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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Use of glucocorticoids in patients with adrenal insufficiency and COVID-19 infection</title><author><name sortKey="Isidori, Andrea M" sort="Isidori, Andrea M" uniqKey="Isidori A" first="Andrea M" last="Isidori">Andrea M. Isidori</name><affiliation><nlm:aff id="aff1">Policlinico Umberto I, COVID Hospital, Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy</nlm:aff></affiliation></author><author><name sortKey="Pofi, Riccardo" sort="Pofi, Riccardo" uniqKey="Pofi R" first="Riccardo" last="Pofi">Riccardo Pofi</name><affiliation><nlm:aff id="aff1">Policlinico Umberto I, COVID Hospital, Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy</nlm:aff></affiliation></author><author><name sortKey="Hasenmajer, Valeria" sort="Hasenmajer, Valeria" uniqKey="Hasenmajer V" first="Valeria" last="Hasenmajer">Valeria Hasenmajer</name><affiliation><nlm:aff id="aff1">Policlinico Umberto I, COVID Hospital, Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy</nlm:aff></affiliation></author><author><name sortKey="Lenzi, Andrea" sort="Lenzi, Andrea" uniqKey="Lenzi A" first="Andrea" last="Lenzi">Andrea Lenzi</name><affiliation><nlm:aff id="aff1">Policlinico Umberto I, COVID Hospital, Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy</nlm:aff></affiliation></author><author><name sortKey="Pivonello, Rosario" sort="Pivonello, Rosario" uniqKey="Pivonello R" first="Rosario" last="Pivonello">Rosario Pivonello</name><affiliation><nlm:aff id="aff2">Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32334645</idno><idno type="pmc">7180011</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180011</idno><idno type="RBID">PMC:7180011</idno><idno type="doi">10.1016/S2213-8587(20)30149-2</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000486</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000486</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Use of glucocorticoids in patients with adrenal insufficiency and COVID-19 infection</title><author><name sortKey="Isidori, Andrea M" sort="Isidori, Andrea M" uniqKey="Isidori A" first="Andrea M" last="Isidori">Andrea M. Isidori</name><affiliation><nlm:aff id="aff1">Policlinico Umberto I, COVID Hospital, Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy</nlm:aff></affiliation></author><author><name sortKey="Pofi, Riccardo" sort="Pofi, Riccardo" uniqKey="Pofi R" first="Riccardo" last="Pofi">Riccardo Pofi</name><affiliation><nlm:aff id="aff1">Policlinico Umberto I, COVID Hospital, Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy</nlm:aff></affiliation></author><author><name sortKey="Hasenmajer, Valeria" sort="Hasenmajer, Valeria" uniqKey="Hasenmajer V" first="Valeria" last="Hasenmajer">Valeria Hasenmajer</name><affiliation><nlm:aff id="aff1">Policlinico Umberto I, COVID Hospital, Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy</nlm:aff></affiliation></author><author><name sortKey="Lenzi, Andrea" sort="Lenzi, Andrea" uniqKey="Lenzi A" first="Andrea" last="Lenzi">Andrea Lenzi</name><affiliation><nlm:aff id="aff1">Policlinico Umberto I, COVID Hospital, Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy</nlm:aff></affiliation></author><author><name sortKey="Pivonello, Rosario" sort="Pivonello, Rosario" uniqKey="Pivonello R" first="Rosario" last="Pivonello">Rosario Pivonello</name><affiliation><nlm:aff id="aff2">Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy</nlm:aff></affiliation></author></analytic><series><title level="j">The Lancet. Diabetes & Endocrinology</title><idno type="ISSN">2213-8587</idno><idno type="eISSN">2213-8595</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Baud, D" uniqKey="Baud D">D Baud</name></author><author><name sortKey="Qi, X" uniqKey="Qi X">X Qi</name></author><author><name sortKey="Nielsen Saines, K" uniqKey="Nielsen Saines K">K Nielsen-Saines</name></author><author><name sortKey="Musso, D" uniqKey="Musso D">D Musso</name></author><author><name sortKey="Pomar, L" uniqKey="Pomar L">L Pomar</name></author><author><name sortKey="Favre, G" uniqKey="Favre G">G Favre</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Teblick, A" uniqKey="Teblick A">A Teblick</name></author><author><name sortKey="Peeters, B" uniqKey="Peeters B">B Peeters</name></author><author><name sortKey="Langouche, L" uniqKey="Langouche L">L Langouche</name></author><author><name sortKey="Van Den Berghe, G" uniqKey="Van Den Berghe G">G Van den Berghe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ruan, Sy" uniqKey="Ruan S">SY Ruan</name></author><author><name sortKey="Lin, Hh" uniqKey="Lin H">HH Lin</name></author><author><name sortKey="Huang, Ct" uniqKey="Huang C">CT Huang</name></author><author><name sortKey="Kuo, Ph" uniqKey="Kuo P">PH Kuo</name></author><author><name sortKey="Wu, Hd" uniqKey="Wu H">HD Wu</name></author><author><name sortKey="Yu, Cj" uniqKey="Yu C">CJ Yu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Russell, Cd" uniqKey="Russell