Newly diagnosed autoimmune Addison's disease in a patient with COVID-19 with autoimmune disseminated encephalomyelitis.

A man in his 20s with a history of acute disseminated encephalomyelitis (ADEM) was brought into the emergency department (ED) after his family found him at home collapsed on the floor unresponsive with a blood glucose of 28 mg/dL at the field. In the ED, the patient was tachycardic, tachypnoeic and hypotensive, requiring pressors and intubation at 9 hours and 12 hours after arrival, respectively. Laboratory results revealed a positive COVID-19 test, serum sodium of 125 mmol/L and persistent hypoglycaemia. The patient was given a high dose of dexamethasone for COVID-19 treatment 1 hour before pressors were started. He was then continued on a stress dose of intravenous hydrocortisone with rapid clinical improvement leading to his extubation, and discontinuation of vasopressors and glucose on day 2 of admission. The patient received his last dose of intravenous hydrocortisone on day 4 in the early afternoon with the plan to order adrenal testing the following morning prior to discharge. On day 5, the aldosterone <3.0 ng/dL, adrenocorticotropic hormone (ACTH) level >1250 pg/mL, and ACTH stimulation test showed cortisol levels of 3 and 3 µg/dL at 30 and 60 min, respectively. The anti-21-hydroxylase antibody was positive. The patient was discharged on hydrocortisone and fludrocortisone. The patient's symptoms, elevated ACTH, low cortisol and presence of 21-hydroxylase antibodies are consistent with autoimmune Addison's disease. This is the first case reporting autoimmune Addison's disease in a patient with COVID-19 with a history of ADEM. The case highlights the importance of considering adrenal insufficiency as a diagnostic differential in haemodynamically unstable patients with COVID-19.

[Hypophysitis and reversible hypopituitarism developed after COVID-19 infection - a clinical case report].

AIM: To present a clinical case of reversible hypopituitarism due to hypophysitis developed after COVID-19 infection. MATERIALS AND METHODS: A patient with residual clinical manifestations of hypopituitarism underwent clinical evaluation at the time of symptoms of hypopituitarism and in follow-up. Morning serum cortisol (171-536 nmol/l) was measured by electrochemiluminescence immunoassay. Morning ACTH (7.2-63.3 pg/ml), prolactin (66-436 mU/l), TSH (0.25-3.5 mIU/L), fT4 (9-19 pmol/l) and fT3 (2.6-5.7 pmol/l) were measured by chemiluminescence immunoassay. Data were analyzed throughout the course of the disease. RESULTS: A 35-year-old female developed clinical symptoms of hypopituitarism two months after recovery from a confirmed COVID-19 infection. Laboratory investigation confirmed hypocorticism, hypothyroidism, hypogonadism and the patient was prescribed appropriate hormonal therapy in January 2021. Four months later the symptoms were alleviated (April 2021) and there were signs of recovery shown by imaging and hormonal: morning serum cortisol 227 nmol/l, morning ACTH 33.96 pg/ml, prolactin 68.3 mU/l, TSH 2.626 mIU/L, fT4 10.75 pmol/l, fT3 3.96 pmol/l. Thyroid hormone was discontinued, but hypogonadism and hypocorticism persisted with estradiol - 51.48 pmol/l, 24h urine cortisol level - 41.8 nmol/day. MRI results showed that the signs of hypophysitis were alleviated in comparison with MRI from January 2021. Full recovery of pituitary axis was reported in October 2021, with recovery of normal menstrual cycle. Furthermore, hormonal profile was likewise normal. CONCLUSION: This report provides evidence of delayed damage to the pituitary gland after infection with the COVID-19, with recovery of its function and structure. To date, the mechanisms of such an impact are not entirely clear; further collection of data on such cases and analysis is required.

Coexistence of growth hormone, adrenocorticotropic hormone, and testosterone deficiency associated with coronavirus disease 2019: a case followed up for 15 months.

