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Lack of Marked Association Between Gastrointestinal Symptoms and COVID-19 Mortality: An Updated Meta-analysis Based on Adjusted Effect Estimates

      To the Editor:
      Recently, a meta-analysis by Tariq et al has reported that the mortality of patients with coronavirus disease 2019 (COVID-19) and gastrointestinal (GI) symptoms (0.4%; 95% CI, 0% to 1.1%) was similar to the overall mortality (2.1%; 95% CI, 0.2% to 4.7%).
      • Tariq R.
      • Saha S.
      • Furqan F.
      • Hassett L.
      • Pardi D.
      • Khanna S.
      Prevalence and mortality of COVID-19 patients with gastrointestinal symptoms: a systematic review and meta-analysis.
      This is an extremely interesting study. However, their findings were based on limited sample sizes. Moreover, the pooled effects of the study by Tariq et al were based on crude effect estimates. Various factors such as age, sex, and comorbidities (such as diabetes, hypertension, and cerebrovascular disease) affected the clinical outcomes of patients with COVID-19,
      • Fang X.
      • Li S.
      • Yu H.
      • et al.
      Epidemiological, comorbidity factors with severity and prognosis of COVID-19: a systematic review and meta-analysis.
      • Liang X.
      • Shi L.
      • Wang Y.
      • et al.
      The association of hypertension with the severity and mortality of COVID-19 patients: evidence based on adjusted effect estimates.
      • Liang X.
      • Xu J.
      • Xiao W.
      • Shi L.
      • Yang H.
      The association of diabetes with COVID-19 disease severity: evidence from adjusted effect estimates.
      • Xu J.
      • Xiao W.
      • Liang X.
      • et al.
      The association of cerebrovascular disease with adverse outcomes in COVID-19 patients: a meta-analysis based on adjusted effect estimates.
      suggesting that these factors might influence the relationship between GI symptoms and COVID-19 mortality. So, an updated meta-analysis based on adjusted effect estimates is needed to clarify the association between GI symptoms and COVID-19 mortality.
      We carried out an electronic search in PubMed, Web of Science, and EMBASE until March 9, 2021. The following keywords were used: (COVID-19 or 2019-nCoV or SARS-CoV-2 or coronavirus disease 2019) and (GI or gastrointestinal symptoms) and (mortality or death or fatality or deceased or non-survivor or died). All peer-reviewed studies written in English investigating the relationship between GI symptoms and COVID-19 mortality on the basis of adjusted effects were included. We excluded reviews, case reports, duplicated papers, and studies without complete data. All data analyses were performed using STATA 11.2 (StataCorp, College Station, TX).
      The main characteristics of the included studies are presented in the Table. We observed that there was not a significant association between GI symptoms and COVID-19 mortality on the basis of 20 studies with 58,423 patients with COVID-19 reporting adjusted effect estimates (pooled effect size, 0.93; 95% CI, 0.75 to 1.16; P=.535; random effects model) (Figure A). We observed consistent results in the subgroup analyses by effect estimates (pooled odds ratio, 0.97; 95% CI, 0.75 to 1.26 and pooled hazard ratio, 0.78; 95% CI, 0.45 to 1.36), region (Asia: pooled effect size, 1.25; 95% CI, 0.69 to 2.24; Americas: pooled effect size, 0.90; 95% CI, 0.73 to 1.11; Europe: pooled effect size, 0.83; 95% CI, 0.55 to 1.27; and Africa: pooled effect size, 1.17; 95% CI, 0.65 to 2.09), study design (retrospective studies: pooled effect size, 0.92; 95% CI, 0.70 to 1.21; prospective studies: pooled effect size, 0.63; 95% CI, 0.22 to 1.84; and ambispective studies: pooled effect size, 1.06; 95% CI, 0.81 to 1.38), sample size (≤2000 cases: pooled effect size, 0.92; 95% CI, 0.60 to 1.40 and >2000 cases: pooled effect size, 0.98; 95% CI, 0.83 to 1.15), age (≤65 years old: pooled effect size, 1.13; 95% CI, 0.81 to 1.57 and >65 years old: pooled effect size, 0.81; 95% CI, 0.59 to 1.11), and percentage of male patients (≤60%: pooled effect size, 1.04; 95% CI, 0.77 to 1.40 and >60%: pooled effect size, 0.81; 95% CI, 0.58 to 1.15). Sensitivity analysis indicated that our results were reliable and robust (Figure B). Publication bias was not found in the Begg test and Egger test (Figure C and D).
