Introduction
On December 31st 2019, the World Health Organization (WHO) were notified
about a cluster of pneumonia cases of unknown cause detected in the city of Wuhan
in
Hubei province, China [1]. Investigations
showed that the causing factor was a previously unknown virus, the severe acute
respiratory syndrome-coronavirus-2 (SARS-CoV-2) and the relative disease was named
coronavirus disease 2019 (COVID-19) [1] and
was characterized as a pandemic on March 11th 2020 [1]. According to a recent update by WHO on
April 19th 2020, laboratory confirmed cases for COVID-19 have risen to 2
245 872 worldwide, including 152 707 deaths [2]. Reasonably, in the case of such a massive health crisis as the
COVID-19 outbreak, questions regarding increased vulnerability in specific
population groups arise. One of the potentially high-risk populations is the
pediatric population and particularly children with chronic diseases.
It has become evident that the disease can occur amongst all age groups, including
the pediatric population [3]. However, early
data suggest that the impact of the COVID-19 pandemic in children is modest [4], as it presents less frequently and with
milder symptoms and severity [3]. In a
population-based study in Iceland, children under 10 years of age and females had
a
lower incidence of SARS-CoV-2 infection than adolescents or adults and males [5]. The rate of mortality is reported to be
much lower in children (<0.1%) compared to adults [6]. Suggested possible mechanisms for the
milder clinical picture in children include: i) age-related high nasal gene
expression of the angiotensin-converting enzyme 2 (ACE2) receptor (the functional
receptor of SARS-Cov-2) in children aged >10 years [7]; ii) a constitutional high lymphocyte count;
and iii) trained immunity, an innate immune memory formed by “memory
cells” after antigen exposure [8]
[9].
Thus far, limited data are available about the possible consequences of COVID-19 on
children and adolescents with a chronic illness. The Royal College of Paediatrics
and Child Health (RCPCH) in the UK have published “shielding”
guidance for children and young people with recent transplantation,
immunosuppression, hemato-oncological, cardio-respiratory, renal, and
gastrointestinal disorders [10]. Also, the
British Society of Gastroenterology has published recommendations for management of
inflammatory bowel disease during the COVID-19 pandemic [11]. However, to our knowledge, no reliable
data exist associating endocrine disorders and vulnerability to COVID-19, expressed
as increased morbidity or mortality and development of endocrine complications
related to SARS-Cov-2.
Discussion
To date, none of the endocrine conditions have been classified as predisposing
factors for the Covid-19 infection [12] and
hence, children with endocrine diseases have not shown a different disease pattern
compared to children without an endocrine disorder. Nonetheless, there are
multifaceted endocrine implications of COVID-19.
As for the general population, since SARS-Cov-2 is a virus of particularly increased
emergence and spread capacity, children and adolescents with endocrine disorders are
strongly encouraged to adhere to preventive and protective measures against viral
spread, such as social distancing, home confinement, self-hygiene (hand-washing,
avoidance of touching their face, coughing/sneezing into elbow or tissue)
and disinfecting frequently-touched surfaces [13]. Furthermore, adherence to local regulations regarding general
preventive measures and schooling is of major importance [13]. Remote learning from home, if plausible,
is the safest method [12].
In the case of symptoms of infection, such as fever, cough, and dyspnoea in
particular, medical advice should be sought and if the symptoms are of increasing
severity, visiting the nearest hospital and taking all the necessary measures
(e. g., face mask), is imperative. Like with any other pediatric infection,
it is important to maintain adequate hydration with frequent fluid intake. If
COVID-19 is confirmed, recommended control measures should be promptly implemented
together with supportive management of complications [14]. If hospitalization is needed, the health
care team should be aware so as to modulate management, particularly in endocrine
diseases such as type 1 diabetes mellitus, hypoglycemia disorders and adrenal
insufficiency.
Furthermore, it is important that children with endocrine diseases who receive
replacement or supplementation therapy maintain a euhormonal status. The necessity
of dose adjustment according to the individual needs should be discussed with the
treating physician, since no universal recommendation is applicable in all cases.
