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      A COVID-19 pneumonia case report of autoimmune polyendocrine syndrome type 1 in Lombardy, Italy: letter to the editor

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          Abstract

          We thank the European Society of Endocrinology (ESE) for providing the global endocrinology community with the statement on coronavirus disease (COVID-19) and endocrine disorders [1]. Regarding Addison’s disease, the ESE statement affirms that there is no evidence that patients with adrenal insufficiency are at increased risk of contracting COVID-19, and there are no reported data on the outcomes of COVID-19 infection in adrenal-insufficient individuals. Herein, we present the case of a 32-year-old woman with autoimmune polyglandular syndrome type 1 who developed COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); she lived closed to the first Lombardy cluster spreading from Codogno, Italy. Her clinical, immunological, and genetic patterns have been previously described (as patient no. 4) in a case series of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyendocrine syndrome type 1 (APS-1) [2]. In summary, she carries a homozygous R203X mutation in exon five of the autoimmune regulator (AIRE) gene, resulting in primary adrenal insufficiency (PAI), hypoparathyroidism, hypogonadism, ectodermal dystrophy, candidiasis, pernicious anemia, and gastrointestinal dysfunction. Because her chronic hypoparathyroidism was inadequately controlled by standard treatment alone, the patient had been on hormonal replacement therapy with recombinant human parathyroid hormone (rhPTH) (1–84) since January 2018. After starting rhPTH (1–84) 50 µg once daily as a subcutaneous injection, she stopped calcitriol and calcium supplementation, having achieved optimal and stable serum calcium levels. Her treatment was specifically approved by the Italian Medicines Agency (AIFA) before the marketing authorization in Italy, and the patient underwent regular follow-up at the University of Turin (Piedmont, Italy). On February 19, the patient presented to the emergency department of the Cremona Hospital (Lombardy, Italy) with fever, cough, and dyspnea. High-resolution computed tomography showed multiple and bilateral ground-glass opacities of the lungs. Bronchoalveolar lavage fluid was positive for SARS-CoV-2. After an unsuccessful trial of non-invasive ventilation, her progressive respiratory failure required endotracheal intubation and mechanical ventilation. Therefore, she was transferred to the Intensive Care Unit (ICU) of San Matteo Hospital in Pavia (Lombardy, Italy) on February 22. Pharmacological treatment included empirical antiviral regimens with lopinavir/ritonavir and ribavirin, and prophylaxis with hydroxychloroquine, azithromycin, piperacillin/tazobactam, and trimethoprim-sulfamethoxazole. Hemodynamic support required norepinephrine and dobutamine infusion; intravenous hydrocortisone was subsequently introduced at a dose of 300 mg divided in bolus injections over 24 h. After 6 days, the patient was extubated and started helmet continuous positive airway pressure. During hospitalization, the intravenous glucocorticoid dose was gradually tapered and eventually switched back to the pre-admission oral regimen. Unfortunately, the patient’s rhPTH treatment was interrupted after admission. Although the summary of product characteristics (SmPC) does not include diseases requiring intensive care among reasons for discontinuation, rhPTH has not been studied in this specific clinical setting. Therefore, calcitriol and calcium supplementation was needed again, leading to suboptimal serum calcium concentrations. A few days before discharge, the patient resumed treatment with rhPTH (1–84), with sufficient 25-hydroxy vitamin D stores. Following the instructions in the SmPC, oral calcium supplementation was progressively reduced, and calcitriol supplementation was stopped within 4 days, as the patient achieved adequate serum calcium concentrations. The patient was discharged on March 27, after 37 days of hospitalization, with complete resolution of symptoms and two negative tests for SARS-CoV-2 at an interval of 24 h. Her last chest X-ray showed bronchiolitis obliterans organizing pneumonia-like features that will need radiological and clinical follow-up. As of March 27, among 86,498 confirmed COVID-19 patients in Italy, 4.3% required intensive care (data from the Italian Civil Protection Department website https://www.protezionecivile.it—English version available; last access on May 20). Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs in Lombardy have been recently published; median length of stay in ICU was 9 days, and almost all the patients required respiratory support, mainly invasive mechanical ventilation (88%) [3]. As soon as information is also available on the characteristics of non-ICU hospitalized COVID-19 patients in Italy, it would be interesting to explore whether PAI may worsen COVID-19 outcomes, such as length of hospital stay, incidence of acute respiratory distress syndrome, and the need for CPAP therapy and mechanical ventilation. The ESE statement notes the occurrence of impaired natural immunity function in PAI, with defective action of neutrophils and natural killer cells, independent of the underlying etiology [4], suggesting that exogenous glucocorticoids play a role in modulating the immune system. Our case might not be considered a paradigmatic example of PAI; at variance with other forms of autoimmune Addison disease, patients with APS-1 have primary immunodeficiency, which explains the T-cell deficiency-related chronic mucocutaneous candidiasis. This feature has relevant clinical consequences; in fact, a recent prospective study showed that the Finnish APS-1 cohort had an increased mortality from infections (standardized mortality ratio 36; 95% CI 6.4–110) in comparison to the general population [5]. Similarly, an increased risk of infections has been observed also in other forms of Addison’s disease, with autoimmune or genetic basis. However, in these forms, there is no clear demonstration of primary immunodeficiency, and the infection risk in Addison's disease could be linked to the types or doses of glucocorticoid replacement. A population-based, retrospective, open cohort study in the United Kingdom from 1995 to 2018 showed that the Addison’s disease cohort, compared with matched controls, had a higher risk of infections of the lower respiratory [adjusted incidence rate ratio (aIRR) 2.11; 95% CI 1.64–2.69], urinary (aIRR 1.51; 95% CI 1.29–1.77), and gastrointestinal (aIRR 3.80; 95% CI 2.99–4.84) tracts, leading to increased use of antimicrobial agents in the primary care setting [6]. Interestingly, the same study showed no increased risk of infection in patients with untreated congenital adrenal hyperplasia (CAH), but an increased infection risk in patients treated for CAH, suggesting that non-physiological delivery of glucocorticoid replacement may represent a risk factor for the development of infections [6]. All of these findings are in line with the increased infection-related mortality described in the literature. A population-based, retrospective study on the Swedish population from 1987 to 2001 found that the mortality rate resulting from infections in Addison’s disease was five times higher than expected (risk ratio 5.57; 95% CI 2.04–12.14 in women; risk ratio 6.57; 95% CI 2.56–15.17 in men) [7]. Another Swedish population-based, retrospective study from 1964 to 2004 reported increased mortality from infections in patients with autoimmune PAI (standardized mortality ratio 5.9; 95% CI 4.0–8.4) [8]. In Norway, a population-based, retrospective study from 1943 to 2005 reported an increase in mortality from infections associated with Addison’s disease [10% among causes of death (95% CI 5.1–14.9) vs. 6.0% in the general population] [9]. The first prospective study investigating causes of death in PAI and secondary adrenal insufficiency (SAI) was based on real-world data from 2034 patients (801 PAI, 1,233 SAI) in the European Adrenal Insufficiency Registry (EU-AIR; ClinicalTrials.gov identifier NCT01661387). The primary objective of EU-AIR is to monitor the safety of long-term treatment with once-daily, modified-release hydrocortisone and other glucocorticoid replacement therapies in adrenal insufficiency. Of the 26 deaths registered from 2012 to 2017, only 8% occurred to subjects with Addison’s disease. Infections accounted for 15% of the deaths. With the limitations of a small percentage of autoimmune PAI among infection-related deaths and the EU-AIR inclusion of European adrenal insufficiency patients treated in highly specialized centers, the results of this observational, open-ended study appear to be consistent with the previous evidence from retrospective studies [10]. In conclusion, it is not clear whether the disease per se or the hormonal replacement without physiological glucocorticoid rhythm plays a pre-eminent role in the impaired immune function of PAI. Our case report, along with the aforementioned studies, calls attention to the increased risk of infections in Addison’s disease, with or without associated primary immunodeficiency. Further research worldwide is required to conclude that a predisposition to COVID-19 exists and to assess its adverse short- and long-term outcomes.