      TableCharacteristics of the Included Studies
      A, ambispective study; ARDS, acute respiratory distress syndrome; ASCVD, atherosclerotic cardiovascular disease; AST, aspartate transaminase; BMI, body mass index; BUN, blood urea nitrogen; CAD, coronary artery disease; CFS, clinical frailty scale; CHF, congestive heart failure; CKD, chronic kidney disease; CLD, chronic liver disease; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; Ct, cycle threshold; CVD, cardiovascular disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HIV, human immunodeficiency virus; HR, hazard ratio; hs-CRP, high-sensitivity C-reactive protein; IHD, ischemic heart disease; LDH, lactate dehydrogenase; MAS, macrophage activation syndrome; NLR, neutrophil-to-lymphocyte ratio; NR, not reported; NT-proBNP, N-terminal pro-B-type natriuretic peptide; OR, odds ratio; P, prospective study; q-SOFA, quick sequential organ failure assessment; R, retrospective study; SBP, systolic blood pressure; SES, socioeconomic status; SpO2, saturation of pulse oxygen; WBC, white blood cell.
      ,
      SI conversion factors: To convert ng/dL values to mg/L, divide by 100000; to convert g/L values to mg/L, multiply by 1000; to convert mg/dL values to mmol/L, multiply by 0.055551 (glucose); to convert g/L values to mol/L, multiply by 0.000015 (albumin).
      ,
      The values of age are mean ± SD or median (interquartile range); the values of male are n (%).
      AuthorCountryNo. of casesAge (y)MaleStudy designOutcomesAdjusted effect estimate (95% CI)Confounders
      Yan XChina100460.98±14.97493 (49.1)RMortalityOR 39.463 (3.851-404.357)NLR >11.75, hs-CRP, BUN, hypertension, respiratory failure, NT-proBNP, cerebrovascular disease
      Magleby RUnited States67867.05±16.65414 (61.1)RMortalityOR 0.5 (0.21-1.19)Age, race, CAD, CHF, cerebrovascular disease, hypertension, COPD, days of symptoms before admission, symptoms on admission (fever, cough, headache, myalgias, altered mental status, aguesia), oxygen by nasal cannula, oxygen by a non-rebreather mask, high-flow nasal cannula or noninvasive mechanical ventilation, mechanical ventilation, Chest radiography findings (unilateral infiltrates, bilateral infiltrates), viral load by nasal pharyngeal swab (medium viral load [Ct, 25-30], high viral load [Ct, <25])
      Zhang LChina40965 (56-71)234 (57.2)RDeathOR 1.547 (1.029-2.325)Neutrophil count, lymphocyte count
      Knopp PUnited Kingdom21780±6.8134 (62)PMortalityHR 0.45 (0.11-1.91)Age, sex, CFS, cough, fever, dyspnea, imaging abnormalities, falls, reduced mobility, delirium, CRP, NLR
      Russell BUnited Kingdom15665.18±14.8090 (57.70)ADeathHR 1.44 (0.64-3.26)Age, sex, SES, ethnicity, number of comorbidities, smoking history, cancer type, treatment paradigm, time since cancer diagnosis, performance status, symptoms (cough, fever, dyspnea), time between first symptom and diagnosis, CRP, lymphocytes, albumin
      Ioannou GNUnited States10,13163.6±16.29221 (91.0)AMortalityHR 1.02 (0.77-1.35)Age, sex, race, ethnicity, COVID-19–related deaths per million residents, urban vs rural, BMI at index date, diabetes, cancer, hypertension, CAD, CHF, cerebrovascular disease, dialysis, CKD, cirrhosis, asthma, COPD, obstructive sleep apnea, obesity hypoventilation, alcohol dependence, hyperlipidemia, smoking, Charlson Comorbidity Index score, fever, cold, chills, myalgia, fatigue, cough, dyspnea, sore throat, nausea, abdominal pain, headache
