SARS-CoV-2-induced adrenal crisis in a patient with autoimmune polyglandular syndrome type 1: case report.

Background:Autoimmune polyglandular syndrome type 2 (APS-2), also known as Schmidt's syndrome, is an uncommon disorder characterized by the coexistence of Addison's disease with thyroid autoimmune disease and/or type 1 diabetes mellitus. Addison's disease as the obligatory component is potentially life-threatening. Unfortunately, the delayed diagnosis of Addison's disease is common owing to its rarity and the nonspecific clinical manifestation.Methods:Here we reported a case of 38-year-old female patient who presented with 2 years’ history of Hashimoto's thyroiditis and received levothyroxine replacement. One year later, skin hyperpigmentation, fatigue, loss of appetite, and muscle soreness occurred. She was advised to increase the dose of levothyroxine, but the symptoms were not relieved. After 4 months, the patient accompanied with dizziness, nausea, nonbloody vomiting, and fever. However, she was diagnosed with acute gastroenteritis and fell into shock and ventricular fibrillation subsequently. Further evaluation in our hospital revealed elevated adrenocorticotrophic hormone and low morning serum cortisol, associated with hyponatremia and atrophic adrenal gland. Hypergonadotropic hypogonadism and Hashimoto's thyroiditis were also demonstrated.Results:After the supplementation with hydrocortisone and fludrocortisone was initiated, the physical discomforts were alleviated and plasma electrolytes were back to normal.Conclusion:The uncommon case involving 3 endocrine organs reinforced the significance of a timely diagnosis and appropriate treatment of APS-2, and physicians needed to sharpen their awareness of the potentially life-threatening disease.

SummaryWe report on a boy of Albanian descent with the history of juvenile myelomonocytic leukemia (JMML). JMML was diagnosed at the age of 17 months and treated by hematopoietic stem cell transplantation (HSCT). At the age of 14.3 years, about 12 years after HSCT, he was hospitalized with an adrenal crisis. Hormone findings were consistent with primary adrenal insufficiency. Autoimmune adrenalitis was confirmed by positive autoantibodies against 21-hydroxylase and adrenal tissue. Since autoimmune Hashimoto thyroiditis was already known from the age of 9 years, we assume that both diseases are part of the spectrum of autoimmune polyglandular syndrome (APS) type 2. APS type 2 is a rare endocrine disease characterized by Addison’s disease along with autoimmune thyroid disease and/or type 1 diabetes.Learning points:Endocrine sequelae after hematopoietic stem cell transplantation (HSCT) are common and can develop over a long period.Primary adrenal insufficiency after HSCT is absolutely rare.The combination of adrenal autoimmune disease and Hashimoto thyroiditis is consistent with autoimmune polyglandular syndrome type 2.

Autoimmune polyglandular syndrome (APS) type 2 is characterized by the presence of Addison's disease (AD) along with autoimmune thyroid disease and/or type 1 diabetes. APS type 2 is known as Schmidt's syndrome when autoimmune adrenal insufficiency is associated with chronic lymphocytic thyroiditis. We report a very rare case of a 28-year-old female patient who had Schmidt's syndrome revealed by a thyroid storm (TS) concomitant with an acute adrenal crisis. The onset of AD resulted in a surgical emergency. The patient presented with cardiogenic shock and an acute abdomen. The precipitation factor was Hashitoxicosis presented as TS. This life-threatening condition was successfully reversed with aggressive medical therapy based on antithyroid drugs and intravenous glucocorticoids. This hyperthyroid phase lasted for a period of 8 months. The patient eventually developed hypothyroidism, suggesting that Hashimoto's thyroiditis was the most likely diagnosis. She was started on levothyroxine replacement therapy and remained euthyroid on levothyroxine. The case we describe had several diagnostic pitfalls that are discussed both at the start as well as during the evolution. Autoimmune diseases can appear concomitantly or succeed each other over time. The clinician must be vigilant to detect these diseases in time in order to avoid a misdiagnosis of a life-threatening emergency such as adrenal insufficiency or thyroid storm. Thyroid storm is an uncommon but life-threatening manifestation of hyperthyroidism. Diagnosis is dependent on clinical symptoms, and no specific laboratory tests are available. Glucocorticoids should be used in the treatment of thyroid storm because they have an inhibitory effect on peripheral conversion of T4 to T3. In patients who have severe thyrotoxicosis, especially in conjunction with hypotension, treatment with glucocorticoids has become standard practice because of the possibility of relative adrenal insufficiency or the possibility of undiagnosed Addison's disease. The differential diagnosis of hyperthyroidism can be challenging. Graves' disease can be discussed in view of the severity of the clinical presentation and the prolonged duration of the hyperthyroid phase. Hashitoxicosis is the initial hyperthyroid phase in chronic autoimmune thyroiditis. The hyperthyroid phase is always followed by definitive resolution, with persistent euthyroidism and no hyperthyroid relapses. Synthetic antithyroid drugs may be prescribed during the hyperthyroid phase of Hashimoto thyroiditis if the clinical presentation is severe and the duration of the hyperthyroid phase is prolonged.

