key: cord-1035832-be3jurfj
authors: Tua Siahaan, Yusak Mangara; Hartoyo, Vinson; Hariyanto, Timotius Ivan; Kurniawan, Andree
title: Coronavirus disease 2019 (Covid-19) outcomes in patients with sarcopenia: A Meta-analysis and Meta-Regression
date: 2022-01-24
journal: Clin Nutr ESPEN
DOI: 10.1016/j.clnesp.2022.01.016
sha: ebd6332dc50fc2852a21583689c8c34d4fdb2c8e
doc_id: 1035832
cord_uid: be3jurfj

Background Sarcopenia has been associated with patients' poor quality of life, disability, and hospitalization. As of today, evidence that highlights the association between sarcopenia and Covid-19 outcomes remains unclear. This study sought to analyze whether patients with sarcopenia are at higher risk for developing poor Covid-19 outcomes. Methods Using specific keywords, we comprehensively go through the potential articles on medRxiv, Europe PMC, and PubMed sources until July 31th, 2021. All published studies on sarcopenia and coronavirus disease 2019 were collected. We were using Review Manager 5.4 and Comprehensive Meta-Analysis 3 software to conduct statistical analysis. Results There were 9 studies with 492,245 Covid-19 patients included in the analysis. Evaluation of the data gathered yielded an association between sarcopenia and increased severity of Covid-19 (OR 1.99; 95%CI: 1.37 – 2.90, p=0.0003, I 2 = 79%, random-effect modelling); and mortality from Covid-19 (OR 1.96; 95%CI: 1.11 – 3.46, p=0.020, I 2 =49%, random-effect modelling). The increased risk of developing severe Covid-19 in a sarcopenic patient is also further influenced by cancer. Conclusions This study proposes that patients with sarcopenia are at risk of developing poor Covid-19 outcomes. Patients with sarcopenia need special attention and should be prioritized to receive the SARS-CoV-2 vaccine. Registration details PROSPERO (CRD42021270725)

More than one and a half years after December 2019, the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still not showing the sign that it will end soon. This coronavirus disease 2019 (Covid-19) pandemic has put together over 193 million confirmed cases, with more than 4 million demises as of July 27 th , 2021. [1] While some SARS-CoV-2 patients may develop mild non-debilitating self-limiting upper-respiratory symptoms, a significant percentage of patients may also develop destructive and progressive symptoms which require hospitalizations and intensive care treatment due to the threat of symptoms progression into acute respiratory distress syndrome (ARDS) and eventually may turn into multi-organ failure (MOF). [2, 3] In light of recent studies, several comorbidities that can increase the probability of developing severe SARS-CoV-2 infections have been well identified such as chronic respiratory disease, diabetes, cardiovascular disease, obesity, and other immunocompromising conditions. [4] [5] [6] [7] [8] [9] [10] Identification of these factors would help give a better risk stratification and reallocation of hospital resources. Sarcopenia is a disorder affecting the muscle characterized by reduced muscle mass and reduced muscle strength. [11] Aging, illness, physical inactivity, and malnutrition has been closely related to the development of this disorder. [11] Sarcopenia may cause several adverse health-related effects which include poor life quality, disability, higher risk of falls, fractures, and hospitalization. [12] In terms of infection, sarcopenia is associated with a higher incidence of nosocomial infection in elderly patients. [13] It also has been demonstrated as a predictor for postoperative infections and delayed recovery in cancer patients. [14, 15] In terms of Covid-19, sarcopenia may be the actual cause of differing Covid-19 courses between patients, but it might also be a mere symptom of other diseases which lead into different J o u r n a l P r e -p r o o f initial step was the identification of eligible articles through screening of titles and abstracts.

Additional evaluation of references from found eligible studies were also conducted to search for more potential articles. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram shows the strategy we employed during our study.

Two authors conducted the data extraction. Extraction form was developed to list information about the study such as its population characteristic, cancer, chronic obstructive pulmonary disease (COPD), body mass index (BMI), sarcopenia assessment tools, sarcopenia parameters, sarcopenia cut-off values, number of patients with sarcopenia, the control group in included studies, as well as the outcome of Covid-19 patients.

