden of IPF has been documented.In the present study, we estimated the adjusted HCRU and cost burden among patients with incident non-IPF progressive fibrosing ILD vs matched patients with incident fibrosing ILD that has not yet progressed.International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification (ICD-9-CM and ICD-10-CM); Current Procedural Terminology or Healthcare Common Procedure Coding System codes; and site of service codes. Pharmacy claims include drug name, National Drug Code, dosage form, drug strength, and fill date for health plan–paid outpatient pharmacy services. Medical and pharmacy claims also contain cost data, including health plan–paid and patient-paid amounts.This was a retrospective observational study conducted using administrative claims data from the Optum Research Database from October 1, 2015, through September 30, 2019 (study period) . The OptNo identifiable protected health information was accessed in the conduct of this study; therefore, institutional review board approval or waiver of approval was not required.9 The proxies were chosen by these experts on the basis of their clinical experience in managing patients with ILDs and comprised procedures, therapies, tests, and other health care utilization associated with management of progressive fibrosing ILD . Although the progression proxies have not yet been validated against medical chart data, the estimates of non-IPF progressive fibrosing ILD prevalence that were generated using these proxies in our previous report9 were similar to those in the existing literature.17Given the lack of a specific diagnosis code for progressive fibrosing ILD during the study period, disease progression was identified using claims-based proxies developed in consultation with multiple practicing pulmonologists with expertise in ILDs, as described in detail previously.9) on different dates of service within 365 days of each other during the identification period and in the same period of continuous health plan enrollment; the date of the first fibrosing ILD diagnosis was designated as the fibrosing ILD diagnosis date. The index date was the first date with evidence of progression for patients identified with progressive disease, and the index date for not-yet-progressed patients was assigned as described in the “Propensity score matching” section below. Included patients were also required to be aged at least 18 years as of the fibrosing ILD diagnosis date, to have continuous health plan enrollment with medical and pharmacy benefits for 12 months prior to the fibrosing ILD diagnosis date (baseline period) and 3 or more months after the index date (follow-up period)  . Patient period) , to havePatients were excluded if they had claims evidence of an IPF diagnosis (ICD-10-CM J84.112) during the study period or had missing/unknown demographic information .Patients who met the study inclusion criteria were eligible for propensity score matching, which was used to generate study populations based on the presence or absence of progressive disease behavior . The progressive cohort included patients who had evidence of progression following the fibrosing ILD diagnosis date, defined as meeting 1 or more progression proxies. The not-yet-progressed cohort included patients who had fibrosing ILD that had not yet progressed and who had 3 or more months of progression-free follow-up. These populations were not mutually exclusive; that is, patients with not-yet-progressed fibrosing ILD could serve as controls for multiple patients in the progressive cohort and were also included in the progressive cohort if they subsequently developed evidence of disease progression.Patients in the progressive population were 1:1 propensity score matched to patients in the not-yet-progressed population on the basis of baseline characteristics. Baseline variables used for matching included age category, sex, geographic region, insurance type, year of fibrosing ILD diagnosis, continuous and categorical Charlson comorbidity score, comorbidities, use of ILD medications, HCRU, and health care costs. For each patient who had fibrosing ILD that had progressed and had 3 or more months of follow-up after progression, a patient with fibrosing ILD that had not yet progressed and with the closest propensity score within a caliper of ± 0.01 was selected. The index date for not-yet-progressed patients was assigned so that the length of time from the fibrosing ILD diagnosis date to the index date was the same for the matched progressive and not-yet-progressed patients. For each matched pair, follow-up continued until the earliest of disenrollment from the health plan for either member of a match, evidence of progression for the matched patient with fibrosing ILD, or the end of the study period. Unmatched