Coronavirus disease 2019 (COVID-19) is associated with endocrine disorders, but their long-term clinical course remains unclear. We here report the 15-month clinical course for an individual with multiple endocrine disorders of the pituitary gland and testis likely triggered by COVID-19. A 65-year-old man with no history of endocrinopathy was admitted for acute COVID-19 pneumonia. Although his respiratory condition improved after administration of antiviral drugs, his blood pressure dropped suddenly to a preshock level and was refractory to vasopressors. The circulating adrenocorticotropic hormone (ACTH) and cortisol concentrations were low, and secondary adrenal insufficiency was suspected. Administration of hydrocortisone rapidly ameliorated the hypotension, and the patient was discharged taking 15 mg of hydrocortisone daily. An insulin tolerance test performed 3 months later revealed impaired ACTH, cortisol, and growth hormone (GH) responses, indicative of combined hypopituitarism. The patient also manifested symptoms of hypogonadism, and a hormonal workup suggested primary hypogonadism. At 12 months after discharge, GH and ACTH responses had recovered completely and partially, respectively. After another 3 months, basal ACTH and cortisol levels had been restored to the normal range and the patient discontinued hydrocortisone replacement without exacerbation of symptoms, although his hypogonadism persisted. The patient thus developed transient GH and ACTH deficiency that lasted for more than a year as well as persistent primary hypogonadism during intensive care for COVID-19. Certain prolonged symptoms of COVID-19 might be accounted for by such hormonal disturbance.

Analysis of Adrenocorticotropic Hormone and Cortisol Levels in Acute Respiratory Distress Syndrome COVID-19 Patients.

Objective: SARS-CoV-2 infection may cause multiple organ failure. However, scarce information can be found on the impact on the endocrine system. This study was conducted to determine plasma Adrenocorticotropic hormone (ACTH) and plasma cortisol levels in a cohort of COVID-19 patients with Acute Respiratory Distress Syndrome (ARDS). Methods: A prospective cohort study was conducted on COVID-19 patients who manifested ARDS and were admitted to the ICU of Dr. Soetomo Tertiary Hospital, Surabaya, Indonesia. Morning plasma ACTH and plasma total cortisol were measured on 45 recruited patients. The outcome of the patient was justified based on the survivance on days 7th and 30th during the follow-up with groupings of surviving for survived patients and nonsurvive for deceased patients. Results: The ACTH and cortisol median were 1.06 (0.5-64.57) pg/mL and 17.61 (0.78-75) µg/dL, respectively. Both parameters were assembled to allow the allocation of the 45 subjects into the survive and nonsurvive groups. There was a moderate correlation between ACTH and cortisol levels in all groups (r = 0.46, p < 0.002) and particularly ACTH and cortisol levels in COVID-19 patients who survived on the 7th-day and 30th-day follow-up (r = 0.518 and r = 0.568, respectively, with p < 0.05). It is important to note that there was no correlation for an individual parameter, either ACTH only or cortisol only, compared to the outcome among patients with various comorbid. Conclusion: ACTH or cortisol alone has no correlation to the outcome of these patients. Therefore, further study of the potential use of corticosteroid treatments guided by ACTH and cortisol levels in reducing the risk of ARDS warrants further investigation.

Isolated ACTH deficiency following immunization with the BNT162b2 SARS-CoV-2 vaccine: a case report.

BACKGROUND: The global COVID-19 pandemic requires urgent development of new vaccines. Endocrinological adverse effects following the new mRNA vaccine against COVID-19 have been reported in several cases. Specific to the involvement of pituitary function; however, only a single case with hypophysis has been reported. This is the first case of isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) following mRNA vaccination against COVID-19. CASE PRESENTATION: A healthy 31-year-old man received the BNT162b2 SARS-CoV-2 mRNA vaccine. The first injection was uneventful. One day after the second injection, he noticed general fatigue and fever. In the following several days, he additionally developed headaches, nausea, and diarrhea. Four days after the vaccine injection, he visited a hospital with worsening of these symptoms. Physical examination revealed slight disorientation but no other deficits. Laboratory tests revealed hyponatremia, hypoglycemia, and extremely low plasma ACTH and serum cortisol levels (ACTH < 1.5 pg/ml, cortisol 1.6 µg/dl). He was diagnosed with adrenal crisis and was emergently treated with hydrocortisone. The symptoms responded well and he recovered within a few days. Magnetic resonance images after the replacement with hydrocortisone revealed an atrophic pituitary gland. The patient was referred to our tertiary hospital for further endocrinological examination. Pituitary endocrine load tests revealed isolated adrenocortical response deficiency. After other clinical assessments, he was diagnosed as having isolated ACTH deficiency. After initiation of hydrocortisone replacement, there has been no recurrence of symptoms related to adrenocortical insufficiency nor involvement of other pituitary functions. CONCLUSION: This is the first reported case of IAD potentially associated with COVID-19 immunization. Recent reports have emphasized the importance of adjuvants in the mRNA vaccine that induce the endocrinological adverse effects through disturbance of the autoimmune system, but details are still unclear. Given the broad and rapid spread of vaccinations against COVID-19, it is clinically important to consider that there could be cases with a rare but emergent adrenal crisis even among those who present common symptoms of adverse effects following inactive SARS-CoV-2 mRNA vaccination.

