Endocrinological Involvement in Children with COVID-19


Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated disease COVID-19 in December 2019, considerable research has been conducted to understand the impact of this virus on various age groups.

While the clinical manifestations of COVID-19 in children have generally been milder compared to adults, there has been growing recognition of potential long-term complications, including multisystem inflammatory syndrome in children (MIS-C) and long COVID.

Additionally, emerging evidence suggests an intricate connection between COVID-19 and endocrine abnormalities, further emphasizing the need for comprehensive research and pediatric long-term monitoring.

Introduction: The outbreak of COVID-19, caused by the novel coronavirus SARS-CoV-2, prompted extensive research into its clinical manifestations and potential long-term consequences. Initially, children were noted to exhibit milder symptoms than adults, with the majority being asymptomatic, mildly symptomatic, or having moderate symptoms. However, further investigations revealed the emergence of severe complications in some children, including MIS-C and long COVID.

Multisystem Inflammatory Syndrome in Children (MIS-C): MIS-C has emerged as a serious and potentially fatal complication of COVID-19 in children. It primarily affects the cardiovascular system but also involves other organs, including the gastrointestinal tract, liver, and intestines. The delayed onset of symptoms, typically occurring four to six weeks after the initial infection, has led to hypotheses suggesting that the virus persists in the gut, causing mucosal irritation. Consequently, viral antigens breach the gut barrier, entering circulation and triggering an intense inflammatory response. The estimated incidence of MIS-C was approximately 316 cases per 1,000,000 children infected with SARS-CoV-2 before vaccine availability.

Long COVID in Children: Long COVID, characterized by persistent symptoms lasting at least two months following the acute phase of COVID-19, has garnered increasing attention. A systematic review conducted by Lopez-Leon et al. revealed a prevalence of long COVID in pediatric patients at approximately 25.24%. The most commonly reported symptoms included mood alterations, fatigue, sleep disorders, headache, and respiratory symptoms. Risk factors for developing long COVID in children mirrored those in adults and included older age, female sex, severe initial COVID-19, overweight/obesity, comorbid allergic diseases, and pre-existing health conditions. However, guidelines for diagnosis and management of long COVID in children remain elusive, necessitating further research.

Endocrine Involvement in COVID-19: SARS-CoV-2’s interaction with host cells occurs through its spike protein binding to angiotensin converting enzyme 2 (ACE2). The subsequent activation of the STAT3/NF-kB pathway triggers the release of proinflammatory cytokines and chemokines, leading to a systemic hyperinflammatory response often referred to as a “cytokine storm.” ACE2 expression extends beyond lung cells to various tissues, including endocrine organs such as the thyroid, ovaries, and testes. This widespread ACE2 expression could explain the multiorgan involvement observed in COVID-19 patients.

Endocrine Anomalies and COVID-19: The pandemic’s advent has coincided with an increase in the incidence and severity of endocrinological anomalies in both adults and children. Emerging evidence suggests a link between COVID-19 and endocrine disorders, prompting the need for detailed investigation. Endocrine tissues, especially the thyroid, ovaries, and testes, express ACE2, which may underpin the observed endocrinological involvement during SARS-CoV-2 infection. A thorough understanding of this relationship is crucial for effective management and long-term monitoring.

Thyroid Dysfunction in Pediatric COVID-19

Since the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the subsequent COVID-19 pandemic, extensive research has been conducted to understand the diverse manifestations of the virus. Although children generally experience milder forms of the disease, recent studies have unveiled intriguing associations between COVID-19 and thyroid dysfunction in pediatric populations. This article aims to provide an in-depth review of the available literature on the topic.

Thyroid Dysfunction and COVID-19 in Pediatrics: Limited research exists concerning the correlation between SARS-CoV-2 infection and thyroid disease in children. McCowan et al. conducted a study on 244 children with thyroid function anomalies before and after the pandemic. They observed an increase in cases of untreated transient thyroid dysfunction, hypothesizing that this may result from SARS-CoV-2-induced thyroiditis that self-resolves before requiring treatment. Similarly, a New York-based retrospective analysis did not find significant differences in thyroid-stimulating hormone (TSH) abnormalities before and after the pandemic; however, the presence of prior COVID-19 infection or vaccination remains unclear.

Thyroid Profile Abnormalities and Severe COVID-19: An analytical study evaluated thyroid profiles in hospitalized children and adults with moderate-to-severe COVID-19 infection. Abnormal thyroid profiles were prevalent, with sick euthyroid syndrome being the most frequent manifestation. This syndrome, characterized by low free thyroxine (fT3) levels and normal TSH levels, correlated with increased mortality risk and severe inflammation. Interestingly, studies have shown a higher incidence of thyroid dysfunction in severe COVID-19 cases, suggesting a link between disease severity and thyroid gland impairment.

Thyroid Dysfunction in Multisystem Inflammatory Syndrome in Children (MIS-C): Thyroid dysfunction’s connection with multisystem inflammatory syndrome in children (MIS-C) has also been explored. Research has consistently shown a high prevalence of nonthyroidal illness syndrome (NTIS) in MIS-C cases, with a common presentation of isolated decreases in fT3 levels. ICU-admitted MIS-C patients exhibited worse clinical presentations and lower fT3 levels, suggesting a possible relationship between severe MIS-C and thyroid dysfunction.

Mechanisms of Thyroid Dysfunction in COVID-19: Several mechanisms have been proposed to explain the link between COVID-19 and thyroid dysfunction in children. The virus could enter thyroid cells through angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease (2TMPRSS2), leading to viral thyroiditis. The cytokine storm associated with severe COVID-19 may contribute to thyroiditis through Th1/Th17 immune response hyperactivity and overexpression of proinflammatory cytokines. Additionally, selective transient pituitary dysregulation might be linked to the cytotoxic effect of the virus on the pituitary or the cytokine storm-induced NTIS.

