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AbstractBackgroundThe menstrual cycle in women is the main indicator of their reproductive health which is affected by the ongoing coronavirus disease 2019 (COVID‐19) pandemic. This review aims to summarize the effects of the COVID‐19 infection and the global pandemic on the menstrual health of women.MethodsThe literature search was conducted in PubMed, Cochrane library, and Google Scholar using keywords “COVID‐19,” “Menstrual Cycle,” “Menstrual Cycle Irregularities,” “Amenorrhea,” “Polymenorrhea,” and “Dysmenorrhea.” The articles were selected according to the following inclusion criteria: (i) cross‐sectional studies, (ii) cohort studies, (iii) surveys, and (iv) other observational studies observing the effects of SARS‐CoV‐2 infection or COVID‐19 pandemic on menstrual health of women. Exclusion criteria included: case reports, gray literature, and website articles regarding menstrual health.ResultsA total of 30,510 articles were shortlisted after a comprehensive search. Sixteen articles were included out of which 13 studies investigated the effects of the COVID‐19 pandemic on the menstrual cycle while 3 evaluated the possible effects of COVID‐19 infection on the menstrual health of women. Menstrual disorders or irregularities were a more common finding during the pandemic as compared to before (p = 0.008). Women affected by pandemic‐related stress were more prone to changes in the duration of their menses (p = 0.0008), reported heavier bleeding (p = 0.028), and increased incidence of painful periods (p < 0.0001). COVID‐19 infected women also reported changes in their menstrual cycle including irregular menstruation, increased symptoms of premenstrual syndrome, and infrequent menstruation.ConclusionsWomen suffering from COVID‐19 infection or pandemic‐associated stress and anxiety were more likely to experience irregular menstruation, dysmenorrhea, amenorrhea, and other menstrual abnormalities compared to those who were less exposed.

ImportanceThere is limited evidence for therapeutic options for pediatric COVID-19 outside of multisystem inflammatory syndrome in children (MIS-C).ObjectiveTo determine whether the use of steroids within 2 days of admission for non–MIS-C COVID-19 in children is associated with hospital length of stay (LOS). The secondary objective was to determine their association with intensive care unit (ICU) LOS, inflammation, and fever defervescence.Design, Setting, and ParticipantsThis cohort study analyzed data retrospectively for children (&amp;lt;18 years) who required hospitalization for non–MIS-C COVID-19. Data from March 2020 through September 2021 were provided by 58 hospitals in 7 countries who participate in the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 registry.ExposureAdministration of steroids within 2 days of admission.Main Outcomes and MeasuresLength of stay in the hospital and ICU. Adjustment for confounders was done by mixed linear regression and propensity score matching.ResultsA total of 1163 patients met inclusion criteria and had a median (IQR) age of 7 years (0.9-14.3). Almost half of all patients (601/1163, 51.7%) were male, 33.8% (392/1163) were non-Hispanic White, and 27.9% (324/1163) were Hispanic. Of the study population, 184 patients (15.8%) received steroids within 2 days of admission, and 979 (84.2%) did not receive steroids within the first 2 days. Among 1163 patients, 658 (56.5%) required respiratory support during hospitalization. Overall, patients in the steroids group were older and had greater severity of illness, and a larger proportion required respiratory and vasoactive support. On multivariable linear regression, after controlling for treatment with remdesivir within 2 days, country, race and ethnicity, obesity and comorbidity, number of abnormal inflammatory mediators, age, bacterial or viral coinfection, and disease severity according to ICU admission within first 2 days or World Health Organization ordinal scale of 4 or higher on admission, with a random intercept for the site, early steroid treatment was not significantly associated with hospital LOS (exponentiated coefficient, 0.94; 95% CI, 0.81-1.09; P = .42). Separate analyses for patients with an LOS of 2 days or longer (n = 729), those receiving respiratory support at admission (n = 286), and propensity score–matched patients also showed no significant association between steroids and LOS. Early steroid treatment was not associated with ICU LOS, fever defervescence by day 3, or normalization of inflammatory mediators.Conclusions and RelevanceSteroid treatment within 2 days of hospital admission in a heterogeneous cohort of pediatric patients hospitalized for COVID-19 without MIS-C did not have a statistically significant association with hospital LOS.