patients were excluded from the analysis.18Patient demographic characteristics  were captured as of the fibrosing ILD diagnosis date or the first claim after the fibrosing ILD diagnosis date, as available. Patient comorbidity burden, baseline medication use, baseline all-cause HCRU, and baseline all-cause health care costs were assessed during the baseline period. Study outcomes were assessed during the follow-up period and included all-cause HCRU and allcause health care costs. HCRU counts  were presented as per-patient-per-month (PPPM) measures weighted by the duration of observation time to account for variable follow-up. Health care costs were calculated as total health plan plus patient–paid weighted PPPM amounts and also subdivided into medical costs  and pharmacy costs. Costs were adjusted to 2019 US$ using the annual medical care component of the Consumer Price Index.19 Differences in study outcomes between cohorts were evaluated using robust standard errors in weighted generalized linear models with clustering by individual to account for the use of some individuals multiple times in the matching. The cohort was the only predictor in this model, as patients were propensity score matched. A Poisson distribution was used for HCRU counts with the exception of inpatient stays, for which a normal distribution was used as suggested by a Park test. A γ distribution was used for health care costs.Postmatch study variables were analyzed descriptively and stratified by study cohort. Numbers and percentages were provided for categorical variables; means, medians, and SDs were provided for continuous variables. To evaluate the effectiveness of the propensity score matching, postmatch differences in baseline characteristics between cohorts were assessed using standardized mean differences (SMDs); by convention, values less than 10% indicate adequate balance.A total of 20,374 patients with ILD diagnoses were eligible for inclusion in the progressive and not-yet-progressed cohorts. The prematch populations included 11,031 patients with evidence of fibrosing ILD progression during the variable follow-up period and continuous enrollment for 3 or more months following the index date and 7,480 patients with no evidence of ILD progression during follow-up. The postmatch cohorts comprised 11,025 patients with evidence of progression matched to 11,025 patients with fibrosing ILD that had not yet progressed and 3 or more months of progressionfree follow-up . The majPostmatch cohorts were well balanced, with SMDs less than 10% for all baseline characteristics . In the HCRU. Follow-up all-cause HCRU for all encounter types was significantly higher for progressive patients than for not-yet-progressed patients . Among patients with an inpatient stay , those with progressive disease also had more inpatient days than those with not-yet-progressed disease .patients . Mean weHealth Care Costs. Mean weighted PPPM (SD) all-cause health care costs were significantly higher for progressive patients than for not-yet-progressed patients, including total costs , medical costs , and pharmacy costs  (P < 0.001).= 0.002) . All medIn a real-world cohort of patients with newly diagnosed non-IPF chronic fibrosing ILD, adjusted all-cause health care costs and HCRU—including ambulatory visits, ED visits, inpatient stays, and pharmacy fills—were significantly higher for those with a progressive phenotype than for matched patients whose disease had not yet progressed. Higher costs among progressive patients were driven primarily by hospitalizations; not only were weighted PPPM inpatient stays 3-fold higher in the progressive cohort than in the not-yet-progressed cohort, but among patients with at least 1 hospitalization, those with a progressive phenotype also had more inpatient days. Accordingly, weighted PPPM hospitalization costs for progressive patients were more than 3 times those for not-yet-progressed patients.15 As in our study, patients with progressive fibrosing ILD had significantly higher health care utilization and related costs than those without a progressive phenotype during the study period.15 Mean annual medical costs per patient for progressive vs not-yet-progressed fibrosing ILD corresponded to PPPM costs of approximately $6,472 vs $5,674, respectively,15 compared with $3,662 vs $1,627 in the present analysis. Although our conclusions are consistent with those of Olson et al, we found the magnitude of cost differences between patients with progressive vs not-yet-progressed fibrosing ILD disease behavior to be substantially higher; medical costs for the progressive cohort in the present study were more than double those of the not-yet-progressed cohort but were only 14% higher in the earlier analysis. This discrepancy may be attributable to methodological