Also, sufficient supply of medications should be ensured at reasonable quantities
[12]. Routine hospital visits should be
avoided for nonurgent reasons so that exposure to COVID-19 is restricted and those
should be replaced by telephone or video consultation to maintain an optimal control
of the underlying disease [15]
[16]. This requires robust telephone triage
and expansion of telehealth visits [16]
[17].
[Table 1] collects pivotal aspects for
managing children and adolescents with endocrine disorders during the COVID-19
pandemic.
Table 1 Key principles for managing children and adolescents with
endocrine disorders during the COVID-19 pandemic.
-
Promote adherence to protective infection control
measures (hand hygiene, face mask, social distancing,
etc.).
-
Provision of reliable information by the health care team
so that anxiety related to misinformation is
prevented.
-
Reassurance of the parents and
children/adolescents that the vast majority of
children with endocrine disorders do not represent a
high-risk population for contamination or severe
presentation of COVID-19.
-
In case of COVID-19 infection, following the specific
“sick day management rules” and seeking
for medical advice without delay are adequate in most
cases for an optimal outcome.
-
Parents should also be reinforced by clinicians to be
involved in entertaining children’s anxiety,
ensuring good nutritional/fluid intake, active
monitoring, and offering supportive therapy for their
children.
|
Endocrine Diseases During COVID-19 – Recommendations
Diabetes Mellitus (DM)
In adults, reports from China [18], Italy
[19], and USA [20] indicate that DM is a risk factor for
severe COVID-19 disease. Longstanding DM involves low-grade chronic
inflammation, which may promote the cytokine storm that seems to be implicated
in the severe evolution of COVID-19, as inflammation markers (C-reactive
protein, fibrinogen, D-dimer, ferritin, erythrocyte sedimentation rate, IL-6)
have been found higher in patients with DM [21]. Hyperglycemia due to the COVID-19-induced stress, hypoglycemia
or sharp glycemic excursions entail detrimental outcomes for DM patients [21]. The identified data from adult studies
do not specifically differentiate type 1 from type 2 DM.
With regard to children and adolescents with DM, it is expected that those with
type 1 DM and good metabolic control will follow the same course of illness as
their peers [12]
[13]. Nonetheless, those with a poor
control could have a debilitated immunity that puts them at a greater risk for
contamination from SARS-Cov-2 [12], and a
more severe presentation [22].
The European Society for Paediatric Endocrinology (ESPE) recommends maintaining
the usual amount of back-up insulin supplies, for at least a week in advance,
without stockpiling copious quantities, as this could jeopardize the supply
chain leading to territorial or worldwide scarcity [12].
In the instance of symptoms that could be related to COVID-19, such as fever,
cough or shortness of breath, it is paramount that medical assistance is sought
without delay [13]. As during any other
intercurrent illness, glycemic control may deteriorate, hence following
“sick day rules” also apply in the case of COVID-19 [13], as well as contacting the therapeutic
team [12]
[16]. Recommendations from the
International Society for Pediatric and Adolescent Diabetes (ISPAD) include
[13]: i) to monitor blood glucose and
ketone bodies more frequently; ii) to target blood glucose concentrations
between 70–180 mg/dl
(4–10 mmol/l) and negative ketones during illness; iii)
to never discontinue insulin administration, since increased insulin
requirements are expected in case of fever; to watch and support hydration,
especially in the presence of fever and/or vomiting/diarrhea;
and iv) to treat the underlying sickness and symptoms. Should there be signs of
metabolic decompensation (namely dehydration, hyperglycemia with persistent
ketosis, hyperventilation, exhaustion), urgent assessment by health care
providers is deemed necessary [13]. A
pediatric case series from Italy reports delayed access to health care secondary
to fear of COVID-19, including two cases of type 1 DM onset with severe
ketoacidosis requiring intensive care unit (ICU) admission due to late access to
the hospital [23].