Background Semiquantitative visual inspection for glomerulosclerosis, interstitial fibrosis, and arteriosclerosis is often used to assess chronic changes in native kidney biopsies. Morphometric evaluation of these and other chronic changes may improve the prognostic assessment. Methods We studied a historical cohort of patients who underwent a native kidney biopsy between 1993 and 2015 and were followed through 2021 for ESKD and for progressive CKD (defined as experiencing 50% eGFR decline, temporary dialysis, or ESKD). Pathologist scores for the percentages of globally sclerosed glomeruli (GSG), interstitial fibrosis and tubular atrophy (IFTA), and arteriosclerosis (luminal stenosis) were available. We scanned biopsy sections into high-resolution images to trace microstructures. Morphometry measures were percentage of GSG; percentage of glomerulosclerosis (percentage of GSG, ischemic-appearing glomeruli, or segmentally sclerosed glomeruli); percentage of IFTA; IFTA foci density; percentage of artery luminal stenosis; arteriolar hyalinosis counts; and measures of nephron size. Models assessed risk of ESKD or progressive CKD with biopsy measures adjusted for age, hypertension, diabetes, body mass index, eGFR, and proteinuria. Results Of 353 patients (followed for a median 7.5 years), 75 developed ESKD and 139 experienced progressive CKD events. Visually estimated scores by pathologists versus morphometry measures for percentages of GSG, IFTA, and luminal stenosis did not substantively differ in predicting outcomes. However, adding percentage of glomerulosclerosis, IFTA foci density, and arteriolar hyalinosis improved outcome prediction. A 10-point score using percentage of glomerulosclerosis, percentage of IFTA, IFTA foci density, and any arteriolar hyalinosis outperformed a 10-point score based on percentages of GSG, IFTA, and luminal stenosis >50% in discriminating risk of ESKD or progressive CKD. Conclusion Morphometric characterization of glomerulosclerosis, IFTA, and arteriolar hyalinosis on kidney biopsy improves prediction of long-term kidney outcomes.

OBJECTIVES: To determine the association of prior use of renin-angiotensin-aldosterone system inhibitors (RAASIs) with mortality and outcomes in hospitalized patients with COVID-19. DESIGN: Retrospective observational study. SETTING: Multicenter, international COVID-19 registry. Subjects: Adult hospitalized COVID-19 patients on antihypertensive agents (AHAs) prior to admission, admitted from March 31, 2020, to March 10, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were compared between three groups: patients on RAASIs only, other AHAs only, and those on both medications. Multivariable logistic and linear regressions were performed after controlling for prehospitalization characteristics to estimate the effect of RAASIs on mortality and other outcomes during hospitalization. Of 26,652 patients, 7,975 patients were on AHAs prior to hospitalization. Of these, 1,542 patients (19.3%) were on RAASIs only, 3,765 patients (47.2%) were on other AHAs only, and 2,668 (33.5%) patients were on both medications. Compared with those taking other AHAs only, patients on RAASIs only were younger (mean age 63.3 vs 66.9 yr; p < 0.0001), more often male (58.2% vs 52.4%; p = 0.0001) and more often White (55.1% vs 47.2%; p < 0.0001). After adjusting for age, gender, race, location, and comorbidities, patients on combination of RAASIs and other AHAs had higher in-hospital mortality than those on RAASIs only (odds ratio [OR] = 1.28; 95% CI [1.19–1.38]; p < 0.0001) and higher mortality than those on other AHAs only (OR = 1.09; 95% CI [1.03–1.15]; p = 0.0017). Patients on RAASIs only had lower mortality than those on other AHAs only (OR = 0.87; 95% CI [0.81–0.94]; p = 0.0003). Patients on ACEIs only had higher mortality compared with those on ARBs only (OR = 1.37; 95% CI [1.20–1.56]; p < 0.0001). CONCLUSIONS: Among patients hospitalized for COVID-19 who were taking AHAs, prior use of a combination of RAASIs and other AHAs was associated with higher in-hospital mortality than the use of RAASIs alone. When compared with ARBs, ACEIs were associated with significantly higher mortality in hospitalized COVID-19 patients.