differences, as the study by Olson et al was not conducted among matched cohorts and also identified disease progression solely on the basis of pulmonologist visit frequency, leaving greater opportunity for results to be affected by possible miscategorization.Few studies have examined the economic burden of non-IPF progressive fibrosing ILD. Our results are comparable to those of Olson et al (2020), who conducted one of the only other claims-based analyses to date of HCRU and costs in a similar patient population.20 Indeed, our results were broadly similar to findings from previous analyses of patients with IPF, which noted substantial HCRU and monthly medical costs ranging from approximately $1,700 to $2,200 per patient .23 Moreover, health care costs among patients with IPF also were found to be dominated by hospitalizations, which generally were responsible for more than 50% of total medical costs.22 The higher monthly medical costs observed for progressive patients in the present analysis compared with patients with IPF in earlier studies may reflect the long-standing unmet need for treatments effective in managing non-IPF progressive fibrosing ILDs.Given that progressive fibrosing ILDs are hypothesized to share a common pathophysiology, it has been proposed that the burden of illness associated with this disease behavior would resemble that of IPF.9 were similar to those in the existing literature.17 Second, the definition of progression was based on use of procedures, therapies, and tests associated with management of progressive fibrosing ILD. This may have influenced the study results, as health care costs occurring on the progression date were not excluded from the analysis. However, results from a sensitivity analysis that excluded progression proxy–associated costs were not substantially different from those of the primary analysis (data not shown). Third, patients were required to have continuous health plan enrollment for 3 or more months after the index date, which may have introduced survival bias resulting in lower HCRU and associated costs. Finally, this study included only US commercial and Medicare Advantage with Part D health plan enrollees; therefore, the findings are most applicable to insured US patients and may not be generalizable to other populations.This study has several limitations. First, the presence of a code on a medical claim is not a confirmation of diagnosis, as codes may be entered incorrectly or included as rule-out criteria. In addition, the claims-based proxies for disease progression that were used in the absence of a specific diagnosis code for progressive fibrosing ILD have not yet been validated against medical chart data. These factors may have contributed to some degree of patient misidentification; however, it should be noted that the prevalence ranges for non-IPF progressive fibrosing ILD estimated previously using these proxiesAmong patients with incident non-IPF fibrosing ILD, all-cause HCRU and costs were significantly higher for those with a progressive phenotype than for those whose disease had not yet progressed. The cost differential was driven primarily by hospitalizations, which were longer and more frequent for progressive vs not-yet-progressed patients. Our findings complement existing data illustrating the detrimental effects of progressive fibrosing ILD on patients’ lives by underscoring the substantial economic and health care burden associated with this disease behavior.


During the past 3 years, the coronavirus disease 2019 (COVID-19) pandemic has had a great impact on people all over the world. However, it has become evident that disease manifestations and severity differ across age groups. Most children have a milder disease course than adults but possibly more pronounced gastrointestinal (GI) symptoms. Given the child’s developing immune system, the impact of COVID-19 on disease development may differ compared to adults. This study reviews the potential bi-directional relationship between COVID-19 and GI diseases in children, focusing on common pediatric conditions such as functional GI disorders (FGID), celiac disease (CeD), and inflammatory bowel disease (IBD). Children with GI diseases, in general, and CeD and IBD, in particular, do not seem to have an increased risk of severe COVID-19, including risks of hospitalization, critical care need, and death. While infections are considered candidate environmental factors in both CeD and IBD pathogenesis, and specific infectious agents are known triggers for FGID, there is still not sufficient evidence to implicate COVID-19 in the development of either of these diseases. However, given the scarcity of data and the possible latency period between environmental triggers and disease development, future investigations