C">CD Russell</name></author><author><name sortKey="Millar, Je" uniqKey="Millar J">JE Millar</name></author><author><name sortKey="Baillie, Jk" uniqKey="Baillie J">JK Baillie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kaiser, Ub" uniqKey="Kaiser U">UB Kaiser</name></author><author><name sortKey="Mirmira, Rg" uniqKey="Mirmira R">RG Mirmira</name></author><author><name sortKey="Stewart, Pm" uniqKey="Stewart P">PM Stewart</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Isidori, Am" uniqKey="Isidori A">AM Isidori</name></author><author><name sortKey="Venneri, Ma" uniqKey="Venneri M">MA Venneri</name></author><author><name sortKey="Graziadio, C" uniqKey="Graziadio C">C Graziadio</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Prete, A" uniqKey="Prete A">A Prete</name></author><author><name sortKey="Taylor, Ae" uniqKey="Taylor A">AE Taylor</name></author><author><name sortKey="Bancos, I" uniqKey="Bancos I">I Bancos</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Alhazzani, W" uniqKey="Alhazzani W">W Alhazzani</name></author><author><name sortKey="Moller, Mh" uniqKey="Moller M">MH Moller</name></author><author><name sortKey="Arabi, Ym" uniqKey="Arabi Y">YM Arabi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Isidori, Am" uniqKey="Isidori A">AM Isidori</name></author><author><name sortKey="Minnetti, M" uniqKey="Minnetti M">M Minnetti</name></author><author><name sortKey="Sbardella, E" uniqKey="Sbardella E">E Sbardella</name></author><author><name sortKey="Graziadio, C" uniqKey="Graziadio C">C Graziadio</name></author><author><name sortKey="Grossman, Ab" uniqKey="Grossman A">AB Grossman</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="letter"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Lancet Diabetes Endocrinol</journal-id><journal-id journal-id-type="iso-abbrev">Lancet Diabetes Endocrinol</journal-id><journal-title-group><journal-title>The Lancet. Diabetes & Endocrinology</journal-title></journal-title-group><issn pub-type="ppub">2213-8587</issn><issn pub-type="epub">2213-8595</issn><publisher><publisher-name>Elsevier Ltd.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32334645</article-id><article-id pub-id-type="pmc">7180011</article-id><article-id pub-id-type="publisher-id">S2213-8587(20)30149-2</article-id><article-id pub-id-type="doi">10.1016/S2213-8587(20)30149-2</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Use of glucocorticoids in patients with adrenal insufficiency and COVID-19 infection</article-title></title-group><contrib-group><contrib contrib-type="author" id="au10"><name><surname>Isidori</surname><given-names>Andrea M</given-names></name><email>andrea.isidori@uniroma1.it</email><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au20"><name><surname>Pofi</surname><given-names>Riccardo</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au30"><name><surname>Hasenmajer</surname><given-names>Valeria</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au40"><name><surname>Lenzi</surname><given-names>Andrea</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au50"><name><surname>Pivonello</surname><given-names>Rosario</given-names></name><xref rid="aff2" ref-type="aff">b</xref></contrib><aff id="aff1"><label>a</label>Policlinico Umberto I, COVID Hospital, Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy</aff><aff id="aff2"><label>b</label>Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy</aff></contrib-group><pub-date pub-type="pmc-release"><day>23</day><month>4</month><year>2020</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="epub"><day>23</day><month>4</month><year>2020</year></pub-date><permissions><copyright-statement>© 2020 Elsevier Ltd. All rights reserved.</copyright-statement><copyright-year>2020</copyright-year><copyright-holder>Elsevier Ltd</copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions></article-meta></front><body><p id="para10">In March 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), reached pandemic level with a high global mortality rate.<xref rid="bib1" ref-type="bibr"><sup>1</sup></xref> The initial immune response to viral load is followed by an uncontrolled cytokine storm with hyperinflammation and immunosuppression. In the patients who are critically ill, infected alveolar epithelial cells trigger the release of inflammatory cytokines, which activates fibroblasts. Subsequently, uncontrolled viral propagation induces cytotoxicity and hyperactivation of immune cells. The cytokine storm leads to increased clotting, vascular inflammation, thromboembolism, and hypotensive shock.</p><p id="para20">Glucocorticoids have both stimulating and inhibitory effects on the immune response. In the initial phases of an infection, physiological glucocorticoid concentrations help to prime the immune system. In turn, this response activates the hypothalamic–pituitary–adrenal (HPA) axis to mild immunosuppression to reduce autoimmunity and cytokine toxicity. In critical illness (eg, COVID-19 pneumonia), HPA activation might be blunted, leading to corticosteroid insufficiency related to critical illness.