Successful Immunomodulatory Treatment of COVID-19 in a Patient With Severe ACTH-Dependent Cushing's Syndrome: A Case Report and Review of Literature.

Introduction: Patients with Cushing's syndrome (CS) represent a highly sensitive group during corona virus disease 2019 (COVID-19) pandemic. The effect of multiple comorbidities and immune system supression make the clinical picture complicated and treatment challenging. Case report: A 70-year-old female was admitted to a covid hospital with a severe form of COVID-19 pneumonia that required oxygen supplementation. Prior to her admission to the hospital she was diagnosed with adrenocorticotropic hormone (ACTH)-dependent CS, and the treatment of hypercortisolism had not been started yet. Since the patient's condition was quickly deteriorating, and with presumend immmune system supression due to CS, we decided on treatement with intraveonus immunoglobulins (IVIg) that enabled quick onset of immunomodulatory effect. All comorbidities were treated with standard of care. The patient's condition quickly stabilized with no direct side effects of a given treatment. Conclusion: Treatment of COVID-19 in patients with CS faces many challenges due to the complexity of comorbidity effects, immunosupression and potential interactions of available medications both for treatment of COVID-19 and CS. So far, there are no guidelines for treatment of COVID-19 in patients with active CS. It is our opinion that immunomodulating therapies like IVIg might be an effective and safe treatment modality in this particularly fragile group of patients.

Neuroleptic Malignant Syndrome with Adrenal Insufficiency After BNT162b2 COVID-19 Vaccination in a Man Taking Valproate: A Case Report.

BACKGROUND Considering the ongoing coronavirus disease 2019 (COVID-19) pandemic, sufficient information about common and serious adverse events is needed to rapidly distribute COVID-19 vaccines worldwide. We report a case of neuroleptic malignant syndrome (NMS) with adrenal insufficiency after initial vaccination with Pfizer/BioNTech BNT162b2. CASE REPORT A 48-year-old man presented to the Emergency Department with fever and an altered mental status 7 days after receiving the first dose of the BNT162b2 COVID-19 vaccine. The patient had a history of end-stage renal disease and epilepsy treated with valproate. He was diagnosed with NMS based on the clinical findings of hyperthermia, muscular rigidity, and an elevated creatine kinase level. Additionally, a reduction in the response of cortisol to adrenocorticotropic hormone (ACTH) stimulation was observed in the rapid ACTH stimulation test. The patient was treated with dantrolene, bromocriptine, and hydrocortisone, and he responded well to treatment. Dantrolene and bromocriptine were tapered off over 4 weeks. Hydrocortisone was also tapered, and the patient was discharged on oral hydrocortisone (30 mg). CONCLUSIONS The present case suggests a possible link between the BNT162b2 COVID-19 vaccine and NMS with adrenal insufficiency based on the temporal relationship between vaccine administration and disease onset, although the patient was taking valproate, a potential cause of NMS. Having a high level of suspicion is important because the diagnosis of NMS with adrenal insufficiency is often challenging due to non-specific clinical manifestations. However, this case does not negate the utility of vaccination because these complications are extremely rare and can be treated with early diagnosis and proper management.

Assessment of Neuroendocrine Changes and Hypothalamo-Pituitary Autoimmunity in Patients with COVID-19.

