SARS‐CoV‐2 infection and paediatric endocrine disorders: Risks and management considerations

Abstract Background Coronavirus‐19 (COVID‐19) is a disease caused by the SARS‐CoV‐2 virus, the seventh coronavirus identified as causing disease in humans. The SARS‐CoV‐2 virus has multiple potential pathophysiologic interconnections with endocrine systems, potentially causing disturbances in glucose metabolism, hypothalamic and pituitary function, adrenal function and mineral metabolism. A growing body of data is revealing both the effects of underlying endocrine disorders on COVID‐19 disease outcome and the effects of the SARS‐CoV‐2 virus on endocrine systems. However, comprehensive assessment of the relationship to endocrine disorders in children has been lacking. Content In this review, we present the effects of SARS‐CoV‐2 infection on endocrine systems and review the current literature on complications of COVID‐19 disease in underlying paediatric endocrine disorders. We provide recommendations on management of endocrinopathies related to SARS‐CoV‐2 infection in this population. Summary and outlook With the surge in COVID‐19 cases worldwide, it is important for paediatric endocrinologists to be aware of the interaction of SARS‐CoV‐2 with the endocrine system and management considerations for patients with underlying disorders who develop COVID‐19 disease. While children and adults share some risk factors that influence risk of complications in SARS‐CoV‐2 infection, it is becoming clear that responses in the paediatric population are distinct and outcomes from adult studies cannot be extrapolated. Evidence emerging from paediatric studies provides some guidance but highlights the need for more research in this area.


| INTRODUC TI ON
Coronavirus disease  is caused by the SARS-CoV-2 virus, the seventh coronavirus identified as causing disease in humans. Angiotensin-converting enzyme 2 (ACE2) is considered to be the primary receptor mediating SARS-CoV-2 infection. 1 Binding of SARS-CoV-2 to ACE2 triggers a cascade leading to activation of the NF-kB pathway, increasing proinflammatory cytokines and chemokines to very high levels, leading to the development of acute respiratory distress syndrome (ARDS) seen in severe COVID-19 disease. 2,3 Lethality of ARDS and non-pulmonary complications in COVID-19 is thought to be due to cytokine storm in which immune and nonimmune cells release large amounts of proinflammatory cytokines that cause damage within and beyond the respiratory system. 4  Children and adolescents were initially thought to experience similar but less severe symptoms and complications of SARS-CoV-2 infection. 5 It is now apparent that children experience unique manifestations of SARS-CoV-2 infection, including multisystem inflammatory syndrome (MIS-C) and distinct endocrine responses. 6 In this paper, we present what is currently known regarding the Thus, it is essential for the paediatric endocrine community to understand the manifestations of this disease and the limits of our current knowledge in order to provide optimal care of children in the COVID-19 era.