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          Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy

          In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) emerged in China and has spread globally, creating a pandemic. Information about the clinical characteristics of infected patients who require intensive care is limited.
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            COVID-19 and endocrine diseases. A statement from the European Society of Endocrinology

            Introduction Coronavirus disease 2019 (COVID-19) outbreak requires that endocrinologists from all over Europe move on, even more, to the first line of care of our patients, also in collaboration with other physicians such as those in internal medicine and emergency units. This will preserve the health status and prevent the adverse COVID-19-related outcomes in people affected by different endocrine diseases. People with diabetes in particular are among those in high-risk categories who can have serious illness if they get the virus, according to the data published so far from the Chinese researchers, but other endocrine diseases such as obesity, malnutrition, and adrenal insufficiency may also be impacted by COVID-19. Therefore, since the responsibilities of endocrinologists worldwide due to the current COVID-19 outbreak are not minor we have been appointed by the European Society of Endocrinology (ESE) to write the current statement in order to support the ESE members and the whole endocrine community in this critical situation. In addition, endocrinologists, as any other healthcare worker under the current COVID-19 outbreak, will need to self-protect from this viral disease, which is demonstrating to have a very high disseminating and devastating capacity. We urge Health Authorities to provide adequate protection to the whole workforce of health professionals and to consistently test for COVID-19 the exposed personnel. A decrease in the number of healthcare professionals available for active medical practice in case they contract the disease as it is happening in certain countries, is itself, a threat for the healthcare system and the well-being of our patients. The virus seems to have spread from infected animals and human-to-human transmission is now more than evident, with a high suspicion that non-symptomatic individuals act as the major vectors. It spreads like any other respiratory infectious disease, through contaminated air-droplets that come out of the mouth of infected persons when talking, coughing, or sneezing. The virus can survive in the environment from a few hours to a few days, depending on surfaces and environmental conditions, and touching affected surfaces. The mouth, nose, and ocular mucosa appears to be the major way of transmission. Symptoms of COVID-19 infection General symptoms are relatively nonspecific and similar to other common viral infections targeting the respiratory system, and include fever, cough, myalgia, and shortness of breath. The clinical spectrum of the virus ranges from mild disease with nonspecific signs and symptoms of acute respiratory illness, to severe pneumonia with respiratory failure and septic shock. Possibly, an overreaction of the immune system leading to an autoimmune aggression of the lungs could be involved in the most severe cases of acute distress respiratory syndrome. There have also been reports of asymptomatic infection and research in this matter is currently ongoing worldwide to elucidate the real prevalence of the disease and the true relative mortality ratio. COVID-19 infection and diabetes mellitus Increased risk of morbidity and mortality in patients with diabetes regarding COVID-19 infection Older adults and those with serious chronic medical conditions like heart disease, lung disease, and diabetes are at the highest risk for complications from COVID-19 infection. Chronic hyperglycemia negatively affects immune function and increases the risk of morbidity and mortality due to any infection and is associated to organic complications. This is also the case for COVID-19 infection [1]. During the Influenza A (H1N1) pandemic, the presence of diabetes tripled the risk of hospitalization and quadrupled the risk of ICU admission once hospitalized. Among COVID-19 mortality cases in Wuhan, China, major associated comorbidities included hypertension (53.8%), diabetes (42.3%), previous heart disease (19.2%), and cerebral infarction (15.4%) [2]. In addition, as for seasonal influenza, new data regarding COVID-19 indicate that the infection potentiates myocardial damage and identifies underlying heart disorders as a new risk factor for severe complications and worsening of prognosis [3]. Among the confirmed COVID-19 cases in China by Feb 11, 2020, the overall mortality reported is 2.3% [4]. This data refers mostly to hospitalized patients [4, 5]. Among persons with no underlying medical conditions, the reported mortality in China is 0.9%. There is a lack of data regarding the number of non-symptomatic cases, as in most countries universal microbiological screening has not been performed. It is presumed that the prevalence of the infection is probably high or very high in the community, thus leading to an overestimation of the prevalence of case fatality. However, mortality is strongly increased with the