Gastrointestinal manifestations are associated with severe pediatric COVID-19: A study in tertiary hospital
Authors: Camila Sanson Yoshino de Paula, Giovanna Gavros Palandri, Taiane Siraisi Fonseca, Thaís Cristina Annibale Vendramini, Sylvia Costa Lima Farhat, Maria Fernanda Badue Pereira, Nadia Litvinov, Ricardo Katsuya Toma, Fernanda Viveiros Moreira de Sá, Katharina Reichmann Rodrigues, Cláudio Schvartsman, Silvana Forsait, Neusa Keico Sakita, Kelly Aparecida Kanunfre, Mussya Cisotto Rocha, Emilly Henrique dos Santos, Thelma Suely Okay, João Renato Rebello Pinho, Werther Brunow de Carvalho, Magda Carneiro-Sampaio, Clovis Artur Almeida Silva, Heloisa Helena de Sousa Marques, Adriana Pasmanik Eisencraft, Alfio Rossi Junior, Artur Figueiredo Delgado, Gabriela Nunes Leal, Juliana Valéria de Souza Framil, Maria Augusta Bento Cicaroni Gibelli, Patricia Palmeira Daenekas Jorge
Journal: Journal of Infection (2021)

It is already known that the spectrum of signs and symptoms of coronavirus disease 2019 (COVID- 19) ranges from asymptomatic infection to fatal illness in children and adolescent.1Safadi M.A.P. Silva C.A.A. The challenging and unpredictable spectrum of COVID-19 in children and adolescents.Rev.paul.pediatr. 2020; 39e2020192https://doi.org/10.1590/1984-0462/2020/38/2020192Crossref PubMed Scopus (26) Google Scholar The most common signs and symptoms of pediatric COVID-19 are milder as cough, sore throat and fever. In fact, Dr. Bin Zhang and colleagues reported in the Journal of Infection characteristics of 46 children hospitalized with COVID-19 and none of them had severe disease.2Zhang B. Liu S. Zhang J. et al.Children hospitalized for coronavirus disease 2019 (COVID-19): A multicenter retrospective descriptive study.J Infect. 2020; 81: e74-e75https://doi.org/10.1016/j.jinf.2020.04.045Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar We have noticed that these children had no gastrointestinal symptoms identified. Nonetheless, manifestations as diarrhea, vomiting and abdominal pain have been described in COVID pediatric patients in up to 50% of the cases.3Bialek S. Gierke R. Hughes M. Coronavirus disease 2019 in children — United States, February 12–April 2, 2020.MMWR Morb Mortal Wkly Rep. 2020 Apr 10; 69: 422-426https://doi.org/10.15585/mmwr.mm6914e4Crossref PubMed Google Scholar, 4Giacomet V. Barcellini L. Stracuzzi M. et al.Gastrointestinal symptoms in severe COVID-19 children.Pediatr Infect Dis J. 2020 Oct 1; 39: e317-e320https://doi.org/10.1097/INF.0000000000002843Crossref PubMed Scopus (43) Google Scholar, 5Xia W. Shao J. Guo Y. Clinical and CT features in pediatric patients with COVID-19 infection: different points from adults.Pediatr Pulmonol. 2020 May 1; 55: 1169-1174https://doi.org/10.1002/ppul.24718Crossref PubMed Scopus (725) Google Scholar, 6Oba J. Carvalho W.B.de Silva C.A. et al.Gastrointestinal manifestations and nutritional therapy during COVID-19 pandemic: a practical guide for pediatricians.Einstein (Sao Paulo). 2020; 18: eRW5774https://doi.org/10.31744/einstein_journal/2020rw5774Crossref PubMed Scopus (19) Google Scholar Furthermore, a systematic review7Abrams J.Y. Godfred-Cato S.E. Oster M.E. et al.Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2: a systematic review.J. Pediatr. 