      de Azambuja EBelgium13,59468.29±16.816584 (48.4)RMortalityOR 1.44 (0.93-2.24)Age, sex, number of comorbidities, comorbidities (CVD, hypertension, diabetes, CKD, CLD, chronic lung disease, chronic neurological disease, cognitive disorder, immunosuppression including HIV), smoking history (noncurrent smoker, current smoker), timing of symptoms onset (before or at the day of admission, during hospitalization), symptoms at diagnosis (systemic symptoms, respiratory symptoms, neurological symptoms), number of symptoms at diagnosis, signs at diagnosis (temperature <38°C, temperature ≥38°C, respiratory signs, neurological signs), number of signs at diagnosis, evolution during hospitalization (pneumonia at imaging examination, ARDS), treatment during hospitalization (hydroxychloroquine, azithromycin, corticosteroids, specific treatment of COVID-19, no treatment reported)
      Rozaliyani AIndonesia405245.8±16.32169 (53.5)RDeathOR 0.79 (0.52-1.21)Age, sex, registered address, symptoms (cough, fever, malaise, dyspnea, headache, sore throat, chills, pneumonia), comorbidity (hypertension, diabetes, heart disease, renal disease, immunological disorder)
      Aksel GTurkey16859.5 (48.3-76)90 (53.6)PMortalityHR 0.97 (0.19-4.91)Age, dyspnea, presence of any comorbid disease, pulse O2 saturation, WBC, CRP
      Abayomi ANigeria217543.0±16.01436 (65.8)RDeathOR 1.12 (0.31-4.02)Fever, cough, weakness, loss of appetite, headache, difficulty in breathing, throat irritation, loss of taste/smell, other symptoms
      Raines AMUnited States44060.76±13.82393 (89.3)RDeathOR 0.81 (0.47-1.39)Age, sex, race, BMI, immunodeficiency syndromes, pulmonary diseases, oncological diseases, renal diseases, hematologic diseases, endocrine diseases, CVD, neurological problems, lifetime tobacco user
      Ramos-Rincon JMSpain277286.3 (83.2-89.6)1367 (49.4)RMortalityOR 0.83 (0.62-1.34)Age, sex, degree of dependence, comorbidities (non-ASCVD, ASCVD, dementia, moderate-severe renal disease), symptoms (shortness of breath, anorexia), physical examination (oxygen saturation <90%, temperature ≥37.8°C, pulmonary rales, q-SOFA score ≥2), chest radiography, laboratory findings (neutrophils ≥7.5 × 103/μL, lymphocytes <0.800 × 103/μL, eosinophils <0.030 × 103/μL, monocytes <0.500 × 103/μL, glucose >126 mg/dL, eGFR <45 mL/min per 1.73 m2, lactate dehydrogenase ≥500 U/L, CRP ≥80 mg/L)
      de Souza CDBrazil980770.21±8.374662 (47.5)RMortalityOR 0.83 (0.54-1.29)Sex, age ≥75 y, initial symptoms reported (cough, fever, fatigue, headache, myalgia, odynophagia, dyspnea), comorbidities (diabetes, CVD, hypertension, chronic lung disease, CKD, obesity)
      Peng XChina4963 (53-73)32 (65)RDeathOR 13.4 (1.9-94.8)Lymphocytes <1.1 × 109/L, fasting blood glucose ≥7.0 mmol/L
      Elimian KONigeria10,51737.2±1 5.77070 (66.7)RDeathOR 1.18 (0.62-2.28)Age, male, geopolitical zone (south-west, south-south, south-east, north-central, north-west, north-east), occupation (housewife, trader/business, health worker, farmer, religious/traditional leader, transporter, other), vomiting, travel history, abdominal pain, chest pain, chills/sweat, confusion, cough, breathing difficulty, fatigue, fever, joint pain, malaise, nausea, rapid breathing
      Jain ACIndia42649 (21-77)313 (73.38)RMortalityOR 0.65 (0.08-5.03)Age, sex, weight, travel, visit: hotspots, contact, fever, symptoms, duration of illness >5 d, sore throat, cough, sputum production, shortness of breath, headache, myalgia/arthralgia, comorbidities, diabetes, hypertension, CKD, CAD/IHD, malignancy, hypothyroidism, medication for chronic disease, SBP, effusions, DBP, temperature, respiratory rate, SpO2, pulse rate, bilateral patchy shadows, local patchy shadows
      Guglielmetti LItaly21868 (59-76)172 (79)RDeathHR 0.31 (0.13-0.72)Sex, presence of bilateral disease at computed tomography scan, treatment with corticosteroids, age >65 y at admission, ≥1 comorbidity, severe ARDS at admission, platelet count <197 × 103/μL at admission, LDH >440 U/L at admission
      Lee JKorea770NR453 (58.8)RDeathOR 0.6 (0.28-1.21)Age, SBP, heart rate, dyspnea at presentation, mental disturbance at presentation, comorbidity (treating cancer, diabetes, hypertension, chronic cardiac disease, chronic pulmonary disease, chronic renal disease, dementia), hemoglobin, Absolute lymphocyte counts (group II, ≥500 to <1000/mm3; group I, <500/mm3), platelet counts <100,000/mm3
