Guidelines for the prevention and management of children and adolescents with COVID-19.

Children are the future of the world, but their health and future are facing great uncertainty because of the coronavirus disease 2019 (COVID-19) pandemic. In order to improve the management of children with COVID-19, an international, multidisciplinary panel of experts developed a rapid advice guideline at the beginning of the outbreak of COVID-19 in 2020. After publishing the first version of the rapid advice guideline, the panel has updated the guideline by including additional stakeholders in the panel and a comprehensive search of the latest evidence. All recommendations were supported by systematic reviews and graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Expert judgment was used to develop good practice statements supplementary to the graded evidence-based recommendations. The updated guideline comprises nine recommendations and one good practice statement. It focuses on the key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin (IVIG) for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health. CONCLUSION: This updated evidence-based guideline intends to provide clinicians, pediatricians, patients and other stakeholders with evidence-based recommendations for the prevention and management of COVID-19 in children and adolescents. Larger studies with longer follow-up to determine the effectiveness and safety of systemic glucocorticoids, IVIG, noninvasive ventilation, and the vaccines for COVID-19 in children and adolescents are encouraged. WHAT IS KNOWN: • Several clinical practice guidelines for children with COVID-19 have been developed, but only few of them have been recently updated. • We developed an evidence-based guideline at the beginning of the COVID-19 outbreak and have now updated it based on the results of a comprehensive search of the latest evidence. WHAT IS NEW: • The updated guideline provides key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health.

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

ObjectiveTo delineate the clinical characteristics of patients with coronavirus disease 2019 (covid-19) who died.DesignRetrospective case series.SettingTongji Hospital in Wuhan, China.ParticipantsAmong a cohort of 799 patients, 113 who died and 161 who recovered with a diagnosis of covid-19 were analysed. Data were collected until 28 February 2020.Main outcome measuresClinical characteristics and laboratory findings were obtained from electronic medical records with data collection forms.ResultsThe median age of deceased patients (68 years) was significantly older than recovered patients (51 years). Male sex was more predominant in deceased patients (83;73%) than in recovered patients (88;55%). Chronic hypertension and other cardiovascular comorbidities were more frequent among deceased patients (54 (48%) and 16 (14%)) than recovered patients (39 (24%) and 7 (4%)). Dyspnoea, chest tightness, and disorder of consciousness were more common in deceased patients (70 (62%), 55 (49%), and 25 (22%)) than in recovered patients (50 (31%), 48 (30%), and 1 (1%)). The median time from disease onset to death in deceased patients was 16 (interquartile range 12.0-20.0) days. Leukocytosis was present in 56 (50%) patients who died and 6 (4%) who recovered, and lymphopenia was present in 103 (91%) and 76 (47%) respectively. Concentrations of alanine aminotransferase, aspartate aminotransferase, creatinine, creatine kinase, lactate dehydrogenase, cardiac troponin I, N-terminal pro-brain natriuretic peptide, and D-dimer were markedly higher in deceased patients than in recovered patients. Common complications observed more frequently in deceased patients included acute respiratory distress syndrome (113;100%), type I respiratory failure (18/35;51%), sepsis (113;100%), acute cardiac injury (72/94;77%), heart failure (41/83;49%), alkalosis (14/35;40%), hyperkalaemia (42;37%), acute kidney injury (28;25%), and hypoxic encephalopathy (23;20%). Patients with cardiovascular comorbidity were more likely to develop cardiac complications. Regardless of history of cardiovascular disease, acute cardiac injury and heart failure were more common in deceased patients.ConclusionSevere acute respiratory syndrome coronavirus 2 infection can cause both pulmonary and systemic inflammation, leading to multi-organ dysfunction in patients at high risk. Acute respiratory distress syndrome and respiratory failure, sepsis, acute cardiac injury, and heart failure were the most common critical complications during exacerbation of covid-19.

Twelve-Month Systemic Consequences of Coronavirus Disease 2019 (COVID-19) in Patients Discharged From Hospital: A Prospective Cohort Study in Wuhan, China.