2020; 226 (e1): 45-54https://doi.org/10.1016/j.jpeds.2020.08.003Abstract Full Text Full Text PDF Scopus (208) Google Scholar showed that the gastrointestinal tract was the system more frequently associated to the multisystem inflammatory syndrome in children (MIS-C), a severe spectrum of disease in children. We evaluated 83 patients with laboratory-confirmed COVID-19, both by real-time RT-PCR exam and serological test and we aimed to compare demographic and anthropometric data, underlying conditions, clinical characteristics, exams, treatments, and outcomes in laboratory-confirmed pediatric COVID-19 patients with and without gastrointestinal signs and symptoms. Patients were enrolled from April to September of 2020, in a tertiary and university hospital in São Paulo, Brazil. We defined gastrointestinal involvement of pediatric COVID-19 required at least one of the following manifestations: diarrhea, abdominal pain or vomiting.8Belhadjer Z. Meot M. Bajolle F. et al.Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic.Circulation. 2020 Aug 4; 142: 429-436https://doi.org/10.1161/CIRCULATIONAHA.120.048360Crossref PubMed Scopus (876) Google Scholar Stool culture and Clostridioides difficile stool toxin were also evaluated in patients with diarrhea. Nausea, upper and lower gastrointestinal bleeding were recorded. Gastrointestinal endoscopy, colonoscopy, abdominal computed tomography and abdominal ultrasonography were also analyzed. None of pediatric COVID-19 patients with diarrhea reported recent antibiotic use. MIS-C was diagnosed according to Center for Disease Control (CDC) criteria.9Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (MIS-C) [CDC web site]. Available from: https://www.cdc.gov/mis-c/hcp/index.html. Accessed Nov 1,2020.Google Scholar In six patients, stool samples were obtained, and a molecular method was performed to assess the presence of SARS-CoV-2 in feces. Gastrointestinal signs/symptoms were evidenced in 25/83 (30.1%) of children and adolescents with COVID-19 confirmed by molecular or serological methods. Gastrointestinal involvement without any respiratory symptoms was observed in 6/25 (24%). Isolated vomiting was the most important symptom occurring in 9/25 (36%) pediatric COVID-19 patients. None of them had upper or lower gastrointestinal bleeding and required gastrointestinal endoscopy or colonoscopy. Clostridioides difficile stool toxin (n=5) and stool culture (n=4) were negative in pediatric COVID-patient with diarrhea. Severe abdominal pain with right lower quadrant tenderness mimicking acute appendicitis was observed in 2/25 (8%). Both had abdominal ultrasonography that confirmed mesenteric adenitis and none of them needed surgical procedure. Two adolescents with inflammatory bowel disease had laboratory-confirmed COVID-19 without MIS-C and without gastrointestinal involvement. They presented mild symptoms, one of them had fever and respiratory manifestations, and another patient had fever and sore throat. Table 1 includes demographic and anthropometric data, clinical features, underlying conditions, outcomes and treatments of pediatric COVID-19 patients with and without gastrointestinal signs/symptoms. The median number of organs and systems involvement [3 (1-5) vs. 1 (0-5), p<0.001] and the involvement of the cardiac system (64% vs. 31%, p=0.007) were significantly higher in patients with gastrointestinal signs/symptoms compared to those without these manifestations (Table 1). Fibrinogen (465.9 ± 184.2 vs. 304.6 ± 170.1 mg/L, p=0.01) and the number of patients with D-dimer > 1000 ng/ml (67% vs 38%, p=0.04) were also significantly higher in the former group (Table 2). Pericarditis or myocarditis confirmed by echocardiogram (69% vs. 19%, p=0.003) were significantly higher in patients with versus without gastrointestinal signs/symptoms, as well as arterial hypotension (20% vs. 4%, p=0.03) and aspirin use (16% vs. 2%, p=0.03) (Table 2).Table 1Demographic data, anthropometric data, clinical