| SAR S -COV-2INFEC TI ONAND CON S EQUENTENDO CRINEDYS FUN C TI ON
The SARS-CoV-2 virus has multiple pathophysiologic interconnections with endocrine systems with the potential to cause disturbances in pituitary, adrenal and thyroid function, glucose metabolism and mineral metabolism. Existing data are generally favourable in terms of endocrine complications of COVID-19 in the paediatric population.
Similarities between COVID-19, SARS and MERS suggest that the virus may gain access to the central nervous system, including the hypothalamus, via the olfactory bulb. 8 Observational studies in adults have demonstrated disruption of posterior pituitary function and acute onset of syndrome of inappropriate antidiuretic hormone (SIADH) in COVID-19. 9-11 Hypothalamic/pituitary dysfunction has been described in SARS survivors. 12 However, the only evidence of pituitary involvement in COVID-19 is a finding of pituitary stalk involvement by MRI in two adult patients; to date, there are no reports of pituitary hormone deficiencies in either adults or children with  There are data to suggest risk of both adrenal and thyroid involvement in adults with COVID-19. Acutely ill adults with COVID-19 disease were found to have higher cortisol levels than those without COVID-19 in one study, but with a reverse correlation between degree of cortisol response and survival rate in those who were COVID-19-positive. 14 Adrenal involvement has also been shown by CT (acute adrenal infarction) and post-mortem studies in adults with severe COVID-19 and SARS-CoV-2 infection. 15,16 Both thyrotoxicosis (via association with higher IL-6 levels) and hypothyroidism have been identified in adults with COVID-19. [17][18][19] ACE2 is highly expressed in thyroid tissue, and to a lesser extent in adrenal tissue, while children may theoretically be at risk, thyroid and adrenal disease in children with COVID-19 and multisystem inflammatory syndrome in children (MIS-C) have not been reported. 20 SARS-CoV-2 infection may have a diabetogenic effect independent of the stress response associated with severe illness, as ACE2 is highly expressed in pancreatic islet cells. 21 New onset of diabetes mellitus has been described in adults with COVID-19 but not children. 22 abnormalities. 31 In patients with DI, the risk of hypernatraemia increases in acute illness due to factors including reduced fluid intake, increased insensible losses and inability to tolerate oral desmopressin; adipsic patients with DI are at marked risk of severe hypernatraemia, which may be complicated by venous thrombosis. [32][33][34][35] As with other viral infections, COVID-19 is likely to increase risk of adrenal crisis and respiratory complications in patients with adrenal insufficiency (including those on corticosteroid replacement therapy); however, this has not specifically been addressed in either adults or children.
Currently, there are no data indicating increased risk of acquiring SARS-CoV-2 infection or altered disease course in children and adolescents with underlying thyroid disorders. However, it is important to keep in mind that patients with Graves' disease treated with antithyroid drug (ATD) therapy are at higher risk of agranulocytosis and secondary infections. 36 This is particularly important as data from one study showed that half of COVID-19 non-survivors experienced a secondary infection. 37 Underlying thyroid disease, including hypothyroidism, does appear to be a risk factor for a more severe disease course in adults with COVID-19. [38][39][40] It has been well documented that adults with diabetes mellitus, obesity and hypertension are at higher risk COVID-19 infection and experience higher rates of complications and death. [40][41][42][43][44] The T1D Exchange has published data on 64 adults with T1D; 33 were COVID-19-positive and 31 had COVID-19-like symptoms but were either not tested or were COVID-19-negative. 65.5% of individuals were <19 years of age. 45 The COVID-19-positive group was found to have a higher mean HbA1C (8.5% vs. 8%) were more likely to present in DKA (45.5% vs. 13.3%) and required a higher level of care compared with the COVID-like group. A population-based study in England showed that people with an HbA1C of 86 mmol/mol (10.0%) or higher compared with people with an HbA1C of 48-53 mmol/mol (6.5-7.0%) had increased COVID-19-related mortality (hazard ratio [HR] 2·23 [95% CI 1·50-3·30, p < .0001] in T1D). 46 T1D Exchange data in the paediatric population demonstrated higher A1C, increased risk of hospitalization, non-Hispanic Black ethnicity and public insurance in children with T1D and COVID-19 (unpublished data). Children presenting with new-onset T1D may also be more likely to present in DKA and may have more severe DKA in during the coronavirus pandemic. 47 However, evidence to date suggests that children with T1D and COVID-19 do not have worse disease outcomes than those without diabetes. 48 Children with diabetes have faced unique challenges related to the COVID-19 pandemic, primarily related to widespread closures of schools and daycare centres. In a study from Greece, 34 children with T1D using insulin pumps and CGM did not have a significant increase in time in range during lockdown but did have greater blood glucose variability when compared to the pre-lockdown period. 49 The children in this study were also noted to have dramatic changes in meal schedules during lockdown. Restrictions related to the COVID-19 pandemic have resulted in decreased physical activity and dietary F I G U R E 1 Interactions between SARS-CoV-2 infection and endocrine systems changes as well as altered diabetes management behaviours, all of which may increase risk of poor nutrition, excessive weight gain and increased stress related to diabetes management. 48 Several studies have observed no difference in obesity rates between children with mild vs. severe COVID-19 disease. [50][51][52] While obesity in paediatric patients hospitalized for COVID-19 is not more frequent than in the general paediatric population, COVID-19 disease severity may be associated with obesity, as in adults. One report of 50 paediatric patients hospitalized with COVID-19 identified obesity as a risk factor for mechanical ventilation. 53

| Hypopituitarism
Children with multiple pituitary hormone deficiencies may be at increased risk for COVID-19 complications and mortality, particularly if central AI is not managed adequately. In the absence of published data or guidelines, we recommend following established practices for managing pituitary hormone deficiencies in children.
Current guidance for adults with growth hormone deficiency recommends stopping growth hormone during hospitalization with COVID-19; however, there is a lack of data regarding the effects of growth hormone treatment during COVID-19 disease in children. 61 Management of adrenal insufficiency is addressed below.

| Centraldiabetesinsipidus
Recommendations for management of central diabetes insipidus in patients with mild COVID-19 disease do not vary from usual recommendations for management of diabetes insipidus in the home setting. However, patients of all ages with diabetes insipidus are at risk of disturbed sodium balance during hospitalization and must be monitored closely. Hypernatraemia can be caused by failure to administer free water to patients who are unable to care for themselves, and inability to rely on thirst mechanism in critically ill patients. 62,63 Patients are also vulnerable to hyponatraemia due to overtreatment of DI and excess ADH in the setting of COVID-19 pneumonia.
Treatment of DI with subcutaneous or oral desmopressin rather than intranasal desmopressin should be considered if there is concern for nasal congestion. In patients with severe COVID-19 illness, desmopressin should be administered intravenously. Urine osmolality and volume should be monitored, and serum sodium should be measured at frequent intervals (every 2-4 h) to help maintain eunatraemia.
Patients with COVID-19 may have severe respiratory disease including pulmonary oedema, as hypernatraemia has not been implicated as a risk factor for mortality in COVID-19, mild hypernatraemia may need to be tolerated under these circumstances to prevent pulmonary oedema. 31