in this field are warranted. In contrast to infected adults, most children and adolescents have only experienced mild disease symptoms.912SARS-CoV-2, a single-stranded RNA virus, commonly causes fever, cough, sore throat, runny nose, loss of smell or taste, and headache.1316 Similarly, GI manifestations are prominent features of the multisystem inflammatory syndrome in children (MIS-C).18 MIS-C is a severe hyperinflammatory condition that can follow a COVID-19 infection in children and often requires aggressive treatment.19Although considered a respiratory disease, children and adults with COVID-19 frequently report gastrointestinal (GI) complaints . there has been a concern that the virus may influence the incidence of GI diseases and their disease course (or vice versa), such that patients with GI diseases may have an increased susceptibility to and risk of severe COVID-19. These questions were also raised for children often susceptible to respiratory viral infections and where viral encounters may imprint on their developing immune system.Because SARS-CoV-2 can infect most parts of the GI tract,2224 this review focuses on more common digestive disorders in children, such as functional GI disorders (FGIDs), celiac disease (CeD), and inflammatory bowel disease (IBD). We also review data on changed diagnostic work-up and management of children with GI diseases during and after the pandemic.This study reviews evidence of potential bi-directional relationships between COVID-19 and pediatric GI diseases. While hepatic and pancreatic manifestations have been described in children with COVID-19,18 However, GI complaints have also become common, especially in the pediatric population.25COVID-19 usually causes respiratory symptoms in the upper and lower airways, as well as fever, headache, myalgia, and loss of smell and taste.2628 Of note, it seems that the expression of these proteins varies across ages. With increasing age, ACE2 and TMPRSS2 expressions decrease in the GI tract while increasing in the lungs. This finding may partly explain the noticeably milder disease course in children than in adults and perhaps age-related differences in COVID-19 symptomatology overall.SARS-CoV-2 can affect the GI system in several ways. The viral spike protein binds to membrane receptors, mediating a fusion between the virus and the membrane. Research has demonstrated that angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane serine protease 2 (TMPRSS2) are crucial in this process. The ACE2 receptor and the TMPRSS2 are co-expressed not only in the lungs but also in the esophageal, gastric, and small and large intestinal mucosa, making the entire GI tract highly susceptible to SARS-CoV-2 infection.31 Fecal excretion of SARS-CoV-2 is common.26 In an early study from China Hua et al. detected SARS-CoV-2 RNA in feces in 32/35 (91%) infected children, with viral shedding persisting up to 70 days. This finding was confirmed in a 2022 meta-analysis reporting a pooled prevalence of fecal SARS-CoV-2 RNA in almost 9 of 10 infected children and 7 of 10 children who had turned negative in the respiratory specimen.Once the virus has entered the cell, new virions are synthesized and assembled. Afterward, they are released into the GI tract, causing direct damage to the enterocyte and viral shedding in the stool.20 Furthermore, SARS-CoV-2 can alter the intestinal microbiota. Through immunological crosstalk between the gut and lungs (the gut-lung axis), a changing gut microbiome may also occur when the GI tract is not directly infected by the virus.33Viral damage of the enterocytes may increase intestinal permeability and release of inflammatory mediators . These cytokines may induce GI symptoms and systemic inflammation. Since then, similar or even higher rates of GI complaints have been reported in adult patients with COVID-19. A North American study including 1992 patients across 36 centers reported GI symptoms in up to 53% of the participants, with diarrhea being most frequently observed.Soon into the pandemic, a Chinese study reported clinical features of 651 hospitalized patients with COVID-19 (average age 46 years), with 11% having at least one GI symptom .35 although comparisons are difficult given the heterogeneity of compared study populations. In contrast to adults, children with COVID-19 usually have a mild disease course that rarely requires medical attention.12 Whether the study cohorts constitute inpatients, outpatients, or household contacts will probably significantly impact the resolution and weighting of reported symptoms.GI complaints may be more common in children with COVID-19 than in adults, Of 1391 tested children, 171 were SARS-CoV-2 positive (median age 6.7 years). Almost 16% of infected children were asymptomatic, but 9% reported