We focused the outcomes of our study on severe Covid-19 and mortality. Severe Covid-19 outcome is defined according to the Guidelines for the Diagnosis and Treatment of New Coronavirus Pneumonia (fifth edition) [16] , which includes any of the following features at the time of, or after, admission: (1) respiratory distress (defined as respiratory rates of ≥30 breaths per min); (2) resting oxygen saturation of ≤93%; (3) ratio of the partial pressure of arterial oxygen (PaO2) to a fractional concentration of oxygen inspired air (fiO2) ≤300 mmHg; or (4) critical complication (respiratory failure, septic shock, and or multiple organ dysfunction/failure) or admission into intensive care unit (ICU). Mortality outcome is described by the number of death cases during the follow-up period with a history of positive SARS-CoV-2 infection.

Two authors assessed the quality of each study involved in this review independently.

Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of case-control and cohort J o u r n a l P r e -p r o o f studies. The assessment process included reviewing the comparability, selection, and outcome of each study, then each research was assigned a total score beginning with zero until nine.

Research is graded good if it scores ≥7. [17] Meanwhile, the quality of the included cross-sectional studies was assessed by using the Joanna Briggs Institute (JBI) Critical Appraisal Tools for Cross-Sectional Studies. [18] 

Meta-analysis was done using Review Manager 5.4 (Cochrane Collaboration) and

Comprehensive Meta-Analysis version 3 software. Application of Generic Inverse-Variance formula with random-effect models, regardless of heterogeneity was employed to calculate odds ratio (OR) and its 95% confidence interval (95% CI) for the severe Covid-19 and mortality outcome. In this meta-analysis, heterogeneity between studies was assessed by the Cochrane Q test, tau-squared (τ 2 ), and I-squared (I 2 ; Inconsistency). The I 2 statistic with a value of <25% considered as a low degree of heterogeneity, 26-50% moderate degree of heterogeneity, and >50% considered high degree of heterogeneity. I 2 of at least 50% is considered substantial heterogeneity; it means that at least half of the total variability among effect sizes is due to true heterogeneity between studies. The tau-squared (τ 2 ) statistic is a function of I 2 , while p values for the I 2 statistic were derived from the chi-square distribution of the Cochran Q test. Metaregression with a random-effects model was performed using a restricted-maximum likelihood for pre-specified variables including age, gender, cancer, COPD, and BMI to see the interaction effect between sarcopenia and these variables in influencing the Covid-19 outcomes. Funnel plot analysis was utilized to assess the qualitative risk of publication bias, while Begg and J o u r n a l P r e -p r o o f Mazumdar's rank correlation method was used to assess the quantitative risk of publication bias. [19] 3. RESULTS

Initial database search found 799 studies, from which 692 studies were registered after duplicates removal. We removed 672 records after screening the titles and abstracts as well as matching the inclusion and exclusion criteria. A total of 20 studies with full-text articles were included from which their eligibility was assessed. Five articles did not have enough information about sarcopenia, three articles had no control group, two articles did not provide the outcome of interest, one article was not in English thus resulting in the final number of 9 studies [20-28] which included a total of 492,245 Covid-19 patients for the analysis (Figure 1 ). Out of 9 studies, seven were retrospective cohort, one was the prospective cohort, and the remaining one article was cross-sectional studies. Table 1 gives out the details of each included research. The details regarding the assessment tools, parameters, and cut-off values used for sarcopenia diagnosis in each of the included studies are summarized in Table 2 . Most of the included studies use skeletal muscle index (SMI) measured through CT-scan at the level of thoracal vertebrae 12 (T12) as diagnostic criteria for sarcopenia.

NOS scale was used to evaluate the quality assessment of cohort and case-control studies, which indicated all included studies had good quality (Table 3) . Meanwhile, we used Joanna J o u r n a l P r e -p r o o f Briggs Institute Critical Appraisal checklist for evaluation of cross-sectional studies and found that all included studies were deemed fit to be included in the meta-analysis.

Nine studies (n = 492,245) reported severe Covid-19 as the outcome of patients with sarcopenia and Covid-19. Our pooled analysis revealed that sarcopenia as a comorbidity was correlated with an enhanced risk of severe Covid-19 (OR 1.99; 95%CI: 1.37 -2.90, p=0.0003, random-effect modeling) ( Figure 2A ). Heterogeneity was statistically significant with I 2 = 79%, τ 2 = 0.18, p < 0.00001.