BACKGROUND: Follow-up study of coronavirus disease 2019 (COVID-19) survivors has rarely been reported. We aimed to investigate longitudinal changes in the characteristics of COVID-19 survivors after discharge. METHODS: A total of 594 COVID-19 survivors discharged from Tongji Hospital in Wuhan from February 10 to April 30, 2020 were included and followed up until May 17, 2021. Laboratory and radiological findings, pulmonary function tests, electrocardiogram, symptoms and signs were analyzed. RESULTS: 257 (51.2%) patients had at least one symptom at 3 months post-discharge, which decreased to 169 (40.0%) and 138 (28.4%) at 6-month and 12-month visit respectively. During follow-up period, insomnia, chest tightness, and fatigue were the most prevalent symptoms. Most laboratory parameters returned to normal, whereas increased incidence of abnormal liver and renal function and cardiovascular injury was evidenced after discharge. Fibrous stripes (213; 42.4%), pleural thickening and adhesions (188; 37.5%) and enlarged lymph nodes (120; 23.9%) were the most common radiographical findings at 3 months post-discharge. The abnormalities of pulmonary function included obstructive, restrictive, and mixed, which were 5.5%, 4.0%, 0.9% at 6 months post, and 1.9%, 4.7%, 0.2% at 12 months. Electrocardiogram abnormalities occurred in 256 (51.0%) patients at 3 months post-discharge, including arrhythmia, ST-T change and conduction block, which increased to 258 (61.1%) cases at 6-month visit and were maintained at high frequency (242;49.8%) at 12-month visit. CONCLUSIONS: Physiological, laboratory, radiological, or electrocardiogram abnormalities, particularly those related to renal, cardiovascular, and liver functions are common in patients who recovered from coronavirus disease 2019 (COVID-19) up to 12 months post-discharge.

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication.

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.

Lower Serum Angiotensin-Converting Enzyme Level in Relation to Hyperinflammation and Impaired Antiviral Immune Response Contributes to Progression of COVID-19 Infection.

INTRODUCTION: As a homologue of the angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2) has been identified as the main receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invasion. We aimed to investigate the role of serum ACE in predicting the coronavirus disease 2019 (COVID-19) disease progression and the underlying mechanisms. METHODS: We retrospectively enrolled 120 patients with confirmed COVID-19 who underwent serum ACE detection on admission. The clinical characteristics and laboratory findings during hospitalization were evaluated dynamically to identify the potential risk factors for disease progression. RESULTS: ACE level was demonstrated as one of the independent risk factors. Patients with ACE level ≤ 33.5 U/L showed a higher cumulative virus RNA detection rate, elevated pro-inflammatory mediators levels, declined lymphocyte count, and decreased SARS-CoV-2-specific antibodies than those with ACE level > 33.5 U/L. CONCLUSION: Lower serum ACE levels in relation to delayed virus elimination, hyperinflammatory condition, and impaired host antiviral immune responses contribute to disease progression of COVID-19.

Immunological Characteristics in Type 2 Diabetes Mellitus Among COVID-19 Patients.

Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04365634. Context: Diabetes mellitus was associated with increased severity and mortality of disease in COVID-19 pneumonia. So far the effect of type 2 diabetes (T2DM) or hyperglycemia on the immune system among COVID-19 disease has remained unclear. Objective: We aim to explore the clinical and immunological features of type 2 diabetes mellitus (T2DM) among COVID-19 patients. Design and Methods: In this retrospective study, the clinical and immunological characteristics of 306 hospitalized confirmed COVID-19 patients (including 129 diabetic and 177 non-diabetic patients) were analyzed. The serum concentrations of laboratory parameters including cytokines and numbers of immune cells were measured and compared between diabetic and non-diabetic groups. Results: Compared with non-diabetic group, diabetic cases more frequently had lymphopenia and hyperglycemia, with higher levels of urea nitrogen, myoglobin, D-dimer and ferritin. Diabetic cases indicated the obviously elevated mortality and the higher levels of cytokines IL-2R, IL-6, IL-8, IL-10, and TNF-α, as well as the distinctly reduced Th1/Th2 cytokines ratios compared with non-diabetic cases. The longitudinal assays showed that compared to that at week 1, the levels of IL-6 and IL-8 were significantly elevated at week 2 after admission in non-survivors of diabetic cases, whereas there were greatly reductions from week 1 to week 2 in survivors of diabetic cases. Compared with survival diabetic patients, non-survival diabetic cases displayed distinct higher serum concentrations of IL-2R, IL-6, IL-8, IL-10, TNF-α, and lower Th1/Th2 cytokines ratios at week 2. Samples from a subset of participants were evaluated by flow cytometry for the immune cells. The counts of peripheral total T lymphocytes, CD4+ T cells, CD8+ T cells and NK cells were markedly lower in diabetic cases than in non-diabetic cases. The non-survivors showed the markedly declined counts of CD8+ T cells and NK cells than survivors. Conclusion: The elevated cytokines, imbalance of Th1/Th2 cytokines ratios and reduced of peripheral numbers of CD8+ T cells and NK cells might contribute to the pathogenic mechanisms of high mortality of COVID-19 patients with T2DM.