diarrhea and 6% vomiting. The Peds COVID-19 Registry, a US study of >6000 hospitalized children reported vomiting in 13% of the cohort, abdominal pain in 10%, and diarrhea in 11% of infected children. Several reviews and meta-analyses have reported diarrhea in 2-33%, nausea or vomiting in 5–35%, and abdominal pain in 4–35%.38 Still, individual studies have reported a higher frequency of GI complaints, including GI symptoms in >50% of children in a North American multicenter study of severe pediatric COVID-19. These high numbers are in analogy with other viral infections ; where children more frequently report GI symptoms than adults.The Chinese Pediatric Novel Coronavirus Study Team assessed children who had been in contact with individuals with known or suspected COVID-19 in early 2020. MIS-C is a hyperinflammatory syndrome with multiorgan dysfunction seen in individuals <21 years of age with a recent history of COVID-19. Next to fever (mandatory criteria), GI symptoms are among the most predominant clinical manifestations of MIS-C, demonstrated in >90% of the patients.4148 While diarrhea and vomiting seem to be the most common symptoms of MIS-C, abdominal pain, described in one-third of the affected children, is the most noticeable symptom, and often severe enough to warrant radiology or even surgery.49 This GI predominance of MIS-C differs from Kawasaki’s disease, a distinct infectious-related hyperinflammatory syndrome with usually no or only mild GI symptoms.5052 Initially, MIS-C was associated with a significant mortality rate, particularly in low- and middle-income countries.54 However, with timely recognition of the condition and the development of improved anti-inflammatory treatment protocols, the morbidity and mortality rates of MIS-C have been reversed. Likewise, when patients are provided anti-inflammatory treatment, GI symptoms of MIS-C often resolve within a few weeks.52Multisystem inflammatory syndrome in children (MIS-C) has proven to be one of the most serious COVID-19 manifestations in children and adolescents. The only available treatment for CeD is a strict gluten-free diet (GFD). In children, the prevalence of CeD is approximately 1% worldwide and possibly higher in Nordic countries.57 Human leukocyte antigen haplotype DQ2 or DQ8 is necessary but insufficient for CeD development.58 Besides gluten, other environmental factors contribute to CeD. Although the timing and nature of such environmental factors are largely unknown,58 multiple studies have acknowledged the implication of infections in disease pathogenesis.5964 Conversely, CeD patients may also be susceptible to infectious diseases.6568Celiac disease (CeD) is a chronic autoimmune enteropathy precipitated by gluten intake in genetically predisposed individuals.6871 These risks likely relate to the higher prevalence of functional hyposplenism and splenic atrophy in patients with CeD. However, also increased intestinal permeability,74 altered intestinal microbiota,76 and impaired nutritional status78 may predispose celiac patients to infections. In this connection, pediatric and adult celiac patients have been linked to an increased risk of nonencapsulated serious infections, including a twofold risk of severe influenza. Although the susceptibility to serious infections seems to persist after introducing a GFD, the risk is likely somewhat higher in untreated CeD.Over the past decades, CeD has consistently been associated with an increased risk of sepsis and infections with encapsulated bacteria . Similar null findings have been reported from Italy and a large international study in which pediatric and adult CeD patients had no significantly increased risk of COVID-19 . Additional international data from the Surveillance Epidemiology Under Research Exclusion for Celiac Disease (SECURE-CELIAC) Registry, collected between March 31, 2020, and February 23, 2021, have also confirmed hospitalization and fatality rates for children and adults to be similar in CeD compared to the general population. Also adult studies have unequivocally shown a similar incidence of COVID-19 in CeD as in the general population.8486 Likewise, a large US study (TriNETX) found no significantly increased risk of hospital admission, critical care, or death from COVID-19.Children with CeD do not seem to have an increased risk of symptomatic COVID-19. A population-based Swedish cohort study of 4490 patients with childhood-onset CeD observed no hospital admissions due to COVID-19 between February and July 2020 . In prospective studies, intestinal viruses, including rotavirus, enterovirus, and parechovirus infections, have been linked to an increased risk of CeD or CeD autoimmunity .8890 Moreover, several respiratory viral infections  have been associated with later CeD.92Numerous viruses