The mortality outcome was revealed in five studies (n = 1,405). The pooled estimate indicated that sarcopenia was associated with higher mortality from Covid-19 (OR 1.96; 95%CI:

1.11 -3.46, p=0.020, random-effect modeling) ( Figure 2B ). Heterogeneity was not statistically significant with I 2 = 49%, τ2 = 0.18, p = 0.10.

Our meta-regression suggested the only statistically significant variables which influence the association between sarcopenia as comorbidity and severe Covid-19 outcome was cancer (p=0.009) ( Figure 3A) , where the increase in cancer prevalence tend to worsen the Covid-19 severity in sarcopenic patients. Our meta-regression also revealed that the Covid-19 severity in sarcopenic patients was also increase by age (p=0.412) ( Figure 3B Our meta-regression also found that the association between sarcopenia as comorbidity and mortality from Covid-19 was affected by gender, where the decrease in male gender prevalence tend to worsen the Covid-19 mortality rate, and this association was statistically significant (p=0.026) ( Figure 4A ). However, the role of increasing age in worsening the Covid-19 mortality rate in sarcopenic patients was not statistically significant (p=0.206) ( Figure 4B ).

Meanwhile, the meta-regression analysis for other variables, such as cancer, COPD, and BMI cannot be done because of not enough information about these variables and mortality outcomes from the included studies.

Because of the limited number of available data, these meta-regression analyses are only based on few number of studies and the results should be interpreted carefully.

Because the number of included studies in each outcomes are fewer than 10 studies, the funnel plots and statistical tests for detecting publication bias are not much reliable when compared with whenever there are more than 10 included studies in each outcomes. [29, 30] Therefore, the test for publication bias was not performed in this study.

According to our pooled analysis, it was discovered that sarcopenia as a comorbidity was associated with increased severity and mortality from Covid-19. Further regression analysis showed that increasing in cancer prevalence may increase the Covid-19 severity in sarcopenic patients and this association is statistically significant. Meanwhile, the other factors such as increasing in age, decreasing in male gender, increasing in COPD prevalence, and increasing in BMI may also influence the Covid-19 outcomes by increasing its severity in patients with sarcopenia, but these associations are not statistically significant. The role of cancer in influencing the relationship between sarcopenia and severe Covid-19 is not surprising as cancer itself has been demonstrated by several meta-analysis to be associated with poor Covid-19 outcomes. [31, 32] Higher expression of transmembrane protease serine 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) in cancer patients may facilitates the entry of SARS-CoV-2 into host cells. [32] Immunocompromised state of cancer patients will also make them more vulnerable to severe complications and contribute to the development of severe Covid-19. [32] Not only that, interleukin-6 (IL-6) as one of the major cytokines in tumor microenvironment has been found to be elevated, deregulated in cancer patients and inhibit the host's immune response to cancer cells. [33, 34] On the other side, IL-6 can contribute to the development of cytokine storm and is a good predictor for poor Covid-19 outcomes. [35] Besides cancer, obesity is also closely related with sarcopenia because there is a condition called sarcopenic obesity where low skeletal muscle mass is coupled with high levels of adiposity. [36] Sarcopenic obesity is commonly seen in older adults. [36] Obesity and BMI itself has been demonstrated to worsen the Covid-19 outcomes. [37, 38] It is also reflected in our meta-regression analysis where BMI also affect the relationship between sarcopenia and Covid-19 severity, although this relationship is not statistically significant. Meanwhile, the association between sarcopenia and higher mortality from Covid-19 was influenced by increasing age and decreasing in male gender prevalence, but only statistically significant for male gender prevalence. interactions. [39, 40] Skeletal muscle can produce several myokines/cytokines which can exert autocrine, paracrine, and endocrine action on numerous tissues. One of the myokines that skeletal muscle produced is interleukin-15 (IL-15). [41] IL-15 plays an important role in immune functions as it induces the NK-cells' proliferation, activation, and distribution. Not only that, but IL-15 also modulates the CD8 T-cell homeostasis and promotes survival of naïve T-cells. [40, 42] Both NK-cells and CD8 T-cells are necessary for the effective clearance of viral pathogens.