| Primaryadrenalinsufficiency
Individuals who are steroid-dependent or suspected of having adrenal suppression should, first and foremost, take caution to avoid SARS-CoV-2 infection. Patients should be managed according to existing guidelines regarding stress dosing during symptomatic COVID-19 disease. 64,65 The RECOVERY trial, a randomized, open-label trial of oral or intravenous dexamethasone (6 mg) daily vs. usual care, showed significant reduction in mortality in those receiving invasive mechanical ventilation and among those receiving oxygen without invasive mechanical ventilation, but not among those who were receiving no respiratory support at the time of randomization. 66 In guidance

| Diabetesmellitus
Viral illnesses can be more difficult to manage in individuals with diabetes due to increased insulin resistance and ketone production. 68,69 As higher A1C is positively correlated with frequency of DKA in children with T1D, a significant proportion of the paediatric T1D population may be at increased risk of developing DKA in the setting of COVID-19 infection. 70,71 It is imperative that clinicians take the time to review sick day guidelines and be available for guidance during times of illness to reduce the risk of developing DKA.
During COVID-19 illness, patients should be counselled to monitor blood glucose levels more frequently either via continuous glucose monitors or finger sticks. 72,73 Insulin doses may need to be titrated more often and additional correction boluses of fast-acting insulin may be required to avoid severe hyperglycae-

| Obesity
The shutting down of schools, camps and extracurricular sports and activities due to the pandemic has already had a profound impact on the health of children and adolescents due to social isolation, lack of activity and food insecurity in socioeconomically disadvantaged households. 75,76 In one of our centres, we have observed a significant increase in children under 19 years of age presenting with newonset diabetes, with most of the increase in new cases accounted for by an increase in type 2 diabetes (RM; unpublished data). It is more important than ever to reinforce healthy eating habits and provide age-appropriate guidance on nutrition and physical activity. Racial/ ethnic and socioeconomic disparities have heightened health inequities particularly related to weight management during the COVID-19 pandemic. Healthcare providers should continue to provide education on healthy eating habits and regular exercise. We encourage access to telehealth interventions as adjuncts to paediatric weight management.
The risk of premature atherosclerotic cardiovascular disease (ASCVD) in youth who have had MIS-C is not yet known; however, patients with a history of Kawasaki Disease with residual aneurysmal dilatation are considered high-risk for ASCVD. In MIS-C, coronary artery aneurisms have been found in 6%-24% of patients and Kawasaki disease features have been documented in up to 40%. 77,78 Recent data suggest that paediatric patients with MIS-C who have been treated with IVIG or IL-6 antagonists such as tocilizumab recover without sequelae. 79 Given the unknown risk of complications, however, longer-term cardiology follow-up is warranted for children who have recovered from MIS-C.

| Metabolicbonedisease
It remains to be determined whether vitamin D replacement will provide protection against COVID-19 or complications. Randomized trials are in progress that will help determine whether vitamin D supplementation can prevent or decrease the severity of COVID-19. • MIS-C appears to increase risk of hypocalcaemia in children, and those who are found to have developed coronary artery aneurisms may be at risk of later ASCVD.
• Children with T1D and higher A1C are more likely to be hospitalized with COVID-19 than children with better diabetes control.
The COVID-19 pandemic has created a number of challenges in paediatric diabetes management related to school closures, disrupted schedules and stress related to diabetes management during periods of lockdown.
• Obesity does not appear to increase risk of acquiring SARS-CoV-2 infection in children, but obesity may be a risk factor for complications of COVID-19 in this population.
• COVID-19 in children with diabetes insipidus requires extra attention to fluid and sodium balance and may require a change in form of desmopressin delivery in those who are using the intranasal form.
We would also like to highlight the importance of recognizing indirect effects of the COVID-19 pandemic on physical activity and eating habits that will worsen the problems of obesity, metabolic syndrome and associated complications due to shelter-in-home mandates and physical distancing restrictions. An acute increase in sedentary behaviour is known to cause decreased insulin sensitivity and elevations in blood glucose and over time increases the risk of incident T2D. [85][86][87] We must continue to provide the support our patients require to minimize the health consequences of this pandemic on the next generation.

ACK N OWLED G EM ENTS
There were no outside funding sources for this manuscript.

DATAAVA I L A B I L I T YS TAT E M E N T
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.