Managing Preterm Infants Born to COVID-19 Mothers: Evidence from a Retrospective Cohort Study in Wuhan, China.

BACKGROUND: COVID-19 has spread rapidly over the world. Little is known about the outcomes of infections in pregnant women. The management and characteristics of preterm infants born to COVID-19 mothers need to be clarified. METHODS: In this retrospective, single-center cohort study, we describe the clinical courses of 6 preterm infants born to COVID-19 mothers, the management protocol, and related outcomes. RESULTS: Six preterm infants were admitted to Tongji Hospital between January 23 and March 19, 2020. Gestational age ranged from 28+5 to 36+3 weeks. One late preterm infant was delivered early due to maternal dyspnea from COVID-19. Five infants were delivered by Caesarean section. None had perinatal asphyxia. Two infants required respiratory support due to respiratory distress syndrome and apnea of prematurity. All infants did not develop severe complications of prematurity and are negative for severe acute respiratory syndrome (SARS)-CoV-2 nucleic acid testing. CONCLUSION: With an expedited and adequate delivery protocol, less invasive treatment principle, and active infection precautious, we found a limited impact of COVID-19 mothers on preterm delivery and neonatal short-term outcomes. The risk of vertical transmission of SARS-CoV-2 is low in preterm infants born to COVID-19 mothers if appropriate management is implemented.

Recommendations for the Diagnosis, Prevention, and Control of Coronavirus Disease-19 in Children-The Chinese Perspectives.

Ever since SARS-CoV-2 began infecting people by the end of 2019, of whom some developed severe pneumonia (about 5%), which could be fatal (case fatality ~3.5%), the extent and speed of the COVID-19 outbreak has been phenomenal. Within 2.5 months (by March 18, 2020) over 191,127 COVID-19 patients have been identified in 161 countries. By then, over 700 pediatric patients were confirmed to have COVID-19 in China, with only about 58 diagnosed elsewhere. By now, there are thousands of children and adolescents infected. Chinese pediatricians would like to share their experience on how these patients were managed in China and the key recommendations that had guided them in meeting the evolving challenges. A group of experts were summoned by the Chinese Pediatric Society and Editorial Board of Chinese Journal of Pediatrics to extract informative data from a survey on confirmed COVID-19 pediatric patients in China. Consensus on diagnosis, management, and prevention of pediatric COVID-19 were drawn up based on the analysis of such data plus insights gained from the past SARS and MERS coronavirus outbreaks. Relevant cumulating experiences from physicians managing adult patients, expedited reports on clinical and scientific COVID-19 and SARS-CoV-2 data, and the National Health Committee guidelines on COVID-19 management were integrated into this proposal.

Children and youth with diabetes are not at increased risk for hospitalization due to COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), responsible for the coronavirus disease COVID-19, was first identified in Wuhan, China in December 2019. Diabetes, as well as other cardiovascular comorbidities, has been recognized as a major risk factor for outcomes and mortality in adults with COVID-19, particularly in the elderly with type 2 diabetes. Based on these conclusions, COVID-19 data on adults have been generalized to youth with diabetes. Nevertheless, experience from pediatric diabetes practices in China (Wuhan), Italy, Spain (Catalonia), and the United States (San Francisco Bay Area) consistently report only a single severe case of COVID-19 in a 20-year-old female youth with type 1 diabetes (T1D) that was hospitalized for bilateral pneumonia and was subsequently discharged without complications. In Italy, information on COVID-19 in all children with diabetes is collected on a weekly basis and those with positive swab test or infection-related symptoms reported to a dedicated national registry. Of a total of 15 500 children tested, 11 subjects with T1D (age 8-17y) tested positive for COVID-19; 6/11 were asymptomatic and the rest presented with mild symptoms. In the rest of locations, youths with T1D diagnosed with COVID-19 were based on clinical suspicion and a confirmatory PCR test (Wuhan:0; Catalonia-HSJD:3; California-Stanford:2). All of them were asymptomatic or had a mild course. We suggest that COVID-19 data from adults should not be generalized to children, adolescents, and youth with diabetes as their outcomes and prognosis seem to be similar to their non-diabetic-peers and consistently milder than adults with diabetes.

Kindergartens Reopening in the Period of Regular Epidemic Prevention and Control, Benefitial or Harmful?

In the period of regular epidemic prevention and control of Coronavirus disease 2019 (COVID-19) in our country, work resumption has been fully advanced. But there are still new sporadic local cases and imported cases across the country. In this situation, whether kindergartens reopening will increase the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread still remains uncertain. We reviewed two pediatric patients with moderate COVID-19, collected the epidemiologic information and monitored the cycle threshold value of rectal specimen and the viral loads, and discussed the transmission of SARS-CoV-2 in pediatric patients and the virulence of feces in children with moderate COVID-19, in order to analyze the risk of kindergartens reopening.