presence of comorbid diseases, including previous cardiovascular disease (10.5%), diabetes (7.3%), chronic respiratory disease, hypertension, and cancer, each at 6%. Among 60-year-old people and older, mortality has been reported to be 14.8% in those >80 years, 8% for those between 70 and 79 years and 3.6% in the group of 60–69 years. Compared with non-ICU patients, critically ill patients are older (median age 66 vs. 51 years) and have more previous comorbidities (72% vs. 37%) [6]. Worldwide mortality rates may vary by region, but this information is not yet consistently available and comparable, as public health policies applied and health registers used in every region of the world are not homogeneous. What people with diabetes should do to prevent infection by COVID-19 Social distancing as well as home confinement of the whole population are now widely adopted in many countries in Europe and worldwide as measures hopefully effective in contrast to the spread of infection. We recommend that due to the increased dangers of developing COVID-19, persons with diabetes should strictly adhere to these preventive measures and adopt them also within their homes in order to avoid being in contact with their relatives. Therefore, under these circumstances, it is recommended that people with diabetes try to plan ahead of time what to do in case they get ill. It is important to maintain a good glycemic control, because it might help reduce the risk of infection itself and may also modulate the severity of the clinical expression of the disease. Contact with healthcare providers, such as endocrinologists in the case of type 1 diabetes, and including also internal medicine specialists and general practitioners for type 2 diabetes patients may be advisable. However, routine appointments in person are not recommended for people with diabetes, as they should avoid crowds (waiting rooms). Therefore, we recommend phone calls, video calls, and emails as the main way for patients to keep in touch with their healthcare provider team, in order to guarantee an optimal control of the disease. Moreover, it is advised to ensure adequate stock of medications and supplies for monitoring blood glucose during the period of home confinement. What people with diabetes should do if they are infected by COVID-19 People with diabetes who are infected with COVID-19 may experience a deterioration of glycemic control during the illness, like in any other infectious episodes. Implementation of “Sick day rules” is therefore mandatory to overcome potential diabetes decompensation. Contacting the healthcare provider team by telephone, email, or videoconference is also mandatory in case of possible symptoms of COVID-19 infection in order to seek advice concerning the measures to avoid risk of deterioration of diabetes control or the possibility to be referred to another specialist (pneumologist or infectious disease doctor) or in the Emergency Services of the referral hospital to avoid the most serious systemic complication of the viral infection itself. COVID-19 and other endocrine and metabolic disorders Obesity There is a general lack of data regarding the impact of COVID -19 in people suffering from obesity. However, as for what is currently being the experience in some hospitals in Spain, cases of young people in which severe obesity is present may evolve toward destructive alveolitis with respiratory failure and death (Puig-Domingo M, personal experience). There is no current explanation for this clinical presentation, although it is well known that severe obesity is associated to sleep-apnea syndrome, as well as to surfactant dysfunction, which may contribute to a worse scenario in the case of COVID-19 infection. Also, deterioration of glycemic control is associated with an impairment of ventilatory function and thus may contribute to a worse prognosis in these patients. In addition, type 2 diabetes and obesity may concur in a given patient, which typically is also frequently accompanied by an age >65. In summary, these patients may be at a higher risk of impaired outcomes in the case of COVID-19 infection. Undernourishment Regarding undernourished subjects, COVID-19 infection is associated to a high risk of malnutrition development, mostly related to increased requirements and the presence of a severe acute inflammatory status. These patients show also a hyporexic state, thus contributing to a negative nutritional balance. Estimated nutritional requirements are 25–30 kcal/kg of weight and 1.5 g protein/kg/day [7]. A nutrient dense diet is recommended in hospitalized cases including high protein supplements (2–3 intakes per day) containing at least 18 g of protein per intake. Adequate supplementation of vitamin D is recommended particularly in areas with large known prevalence of hypovitaminosis D and due to the decreased sun exposure [8, 9]. If nutritional requirements are not met, complementary or complete enteral feeding may be required, and in case that enteral feeding may not be possible due to inadequate gastrointestinal tolerance, the patient should be put on parenteral nutrition. COVID-19 patients’ outcome is expected to improve with nutritional support [10]. Adrenal insufficiency Adrenal insufficiency is a chronic condition of lack of cortisol production. Live-long replacement treatment aiming to mimic