Therefore, the lack of IL-15 in sarcopenic patients may impair the host's defense system against viral infection, including SARS-CoV-2 infection. [43] Besides IL-15, another cytokine involved in the pathogenesis of sarcopenia is IL-6. IL-6 inhibits muscle anabolism and may directly promote muscle catabolism, facilitating muscle atrophy seen in sarcopenic patients. [40, 44] In an experimental study conducted by Tsujinaka et al. [45] , a marked loss of muscle mass was seen in transgenic mice which overexpressing IL-6 chronically and treating these mice with IL-6 receptor antibody could mitigate the detrimental effect of IL-6 on muscle. On the other side, IL-6 is among the inflammatory markers associated with higher severity and mortality in Covid-19 patients. [46] [47] [48] Finally, the loss of skeletal muscle mass seen in patients with sarcopenia may also affect the respiratory muscles, such as pectoralis and intercostal muscles. [49] Respiratory muscles are important during the generation of cough, together with internal laryngeal muscles. The cough itself is one of the body's defense mechanisms against lung infections. [50] Therefore, respiratory muscle impairment in patients with sarcopenia may disrupt the normal cough reflex J o u r n a l P r e -p r o o f and may also cause failure in ventilation which ultimately will lead to a higher risk of developing severe infections, including Covid-19. [51] This study is not free from limitations. Our analyses were based on relatively small number of studies because of limited number of currently available data. Studies included in our analysis are also dominantly from European and Asian countries. However, we are not limiting our inclusion criteria based on region/country and we strictly follow the protocol of our study to minimize the selection bias. We also have performed rigorous searching on the three databases (PubMed, Europe PMC, medRxiv) to capture all potentially eligible articles (published and unpublished studies), and to minimize the publication bias. Notable heterogeneities were also identified on most of the outcomes of interests included in this study. This might be due to differences in the type of sarcopenia assessment tools, parameters, and cut-off values used in each of the included studies. More studies that focus on the course of Covid-19 in patients with sarcopenia with larger sample sizes are still needed to confirm the results from our study.

Our systematic review and meta-analysis indicated that patients with sarcopenia were at higher risk of developing poor outcomes from Covid-19, in terms of severity and mortality rate.

This review proposes that patients with sarcopenia should be considered as the population at risk which needs special attention during the Covid-19 pandemic. They should be prioritized to receive SARS-CoV-2 vaccines, along with other comorbidities which were already established as a risk factor for Covid-19. Even so, more studies with larger sample sizes of patients with sarcopenia and Covid-19 are still required to further verify the results from our study. Kim JW et al. [22] 2021 Cohort *** ** *** 8 Good

Ma Y et al. [23] 2021 Cohort *** ** ** 7 Good

McGovern J et al. [24] 2021 Cohort *** ** *** 8 Good

Moctezuma-Velazquez P et al. [25] 2021 Cohort *** ** *** 8 Good

Schiaffino S et al. [26] 2021 Cohort *** ** *** 8 Good

Wilkinson TJ et al. [27] 2021 Cohort *** ** *** 8 Good

Yi X et al. [28] 2021 Cohort *** ** *** 8 Good a (1) representativeness of the exposed cohort; (2) selection of the non-exposed cohort; (3) ascertainment of exposure; (4) demonstration that outcome of interest was not present at start of study b (1) comparability of cohorts on the basis of design or analysis, (maximum two stars) c (1) assessment of outcome; (2) was follow-up long enough for outcomes to occur; (3) adequacy of follow up of cohorts showed that the association between sarcopenia and higher severity of Covid-19 was significantly affected by an increase in cancer prevalence (A). The association between sarcopenia and higher severity of Covid-19 were also affected by an increase in age ( Figure   3B ), decrease in male gender prevalence ( Figure 3C ), increase in COPD prevalence ( Figure   3D ), and decrease in BMI ( Figure 3E ), however all these associations are not statistically significant. showed that the association between sarcopenia and higher mortality from Covid-19 was

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Were the study subjects and the setting described in detail? Yes

Was the exposure measured in a valid and reliable way? Yes 4. Were objective, standard criteria used for measurement of the condition? Yes

Were confounding factors identified? Yes

Were strategies to deal with confounding factors stated? No

Were the outcomes measured in a valid and reliable way? Yes

Was appropriate statistical analysis used? Yes Quality Include study

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