Clinical characteristics and risk factors of liver injury in COVID-19: a retrospective cohort study from Wuhan, China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has rapidly become a major international public health concern. This study was designed to evaluate the clinical characteristics and risk factors of COVID-19-associated liver injury. METHODS: A fraction of 657 COVID-19 patients were retrospectively analyzed. Clinical and laboratory data were derived from electronic medical records and compared between patients with or without liver injury. Multivariate logistic regression method was used to analyze the risk factors for liver injury. RESULTS: Among 657 patients, 303 (46.1%) patients had liver injury with higher rate in severe/critically ill patients [148/257 (57.6%)] than those in moderate cases [155/400 (38.8%)]. The incidence of liver injury was much higher in male [192/303 (63.4%)] than female [111/303 (36.6%)], and in severe/critical patients [148/303 (48.8%)] with percutaneous oxygen saturation ≤ 93% [89/279 (31.9%)] or peak body temperature ≥ 38.5 °C [185/301 (61.5%)] on admission. Liver injury-related inflammations included increased white blood cells, neutrophils and decreased lymphocytes. More patients with liver injury than without had increased serum IL-2R, TNFα, ferritin, hsCRP, PCT, ESR, γ-GT, and LDH. Multivariate regression analysis revealed that increasing odds of liver injury were related to male, higher serum hsCRP (≥ 10 mg/L), and neutrophil-to-lymphocyte ratio (NLR) (≥ 5). Moreover, more deceased patients (14/82 (17%)) had significantly elevated serum TBIL than discharged patients [25/532 (4.7%)]. CONCLUSION: Liver injury is a common complication in COVID-19 patients. The potential risk factors of liver injury include male, hsCRP and NLR score. A close monitor of liver function should be warned in COVID-19 patients, especially in severe/critical individuals.

Management of haemophilia patients in the COVID-19 pandemic: Experience in Wuhan and Tianjin, two differently affected cities in China.

OBJECTIVE: To identify lessons learned from haemophilia care experience in Wuhan (COVID-19 outbreak epicenter in China) and Tianjin (with relatively low COVID-19 incidence) in the pandemic. METHODS: We compared the challenges in haemophilia management attributed to local COVID-19 containment policies, healthcare resource availability, clotting factors supply, daily living restrictions and coping strategies employed. RESULTS: Wuhan was in lockdown with strict traffic controls, enforced quarantine and overwhelmed resources. Tianjin was in relatively relaxed countermeasures to COVID-19. In Wuhan, haemophilia treatment (for bleeding, prophylaxis, multidisciplinary team care, immune tolerance induction) and patient education were severely affected, while the challenges in Tianjin were less. In both cities, patients' fear for COVID-19 infection also affected their management. Coping strategy in Wuhan included channelling of clotting factors supply from hospitals to nine pharmacies; timely transfers of in-need patients to healthcare facilities by a volunteer service network jointly coordinated by the government, hospitals and the community. Although factor concentrate supply in each city was adequate, patients still worried whether there would be enough supply to last through the pandemics. Consequently, many downgraded their treatment regimens resulting in increased bleeding episodes. In both cities, telemedicine was promoted for patient care and education. CONCLUSIONS: The COVID-19 pandemic had varying adverse impacts on haemophilia care depending on the local infection incidence. Our experience suggests that haemophilia management strategies in the pandemic need to be established according to the local virus containment/mitigation policies, daily living restrictions and resource availability.

Screening of SARS-CoV-2 in 299 Hospitalized Children with Hemato-oncological Diseases: A Multicenter Survey in Hubei, China.

The SARS-CoV-2 infection status of hospitalized children was surveyed in the department of pediatric hematology and oncology in three different hospitals of epidemic areas in Hubei, China. A cross-sectional study was performed to investigate the clinical characteristics, lung CT scan, SARS-CoV-2 nucleic acid test and serum antibodies of hospitalized children with hemato-oncological diseases from January 23 to April 24, 2020. 299 children were enrolled in this study, including 176 males (58.9%) and 123 females (41.1%), aged from 2 months to 16 years. 255 cases (85.3%) received chemotherapy or other immunosuppressive therapies, and there were 44 cases (14.7%) of other benign diseases. Nucleic acid test was performed on 258 children (86.3%) and one case was positive. 163 cases (54.5%) were tested for serum antibodies, and all of them were negative. Lung CT scan was performed on 247 children (82.6%), and 107 of them showed infectious changes. Only one case (0.33%) of COVID-19 was diagnosed in the group. The prevalence rate of COVID-19 in enrolled children with hemato-oncological diseases in Hubei was 0.33%. Immunosuppressed patients are not prone to produce related antibodies. Comprehensive protective measures and ward management can reduce the risk of SARS-CoV-2 infection in the group patients.