Autoimmune polyglandular syndromes are rare autoimmune endocrinopathies, which can be also associated with non endocrine autoimmune diseases. The autoimmune polyglandular syndrome type I (autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy; APECED) is distinguished from autoimmune polyglandular syndrome type 2 (APS-2). Main symptoms of APECED are adrenal insufficiency, hypoparathyroidism and candidiasis. The diagnosis is established when two out of three of these symptoms are present. APECED is associated with mutations of the autoimmune regulator gene (AIRE) and predominantly affects juvenile patients with a family background from Sardinia, Finland and Iranian Jews. The APS-2 is not AIRE associated. It is characterized by the presence of autoimmune thyroid disease, adrenal insufficiency and/or diabetes mellitus type I. APS-2 is more common than APECED and mainly affects adult women without any preference of a certain ethnic group. Therapy consists of hormone replacement therapy and treatment of clinical symptoms. In some APECED patients immunosuppressive therapy seems to be promising.

The immunobiology and clinical features of type 1 autoimmune polyglandular syndrome (APS-1).

To determine if cyclical intermediate dose steroid therapy could improve semen parameters in an infertile man with sperm autoimmunity associated with the polyglandular autoimmune (PGA) syndrome. Sperm agglutination studies performed before, during and after three courses of cyclical intermediate dose prednisolone therapy. A twenty-six-year old man with polyglandular autoimmune syndrome, consisting of Addison's disease, hypoparathyroidism, chronic mucocutaneous candidiasis and alopecia totalis, presented with infertility. He had normal endocrine testicular function but severe exocrine failure evidenced by a low sperm count (4.5 x 10(6)/ml), zero motility and universal sperm agglutination. Sperm agglutination tests. At presentation the gelatin agglutination test (GAT) was strongly positive in serum (1/1204) and seminal plasma (1/64) as was the tray agglutination test (TAT) (1/32). The patient's wife had a regular menstrual cycle with normal luteal phase progesterone levels. Following three courses of cyclical prednisolone (20 mg twice daily on days 1-10 of wife's cycle, and 5 mg on days 11 and 12), sperm quantity and motility improved considerably (12 x 10(6)/ml, 40% respectively) and sperm agglutination tests became negative. After a fourth course of therapy the patient's wife became pregnant. Three months post-treatment sperm motility was very low again and agglutinating activity in serum and seminal plasma increased. This is the first case of male infertility due to sperm autoimmunity in association with the PGA syndrome type 1. The immunosuppressive action of cyclical intermediate dose steroid therapy led to a significant quantitative and qualitative improvement in semen parameters.