Adrenal Insufficiency (congenital and acquired primary adrenal insufficiency,
secondary adrenal insufficiency, adrenal suppression after long-term steroid
medication)
To date, there is no evidence that patients with adrenal insufficiency are at
increased risk of contracting COVID-19. Nonetheless, patients with primary
adrenal insufficiency (e. g., congenital adrenal hyperplasia) are
slightly more susceptible to infections in general. This may partly be explained
by the impaired natural immunity function characterized by a defective action of
neutrophils and natural killer cells, which is known to be associated with
primary adrenal insufficiency [24].
Furthermore, susceptibility to infections may also be explained by an
insufficient increase of the hydrocortisone dosage at the beginning of an
infection. Therefore, recommendations suggest that, if asymptomatic, children
should remain on regular replacement doses of hydrocortisone and not increased
doses. If symptoms suggestive of COVID-19 develop (fever, cough, dyspnoea,
vomiting, diarrhoea), the “sick day rules” are recommended,
including immediately increasing the hydrocortisone doses (e. g.,
> 38°C: 2-fold increase, >39°C: 3-fold
increase) until the fever has subsided and adding an extra doubled dose [12]. Adequate hydration is also
recommended, particularly in the presence of fever [12]. In the case of more severe symptoms,
the health care team should be contacted for further advice and if the
medication cannot be orally received due to vomiting, urgent medical care should
undoubtedly be sought and parenteral glucocorticoids initiated in the form of
intramuscular injection of hydrocortisone, accompanied by glucose, preferably in
the form of oral gel [25].
Among patients with COVID-19, it is of major importance to recognize those with a
history of possible adrenal suppression secondary to prior exposure to
glucocorticoids for more than 3 months, so that parenteral treatment with
glucocorticoids is considered [22].
Physiological stress doses of hydrocortisone and not pharmacological doses are
recommended in this case.
Of note, it has been proposed that all the patients receiving corticosteroids for
other medical reasons and not because of adrenal insufficiency or adrenal
suppression, should be considered as high-risk patients for contracting COVID-19
and experiencing more severe symptoms [22]. Supraphysiologic doses of glucocorticoids may further increase
susceptibility to COVID-19 due to their immunosuppressive effect.
Hypopituitarism
Children diagnosed with hypopituitarism are not at increased risk for COVID-19.
As a significant percentage of these patients have secondary adrenal
insufficiency, the same recommendations apply as for children with adrenal
insufficiency [12]. Identical advice
applies for each of the endocrine deficiencies involved.
Particular attention should be given to children with craniopharyngioma, the most
common pediatric tumor in the hypothalamic and pituitary region and an important
cause of hypopituitarism in children. In this case, the endocrine deficiencies
are attributable to either the tumor itself, due to pressure on the pituitary
and hypothalamus, or the operative procedure and/or irradiation
following the diagnosis. Tumor location or surgical intervention are also the
etiology of the hyperphagia observed in these patients [26], which results in hypothalamic obesity
and increased morbidity and mortality rates due to the associated metabolic
derangement. Due to the complicated pre- and post-operative course of the
disease, the treating health care team should be aware of a possible infection
with COVID-19, in order to guide treatment decisions.
Diabetes Insipidus
In addition, in the case of the presence of both secondary adrenal insufficiency
and diabetes insipidus, it is important that medications for both conditions are
always received. Also, careful monitoring of fluid intake and urinary losses is
important, as well as judicious replacement of water, in order to avoid hypo- or
hypernatremia, particularly in the presence of fever, tachypnea and the
co-existence of impaired ability for fluid intake due to altered level of
consciousness [27].
Since hydrocortisone is essential for the clearance of excess water through the
kidneys, it should be administered at adequate doses to avoid accumulation of
fluid, particularly if the child also receives desmopressin. Therefore, the dose
of hydrocortisone should be immediately doubled in the presence of a symptomatic
COVID-19. In such patients, urination should be monitored closely. If urination
is reduced or stopped, desmopressin should be discontinued. If the child has an
intact thirst mechanism, fluid intake will be adequate. If the thirst mechanism
is not intact, maintenance fluids should be administered, with additional fluids
to replace urinary losses [27]. The
therapeutic team should be aware of the patient’s condition in this
scenario.
