key: cord-0864280-ybdgetms authors: Damara, Fachreza Aryo; Muchamad, Galih Ricci; Ikhsani, Rizkania; Hendro; Syafiyah, Anisa Hana; Bashari, Muhammad Hasan title: Thyroid disease and hypothyroidism are associated with poor COVID-19 outcomes: A systematic review, meta-analysis, and meta-regression date: 2021-10-22 journal: Diabetes Metab Syndr DOI: 10.1016/j.dsx.2021.102312 sha: c22f7d343a98b8d30dd9159a8a069831bfad4039 doc_id: 864280 cord_uid: ybdgetms BACKGROUND AND AIMS: Coronavirus disease (COVID-19) still becomes a global burden that affected people in different groups. The aim of this study was to evaluate the association between thyroid disease and the outcome of COVID-19 patients. METHOD: This was a meta-analysis study from articles obtained through a systematic literature search to investigate the relationship between thyroid disease and COVID-19 outcomes. Composite poor outcomes comprised of severity, mortality, intensive care unit (ICU) admission, and hospitalization. RESULTS: A total of 31339 patients from 21 studies included in this study. Thyroid disorder was associated with increased composite poor outcome (risk ratio (RR) 1.87 [95% confidence interval (CI) 1.53, 2.27], p < 0.001; I2 = 84%, p < 0.01), this included higher disease severity (RR 1.92 [1.40, 2.63], p < 0.05; I2 = 86%, p < 0.01), ICU admission (RR 1.61 [1.12, 2.32], p > 0.05; I2 = 32%, p < 0.05), mortality (RR 2.43 [1.44, 4.13], p < 0.05; I2 = 83%, p < 0.01), and hospitalization (RR 1.28 [1.17, 1.39], p < 0.05; I2 = 0%, p < 0.96). Meta-regression analysis indicated that age (p = 0.002) was a significant influence that affects the association. Also, the presence of unspecified thyroid disease (RR 1.91 [1.38, 2.65], p < 0.05; I2 = 81%, p < 0.01) and hypothyroidism (RR 1.90 [1.45, 2.55], p < 0.05; I2 = 85%, p < 0.01) during admission were associated with poor outcomes. CONCLUSION: Thyroid abnormalities increased the risk of COVID-19 composite poor outcomes and were influenced by the patient's age. Abnormal thyroid and hypothyroidism, but not hyperthyroidism, were associated with poor COVID-19 outcomes. The growing number of cases and the rapidly evolving SARS-CoV-2 has caused coronavirus disease 2019 to become a global burden that affected people from different groups of age. (1, 2) As the spectrum of signs and symptoms among COVID-19-infected individuals is broad-ranging from mild to severe illness requiring intensive care, identifying risk factors that may predict the patients' outcome is imperative for a better resource allocation in mitigating this current COVID-19 outbreak. (3, 4) The interaction between thyroid hormone and immune regulation has been explored extensively in both physiological and pathological settings. As the regulation of the immune system plays an integral part in determining COVID-19 patients' disease progressivity, evidence is required to accentuate the correlation between thyroid hormone and COVID-19 outcomes. (5, 6) In light of this, several studies have been carried out to emphasize the relationship between thyroid status or thyroid abnormalities and the outcome of COVID-19. However, the correlation between the two remains elusive as indicated by the variability of reported study results. Thus, in this present systematic review and meta-analysis, we determined to summarize recent findings on the relationship between thyroid disease and COVID-19 outcome. This systematic review was presented consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRIMSA). (7) A detailed protocol has been previously registered in PROSPERO (CRD42021267278). Inclusion and exclusion criteria were defined according to the PECO (Population, Exposure, Comparison, Outcome) structure. The population of this study was COVID-19 patients confirmed with either polymerase chain reaction (PCR), serum antibody or antigen testing, or highly suspected cases based on clinical presentation. Exposure and comparator were defined as patients with known thyroid disorders, hypothyroidism defined as measured thyroid levels below normal range during admission, and hyperthyroidism defined as measured thyroid levels above normal reference during admission. The inclusion criteria were research articles and letters that report COVID-19 patients with information on thyroid disorders that were presented as categorical data along with measurable composite poor outcomes-mortality/ severity/ critically ill/ intensive care unit (ICU) admission/ patients required hospitalization. The following types of articles were excluded: case report, non-research letter, editorial, invited commentary, review, and abstract-only article. Also, studies that reported only continuous variables of thyroid hormone level were excluded. There was no language restriction applied in this study. ). We used the 'related articles' feature and hand-searched the reference lists of the included articles to expand the search and obtain additional studies. Duplicate results were removed using a reference tool and screening was done manually after the initial search. Data extraction was conducted independently by two authors (FAD and MHB). Standardized forms contained author, year, study design, sample size, cut-off value, gender, age, related comorbidities-hypertension (HT), diabetes mellitus (DM), obesity, and chronic obstructive pulmonary disease (COPD)-and measured outcomes. Data extraction was performed independently, and different perceptions were resolved through discussion and consensus between authors. The primary exposure was thyroid abnormalities preexisting thyroid disease from baseline characteristics or a group of patients with lower-or higher-than-normal measured thyroid hormone levels during admission. The type of thyroid measurement during admission to categorize the patient's type of thyroid level abnormality was thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), or free thyroxine (fT4). The patient was considered hypothyroidism if the level of thyroid hormone was lower than normal reference according to the specified cut-off defined by each study. Conversely, the patient was considered hyperthyroidism if the level of measured thyroid hormone was higher than the normal range. Furthermore, we also performed subgroup analyses on each type of thyroid abnormalities-undefined, hypothyroidism, and hyperthyroidism. The measured outcome of interest was composite poor outcomes that comprised of mortality, COVID-19 