characteristics, underlying conditions, outcomes and treatments of laboratory-confirmed pediatric coronavirus disease 2019 (COVID-19) patients with and without gastrointestinal signs/symptoms.VariablesWith gastrointestinal signs/symptoms (n=25)Without gastrointestinal signs/symptoms (n=58)pDemographic data Male sex15 (60)32 (55)0.81 Current age, years8 (0.5-17.75)10.75 (0-17.92)0.78 Age < 10 years9 (36)31 (53)0.16Anthropometric data Body mass index, kg/m216 (13-25)18 (11-36)0.33Clinical characteristics Duration of signs/symptoms before diagnosis, days4 (1-11)2 (0-114)0.11 Fever17/25 (68)44/58 (76)0.59 Duration of fever, days2 (0-11)1 (0-15)0.29 Nasal discharge7/25 (28)26/57 (46)0.15 Sneezing4/25 (16)12/57 (21)0.77 Cough11/25 (44)27/56 (48)0.81 Sore throat3/21 (14)10/43 (23)0.52 Anosmia2/17 (12)4/32 (13)1.0 Dysgeusia1 /13(8)4/29 (14)1.0 Headache5/21 (24)12/42 (29)0.77 Myalgia7/20 (35)10/45 (22)0.21 Arthralgia0/201/43 (2.3)- Conjunctivitis2/24 (8)1/52 (2)0.23 Dyspnea7/25 (28)24/56 (43)0.23 Hypoxemia7/25 (28)18/56 (32)0.80 Respiratory symptoms19/25 (76)42/58 (72)0.79 Cutaneous rash1/25 (4)4/58 (7)1.0 Fever without a source0/2512/57 (21)- Neurological symptoms1/25 (4)6/58 (10)0.67 Pneumonia8/25 (32)14/56 (25)0.59 Pediatric severe acute respiratory syndrome6/25 (24)12/56 (21)0.78 Multisystem inflammatory syndrome in children (MIS-C)5/25 (20)3/57 (5)0.05 Renal involvement3/25 (12)1/58 (2)0.08 Dermatologic involvement1/25 (4)4/58 (7)1.0 Neurological involvement1/25 (4)6/58 (10)0.67 Hematologic involvement16/24 (67)29/54 (54)0.33 Cardiac involvement16/25 (64)18/58 (31)0.007 Respiratory involvement9/25 (36)17/58 (29)0.61 Number of organs and systems involvement3 (1-5)1 (0-5)<0.001Underlying conditions Pediatric preexisting chronic diseases20/25 (80)43/57 (75)0.78 Diabetes mellitus0/251/58 (2)- Arterial hypertension6/25 (24)8/58 (14)0.34 Immunosuppressive diseases14/25 (56)21/58 (36)0.15 Primary immunodeficiency1/25 (4)1/58 (2)0.51 Solid organ transplantation1/25 (4)2/58 (3)1.0 Hematopoietic stem cell transplantation0/252/58 (3)- Malignancy8/25 (32)12/58 (21)0.28 Current chemotherapy6/24 (25)11/58 (19)0.56 Current radiotherapy00- Chronic kidney disease3/25 (12)5/58 (9)0.69 Autoimmune chronic illnesses1/25 (4)4/58 (7)1.0 Immunosuppressive therapy8/24 (33)19/58 (33)1.0Outcomes Hospitalization20/25 (80)41/58 (71)0.43 Duration of hospitalization, days6 (1-54)7 (0-67)0.46 Pediatric intensive care unit admission9/25 (36)14/57 (25)0,30 Mechanical ventilation5/25(20)6/57 (11)0.30 Vasoactive agents4/25 (16)3/57 (5)0.19 Arterial hypotension5/25 (20)2/56 (4)0.03 Shock5/25 (20)5/57 (9)0.16 Disseminated intravascular coagulation0/252/57 (4)- Thrombosis0/253/57 (5)- Viral co-infection (rhinovirus)0/24/6 (67)- Death4/25 (16)2/58 (3)0.06Treatments Blood products transfusion5/25 (20)8/57 (14)0.52 Red blood cells transfusion5/24 (21)8/57 (14)0.51 Platelets transfusion3/24 (13)5/57 (9)0.70 Plasma transfusion1/24 (4)0/57- Oxygen therapy7/25 (28)21/57 (37)0.61 Antibiotic16/25 (64)32/57 (56)0.63 Oseltamivir6/25 (24)19/57 (33)0.45 Intravenous immunoglobulin6/25 (24)4/57 (7)0.06 Enoxaparin4/25 (16)5/57 (9)0.45 Aspirin4/25 (16)1/57 (2)0.03 Systemic glucocorticoid6/25 (24)8/57 (14)0.34 Intravenous methylprednisolone pulse therapy1/25 (4)1/57 (2)0.52 Dialysis for acute renal injury or shock3/25 (12)1/58 (2)0.08Results are presented in n (%), median (minimum-maximum values) and mean ± standard deviation. Open table in a new tab Table 2Laboratory exams and echocardiographic abnormalities of laboratory-confirmed pediatric coronavirus disease 2019 (COVID-19) patients with and without gastrointestinal