have been suggested to be involved in the development of CeD.9396 Both are critical elements in the pathogenesis of CeD. Likewise, induction of proinflammatory interferons from viral infections, including SARS-CoV-2, has been hypothesized to predispose to CeD.The role of viruses in CeD pathogenesis remains to be elucidated. Still, they might contribute to the immunological loss of gluten tolerance through, for example, bystander activation or by increasing gut permeability, enabling epithelial translocation of gluten, or through increased expression of CeD-specific tissue transglutaminase.n = 47) compared to the years before the pandemic . Of the 47 patients diagnosed during the pandemic, endoscopy was performed in 33 (70%). Although moderate-severe mucosal lesions (>Marsh 3a) were less common during the pandemic compared to the prepandemic years (42% versus 82%), the proportion of patients with classical CeD  seemed to increase during the pandemic. Although this finding was not statistically significant, a potentially harmful delay in CeD diagnosis has been reported by other authors. Nevertheless, the interpretation of the results from the Turkish study is restricted by the retrospective nature of the data and the limited sample size. The potentially harmful delay in the diagnosis of CeD was reported in Italy. Italy had a very strict COVID-19 lockdown, particularly at the pandemic’s beginning. A recent Italian study demonstrated a 14% reduction in newly diagnosed CeD during the pandemic. The authors attributed this reduction to the diminished availability of health care services and possibly the fear of contracting COVID-19. Still, they could not entirely rule out the influence of other pathogenic factors or a natural fluctuation in CeD incidence. However, a prospective German study found that adult patients exposed to mild COVID-19 infection had persistent higher levels of CD-specific anti-tissue transglutaminase antibodies (compared to uninfected blood donors), also months after the infectious period, perhaps indicating a future rise in CeD incidence.Data on COVID-19 and the subsequent risk of CeD are so far limited. A recent study from Türkiye reported a threefold increase in the annual number of CeD diagnoses in children during the pandemic  and ulcerative colitis, is a chronic, complex, and costly immune-mediated inflammatory disease. Although most IBD patients are diagnosed in early adulthood, it is estimated that some 15% of all patients are diagnosed during childhood.114 Opportunistic, skin, and GI infections are among those that may pose problems for patients with IBD. There are numerous factors contributing to the infection susceptibility of IBD. First, vast immunological and genetic data have linked IBD development to an aberrant immune response (including the innate and adaptive immune systems), which alterations may also predispose to infections. Second, IBD-related bowel surgery and medical therapies for IBD, which suppress the immune system, are risk factors for severe infections.118 The highest risks of serious infections have been observed in IBD patients exposed to combinations of immunomodulatory drugs, especially those including corticosteroids.119Children and adults with IBD have an increased risk of serious infections. but was also grounded in the fact that SARS-CoV-2 enters human cells via the ACE2 receptor, expressed on epithelial and endothelial cells of the GI tract,28 and up-regulated during inflammation. Hence, longitudinal studies have examined whether IBD patients are at risk of COVID-19 or severe COVID-19.Early in the pandemic, concerns of an increased risk of COVID-19 and a more severe disease course in patients with IBD were raised. Part of that concern related to the immunosuppressive effect of many IBD-related drugs, Instead, some data suggest a lower risk of COVID-19 in adult IBD patients compared to non-IBD patients,122 a phenomenon that might be related to ‘COVID shielding’, that is, patients with chronic conditions may take extra precautions to reduce the risk of infection. Several studies have reported fears and over-protection in children with IBD compared to their peers.124127A recent comprehensive meta-analysis found no significant overall increased pooled relative risk (RR) of COVID-19 in IBD  or across IBD subtypes. individual adult studies have shown a higher risk of COVID-19 hospitalization in IBD patients compared to general population comparators, but with RR estimates varying considerably from an increase of 17–68%.129, Furthermore, in adults with IBD severe COVID-19 has mostly been observed in those of older age and with cardiovascular comorbidities.Although a recent meta-analysis concluded no overall increased risk of COVID-19 hospitalization in IBD, Also, reports to a European