BACKGROUND: The use of high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) for hypoxemic respiratory failure secondary to COVID-19 are recommended by critical-care guidelines; however, apprehension about viral particle aerosolization and patient self-inflicted lung injury may have limited use. We aimed to describe hospital variation in the use and clinical outcomes of HFNC and NIV for the management of COVID-19. METHODS: This was a retrospective observational study of adults hospitalized with COVID-19 who received supplemental oxygen between February 15, 2020, and April 12, 2021, across 102 international and United States hospitals by using the COVID-19 Registry. Associations of HFNC and NIV use with clinical outcomes were evaluated by using multivariable adjusted hierarchical random-effects logistic regression models. Hospital variation was characterized by using intraclass correlation and the median odds ratio. RESULTS: Among 13,454 adults with COVID-19 who received supplemental oxygen, 8,143 (60%) received nasal cannula/face mask only, 2,859 (21%) received HFNC, 878 (7%) received NIV, 1,574 (12%) received both HFNC and NIV, with 3,640 subjects (27%) progressing to invasive ventilation. The hospital of admission contributed to 24% of the risk-adjusted variation in HFNC and 30% of the risk-adjusted variation in NIV. The median odds ratio for hospital variation of HFNC was 2.6 (95% CI 1.4–4.9) and of NIV was 3.1 (95% CI 1.2-8.1). Among 5,311 subjects who received HFNC and/or NIV, 2,772 (52%) did not receive invasive ventilation and survived to hospital discharge. Hospital-level use of HFNC or NIV were not associated with the rates of invasive ventilation or mortality. CONCLUSIONS: Hospital variation in the use of HFNC and NIV for acute respiratory failure secondary to COVID-19 was great but was not associated with intubation or mortality. The wide variation and relatively low use of HFNC/NIV observed within our study signaled that implementation of increased HFNC/NIV use in patients with COVID-19 will require changes to current care delivery practices. (ClinicalTrials.gov registration NCT04323787.)

Background: Describe the incidence and associated outcomes of gastrointestinal (GI) manifestations of acute coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in hospitalized children (MIS-C). Methods: Retrospective review of the Viral Infection and Respiratory Illness Universal Study registry, a prospective observational, multicenter international cohort study of hospitalized children with acute COVID-19 or MIS-C from March 2020 to November 2020. The primary outcome measure was critical COVID-19 illness. Multivariable models were performed to assess for associations of GI involvement with the primary composite outcome in the entire cohort and a subpopulation of patients with MIS-C. Secondary outcomes included prolonged hospital length of stay defined as being >75th percentile and mortality. Results: Of the 789 patients, GI involvement was present in 500 (63.3%). Critical illness occurred in 392 (49.6%), and 18 (2.3%) died. Those with GI involvement were older (median age of 8 yr), and 18.2% had an underlying GI comorbidity. GI symptoms and liver derangements were more common among patients with MIS-C. In the adjusted multivariable models, acute COVID-19 was no associated with the primary or secondary outcomes. Similarly, despite the preponderance of GI involvement in patients with MIS-C, it was also not associated with the primary or secondary outcomes. Conclusions: GI involvement is common in hospitalized children with acute COVID-19 and MIS-C. GI involvement is not associated with critical illness, hospital length of stay or mortality in acute COVID-19 or MIS-C.

AbstractIntroductionCoronavirus disease 2019 (COVID‐19) is associated with high rates of morbidity and mortality. Primary hypothyroidism is a common comorbid condition, but little is known about its association with COVID‐19 severity and outcomes. This study aims to identify the frequency of hypothyroidism in hospitalized patients with COVID‐19 as well as describe the differences in outcomes between patients with and without pre‐existing hypothyroidism using an observational, multinational registry.MethodsIn an observational cohort study we enrolled patients 18 years or older, with laboratory‐confirmed severe acute respiratory syndrome coronavirus‐2 infection between March 2020 and February 2021. The primary outcomes were (1) the disease severity defined as per the World Health Organization Scale for Clinical Improvement, which is an ordinal outcome corresponding with the highest severity level recorded during a patient's index COVID‐19 hospitalization, (2) in‐hospital mortality and (3) hospital‐free days. Secondary outcomes were the rate of intensive care unit (ICU) admission and ICU mortality.ResultsAmong the 20,366 adult patients included in the study, pre‐existing hypothyroidism was identified in 1616 (7.9%). The median age for the Hypothyroidism group was 70 (interquartile range: 59–80) years, and 65% were female and 67% were White. The most common comorbidities were hypertension (68%), diabetes (42%), dyslipidemia (37%) and obesity (28%). After adjusting for age, body mass index, sex, admission date in the quarter year since March 2020, race, smoking history and other comorbid conditions (coronary artery disease, hypertension, diabetes and dyslipidemia), pre‐existing hypothyroidism was not associated with higher odds of severe disease using the World Health Organization disease severity index (odds ratio [OR]: 1.02; 95% confidence interval [CI]: 0.92, 1.13; p = .69), in‐hospital mortality (OR: 1.03; 95% CI: 0.92, 1.15; p = .58) or differences in hospital‐free days (estimated difference 0.01 days; 95% CI: −0.45, 0.47; p = .97). Pre‐existing hypothyroidism was not associated with ICU admission or ICU mortality in unadjusted as well as in adjusted analysis.ConclusionsIn an international registry, hypothyroidism was identified in around 1 of every 12 adult hospitalized patients with COVID‐19. Pre‐existing hypothyroidism in hospitalized patients with COVID‐19 was not associated with higher disease severity or increased risk of mortality or ICU admissions. However, more research on the possible effects of COVID‐19 on the thyroid gland and its function is needed in the future.