      Viana-Llamas MCSpain60971 (58-82)367 (60.3)RMortalityOR 0.735 (0.422-1.281)Sex, BMI, symptoms on admission (dyspnea, dysgeusia/anosmia, arthralgia/myalgia, asthenia, cough, high temperature, vomiting), vital signs on admission (blood O2 saturation <92%, tachypnea >22 beats/min, disorder of consciousness, SBP <90 mm Hg or/and DBP <60 mm Hg, q-SOFA score ≥2), chest radiography on admission (bilateral infiltration), laboratory findings on admission (albumin <34 g/L, lymphocytes ≤800/μL, creatinine, D-dimer >0.49 ng/dL, hs-CRP >8 mg/L, lactate dehydrogenase >250 U/L, hemoglobin, leukocyte count, platelet count, fibrinogen, sodium, AST, ferritin), adverse events (ARDS, sepsis, acute respiratory failure, bilateral pneumonia, acute kidney injury, MAS, acute heart failure, bleeding events, embolic events)
      Aoun MLebanon23161.46±13.99128 (55.4)RDeathOR 0.705 (0.33-1.51)Age, sex, dialysis vintage, multimorbidities, smoking, diabetes, obesity, heart failure, CAD, lung disease, cancer, history of stroke, dementia, fever, dyspnea, hypotension, pneumonia, CRP, admission to hospital
      a A, ambispective study; ARDS, acute respiratory distress syndrome; ASCVD, atherosclerotic cardiovascular disease; AST, aspartate transaminase; BMI, body mass index; BUN, blood urea nitrogen; CAD, coronary artery disease; CFS, clinical frailty scale; CHF, congestive heart failure; CKD, chronic kidney disease; CLD, chronic liver disease; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; Ct, cycle threshold; CVD, cardiovascular disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HIV, human immunodeficiency virus; HR, hazard ratio; hs-CRP, high-sensitivity C-reactive protein; IHD, ischemic heart disease; LDH, lactate dehydrogenase; MAS, macrophage activation syndrome; NLR, neutrophil-to-lymphocyte ratio; NR, not reported; NT-proBNP, N-terminal pro-B-type natriuretic peptide; OR, odds ratio; P, prospective study; q-SOFA, quick sequential organ failure assessment; R, retrospective study; SBP, systolic blood pressure; SES, socioeconomic status; SpO2, saturation of pulse oxygen; WBC, white blood cell.
      b SI conversion factors: To convert ng/dL values to mg/L, divide by 100000; to convert g/L values to mg/L, multiply by 1000; to convert mg/dL values to mmol/L, multiply by 0.055551 (glucose); to convert g/L values to mol/L, multiply by 0.000015 (albumin).
      c The values of age are mean ± SD or median (interquartile range); the values of male are n (%).
      Figure thumbnail gr1ab
      FigureA, The forest plot depicted that gastrointestinal symptoms were not markedly associated with coronavirus disease 2019 mortality on the basis of adjusted effect estimates. B, Sensitivity analysis indicated that our results were stable and robust. C and D, Publication bias was evaluated using the Begg test (panel C) and Egger test (panel D).
      Figure thumbnail gr1cd
      FigureA, The forest plot depicted that gastrointestinal symptoms were not markedly associated with coronavirus disease 2019 mortality on the basis of adjusted effect estimates. B, Sensitivity analysis indicated that our results were stable and robust. C and D, Publication bias was evaluated using the Begg test (panel C) and Egger test (panel D).
      In summary, our findings based on adjusted effect estimates suggested that GI symptoms were not markedly associated with COVID-19 mortality. Further well-designed studies with large sample sizes are needed to confirm our conclusions.

      References

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        Prevalence and mortality of COVID-19 patients with gastrointestinal symptoms: a systematic review and meta-analysis.
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