IBD database suggest a mild disease course of COVID-19 in children with IBD.The age-related risk of COVID-19 hospitalization in IBD patients has been illustrated in the SECURE-IBD Registry. In this registry, where some 800 of more than 7000 reports concerned pediatric IBD, COVID-19 hospitalization rates ranged from 5% in 10 to 19-year-olds to 47% in those ⩾80 years.134 Propensity-score matched data from US healthcare organizations showed adult IBD patients to have an incidence rate ratio of 0.85 (95% CI 0.69–1.06) for critical care needs after COVID-19 infection compared to the general population. The COVID-19 mortality rate appears similar in people with and without IBD.122 As expected, case fatality for inpatients with IBD is primarily confined to older patients and those having comorbidities. In contrast, few deaths have been reported in pediatric IBD patients. The mortality rate of children <19 years in the SECURE-IBD Registry is 0%.Rates of severe COVID-19  in IBD have been similar to those of the general population.136 Pooled estimates from a recent meta-analysis linked corticosteroid use with a nearly twofold increase in RR for hospitalization and a threefold risk of critical care need or death. These results have prompted expert consensus recommendations to perform individual risk-benefit assessments of COVID-19 severity and IBD activity and consider gradual tapering of systemic corticosteroids and switch to budesonide in IBD patients who test positive for SARS-CoV-2.Evidence in adults with IBD suggests that corticosteroids, but not biologicals, were associated with adverse outcomes to COVID-19.138 neither pediatric IBD nor its treatment seems linked to the COVID-19-associated hyperinflammatory syndrome MIS-C.Finally, besides case reports, Infections are also important determinants for the maturation of the immune system and maintenance of mucosal barrier integrity. Various forms of gastroenteritis have been consistently shown to increase the risk of IBD. However, in early childhood also, respiratory infections have been associated with up to a three times higher risk of pediatric IBD. We also know that respiratory infections, the predominant infectious subtype of young children worldwide, usually cause GI manifestations in early life and influence the intestinal microbiome.Childhood infections have been suggested to impact the risk of IBD development, possibly mediated through perturbations of the gut microbiome. In contrast, the most extensive study of some 4300 IBD patients reported a lower risk of incident IBD following SARS-CoV-2 compared to a propensity-score matched cohort who tested negative for SARS-CoV-2 . The lower IBD incidence post-COVID remained essentially unchanged when restricted to IBD diagnosed >6 months after testing for COVID-19. The same study showed that IBD patients with COVID-19 were 1.3 times more likely to have a flare  at a 3-month follow-up than those without prior COVID-19 . Still, another large adult IBD study reported no significant impact of COVID-19 on clinical IBD activity.A US study with data on 587 pediatric IBD cases showed an increased incidence of pediatric IBD diagnoses during the COVID-19 pandemic compared to the expected number based on historic time trend data.127Patients with IBD have been reported to continue to adhere to their medication regimens during the COVID-19 pandemic.147 While the etiology of FGIDs is undetermined, several factors proposed to be relevant to its pathophysiology, including increased intestinal permeability, dysbiosis, and immune functioning, have also been linked to COVID-19 and other infections.FGIDs are common in children and consist of various disorders believed to be associated with the GI tract but without structural or biochemical abnormality findings at routine examinations. According to the Rome IV criteria from 2016, pediatric FGIDs could be divided into over 15 subdiagnoses. The most common subtypes are irritable bowel syndrome, functional abdominal pain, constipation, and dyspepsia.149152 In particular, bacterial enteritis  and parasite infections  seem to enhance the risk of FGID.154 Research on viral infections and postinfectious FGID in children is limited. A 2009 study examining rotavirus infection as a potential trigger for chronic GI complaints of children in the US and Italy found a higher, albeit not statistically significant, prevalence of functional abdominal pain after rotavirus infection compared to controls .An increasingly recognized subset of patients develops FGID after a GI infection. This association has mainly been studied in adult patient cohorts with laboratory-confirmed gastroenteritis, though the results have also been confirmed in some cohorts of children with GI infection. but have yet to be observed in recovering