Thyroid Disorders (Hypothyroidism/Hyperthyroidism)
Children with thyroid disease, even if poorly controlled, are not at increased
risk of COVID-19 and no extra measures are needed than those that apply to the
general population [28]. However, patients
with poorly controlled thyroid disease (e. g., thyrotoxicosis) may be at
higher risk of complications from an infection [28]. Furthermore, it is well established that autoimmune thyroid
disease does not cause immunosuppression [28]. Medications used for the treatment of thyroid disease, including
thyroxine, carbimazole, methimazole, and propylthiouracil do not affect the
immune function and do not pose the patients at a heightened risk for COVID-19
[28].
Recommendations from the British Thyroid Association about adults with thyroid
eye disease who are on high-dose steroid or mycophenolate or rituximab and are
considered as immunocompromized and susceptible to infections, include following
the confinement and health protection measures very strictly [28]. Depending on the severity of the eye
problem, high-dose steroids or immunosuppressives might need to be suspended
[28]. No different recommendations
exist for the pediatric population.
Furthermore, for patients who had radioiodine therapy or thyroid surgery for
benign thyroid disease, no evidence is available to suggest that these patients
are at increased risk of a viral infection [28].
With regard to the treatment when COVID-19 is confirmed in an adult or a
pediatric patient, the normal dose of thyroxine should be continued. If
gastrointestinal disturbances are severe, the dose may need to be repeated when
feasible [28]. In the case of symptoms
that may be related to COVID-19, patients with hyperthyroidism who are on
anti-thyroid drugs should immediately suspend the medication and be tested for
possible agranulocytosis by performing a full blood count, as the symptoms of
agranulocytosis (sore throat, mouth ulceration, fever, flu-like illness) may
overlap with those from COVID-19 [28].
Hypoglycemia (hyperinsulinemic hypoglycemia and ketotic hypoglycemia)
Receiving the proper medications and regular glucose monitoring should be ensured
in children who are prone to have hypoglycemia during illness, especially those
with ketotic hypoglycemia or hyperinsulinemic hypoglycemia. These children are
not considered vulnerable, with the exception of a minority that receive
Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor with
immunosuppressive action. For the latter, strict hygiene and confinement
measures should be taken during the COVID-19 pandemic. Adequate hydration (small
volumes of fluid at frequent intervals) is also highly recommended [29]. In addition, side effects of the
medications used to treat hyperinsulinemic hypoglycemia (e. g.,
diazoxide: water retention and pulmonary hypertension; somatostatin analogues:
cardiac arrhythmias and cardiac conduction disorders) should be taken into
consideration in the case of COVID-19.
During this pandemic, children should follow the “sick-day rules”
for hypoglycemia, which include close monitoring of glucose levels, adequate
hydration, ensuring availability of medications and emergency regime, preferably
in the form of a glucose gel/juice or glucose powder solution, and
contacting the medical team in the instance of hypoglycemia of unusual frequency
and severity.
Cushing Syndrome
Cushing syndrome represents an immunocompromised state, which can increase
susceptibility to infections, hence COVID-19 also [30]. Susceptibility to opportunistic
infections is caused by prolonged exposure to elevated cortisol concentrations.
Glucocorticoids have a potent anti-inflammatory and immunosuppressive action,
resulting in the suppression of cellular and humoral immune functions.
Hyperglycemia in patients with Cushing syndrome resulting from increased insulin
resistance, further contributes to immunosuppression. The higher the
concentrations of circulating cortisol, the more severe the infections.
Therefore, adherence to preventive self-protective measures, complying with the
regular treatment and seeking medical advice in the case of even minor symptoms,
is crucial.