<xref rid="bib2" ref-type="bibr"><sup>2</sup></xref></p><p id="para30">The rationale for use of glucocorticoids in lung damage lies in their ability to reduce inflammation and, ideally, fibrosis. However, the absence of benefit on overall survival has discouraged their use<xref rid="bib3" ref-type="bibr"><sup>3</sup></xref> to the point that WHO guidance on management of COVID-19 advises against corticosteroids, unless indicated for other reasons.<xref rid="bib4" ref-type="bibr"><sup>4</sup></xref> Adrenal insufficiency is one of those reasons and standard care suggests to apply the so-called sick day rules when COVID-19 is suspected.<xref rid="bib5" ref-type="bibr"><sup>5</sup></xref></p><p id="para40">Patients with adrenal insufficiency have an increased risk of infection due to their depleted innate immunity, characterised by increased monocytes and decreased cytotoxic natural killer cells,<xref rid="bib6" ref-type="bibr"><sup>6</sup></xref> which could facilitate the worsening of a SARS-CoV-2 infection into severe acute respiratory distress syndrome. Given the role of the HPA axis in stress priming the immune response, patients with adrenal insufficiency are intuitively at high risk of infection, especially as corticosteroid therapy during infection is still largely tailored empirically, often disregarding timing and dosage. The rationale of the more the better avoids risking inadequate concentrations of corticosteroids. However, mild COVID-19 symptoms such as fatigue, malaise, gastrointestinal symptoms, and diarrhoea are common in patients with adrenal insufficiency, and patients' fears might lead them to increase their dose unnecessarily. Establishing the correct timing of stress dose administration relative to the degree of inflammatory damage and the desired effect on the immune system is crucial—ie, not too early, not too late.</p><p id="para50">Given that hydrocortisone clearance decreases with stress, in mild symptomatic COVID-19 it seems safe to replace the missing stress-induced cortisol rise with additional doses (at least doubling the original regimen). In cases of persistent fever or progression of respiratory damage to severe pneumonia, an initial bolus of 50–100 mg of hydrocortisone followed by continuous intravenous infusion of 200 mg of hydrocortisone would be the most appropriate replacement for patients with adrenal insufficiency.<xref rid="bib7" ref-type="bibr"><sup>7</sup></xref> Such regimen can reduce the harmful effects of peaks and troughs of hydrocortisone on the immune system,<xref rid="bib7" ref-type="bibr"><sup>7</sup></xref> and the length of stay in an intensive care unit.<xref rid="bib8" ref-type="bibr"><sup>8</sup></xref> Hydration and electrolyte balance should also be corrected promptly, as severe hypotension is very frequent with disease progression. There is also increasing concern over the disseminated thromboembolic disease observed in severe COVID-19. Given the coagulation abnormalities associated with glucocorticoid use, low molecular weight heparin should be introduced early.<xref rid="bib9" ref-type="bibr"><sup>9</sup></xref></p><p id="para60">In summary, tailoring of glucocorticoid stress regimens in COVID-19 requires a more evidence-based approach. The pathophysiology of immune response and the systemic complications associated with a SARS-CoV-2 infection set the pace, and the protocol should be adapted to the patient's clinical stage.</p></body><back><ref-list id="bibl10"><title>References</title><ref id="bib1"><label>1</label><element-citation publication-type="journal" id="sbref10"><person-group person-group-type="author"><name><surname>Baud</surname><given-names>D</given-names></name><name><surname>Qi</surname><given-names>X</given-names></name><name><surname>Nielsen-Saines</surname><given-names>K</given-names></name><name><surname>Musso</surname><given-names>D</given-names></name><name><surname>Pomar</surname><given-names>L</given-names></name><name><surname>Favre</surname><given-names>G</given-names></name></person-group><article-title>Real estimates of mortality following COVID-19 infection</article-title><source>Lancet Infect Dis</source><year>2020</year><comment>published online March 12.</comment><pub-id 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Endocrinol</source><volume>173</volume><year>2015</year><fpage>R101</fpage><lpage>R113</lpage><pub-id pub-id-type="pmid">25987566</pub-id></element-citation></ref></ref-list><ack><p>AMI reports personal fees from Takeda; non-financial support from Takeda and Ipsen; and grants from Shire and Pfizer. RP reports personal fees; non-financial support; and grants from HRA, Novartis, Ipsen, Corcept, and Shire. All other authors declare no competing interests.</p></ack></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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