Introduction: Currently, the need to expand knowledge about the mechanisms of impaired immune tolerance in autoimmune adrenal insufficiency (AAI) remains relevant. It is not excluded that in AAI there are disturbances in the system of regulatory B-lymphocytes (Breg).Objective: To assess the state of the B-regulatory cells system of immunity in AAI.Material and methods: the content of Breg was evaluated in patients with AAI, including isolated AAI and AAI as part of autoimmune polyglandular syndrome type 2 (APS-2) and as part of APS-1, in patients with primary adrenal insufficiency (1-AI) of non-autoimmune genesis, conditionally healthy individuals without AI and autoimmune diseases.Results: A decrease in the content of Breg in vivo was revealed in patients with isolated AAI and AAI in the composition of APS-2 compared with conditionally healthy participants. The content of Breg in vivo in patients with 1-AI of non-autoimmune genesis did not statistically differ from the indicators of conditionally healthy participants.Conclusion: for the first time in the world, a tendency to a decrease in the content of Breg in AAI, caused by a disturbance of peripheral immune tolerance, was found. Thus, these cells can be considered as promising markers for the prognosis, early diagnosis, and differential diagnosis of AAI.

The coexistence of adrenal failure with either autoimmune thyroid disease and/or type 1 diabetes is defined as autoimmune polyglandular syndrome (APS) type 2 or Schmidt’s syndrome. Vitiligo, hypergonadotropic hypogonadism, chronic...

Autoimmune diseases and sarcoidosis may be related and, especially, the association between sarcoidosis and autoimmune thyroid disease has long been recognized. The frequency and type of endocrine autoimmunity was examined in a series of Swedish patients with sarcoidosis. Of all patients (N = 89) with documented sarcoidosis attending the Department of Pulmonary Medicine between January 1980 and December 1991, 78 patients (44 males and 34 females; median age at the time of the study 48 years. range 22-81 years) were examined at the Department of Endocrinology, Malmö University Hospital, in the present study. Fifteen patients (19.2%) had clinical or serological evidence of endocrine autoimmunity. Two patients had Addison's disease, both with polyglandular autoimmune (PGA) syndrome type II: evidence of thyroid autoimmunity was found in 13 patients, eight with clinical autoimmune thyroid disease (ATD) (two with Graves' disease and six with autoimmune thyroiditis), of whom two had PGA syndrome type III, and five with isolated positive thyroid serology; two patients had insulin-dependent diabetes mellitus and one had premature ovarian failure. The frequencies of Addison's disease, clinical ATD and PGA syndrome type II were significantly higher compared with the frequencies found in the general population. In conclusion, a high frequency of endocrine autoimmunity in patients with sarcoidosis, occurring in about 20% of the cases, was demonstrated. Thyroid autoimmunity and polyglandular autoimmune syndromes occurred most frequently. Complex immunological and genetic mechanisms might explain the association of sarcoidosis and endocrine autoimmune diseases.

We report a patient with combined pulmonary arterial hypertension (PAH) and autoimmune polyglandular syndrome (APS) type 2. A 41 y/o woman with hypothyroidism presented for right heart (RHC) in the work up of PAH. Pt had a medical history of PAH diagnosed by transthoracic echocardiogram (TTE) and hypothyroidism. She reported symptoms of fatigue, shortness of breath with increased pigmentation of her skin progressive for several years. Preadmission lab found hyponatremia of 126 and potassium of 6.6. She was admitted and treated with IV insulin with D50, kayexalate, IV fluids. A random 11 AM cortisol was 0.57 mcg/dl N: AM: 6. 0–30. 0 mcg/dl; PM: 3. 0–16. 0 mcg/dl. Acosyntropin test was ordered. Pt failed the stimulation test (baseline 0.39, 30 min 0.49, 60 min 0.50, with an ACTH at baseline of 1423 pg/ml N: 7.2-63.3). Pt was started on hydrocortisone 20 mg AM/10 mg PM with fludrocortisone 0.1mg. On follow up at 2 weeks, her energy, mood, appetite and breathing tolerance had improved. Follow up RHC in 4 weeks found normalization of right heart pressures. APS is a collection of autoimmune diseases. Type I APS, caused by a defect in the autoimmune regulator (AIRE) gene, is diagnosed with two of three conditions, chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal cortical insufficiency. Type II APS (formally "Schmidt's Syndrome"), associated with HLA haplotypes DR3 (DQB*0201) and DR4 (DQB1*0302), is diagnosed with chronic autoimmune adrenal insufficiency with either Type 1 DM or chronic autoimmune thyroid disease (commonly Hashimotos but can be Graves). It typically presents later in life compared to APS I, age 30-40s. The association between PAH is rare but has been noted in several case studies. It has been associated with APS I in Korniszewski et al. and Bhansali et al. For APS II, the first association was reported by Barrou et al. of a patient with hypothyroidism, hypogonadism, and adrenal insufficiency who later developed PAH. Two cases reported by García-Hernández et al found PAH with positive adrenal antibodies without adrenal insufficiency. In 2009 Walid R. et al. reported a case of severe adrenal insufficiency (hypotension, hypokalemia) with PAH. She improved with steroids, but her PAH was present on TTE four years after treatment started. Pt in that case declined RHC. The patient in this case study proceeded with a RHC which did show normalization of right heart pressures, the first reported case to document normalization of PAH with replacement steroid treatment. Presentation: No date and time listed