SARS-CoV-2 may affect the hypothalamic-pituitary axis and pituitary dysfunction may occur. Therefore, we investigated neuroendocrine changes, in particular, secondary adrenal insufficiency, using a dynamic test and the role of autoimmunity in pituitary dysfunction in patients with COVID-19. The single-center, prospective, case-control study included patients with polymerase chain reaction (PCR)-confirmed COVID-19 and healthy controls. Basal hormone levels were measured, and the adrenocorticotropic hormone (ACTH) stimulation test was performed. Antipituitary (APA) and antihypothalamic antibodies (AHA) were also determined. We examined a total of 49 patients with COVID-19 and 28 healthy controls. The frequency of adrenal insufficiency in patients with COVID-19 was found as 8.2%. Patients with COVID-19 had lower free T3, IGF-1, and total testosterone levels, and higher cortisol and prolactin levels when compared with controls. We also demonstrated the presence of APA in three and AHA in one of four patients with adrenal insufficiency. In conclusion, COVID-19 may result in adrenal insufficiency, thus routine screening of adrenal functions in these patients is needed. Endocrine disturbances in COVID-19 are similar to those seen in acute stressful conditions or infections. Pituitary or hypothalamic autoimmunity may play a role in neuroendocrine abnormalities in COVID-19.

Results from a multicenter, randomized, double-blind, placebo-controlled study of repository corticotropin injection for multiple sclerosis relapse that did not adequately respond to corticosteroids.

INTRODUCTION: About 20%-35% of multiple sclerosis (MS) patients fail to respond to high-dose corticosteroids during a relapse. Repository corticotropin injection (RCI, Acthar® Gel) is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and pituitary peptides that has anti-inflammatory and immunomodulatory effects. AIMS: The study objective was to determine the efficacy and safety of RCI in patients with MS relapse that inadequately responded to corticosteroids. This was a multicenter, double-blind, placebo-controlled study. Nonresponders to high-dose corticosteroids were randomized to receive RCI (80 U) or placebo daily for 14 days. Assessments included improvements on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Impact Scale (MSIS-29), Clinical Global Impression of Improvement (CGI-I), and adverse events (AEs). RESULTS: Eighteen patients received RCI, and 17 received placebo. A greater proportion of EDSS responders was observed in the RCI group at Day 7, 21, and 42 compared with the placebo group. Qualitative CGI-I showed that more patients receiving RCI were much improved or very much improved than with placebo. No meaningful differences were observed between treatment groups for MSIS-29. No serious AEs or deaths were reported. CONCLUSION: RCI is safe and effective for MS relapse patients who do not respond to high-dose corticosteroids.

Investigation of pituitary functions after acute coronavirus disease 2019.

Although coronavirus disease 2019 (COVID-19) mainly involves the lungs, it also affects many systems. The hypothalamic/pituitary axis is vulnerable to hypoxia, hypercoagulation, endothelial dysfunction and autoimmune changes induced by COVID-19 infection. Given that there is no extensive investigation on this issue, we investigated the pituitary functions three to seven months after acute COVID-19 infection. Forty-three patients after diagnosis of COVID-19 infection and 11 healthy volunteers were included in the study. In addition to the basal pituitary hormone levels, growth hormone (GH) and hypothalamo-pituitary adrenal (HPA) axes were evaluated by glucagon stimulation test (GST) and low-dose adrenocorticotropic hormone (ACTH) stimulation test, respectively. The peak cortisol responses to low-dose ACTH test were insufficient in seven (16.2%) patients. Twenty (46.5%) and four (9.3%) patients had inadequate GH and cortisol responses to GST, respectively. Serum insulin-like growth factor-1 (IGF-1) values were also lower than age and sex-matched references in four (9.3%) patients. The peak GH responses to GST were lower in the patient group when compared to the control group. Other abnormalities were mild thyroid-stimulating hormone elevation in four (9.3%) patients, mild prolactin elevation in two (4.6%) patients and central hypogonadism in four (9.3%) patients. Mean total testosterone values were lower in male patients when compared to male controls; however, the difference was not significant. These findings suggest that COVID-19 infection may affect pituitary functions, particularly the HPA and GH axes. These insufficiencies should be kept in mind in post-COVID follow-up. Long-term data are needed to determine whether these deficiencies are permanent or not.

[Clinical and laboratory characteristics and results of treatment of patients with ACTH-producing neuroendocrine tumors of various localization].