signs/symptoms.VariablesWith gastrointestinal signs/symptoms (n=25)Without gastrointestinal signs/symptoms (n=58)pHematological parameters Hemoglobin, g/dL11.0 (± 2.2)11.4 (± 2.2)0.44 Hemoglobin < 10 g/dL7/24 (29)10/56 (18)0.37 Leucocyte count/mm36,678 (100-25,890)6,795 (430-39,900)0.78 Leucopenia < 4,000/mm34/24 (17)9/56 (16)1.0 Neutrophil count/ mm34,020 (0-19,500)5,063 (0-27,900)0.42 Neutropenia < 1,000/ mm33/24 (13)11/56 (20)0.54 Lymphocyte count/mm31,084 (0-17,860)1,802 (0-13,300)0.14 Lymphopenia < 1,500/ mm314/24 (58)20/56 (36)0.08 Thrombocyte count/mm3219,416.7 (± 141,953.0)234,535.7 (± 142,177.8)0.66 Thrombocytosis > 450,000/ mm32/24 (8)5/56 (9)1.0 Thrombocytopenia < 100,000/ mm33/24 (13)11/56 (20)0.54Inflammatory markers C-reactive protein, mg/L30.4 (0.2-272.8)6.4 (0.29-407)0.08 Fibrinogen, mg/dL465.9 (±184.2)304.6 (±170.1)0.01 D-dimer, ng/mL1,908 (232-95,040)1,957 (0-44,251)0.02 D-dimer > 1000 ng/mL14/21 (67)17/45 (38)0.04 Ferritin, ng/mL447 (25-35,976)148 (0-8,000)0.18 Ferritin > 391 ng/mL11/19 (58)10/30 (33)0.14Other exams Lactate dehydrogenase, U/L312 (159-4,476)295 (0-2,078)0.57 Serum albumin, g/dL3.5 (±0.8)3.7 (±0.7)0.30 Aspartate aminotransferase, U/L30 (13-2,002)31 (10-374)0.78 Alanine aminotransferase, U/L20 (6-560)24 (5-495)0.87 Gamma-glutamyl transferase, U/L41 (6-1,496)35 (11-251)0.76 Alkaline phosphatase, U/L146 (87-1,559)144 (69-545)0.33 Blood urea, mg/dL23 (8-118)22 (8-186)0.83 Serum creatinine, mg/dL3.3 (±10.3)0.8 (±1.5)0.25 Triglycerides, mg/dL163 (51-750)132 (77-308)0.94 CK, U/L86 (13-443)72 (14-2,291)0.62 CK-MB, ng/ml1.6 (0.3-15.7)1.8 (0.3-28.9)0.54 Troponin T, ng/mL0.016 (0.003-1.05)0.009 (0.002-0.08)0.11 Prothrombin time, sec14 (11-100)13 (11-34)0.16 INR1.1 (1-7.0)1 (1-3)0.27 Activated partial thromboplastin time, sec34 (12-51)34 (22-53)0.86 Hematuria > 5 erythrocytes/ml3/14 (21)4/27 (15)0.67 Proteinuria > 0.5 g/day1/11 (9)2/23 (9)1.0 Pyuria > 5 leucocytes/field1/14 (7)2/27 (7)1.0Chest X-ray abnormalities11/17 (64.7)20/42 (47.6)0.26Pulmonary CT abnormalities10/11 (90.9)9/16 (56.2)0.09Cardiac abnormalities confirmed by echocardiogram2/16 (13)1/25 (4)0.55 Pericarditis or myocarditis11/16 (69)5/26 (19)0.003Results are presented in n (%), median (minimum-maximum values), mean (± standard deviation), CK creatine phosphokinase, INR - international normalized ratio, CT- computer tomography. Open table in a new tab Results are presented in n (%), median (minimum-maximum values) and mean ± standard deviation. Results are presented in n (%), median (minimum-maximum values), mean (± standard deviation), CK creatine phosphokinase, INR - international normalized ratio, CT- computer tomography. Logistic regression analysis identified that laboratory-confirmed COVID-19 pediatric patients with gastrointestinal signs/symptoms increased risk of cardiac abnormalities confirmed by echocardiogram [odds ratio (OR) 6.316; 95% confidence interval (CI) 1.717-79.043; p=0.012]. Using a molecular method, the presence of SARS-CoV-2 in feces was performed in six patients. In two stool samples the virus was detected, in two the molecular test were negative and inconclusive results were observed in another two patients. The two children that had detection of SARS-CoV-2 in feces were under the age of one year and had preexisting chronic disease (Down´s syndrome and renal rhabdoid tumor, respectively). One of them presented vomiting. No one had diarrhea or abdominal pain. On the other hand, the two patients with no detection of the virus in the feces were older than 10 years and one had nausea, vomiting, diarrhea and abdominal pain. The present study showed that laboratory-confirmed