There are many types of polyglandular autoimmune syndrome (PAS). PAS type 2 is the most common type among adults. For PAS type 2 (PAS-2) diagnosis, detection of Addison's disease with autoimmune thyroid disease and/or type 1 diabetes mellitus are required. Premature ovarian insufficiency, pernicious anemia, vitiligo, alopecia, myasthenia gravis, celiac disease and autoimmune diabetes insipidus may be comorbidities of this condition. Contrary to the common belief, latent PAS is more common than the manifest forms. Here, we present a PAS-2 case diagnosed via adrenal crisis. At the time of diagnosis, the case was observed to have thyroid, adrenal and ovarian involvement. Therefore, PAS-2 and possible immunologic disorders were discussed.

Autoimmune polyglandular syndrome type 1 (APS-1) is an extremely rare monogenic autosomal recessive disease characterized by development of multiple organ failure with predominant endocrine glands involvement. The challenges of patient management are related to low adherence to the lifelong multicomponent therapy, high risk of complications, including pneumonia, adrenal insufficiency decompensation, necrotic colitis and other acute infectious and inflammatory diseases. Due to the rarity of this disorder, clinicians lack sufficient experience with management of such patients, which could lead to delayed medical care and patient death. Patient A., 28 years old, was followed up for 10 years in the Endocrinology clinic with the diagnosis of “Autoimmune polyglandular syndrome type 1. Mucocutaneous candidiasis. Primary hypoparathyroidism. Primary chronic adrenal insufficiency. Primary hypothyroidism. Chronic gastroduodenitis. Chronic colitis. Autoimmune alopecia.” The onset of the disease with chronic mucocutaneous candidiasis at the age below 1 year had defined the severe course of the disease, including a wide range of consequently occurring autoimmune diseases associated with recurrent episodes of decompensation of hypoparathyroidism and adrenal insufficiency, as well as the development of acute necrotic colitis at the age of 26. As an adult, the patient admitted that he had previously been insufficiently responsible and attentive to his disease and regular medication intake, with resulting episodes of adrenal insufficiency decompensation and occurrence of the symptoms related to serum calcium fluctuations. Due to abnormalities of cellular and humoral immunity, APS-1 patients are at an extremely high risk for a critical course of COVID-associated pneumonia. In 2020, the patient contracted the coronavirus infection complicated by bilateral pneumonia, followed by respiratory failure, bacterial sepsis and acute renal failure. Despite the timely hospitalization, administration of the state-of-the-art antibacterials and antifungals and all the necessary resuscitation measures, it was not possible to save his life. This clinical observation demonstrates the difficulties of therapeutic management of APS-1 patients with an early disease manifestation, who, due to severe genetically determined impaired immunity, are at high risk of death from an intercurrent infection. The combination of several chronic comorbidities and the need to take a large number of replacement treatments require an individual therapeutic approach, as well as psychological and social adaptation of the patients, starting from their childhood and throughout the whole life, taking into account the frequent psychological problems could lead to low treatment adherence. The timely diagnostics of the disease, understanding of pathophysiology and specifics of its course could contribute to increased qualityadjusted life years of APS-1 patients.

