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      Pediatric Endocrinology in the Time of the COVID-19 Pandemic

      a , b , *

      Hormone Research in Pædiatrics

      S. Karger AG

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          Abstract

          Getting Back to Our Pediatric Roots The current pandemic of coronavirus disease 2019 (COVID-19) is severely affecting health systems worldwide and changing both our lifestyles and our work. In these difficult times, the priority of all health care professionals is to take care of the infected sick. The pediatric endocrinology (PedEndo) community is currently actively committed to the daily care of children suspected of having COVID-19 infection or being affected by it, in addition to those with endocrine diseases. In contrast to findings in the majority of adults, children with CO­VID-19 have mild clinical manifestations, and are mostly asymptomatic [1, 2, 3]. Nevertheless, pediatric endocrinologists worldwide, especially the younger ones, have been forced by current events to divert the focus of their clinical practice as well as scientific interest and reading to general pediatrics and even to infectious diseases and epidemiology. This sudden and unexpected challenge has, ultimately, urged pediatric subspecialists to rediscover the original appeal and importance of general pediatrics. My mentor, Prof. Brunetto Boscherini, used to say that only a skilled pediatrician may become a skilled pediatric endocrinologist. Therefore, this awful epidemic may ultimately lead to a significant improvement in training and expertise as well as the global view of the sick child in the PedEndo community. PedEndo Research during the COVID-19 Epidemic The primary scientific effect of the COVID-19 pandemic is to boost research in the fields of virology, immunology, and epidemiology. However, other disciplines, including PedEndo, can also contribute to a better knowledge of pathogenesis and consequences of COVID-19. I provide a few examples here of the potential role of PedEndo in investigating the endocrine implications of SARS-CoV-2 infection. To enter host cells, SARS-CoV-2 (the virus responsible for the COVID-19 pandemic) and SARS-CoV-1 (responsible for the SARS epidemic in 2002) need to bind to cell surface receptor angiotensin-converting enzyme 2 (ACE2) [4]. ACE2 degrades angiotensin II to angiotensin-(1–7) and participates in the hydrolysis of other peptides including angiotensin I. ACE2 is expressed in many human tissues, including the lungs, heart, and kidneys. It has been postulated that inhibitors of the renin-angiotensin-aldosterone system, commonly used as antihypertensive drugs, may increase the expression of ACE2, ultimately facilitating the viral invasion. However, data in favor of this hypothesis are largely insufficient and experimental and clinical research is warranted [5]. The entry of SARS-CoV-2 into the host cells depends not only on ACE2 but requires a more complex mechanism. In fact, the spike (S) protein of the coronavirus surface plays a key role in viral entry into the target cells. S protein must first be cleaved by a specific protease to be able to attach to the cell surface. The main protease involved in S protein priming is transmembrane protease serine 2 (TMPRSS2), which thus represents a critical host cell factor for the invasion and spread of the virus [6, 7]. It is noteworthy that TMPRSS2 expression is upregulated by androgens [8] and modulated by specific microRNAs [9]. These findings suggest that the endocrine system may play a role in viral entry into target cells. From the clinical perspective, a follow-up study was conducted in a cohort of 61 adult survivors of the SARS outbreak in 2002 to investigate the potential long-term endocrine impact of the disease [10]. Twenty-four patients (39%) showed central hypocortisolism which resolved within a year in most of them, and three showed central hypothyroidism. The authors speculated that the coronavirus infection could have caused a reversible hypophysitis. No similar follow-up studies have been conducted on children. Finally, the impact of coronavirus infection in adult diabetic patients is well established, with the evidence showing a link between type 2 diabetes and disease severity [11, 12]. To date, no study has reported data on the interaction between SARS-CoV-2 infection and type 1 diabetes in children. PedEndo Is Not Locked Down PedEndo may appear as a minor discipline at a time of worldwide emergency like what we are currently experiencing, but the PedEndo community is adapting to this crisis. We are not only sticking to the primary duty of taking care of children with endocrine diseases, but also contributing substantially to the daily care of children with COVID-19 and general pediatric diseases. Furthermore, pediatric endocrinologists may concur, with their research, in improving the knowledge of SARS-CoV-2 infection dynamics from the viral entry into cells to long-term sequelae. Finally, though many important international conferences have been cancelled or postponed, we are absolutely committed to stay up to date on the latest research in endocrinology by means of journals, books, videos, and Web-meetings. Disclosure Statement The author has no conflict of interests.

