Here we have described a 60-year-old male patient with new-onset T1D and primary adrenal insufficiency, both of which were associated with high titers of disease-specific autoantibodies, and jointly manifested with an abrupt and robust onset three weeks following PCR test positivity for COVID-19. The course of COVID-19 in the patient was mild without pulmonary involvement or laboratory signs of severe disease. Our patient also had hypothyroidism due to autoimmune thyroiditis, which he may probably have for several years since we have discovered a former test result compatible with primary hypothyroidism; however, prior laboratory data up on the thyroid autoantibodies were unavailable. To the best of our knowledge, this is the first reported case of new-onset autoimmune T1D and new-onset autoimmune adrenal insufficiency (Addison’s disease) co-occurring in an individual patient with COVID-19.
New-onset diabetes has been reported in an increasing number of cases with COVID-19 [8–17], however, it is unclear whether there is a true link between COVID-19 and new-onset T1D. Although various cohorts reported increased number of children presenting with diabetic ketoacidosis (DKA) during the pandemic [18–21], it may reflect patients attempting to delay hospital admission due to their fear of being infected with SARS-CoV-2, since the rate of new-onset T1D was not far from that estimated . As to the adult population, the prevalence of new-onset T1D was reported to be 9.8% among a small cohort of adolescents and young adults with confirmed or suspected COVID-19 . In fact, the type of new-onset diabetes in the course of COVID-19 has usually been determined based on parameters such as patient age, absence or presence of risk factors for T2D such as obesity, prediabetes, family history, etc. Autoantibodies were not always examined despite the presence of DKA [11, 12, 14–16]. GAD-65, islet cell, and insulin antibodies, on the other hand, were all negative in certain patients with COVID-19 presenting with DKA [13, 17]. Exceptionally, even though our case did not present with DKA, he had remarkably high titers of GAD-65 antibodies at the time of diabetes diagnosis, and despite having certain risk factors for T2D such as older age and a strong family history, he was diagnosed with T1D. A case similar to ours, but involving a younger patient (29-year-old woman) who had previously undergone bariatric surgery, was reported. Four weeks after testing positive for COVID-19, the patient had new-onset diabetes without ketoacidosis, and GAD-65 antibody was positive. Both type 1 and type 2 diabetes were present in the family history, yet no additional autoimmune disorders were mentioned in the patient . In another case of 32-year-old male presenting with COVID-19 pneumonia and DKA, GAD and zinc transporter 8 antibodies were both positive, although no further information on family history or metabolic risk factors was provided .
SARS-CoV-2 infects humans by binding to the cellular Angiotensin-converting enzyme 2 (ACE2) receptor . ACE2 expression has been found in a wide range of human tissues, including the pancreas . According to autopsy studies, SARS-CoV-2 can infect and damage pancreatic beta cells [26–28], which could be one, but not the only, underlying cause of development of DKA as well as new-onset diabetes in patients with COVID-19. Proinflammatory state causing insulin resistance, and decreased insulin delivery to tissues as a result of endothelial dysfunction could be counted among the probable links between COVID-19 and diabetes, as well as triggered autoimmunity [29, 30]. It is well-known that several viruses, including cytomegalovirus, Epstein-Barr virus, rotavirus and especially coxsackievirus, have been implicated in the autoimmune processes that lead to T1D [31–34]. Molecular mimicry between viral and human proteins, immunologic cross-reactivity with autoantigens, and bystander activation of autoreactive T cells are among proposed mechanisms for the role of viruses in the pathogenesis of T1D . In combination with immune system hyperstimulation, SARS-CoV-2 appears be capable of triggering autoimmunity in subjects who are prone to autoimmune disorders by utilizing similar processes . For example, one might speculate that release of self-antigens as a consequence of SARS-CoV-2-induced beta cell damage, and presentation of these antigens to pre-existing autoreactive T cells might accelerate T1D onset, as this is considered as one of the possible mechanisms by which viruses trigger T1D in susceptible individuals . For the time being, the data from studies looking into the relationship between COVID-19 and diabetes are insufficient to shed light on the role of autoimmunity.
Primary adrenal insufficiency in patients infected with SARS-CoV-2 has been reported less frequently, all of which (n=6 confirmed cases) were associated with hemorrhagic or non-hemorrhagic infarction of adrenal glands . In fact, autopsy studies [38, 39] and a retrospective analysis of computed tomography examinations in severe COVID-19 patients  revealed that inflammatory and/or hemorrhagic changes in the adrenal glands are not uncommon in patients with severe COVID-19. These findings are consistent with the thrombo-inflammatory nature of COVID-19. While no other cases of COVID-19 related Addison’s disease have been reported to date, two reported cases of COVID-19 associated bilateral adrenal hemorrhage were diagnosed with primary antiphospholipid syndrome, one of whom had an additional autoimmune disease (autoimmune hepatitis) [37, 41]. However, both patients with COVID-19 associated bilateral adrenal hemorrhage appeared to have undiagnosed antiphospholipid syndrome prior to COVID-19 [37, 41]. The normal appearing adrenal glands, positive antibodies to the adrenal cortex, and co-existence of T1D and autoimmune thyroiditis in our patient, in whom SARS-CoV-2 infection was the most likely precipitating factor for the occurrence of acute adrenal crisis, suggest that he might possibly have previously undiagnosed APS II. However, while the most common presentation of APS II is as adrenal insufficiency and T1D , hypothyroidism was the first manifestation of the syndrome in our patient. Besides, it is not common for adrenal insufficiency to emerge in 6th decade of life in patients with APS II . Furthermore, although development of adrenal insufficiency in Addison’s disease is usually gradual , our patient had no prior symptoms or laboratory records in support of progressing adrenal insufficiency such as progressive fatigue or electrolyte abnormalities. In addition, because he was not being treated for his hypothyroidism, if he had a gradual disease course, one can expect that symptoms of adrenal insufficiency to be more evident, and he would have been diagnosed earlier. Also, very high levels of both GAD-65 antibody and antibodies to the adrenal cortex might imply that both T1D and Addison’s disease in our case have an acute onset.
COVID-19 related APS II has never been reported in the literature to date. However, there have been reports of patients in whom APS II was precipitated by EBV  and Influenza  infections. The presentation of the latter patient was quite similar to ours: adrenal crisis was induced by Influenza infection in a 57-year-old female patient with known autoimmune thyroiditis; however, unlike our patient, some symptoms and findings of adrenal insufficiency had gradually developed over the previous year . Because the autoantibody status of our case was unknown prior to COVID-19, and we did not screen for human leukocyte antigen (HLA) haplotypes that confer the risk of having multiple autoimmune disorders , it was impossible to make a definitive judgment whether the patient had unrecognized APS II or not. Nevertheless, SARS-CoV-2 infection appears to be the triggering factor that accelerated, if not initiated, the occurrence of T1D and Addison’s disease in our patient.