Autoimmune polyglandular syndrome (APS) type 2 is defined by the manifestation of at least two autoimmune endocrine diseases. Only few data exist on genetic associations of APS type 2. In this controlled study, 98 patients with APS type 2, 96 patients with type 1 diabetes (T1D), and 92 patients with autoimmune thyroid disease, both as a single autoimmune endocrinopathy, were tested for association with alleles of the human leukocyte antigen (HLA) class II loci DRB1, DQA1, and DQB1. Patients with APS type 2 had significantly more often the alleles DRB1*03 (P(c) < 0.0001), DRB1*04 (P(c) < 0.000005), DQA1*03 (P(c) < 0.0001), and DQB1*02 (P(c) < 0.05), when compared with controls. Less frequent in APS were DRB1*15 (P(c) < 0.05), DQA1*01 (P(c) < 0.0005), and DQB1*05 (P(c) < 0.005). With regard to frequency and linkage of these alleles, the susceptible haplotypes DRB1*0301-DQA1*0501-DQB1*0201 and DRB1*0401/04-DQA1*0301-DQB1*0302 were deduced. Protective haplotypes in this study were DRB1*1501-DQA1*0102-DQB1*0602 and DRB1*0101-DQA1*0101-DQB1*0501. Comparing APS patients with vs without AD, no significant differences regarding HLA class II alleles were noted in our collective. Patients with T1D as a singular disease had the same susceptible and protective HLA alleles and haplotypes. The prevalence of DRB1*03 and DRB1*04 in APS patients was not because of the presence of diabetes, as the APS type 2 patients without diabetes had the same allele distribution. In conclusion, these data suggest a common immunogenetic pathomechanism for T1D and APS type 2, which might be different from the immunogenetic pathomechanism of other autoimmune endocrine disease.

This article presents a review and a case report of autoimmune polyglandular syndrome type 1 (APS-1) in a child with autoimmune hepatitis (AIH) as a first clinical manifestation. The duration of the disease was 9 years. The first signs of hepatitis (jaundice, hepatosplenomegaly, impaired pigment metabolism, cytolysis) with a high degree of activity and a morphological picture of monolobular liver cirrhosis with stromal and parenchymal activity were noted at the age of 2.5 years. The child received therapy with prednisolone. After one year, symptoms not typical of AIH were noted: salting food, candidiasis of the nail plates on hands and feet. Upon repeated examination, the diagnosis of APS-1 (hypoparathyroidism, candidiasis, autoimmune thyroiditis, chronic adrenal insufficiency, autoimmune hepatitis) was confirmed genetically – the homozygous R257X mutation was detected. The therapy was corrected: fludrocortisone and diflucan were added, therapy was continued with gradual transition to a maintenance dose of prednisolone. This case report demonstrates the difficulty of early APS-1 diagnosis, resulting in late initiation of baseline therapy, which can determine the prognosis of the disease. Key words: children, autoimmune polyglandular syndrome, autoimmune hepatitis

BACKGROUND. Clinical course of coronavirus disease (COVID-19) in patients infected by SARS-CoV-2 varies from the absolute absence of symptoms to the extremely severe viral pneumonias with the development of acute respiratory distress syndrome. In this context, investigation of the peculiarities of disease course in dependence of viral load (VL) is very interesting. OBJECTIVE. The aim of this paper is to analyze the results of novel clinical studies, dedicated to VL estimation in different biological specimens and its correlation with the severity of COVID-19 clinical course. RESULTS AND DISCUSSION. During the first months of 2020 there were published some scientific studies, which analyzed the association between VL and the severity of COVID-19 clinical course. It was established that VL was high at the beginning of the disease; in the sputum its value was higher than in throat and nasal swabs. In comparison to the mild course of COVID-19, severe course is characterized by higher VL and longer release of the virus into the environment. Apart from that, high VL is associated with the significant increase of proinflammatory cytokines’ levels, risk of disease progress and unfavorable prognosis. CONCLUSIONS. VL can be considered a risk factor and the predictor of severe course of COVID-19. Measures, aimed at the effective decrease of VL on each stage of the disease, and the improvement of antiepidemic control must help to optimize the treatment and prevent the spread of infection.