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          Most cited references 6

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          Detection of Covid-19 in Children in Early January 2020 in Wuhan, China

          To the Editor: A small number of cases of coronavirus disease 2019 (Covid-19) have been described in children, 1,2 and our understanding of the spectrum of illness is limited. 3 We conducted a retrospective analysis involving hospitalized children in Wuhan, China. From January 7 to January 15, 2020, a total of 366 hospitalized children (≤16 years of age) were enrolled in a retrospective study of respiratory infections at three branches of Tongji Hospital, which are located 14 km to 34 km from one another in central Wuhan (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The study was approved by the ethics committee of Tongji Hospital. Among the 366 children, the most frequently detected pathogens were influenza A virus (in 23 patients [6.3%]) and influenza B virus (in 20 [5.5%]). SARS-CoV-2, the virus that causes Covid-19, was detected in 6 patients (1.6%). Informed consent was obtained from the parents or guardians of the patients with Covid-19 for the publication of their clinical data. The dates of illness onset in the six patients with Covid-19 were between January 2 and January 8, 2020, and the patients were hospitalized between January 7 and January 13 (Fig. S2). Details of the study methods are provided in the Supplementary Appendix. The median age of the six patients was 3 years (range, 1 to 7) (Table 1). All six children had previously been completely healthy. Common clinical characteristics included high fever (>39°C) (in all six patients), cough (in all six), and vomiting (in four). Laboratory investigations showed that the levels of lymphocytes, white cells, and neutrophils were below the normal range in six, four, and three patients, respectively. Four of the six patients had pneumonia, as assessed radiographically, with computed tomographic scans of the chest showing typical viral pneumonia patterns (Fig. S3). One child was admitted to the pediatric intensive care unit (ICU) and received pooled immune globulin from healthy donors. All the patients were treated empirically with antiviral agents, antibiotic agents, and supportive therapies. All the patients recovered after hospitalization for a median of 7.5 days (range, 5 to 13). This study showed that Covid-19 occurred in children, causing moderate-to-severe respiratory illness, in the early phase of the SARS-CoV-2 outbreak in Wuhan and was associated with ICU admission in one patient. None of the patients or their family members had had direct exposure to Huanan Seafood Wholesale Market (the initial location to which cases of Covid-19 were linked) or to one another. It is worth mentioning that we unexpectedly found a case of Covid-19 in one patient (Patient 3) who resided outside Wuhan; this patient had illness onset on January 2, 2020. The patient and her family were residents of the Yangxin area of Huangshi and had not traveled outside the city in the month before illness onset. We have not identified the source of infection for this patient. Our findings indicate that SARS-CoV-2 infections in children were occurring early in the epidemic. 4
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            Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2.

            Genes regulated by androgenic hormones are of critical importance for the normal physiological function of the human prostate gland, and they contribute to the development and progression of prostate carcinoma. We used cDNA microarrays containing 1500 cDNAs to profile transcripts regulated by androgens in prostate cancer cells and identified the serine protease TMPRSS2 as a gene exhibiting increased expression upon exposure to androgens. The TMPRSS2 gene is located on chromosome 21 and contains four distinct domains, including a transmembrane region, indicating that it is expressed on the cell surface. Northern analysis demonstrated that TMPRSS2 is highly expressed in prostate epithelium relative to other normal human tissues. In situ hybridization of normal and malignant prostate tissues localizes TMMPRSS2 expression to prostate basal cells and to prostate carcinoma. These results suggest that TMPRSS2 may play a role in prostate carcinogenesis and should be investigated as a diagnostic or therapeutic target for the management of prostate cancers.
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              Hypocortisolism in survivors of severe acute respiratory syndrome (SARS)

              Summary Objective  Following the severe acute respiratory syndrome (SARS) outbreak, many survivors were observed to suffer from psychosomatic symptoms reminiscent of various endocrine disorders. Hence, we sought to determine the existence of any chronic endocrine sequelae in SARS survivors. Design, patients, measurements  Sixty‐one survivors of SARS prospectively recruited were analysed for hormonal derangements 3 months following recovery. Patients with pre‐existing endocrine disorders were excluded. Any endocrine abnormalities diagnosed were investigated and treated where indicated up to a year. Serial evaluation facilitated characterization of trends and prognostication of any endocrinological aberrations. Results  Twenty‐four (39·3%) patients had evidence of hypocortisolism. The hypothalamic–pituitary–adrenal (HPA) axis dysfunction of the majority resolved within a year. Two (3·3%) of the hypocortisolic cohort had transient subclinical thyrotoxicosis. Four (6·7%) were biochemically hypothyroid, being comprised of three with central hypothyroidism and one with primary hypothyroidism. Two of the three with central hypothyroidism had concomitant central hypocortisolism. Eight had subnormal DHEAS levels. Conclusions  These preliminary findings highlight a possible aetiologic role of SARS‐associated coronavirus in causing a reversible hypophysitis or direct hypothalamic effect, with the HPA axis affected more frequently than the HPT axis.
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                Author and article information

                Journal
                Horm Res Paediatr
                Horm Res Paediatr
                HRP
                Hormone Research in Pædiatrics
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
                1663-2818
                1663-2826
                9 April 2020
                : 1-2
                Affiliations
                aDipartimento Pediatrico Universitario Ospedaliero “Bambino Gesù” Children's Hospital − Tor Vergata University, Rome, Italy
                bDepartment of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden
                Author notes
                *Prof. Stefano Cianfarani, Dipartimento Pediatrico Universitario Ospedaliero, “Bambino Gesù” Children's Hospital − Tor Vergata University, Piazza S. Onofrio 4, IT–00165 Rome (Italy), stefano.cianfaraniuniroma2.it and stefano.cianfarani@ 123456opbg.net
                Article
                hrp-0001
                10.1159/000507703
                7206355
                32272473
                Copyright © 2020 by S. Karger AG, Basel

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                Page count
                References: 12, Pages: 2
                Categories
                Editorial

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