children. A recently published study from India found that 36/320 (11%) adults with COVID-19 developed FGID-like symptoms at a 1-month follow-up; symptoms remained in some 7% of the COVID-19 patients at 6 months of follow-up. Moderate to severe COVID-19 and the presence of GI symptoms at the time of infection were negative predictors for persistent long-term FGID-like symptoms.New-onset GI symptoms have been reported in adults who have recovered from COVID-19160 However, GI symptoms of long COVID are usually not predominant but may represent up to 2% of affected children.161Long COVID  refers to the potential long-term effects of COVID-19, including fatigue, dyspnea, and cognitive problems that persist or return at least 3 months after the onset of COVID-19. While this condition has primarily been reported in adults, systematic reviews suggest that long COVID may also occur in children and adolescents. For example, the pandemic necessitated a rapid adaptation to remote care delivery,164 and a rise in virtual care for chronic GI conditions (e.g. IBD and CeD). While patient satisfaction with virtual care is typically reported to be high, and its use has been linked to reduced travel costs and school absences, the effectiveness of virtual GI clinics has not been thoroughly studied. Also, physical examination and growth monitoring, important features of clinical decision-making, are typically not part of remote care.Related to the generally milder disease course in children than in adults with COVID-19, pediatric health care, compared to adult care, has been less impacted by the pandemic. Still, routines to practice pediatric care, including pediatric gastroenterology, have been affected. but even more so in children, where for safety and comfort concerns, endoscopy is recommended to be performed under general anesthesia or deep sedation. Because the pandemic consumed almost all anesthetic support on a worldwide scale, pediatric gastroenterologists had to adapt to a clinical praxis with a significantly reduced capacity to perform endoscopic procedures essential to the assessment, treatment, and care of children with many GI conditions . To counter the effects of reduced endoscopy capacity, pediatric papers suggested temporary reductions in required immunoglobulin A anti-tissue transglutaminase antibody thresholds for nonbiopsy-verified CeD diagnoses. In addition, there has likely been an increase in nonendoscopic monitoring of IBD activity, such as fecal calprotectin testing. Still, the effects on care quality related to the modified pediatric endoscopy practice remain largely unknown. The restrictions associated with the COVID-19 pandemic have also had a negative impact on pediatric gastroenterology training programs in North America and Europe.171The pandemic has had repercussions on digestive endoscopy in adults,132 While these registers have mainly focused on adults, their data include children and adolescents, which has enabled updated information on COVID-19 risks and real-time data to support management and treatment decisions.Finally, the COVID-19 pandemic spurred a rapid set-up of studies and surveillance registers of different patient groups .In summary, the risk of contracting and being seriously ill with COVID-19 seems comparable for children with CeD or IBD as for the general population.124127 The reduced endoscopic capacity might have delayed the work-up of those symptoms.Also, so far no firm evidence links COVID-19 with an increased risk of CeD, IBD, or FGID. Still, 3 years into the COVID-19 pandemic, its potential impact on CeD, IBD, and FGID has not been fully determined. Speculatively, there may be a long latency period between infectious exposures and the possible development of these diseases. Hence, given the ongoing intense spread of SARS-CoV-2 worldwide, the potential bi-directional association between COVID-19 and pediatric GI conditions needs further investigation. The pandemic might also have resulted in delayed GI diagnosis: families with children with GI complaints might have avoided hospitals for fear of contracting the virus. which may be even greater in children with chronic illness.This review discusses the evidence of the development or exacerbation of pediatric GI conditions amidst COVID-19. However, we acknowledge that the COVID-19 pandemic has also carried a significant mental health burden on children globally,The COVID-19 pandemic significantly impaired pediatric gastroenterology training programs and hampered our capacity to diagnose and follow children with GI complaints endoscopically. The pandemic’s effects on pediatric gastroenterology practices could last for years. On the other hand, concerted efforts and investments to combat delayed training and backlogs can likely limit these adverse effects.