Hypoparathyroidism
Children with hypoparathyroidism have no susceptibility to infections, unless
hypoparathyroidism exists in the context of 22q11.2 deletion syndrome, which in
the majority (64–77%) of the patients, encompasses
immunodeficiency of variable severity. In the case of 22q11.2 deletion syndrome,
the predominant cause of immunodeficiency is compromised T cell production due
to thymic hypoplasia or aplasia, and recurrent infections of the respiratory
tract, albeit usually not severe, they represent a common clinical
manifestation. Therefore, susceptibility to COVID-19 is increased and special
attention should be paid during COVID-19 infection.
If COVID-19 is confirmed and the child is unable to receive oral tablets,
parenteral treatment should be initiated with intravenous calcium. Of note,
hypocalcaemia may worsen breathing capacity due to weakening of the chest
muscles [31].
Obesity
It is well established in the literature that excess weight promotes immune
dysregulation and chronic inflammation, which result in the cytokine storm
associated with the Acute Respiratory Distress Syndrome seen in influenza and
other viral infections [32]. Limited data
is available regarding the impact of COVID-19 in patients with obesity. It has
been reported that severe obesity may be a risk factor for respiratory
complications during the course of COVID-19 [12]. It has also been reported that young people suffering from
severe obesity may develop destructive alveolitis resulting in respiratory
failure and death (author´s personal experience) [16]. In addition, it is well known that
obesity is associated with sleep apnoea syndrome and surfactant dysfunction,
which may worsen the clinical course of COVID-19 infection. Therefore, it is
important that children with obesity, and those with severe obesity in
particular, strictly follow self-protective strategies to avoid COVID-19.
For these patients, COVID-19 may have an additional negative impact on obesity
itself. Due to the confinement measures that include school closure and
prohibition of outdoor exercise or exercise in a gymnasium, regular exercise may
be restricted. Furthermore, home restriction can lead to increased caloric
intake and especially of calorie-dense comfort foods. Additionally, sedentary
activities and screen time are expected to expand [33]. For these reasons, it is estimated
that the COVID-19 pandemic may result in exacerbation of childhood obesity [33]. It is important that these patients
continue exercise through home-based exercise programs and that they follow a
well-balanced diet.
COVID-19 and Psychological Consequences in Children and Adolescents with
Endocrine Disorders
It becomes evident that as the COVID-19 pandemic peaks, it is causing widespread
concern, fear and stress. This is understandable due to the high morbidity and
mortality rates of the disease in adults, the restrictive preventive measures
that result in a drastic change of everyday life, affecting work, education,
social life, entertainment, and the long period sustained fear of the unknown
outcome of this outbreak [34]
[35]
[36]
[37]
[38]
[39]
[40].
The impact of the COVID-19 pandemic to the pediatric population may be worsened
by the co-existence of a chronic disease. It is well established that a chronic
illness may impair the immunologic reaction of an individual to infections.
Specifically, chronic stress from a permanent disease may erode immunologic
mediators, increase risk of infections and cytokine production and decrease
antibodies and defensive mechanisms [41]
[42]
[43].
On the other hand, children suffering from a chronic disease are already
experiencing higher stress and additional pressure compared to healthy children
due to the need for compliance to chronic medication and regular doctor visits,
but also because of school disruption and fear of death [44]
[45]
[46]. Children’s stress due to a
chronic endocrine disease can be magnified by a pandemic, as children are likely
to experience anxiety and fear of death or of their relatives dying and they may
also see the supportive family structure previously provided, to fall apart. Of
note, parental anxiety about children exposure to COVID-19, potentially further
complicating their chronic endocrine disease, should not be ignored. This may
lead to retaining children out of school, thereby adding to social
marginalization of the patients as well as aggravating their feeling of distress
and impacting their wellbeing.
Hence, therapeutic teams should be aware of the possible psychological
consequences of the current pandemic and monitor psychological responses, even
screen for psychological distress using psychometric tools, such as validated
questionnaires. This could promote the implementation of stress management
strategies and interventions in order to avoid potential future psychological
distress that may affect the feeling of wellbeing and adherence to treatment,
allowing an optimal control and outcome of the endocrine disease.