AIM: To study the clinical, biochemical characteristics, treatment results and follow-up of patients with ectopic ACTH syndrome EAS (ACTH adrenocorticotropic hormone ). MATERIALS AND METHODS: A retrospective, observational, single-center study of 130 patients with EAS. Demographic information of patients, medical history, results of laboratory and instrumental investigations at the pre- and postoperative stages and follow-up of EAS were analyzed. RESULTS: The mean age at the diagnosis ranged from 12 to 74 years (Me 40 years [28; 54]). The duration of the disease from the onset of symptoms to the verification of the diagnosis varied from 2 to 168 months (Me 17.5 months [7; 46]). Eighty-one (62,3%) patients had bronchopulmonary NET, 9 thymic carcinoid, 7 pancreatic NET, 5 pheochromocytoma, 1 cecum NET, 1 appendix carcinoid tumor, 1 medullary thyroid cancer and 25 (19.2%) had an occult source of ACTH. The median follow-up period of patients was 27 months [9.75; 61.0] with a maximum follow-up of 372 months. Currently, primary tumor was removed in 82 (63.1%) patients, bilateral adrenalectomy was performed in 23 (18%) patients, in 16 of them there was an occult source of ACTH-producing NET and in 7 patients in order to control hypercortisolism after non-successful surgical treatment. Regional and distant metastases were revealed in 25 (19.2%) patients. At the time of the last observation 59 (72%) patients were exhibited a full recovery, 12 (14.6%) had relapse of the disease and 26 (20%) died from multiple organ failure (n=18), pulmonary embolism (n=4), surgical complications (n=2), disseminated intravascular coagulation syndrome (n=1) or COVID-19 (n=1). CONCLUSION: In our cohort of patients bronchopulmonary NET are the most frequent cause of EAS (62.3%). Surgical treatment leads to remission of hypercortisolism in 72% cases; the proportion of relapse (14.6%) and fatal outcome (20%) remains frequent in EAS.

Cushing's syndrome due to adrenocorticotropic hormone-secreting metastatic neuroendocrine tumor of unknown primary origin: a case report and literature review.

BACKGROUND: In this article, we present a case of neuroendocrine neoplasm of unknown primary origin (UPO NEN), which is a rare cause of ectopic Cushing's syndrome (ECS) presenting numerous challenges, together with a literature review. CASE REPORT: A 43-year-old male patient presented with clinical features consistent with Cushing's syndrome (CS) and adrenocorticotropic hormone (ACTH)-dependent hypercortisolemia. Despite a suspicious lesion on pituitary MRI, the high-dose dexamethasone suppression test and bilateral inferior petrosal sinus sampling results were not compatible with Cushing's disease. Bilateral non-homogeneous opacities were observed in the thorax CT of the patient, who also had a history of COVID-19 infection, but no tumoral lesion was detected. When 68Ga-SSTR PET/CT and 18FDG-PET/CT were performed, multiple metastatic foci were detected in mediastinal and hilar lymph nodes and the axial skeleton. Paratracheal-subcarinal lymph nodes were excised mediastinoscopically, and the diagnosis of NEN was made. Histopathological findings indicated that the possible origin was an atypical pulmonary carcinoid with a low Ki-67 labeling index. After controlling hypercortisolemia, a regimen of somatostatin analogs and capecitabine plus temozolomide was decided upon as treatment by a multidisciplinary council. CONCLUSION: This is a challenging case of UPO NEN presenting with ECS and confounding factors, such as previous infection and incidental lesions, during the diagnosis process. The case in question highlighted the fact that atypical pulmonary carcinoid with a low proliferation index may cause visible metastases even when radiologically undetectable.

Clinical course and outcome of patients with ACTH-dependent Cushing's syndrome infected with novel coronavirus disease-19 (COVID-19): case presentations.