Possible intrauterine SARS-CoV-2 infection: Positive nucleic acid testing results and consecutive positive SARS-CoV-2-specific antibody levels within 50 days after birth.

Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the fetus in utero is important to the well-being of the mother and neonate. We report the case of a full-term neonate born to a mother who developed symptoms of coronavirus disease 2019 (COVID-19) at 32 weeks of gestation. The placental pathology showed slight local inflammation. Serial quantitative antibody measurements in the neonate showed elevated levels of IgM on the day of birth and a gradual decline to negative levels within 28 days of life; the levels of IgG declined gradually, but IgG was still positive on day 50 of life. The sequential dynamic changes in antibody levels in the neonate were consistent with those in his mother. One-step reverse transcriptase droplet digital PCR testing for SARS-CoV-2 nucleic acid in throat and anal swabs showed positive results (750 and 892copies/ml) on day 7 of life and negative results on day 14 of life. The neonate had no symptoms of COVID-19. This report enables us to re-evaluate the significance of IgM detection in intrauterine SARS-CoV-2 infection and presents a favorable prognosis for the neonate with long-term exposure to maternal COVID-19, despite a high possibility of intrauterine infection.

Erratum to rapid advice guidelines for management of children with COVID-19.

[This corrects the article DOI: 10.21037/atm-20-3754.].

Disappearance of SARS-CoV-2 Antibodies in Infants Born to Women with COVID-19, Wuhan, China.

We report the detection and decline over time of severe acute respiratory syndrome coronavirus 2 antibodies in infants born to women with coronavirus disease. Among 11 infants tested at birth, all had detectable IgG and 5 had detectable IgM. IgG titers with positive IgM declined more slowly than those without.

Are They Just Two Children COVID-19 Cases Confused With Flu?

COVID-19, an emerging infectious disease, has quickly spread all over the world. All human populations are susceptible to this disease. Here we present two pediatric COVID-19 cases, both of whom exhibited negative SARS-CoV-2 nucleic acid tests upon nasopharyngeal swab and were initially diagnosed with influenza A infection. COVID-19 was later confirmed in both patients by serum antibodies of SARS-CoV-2 and nucleic acid test on stool samples. Because children are susceptible to many respiratory pathogens, especially influenza, we concluded that children can be coinfected with multiple pathogens, and more attention should be paid to the exploration of SARS-CoV-2 during the pandemic of COVID-19. This report shows the possibility of misdiagnosis or missed diagnosis of children with COVID-19. We suggest that highly suspected pediatric COVID-19 cases with negative nucleic acid tests on nasopharyngeal swabs should be further checked by performing a nucleic acid test on stool samples and testing serum for antibodies against SARS-CoV-2.

A Case of Critically Ill Infant of Coronavirus Disease 2019 With Persistent Reduction of T Lymphocytes.

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) is becoming a global threat. However, our understanding of the clinical characteristics and treatment of critically ill pediatric patients and their ability of transmitting the coronavirus that causes COVID-19 still remains inadequate because only a handful pediatric cases of COVID-19 have been reported. METHODS: Epidemiology, clinical characteristics, treatment, laboratory data and follow-up information and the treatment of critically ill infant were recorded. RESULTS: The infant had life-threatening clinical features including high fever, septic shock, recurrent apnea, petechiae and acute kidney injury and persistent declined CD3+, CD4+ and CD8+ T cells. The duration of nasopharyngeal virus shedding lasted for 49 days even with the administration of lopinavir/ritonavir for 8 days. The CD3+, CD4+ and CD8+ T cells was partially recovered 68 days post onset of the disease. Accumulating of effector memory CD4+ T cells (CD4+TEM) was observed among T-cell compartment. The nucleic acid tests and serum antibody for the severe acute respiratory syndrome coronavirus 2 of the infant's mother who kept intimate contact with the infant were negative despite no strict personal protection. CONCLUSIONS: The persistent reduction of CD4+ and CD8+ T cells was the typical feature of critically ill infant with COVID-19. CD4+ and CD8+ T cells might play a key role in aggravating COVID-19 and predicts a more critical course in children. The prolonged nasopharyngeal virus shedding was related with the severity of respiratory injury. The transmission of SARS-CoV-2 from infant (even very critical cases) to adult might be unlikely.