severity, intensive care unit (ICU) admission, and hospitalization requirement. Severe COVID-19 generally was characterized as patients who met the criteria of respiratory distress (respiratory rate ≥ 30 breaths/min); pulse oxygen saturation ≤93% on room air; and low arterial oxygenation ratio (PaO2/fraction of inspired oxygen ≤ 300). Subsequently, critically ill patients were indicated if they had respiratory failure requiring a form of mechanical ventilation; shock; or had complications with other organ failures that require monitoring and treatment in the ICU. Further, when the outcome was split into multiple groups (mild, moderate, severe, and critically ill COVID-19), mild and moderate subjects were combined into a single group, and severe to critically ill patients were also considered into one group. We used Newcastle-Ottawa Scale (NOS) to assess the quality of included observational cohort studies. Assessment of the included studies was done independently by four authors (GRM, RI, AHS, and H). The following aspects were taken into consideration in the assessment: cohort selection, the comparability of cohort-based design or analysis, the way exposure is determined, and the way of outcomes of interest is evaluated. Discrepancies of perception in determining study quality were resolved by discussion. All statistical analysis was performed using R (version 4.0.4, The R Foundation, Vienna, Austria).(8) We used the Mantel-Haenszel method formula to generate pooled effect estimates in a form of risk ratio (RR) along with their 95% confidence interval (CI). The inconsistency index (I 2 ) and subgroup analysis using the Chi-square test was used to investigate potential sources of heterogeneity. An I 2 of more than 50% and a p-value of less than 0.05 were considered significant for heterogeneity.(9) To consider interstudy variability, a random-effects model was J o u r n a l P r e -p r o o f used regardless of study heterogeneity.(10) We used a two-tailed p-value with statistical significance was accounted with p ⩽ 0.05. Subgroup analyses were performed only when at least two studies on each at least two subsets were available. Subgroup analysis was carried out on each component of composite poor outcome and the type of thyroid abnormalities specified in the studies. Further, we also conducted a restricted-maximum likelihood random-effects meta-regression analysis to study the influence of the following covariates-gender, age, hypertension, coronary artery disease/cardiovascular disease (CAD/CVD), diabetes mellitus (DM), obesity, and chronic obstructive pulmonary disease (COPD). Analyses of publication bias were presented qualitatively using a contour-enhanced funnel plot and quantitatively assessed using Egger's linear regression test to indicate small-study effects. (11, 12) Sensitivity analysis was performed under the leave-one-out method to single out the cause of study heterogeneity and statistical significance. When publication bias was detected, trim-and-fill analysis was carried out to evaluate the potential sources of publication bias. The selection flow to obtain included studies in this meta-analysis is shown in (Figure 1 Thereby, 21 studies were included for further qualitative and quantitative analyses. . The characteristics of all included studies are available in Table 1 Table 2 ). In addition, we extracted the cumulative incidence of comorbidities reported in each study. Meta-analysis showed that abnormal thyroid was associated with higher risk of COVID-19 composite poor outcome (RR 1.87 [1.53, 2.27], p < 0.001; I2 = 84%, p < 0.01) (Figure 2 In addition, subgroup analyses on different type of thyroid abnormalities were also conducted. Meta-regression showed that the association between thyroid abnormalities and composite poor outcome was significantly influenced by age (p = 0.002), but not affected by gender (p = 0. Publication bias assessment demonstrated an asymmetrical funnel plot for the association between thyroid abnormalities and composite poor outcome (Supplementary figure 1a) . Regression-based Egger's test indicated small-study effects in the association between thyroid abnormalities and composite poor outcomes (p = 0.007) (Supplementary figure 3) . Trim-and-fill analysis showed a reduced pooled effect estimate after imputing 9 studies without altering its significance (RR 1.33 [1.08, 1.63], p = 0.007; I2 = 88%, p < 0.01) (Supplementary figure 1b) . Furthermore, meta-regression analyses showed that the correlation between thyroid abnormalities and poor outcomes was affected by the increasing age, not due to other comorbidities. This association because the levels of TSH and thyroxine will decrease gradually and deteriorated physiological response that occurs with increasing age. Although this present analysis addresses the association between thyroid hormones and COVID-19 outcomes in a larger population, this study has several limitations. Studies that were included in our analyses were largely conducted in a retrospective fashion that may impose a relatively greater potential risk of bias. The association between COVID 19 severity and the degree of thyroid dysfunction could not be assessed due to the paucity of reported studies on each subset. In addition, one cross-sectional study with a relatively larger sample was included that potentially affects cumulative effect estimates. It is important to note that iodine intake may vary across the country. Similarly, ethnicity may also take place to the varied iodine intake levels, especially in a large country.(50) However, we did not perform subgroup analysis under the sociodemographic subset due to study paucity and underreported characteristics on each country or ethnic group of each study. Nevertheless, our study demonstrated a moderate-to-high quality of evidence illustrating those thyroid abnormalities and hypothyroidisms were associated with COVID-19 poor outcomes. Moreover, the generalizability of our findings can be ascertained as the populations included in the analyses were diverse. Thyroid abnormalities are associated with a higher risk of disease severity, mortality, ICU admission, and hospitalization among COVID-19 patients. This association was significantly influenced by an increase in age. Also, the presence of thyroid disorder and hypothyroidism, but not hyperthyroidism, are associated with a higher risk of poor outcomes. 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