IMPORTANCE: At the start of the coronavirus disease 2019 pandemic, medications repurposed for management of coronavirus disease 2019 were used in the absence of clinical trial evidence. OBJECTIVES: To describe the variation and evolution in use of repurposed medications for coronavirus disease 2019. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study of adults hospitalized with coronavirus disease 2019 between February 15, 2020, and April 12, 2021, across 76 United States and international hospitals within the Society of Critical Care Medicine’s Discovery Viral Infection and Respiratory Illness Universal Study coronavirus disease 2019 registry. MAIN OUTCOMES AND MEASURES: Hospital variation was quantified using multivariable adjusted random effects logistic regression models and unsupervised clustering. Repurposed medications included antivirals, corticosteroids, hydroxychloroquine, immunomodulators, and therapeutic dose anticoagulants. RESULTS: Among 7,069 adults hospitalized with coronavirus disease 2019, 1,979 (28%) received antivirals, 2,876 (41%) received corticosteroids, 1,779 (25%) received hydroxychloroquine, 620 (9%) received immunomodulators, and 2,154 (31%) received therapeutic dose anticoagulants. Contribution of hospital site to risk-adjusted variation was 46% for antivirals, 30% for corticosteroids, 48% for hydroxychloroquine, 46% for immunomodulators, and 52% for therapeutic dose anticoagulants. Compared with the early pandemic, the later pandemic practice phenotypes converged with increased use of antivirals (odds ratio, 3.14; 95% CI, 2.40–4.10) and corticosteroids (odds ratio, 5.43; 95% CI, 4.23–6.97), with decreased use of hydroxychloroquine (odds ratio, 0.02; 95% CI, 0.01–0.04) and immunomodulators (odds ratio, 0.49; 95% CI, 0.34–0.70). There was no clinically significant change in the use of therapeutic dose anticoagulants (odds ratio, 1.01; 95% CI, 1.01–1.02). There were no differences in risk-adjusted mortality between hospitals with high rates of repurposed medication use compared with hospitals with low rates of use. CONCLUSIONS AND RELEVANCE: Hospital variation in the use of repurposed medications varied widely across hospitals early in the pandemic and later converged with the emergence of randomized clinical trials. Platforms developed for rapid activation and enrollment in clinical trials of repurposed medications are needed prior to the next pandemic to expedite effective, evidence-based practice.

OBJECTIVE To describe the impact of obesity on disease severity and outcomes of coronavirus disease 2019 (COVID-19) among hospitalized children. METHODS This retrospective cohort study from the Society of Critical Care Medicine Viral Respiratory Illness Universal Study registry included all children hospitalized with COVID-19 from March 2020 to January 2021. Obesity was defined by Centers for Disease Control and Prevention BMI or World Health Organization weight for length criteria. Critical illness definition was adapted from National Institutes of Health criteria of critical COVID. Multivariate mixed logistic and linear regression was performed to calculate the adjusted odds ratio of critical illness and the adjusted impact of obesity on hospital length of stay. RESULTS Data from 795 patients (96.4% United States) from 45 sites were analyzed, including 251 (31.5%) with obesity and 544 (68.5%) without. A higher proportion of patients with obesity were adolescents, of Hispanic ethnicity, and had other comorbidities. Those with obesity were also more likely to be diagnosed with multisystem inflammatory syndrome in children (35.7% vs 28.1%, P = .04) and had higher ICU admission rates (57% vs 44%, P &lt; .01) with more critical illness (30.3% vs 18.3%, P &lt; .01). Obesity had more impact on acute COVID-19 severity than on multisystem inflammatory syndrome in children presentation. The adjusted odds ratio for critical illness with obesity was 3.11 (95% confidence interval: 1.8–5.3). Patients with obesity had longer adjusted length of stay (exponentiated parameter estimate 1.3; 95% confidence interval: 1.1–1.5) compared with patients without obesity but did not have increased mortality risk due to COVID-19 (2.4% vs 1.5%, P = .38). CONCLUSION In a large, multicenter cohort, a high proportion of hospitalized children from COVID-19 had obesity as comorbidity. Furthermore, obesity had a significant independent association with critical illness.