COVID-19 pediatric patients with gastrointestinal manifestations, particularly vomiting, had a severe systemic involvement and high mortality rate. Moreover, cardiac abnormalities were a relevant finding in this setting. We extended previous report of laboratory-confirmed pediatric COVID-19 with at least one gastrointestinal sign/symptom demonstrating that cardiac abnormalities and hyperinflammation may occur in these patients.4Giacomet V. Barcellini L. Stracuzzi M. et al.Gastrointestinal symptoms in severe COVID-19 children.Pediatr Infect Dis J. 2020 Oct 1; 39: e317-e320https://doi.org/10.1097/INF.0000000000002843Crossref PubMed Scopus (43) Google Scholar,7Abrams J.Y. Godfred-Cato S.E. Oster M.E. et al.Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2: a systematic review.J. Pediatr. 2020; 226 (e1): 45-54https://doi.org/10.1016/j.jpeds.2020.08.003Abstract Full Text Full Text PDF Scopus (208) Google Scholar Indeed, Belhadjer et al., reported that the vast majority of 35 pediatric COVID-19 patients with severe cardiac involvement had at least one gastrointestinal manifestation (diarrhea, abdominal pain or vomiting).8Belhadjer Z. Meot M. Bajolle F. et al.Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic.Circulation. 2020 Aug 4; 142: 429-436https://doi.org/10.1161/CIRCULATIONAHA.120.048360Crossref PubMed Scopus (876) Google Scholar In this study the number of organs and systems involvement, intravenous immunoglobulin and aspirin were more frequently observed in patients with digestive signs/symptoms. These findings support the idea that the involvement of the gastrointestinal tract may be an expression of systemic disease and hyperinflammation. The mortality rate in this study was 7%. The high frequency of chronic and immunosuppressed conditions in our laboratory-confirmed pediatric COVID-19 population may contribute to high lethality. We also confirmed previous reports that gastrointestinal involvement had high levels of serum biomarkers, indicating acute inflammation, predominantly with increase of fibrinogen and D-dimer parameters. The elevated levels of these parameters have been also correlated with cytokine storm, multi-organ dysfunction and unfavorable outcome in severe patients with COVID-19.10Akbari H. Tabrizi R. Lankarani K.B. et al.The role of cytokine profile and lymphocyte subsets in the severity of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis.Life Sci. 2020 Oct 1; 258118167https://doi.org/10.1016/j.lfs.2020.118167Crossref PubMed Scopus (142) Google Scholar Further studies with a systematic analysis of pro-inflammatory and anti-inflammatory cytokines profile, and lymphocyte subpopulations will be necessary in laboratory-confirmed pediatric COVID-19 populations to clarify these findings. In conclusion, pediatric COVID-19 patients, mainly in those with underlying conditions and gastrointestinal manifestations, may have a severe and systemic involvement, with high mortality rate. Therefore, our study suggested that laboratory-confirmed COVID-19 pediatric patients with digestive signs/symptoms require attention for hyperinflammation condition and cardiac abnormalities. The authors have no conflict of interest. We thank Lucia Maria Mattei de Arruda Campos, Nadia Emi Aikawa, Mayra de Barros Dorna, Ana Paula Beltran Moschione, Ana Cristina Aoun Tannuri, Uenis Tannuri, Ana Carolina B. Navega, Juliana Folloni Fernandes, Beatriz Perondi, Aurora Rosaria Pagliara Waetge, Sonia Regina Testa da Silva Ramos, Mariana Nutti de Almeida Cordon, Vera Aparecida dos Santos, Simone Aparecida Lima Pavani and Katia Regina de Oliveira for their assistance.