OBJECTIVE: To analyze the clinical presentations of patients with endogenous Cushing's syndrome (CS) affected by Coronavirus disease-19 (COVID-19). MATERIALS AND METHODS: Patients who were referred to our clinic with active CS from 31st March to 15th May 2020 were screened for COVID-19 using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Late-night serum cortisol (64-327 nmol/L), late-night salivary cortisol (LNSC) (0.5-9.4 nmol/L), or 24-h urinary free cortisol (24 hUFC) (100-379 nmol/24 h) were measured by electrochemiluminescence immunoassay. RESULTS: Among 22 patients with active CS we found three cases affected by COVID-19. Nonspecific inflammation markers were within the reference range or slightly elevated in these patients. A 71-year-old woman with newly diagnosed CS (late-night serum cortisol >1750 nmol/L, LNSC 908.6 nmol/L) developed dyspnea as an only symptom and died from bilateral polysegmantal hemorrhagic pneumonia 7 days later. A 38-year-old woman with a 5-year medical history of active Cushing's disease (CD) (late-night serum cortisol 581.3 nmol/L, 24 hUFC 959.7 nmol/24-h) suffered from dyspnea, cough, fever (39.3 °C) and chest pain. Oxygen therapy, antibiotics and symptomatic treatments lead to full recovery 24 days later. A 66-year-old woman with a 4-year medical history of mild CD (late-night serum cortisol 603.4 nmol/L, LNSC 10.03 nmol/L) tested positive for COVID-19 in routine screening and remained asymptomatic. CONCLUSIONS: The outcome of COVID-19 in patients with CS depends on the severity of hypercortisolism. Thus, severe hypercortisolism is a warning sign that CS affected by COVID-19 could require emergency care despite a lack of clinical presentations and low inflammation biomarkers.

The Impact of COVID-19 Viral Infection on the Hypothalamic-Pituitary-Adrenal Axis.

OBJECTIVE: To study the adrenocortical response to an acute coronavirus disease-2019 (COVID-19) infection. METHODS: Morning plasma cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate levels were measured in 28 consecutive patients with COVID-19 (16 men, 12 women, median age 45.5 years, range 25-69 years) on day 1 to 2 of hospital admission. These tests were repeated twice in 20 patients and thrice in 15 patients on different days. The hormone levels were correlated with severity of the disease. RESULTS: The median morning cortisol level was 196 (31-587) nmol/L. It was <100 nmol/L in 8 patients (28.6%), <200 nmol/L in 14 patients (50%), and <300 nmol/L in 18 patients (64.3%). The corresponding ACTH values had a median of 18.5 ng/L (range 4-38 ng/L), and the ACTH level was <10 ng/L in 7 patients (26.9%), <20 ng/L in 17 patients (60.7%), and <30 ng/L in 23 patients (82.1%). The repeated testing on different days showed a similar pattern. Overall, if a cutoff level of <300 nmol/L is considered abnormal in the setting of acute disease, 9 patients (32%) had cortisol levels below this limit, regardless of whether the test was done only once (3 patients) or 3 times (6 patients). When the disease was more severe, the patients had lower cortisol and ACTH levels, suggesting a direct link between the COVID-19 infection and impaired glucocorticoid response. CONCLUSION: Unexpectedly, the adrenocortical response in patients with COVID-19 infection was impaired, and a significant percentage of the patients had plasma cortisol and ACTH levels consistent with central adrenal insufficiency.

Management of West syndrome during COVID-19 pandemic: A viewpoint from South Asian West Syndrome Research Group.

In the wake of the pandemic COVID-19 and nationwide lockdowns gripping many countries globally, the national healthcare systems are either overwhelmed or preparing to combat this pandemic. Despite all the containment measures in place, experts opine that this novel coronavirus is here to stay as a pandemic or an endemic. Hence, it is apt to be prepared for the confrontation and its aftermath. From protecting the vulnerable individuals to providing quality care for all health conditions and maintaining essential drug supplies, it is going to be a grueling voyage. Preparedness to sustain optimal care for each health condition is a must. With a higher risk for severe COVID-19 disease in infants, need of high-dose hormonal therapy with a concern of consequent severe disease, presence of comorbidities, and a need for frequent investigations and follow-up; children with West syndrome constitute a distinctive group with special concerns. In this viewpoint, we discuss the important issues and concerns related to the management of West syndrome during COVID-19 pandemic in the South Asian context and provide potential solutions to these concerns based on the current evidence, adeptness, and consensus. Some plausible solutions include the continuation of containment and mitigation measures for COVID-19, therapeutic decision- making for West syndrome based on risk stratification, and tele-epileptology.