physiologic plasma cortisol concentrations is not easy for these patients. Based on current data, there is no evidence that patients with adrenal insufficiency are at increased risk of contracting COVID-19. However, it is known that patients with Addison’s disease (primary adrenal insufficiency) and congenital adrenal hyperplasia have a slightly increased overall risk of catching infections. Moreover, primary adrenal insufficiency is associated to an impaired natural immunity function with a defective action of neutrophils and natural killer cells [11]. This may explain, in part, this slightly increased rate of infectious diseases in these patients, as well as an overall increased mortality. This latter could also be accounted by an insufficient compensatory increase of the hydrocortisone dosage at the time of the beginning of an episode of infection. For all these reasons, patients with adrenal insufficiency may be at higher risk of medical complications and eventually at increased mortality risk in the case of COVID-19 infection. So far, there are no reported data on the outcomes of COVID-19 infection in adrenal insufficient subjects. In the case of suspicion of COVID-19, a prompt modification of the replacement treatment as indicated for the “Sick days” should be established when minor symptoms appear. This means in the first instance to at least double the usual doses of glucocorticoid replacement, to avoid adrenal crisis. In addition, patients are also recommended to have sufficient stock at home of steroid pills and injections in order to maintain the social confinement that is required in most of the countries for impeding the COVID-19 outbreak spread. Actions to be taken if infection by COVID-19 is suspected If a person with endocrine and metabolic diseases has fever with cough or trouble breathing and may have been exposed to COVID-19 (if living in or visited a country affected in the 14 days before getting sick, or if having been around a person who may have had the virus), a call to the physician or nurse for advice should be made. Some countries have set up COVID-19 phone lines for the public. The personnel in charge of these phone lines will prioritize arrangements, if needed, regarding what should be the next step in the healthcare protocol. If the person is advised to go to the hospital, it is recommended to put on a face mask. In countries with explosive outbreak, most of the people have already bought a face mask by their own initiative. Fluid samples taken from the nose or throat will be used for microbiologic diagnosis. There is currently no specific treatment for COVID-19, but since the majority of cases are mild, only a limited amount of people will require hospitalization for supportive care. However, in most of the countries in which the outbreak has been declared and recognized, particularly in China, the Northern regions of Italy, Iran, and Spain, the situation has been very challenging and the requirement of hospitalization has led national health systems to the limit of their capacities [12]. What to do in case of confinement at home? Individuals and families affected or suspected to be affected by COVID-19 that stay at home should follow proper measures for infection prevention and control. Management should focus on prevention of transmission to others and monitoring for clinical deterioration, which may prompt hospitalization. Affected persons should be placed in a well-ventilated single room, while household members should stay in a different room or, if that is not possible, maintain a distance of at least one meter from the person affected (e.g., sleep in a separate bed) and perform hand hygiene (washing hands with soap and water) after any type of contact with the affected person or their immediate environment. When washing hands, it is preferable to use disposable paper towels to dry them. If these are not available, clean cloth towels should be used and replaced when wet. To contain respiratory secretions, a medical mask should be provided to the person affected and worn as much as possible. Individuals who cannot tolerate a medical mask should use rigorous respiratory hygiene—i.e., the mouth and nose should be covered with a disposable paper tissue when coughing or sneezing. Caregivers should also wear a tightly fitted medical mask that cover their mouth and nose when in the same room is present the person affected. Conclusions An ESE “decalog” for endocrinologists in the COVID-19 pandemic Adequately protect yourself and ask for COVID-19 testing if exposed. Avoid unnecessary routine appointments in person. Put in place online/email/phone consultation services. Closely monitor glycemic control in patients with diabetes. Recommend to persons with diabetes a strict adherence to general preventive measures. Counsel persons with diabetes about specific measures related to their disease management (sick day rules) in case of infection by COVID-19. Counsel persons with diabetes particularly if aged over 65 and obese about referrals for management in case of suspected infection by COVID-19. Avoid undernourishment with dietary or adjunctive measures if clinically indicated. Closely monitor clinical conditions of patients with adrenal insufficiency. Adapt increased replacement treatment if clinically indicated in patients with adrenal insufficiency.