Adrenal Gland Involvement in Pediatric COVID-19: Implications and Considerations

As the COVID-19 pandemic continues to unfold, researchers and clinicians are uncovering various facets of the disease’s impact on children. In addition to the respiratory symptoms commonly associated with SARS-CoV-2 infection, emerging evidence suggests a potential link between the virus and adrenal gland dysfunction in pediatric populations. This article delves into the current understanding of adrenal gland involvement in children with COVID-19.

Adrenal Glands and COVID-19 in Children: COVID-19’s effects on children extend beyond respiratory symptoms, involving the adrenal glands as well. Primary adrenal insufficiency can result from the activation of cytokines such as IL-6 and toll-like receptors, while secondary failure may be induced by glucocorticoid treatment used in cases of Multisystem Inflammatory Syndrome in Children (MIS-C). A study conducted in the U.K. focused on children with MIS-C and highlighted the potential for prolonged and high-dose steroid therapy to cause hypothalamic–pituitary–adrenal (HPA) axis suppression.

Adrenal Insufficiency and MIS-C: Children with adrenal insufficiency are vulnerable to infections, including COVID-19. SARS-CoV-2 infection can trigger an adrenal crisis due to increased demand for glucocorticoids. Clinical guidelines recommend dose adjustments in such cases to prevent potential life-threatening situations. A multicentric study across European countries involving patients with adrenal insufficiency and acute SARS-CoV-2 infection reported generally positive clinical outcomes with appropriate glucocorticoid dose modifications.

Adrenal Insufficiency and Disease Severity: Contradictory findings exist regarding the severity of COVID-19 in children with pre-existing adrenal insufficiency. Some studies suggest that children with endocrine conditions such as adrenal insufficiency could experience more severe clinical presentations, leading to increased hospitalization and intensive care unit admissions. Cases have been reported wherein prompt hydrocortisone administration alleviated neurological symptoms in pediatric patients with COVID-19 and pre-existing conditions like brain tumors or Addison’s disease.

Tertiary Adrenal Insufficiency and Hypercortisolism: Chronic corticosteroid treatment for various medical conditions can lead to tertiary adrenal insufficiency due to immune impairment, heightening the risk of SARS-CoV-2 infection and a severe clinical course. Additionally, hypercortisolism, as seen in Cushing’s syndrome, may represent a risk factor for severe COVID-19 outcomes in children, although data on this aspect are lacking.

Hypothalamic-Pituitary Axis Involvement in Pediatric COVID-19

While the primary impacts of SARS-CoV-2 infection in children often center on respiratory symptoms, recent studies suggest that the virus might exert effects on the hypothalamic-pituitary axis (HPA). Limited research exists on this topic, but the potential mechanisms and implications for endocrine health in pediatric COVID-19 patients are gaining attention. This article delves into the sparse literature to examine the potential links between SARS-CoV-2 and the HPA in children.

Hypothesized Mechanisms of Involvement: SARS-CoV-2 may infiltrate the central nervous system, including the hypothalamus and pituitary, via the olfactory bulb. The presence of ACE-2 receptors and TMPRSS2 on these cells has led to speculation that the virus could target the HPA. Different hypotheses have been proposed, including direct hypothalamic injury, immune-mediated hypophysitis, molecular mimicry between virus sequences and ACTH, cytokine-induced reduction of ACTH release, and cross-reactions leading to secondary effects on the adrenal glands.

Pituitary Gland Involvement in Pediatric Cases: There have been isolated reports of SARS-CoV-2 affecting the pituitary gland in pediatric patients. One case described a 4-year-old girl who exhibited a ROHHAD-syndrome-like phenotype after COVID-19 infection, presenting symptoms such as electrolyte imbalances, hypocorticism, and hypothyroidism. Another instance involved an 18-year-old girl who developed symptomatic lymphocytic hypophysitis three weeks post-COVID-19. Both cases highlighted the need for further research into potential pituitary involvement.

Children with Pre-Existing HPA Dysfunction and COVID-19: Research has yet to demonstrate a higher risk of COVID-19 contraction or severity in children with pre-existing HPA dysfunction, including those with hypopituitarism. For instance, a 9-year-old boy with a suprasellar germ cell tumor and HPA dysfunction experienced an asymptomatic course during his SARS-CoV-2 infection. However, these children may be at increased risk of adrenal crisis during infections, including COVID-19.

Impact on Growth Hormone and Precocious Puberty: COVID-19 has triggered contrasting effects on growth hormone (GH) deficiency and central precocious puberty (CPP) diagnoses in children. Pediatric GH deficiency diagnoses have decreased, potentially due to reduced well-child visits and hospital avoidance. On the other hand, CPP diagnoses and pubertal progression rates have risen during the pandemic, likely due to a complex interplay of physical and psychosocial factors including weight gain, stress, and reduced physical activity.

Conclusion: The COVID-19 pandemic has shed light on the diverse and complex manifestations of the virus in children. While their acute phase symptoms tend to be milder, the emergence of MIS-C and long COVID has highlighted the need for comprehensive research and long-term monitoring. Furthermore, the intricate connection between SARS-CoV-2 and endocrine abnormalities necessitates further investigation to guide clinical management and ensure the holistic well-being of affected children. As the world continues to navigate the challenges posed by this pandemic, a multidisciplinary approach to understanding and addressing these intricate interactions becomes paramount.

reference link : https://www.mdpi.com/2077-0383/12/16/5248



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