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              Normal overall mortality rate in Addison's disease, but young patients are at risk of premature death.

              Primary adrenal insufficiency (Addison's disease) is a rare autoimmune disease. Until recently, life expectancy in Addison's disease patients was considered normal. To determine the mortality rate in Addison's disease patients. i) Patients registered with Addison's disease in Norway during 1943-2005 were identified through search in hospital diagnosis registries. Scrutiny of the medical records provided diagnostic accuracy and age at diagnosis. ii) The patients who had died were identified from the National Directory of Residents. iii) Background mortality data were obtained from Statistics Norway, and standard mortality rate (SMR) calculated. iv) Death diagnoses were obtained from the Norwegian Death Cause Registry. Totally 811 patients with Addison's disease were identified, of whom 147 were deceased. Overall SMR was 1.15 (95% confidence intervals (CI) 0.96-1.35), similar in females (1.18 (0.92-1.44)) and males (1.10 (0.80-1.39)). Patients diagnosed before the age of 40 had significantly elevated SMR at 1.50 (95% CI 1.09-2.01), most pronounced in males (2.03 (1.19-2.86)). Acute adrenal failure was a major cause of death; infection and sudden death were more common than in the general population. The mean ages at death for females (75.7 years) and males (64.8 years) were 3.2 and 11.2 years less than the estimated life expectancy. Addison's disease is still a potentially lethal condition, with excess mortality in acute adrenal failure, infection, and sudden death in patients diagnosed at young age. Otherwise, the prognosis is excellent for patients with Addison's disease.
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                Author and article information

                Contributors
                guglielmo.beccuti@unito.it
                Journal
                J Endocrinol Invest
                J. Endocrinol. Invest
                Journal of Endocrinological Investigation
                Springer International Publishing (Cham )
                0391-4097
                1720-8386
                9 June 2020
                : 1-3
                Affiliations
                [1 ]GRID grid.7605.4, ISNI 0000 0001 2336 6580, Department of Medical Sciences, Division of Endocrinology, Diabetes and Metabolism, , University of Turin, ; Corso Dogliotti 14, 10126 Turin, Italy
                [2 ]Department of Medical Sciences and Infectious Diseases, Division of Rheumatology, Foundation IRCCS Polyclinic San Matteo, Pavia, Italy
                [3 ]Department of Medical Sciences and Infectious Diseases, Division of Infectious and Tropical Diseases, Foundation IRCCS Polyclinic San Matteo, Pavia, Italy
                [4 ]Department of Medical Sciences and Infectious Diseases, Division of General Medicine 1, Foundation IRCCS Polyclinic San Matteo, Pavia, Italy
                [5 ]Department of Anesthesia and Intensive Care Unit, Foundation IRCCS Polyclinic San Matteo Pavia, Pavia, Italy
                [6 ]GRID grid.8982.b, ISNI 0000 0004 1762 5736, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, , University of Pavia, ; Pavia, Italy
                Article
                1323
                10.1007/s40618-020-01323-4
                7282538
                32519200
                © Italian Society of Endocrinology (SIE) 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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