The existence of adrenal insufficiency in patients with COVID-19 pneumonia.

Introduction: Infection with SARS-CoV-2 virus may result in long COVID, a syndrome characterized by symptoms such as dyspnea, cardiac abnormalities, cognitive impairment, and fatigue. One potential explanation for these symptoms is hypocortisolism. Objective: To evaluate the prevalence of hypocortisolism in patients with a history of COVID-19 pneumonia. Methods: Cross-sectional study of patients who were aged ≥18 years and had a 3-month history of radiography-confirmed COVID-19 pneumonia. Exclusion criteria included current or previous treatment with glucocorticoids and use of an oral contraceptive. Adrenal function was evaluated using a low dose (1ug) corticotropin stimulation test (CST). Serum cortisol levels were measured at 0, 30, and 60 minutes, and baseline plasma ACTH was also measured. Results: Of the 41 patients enrolled, the median age was 62 years, 17 (42%) were female, and all 41 (100%) had severe pneumonia at baseline. Eleven patients (27%) had hypocortisolism, as evidenced by peak cortisol of less than 402.81 nmol/l after low dose (1 µg) CST. Of these 11 patients, 10 (91%) had secondary hypocortisolism (median ACTH 6.27 pmol/L, range 4.98-9.95 pmol/L) and one had primary hypocortisolism (mean ACTH 32.78 pmol/L). Six of the 11 patients with hypocortisolism (54.5%) reported symptoms of persistent fatigue and 5 (45.5%) required regular glucocorticoid replacement. Conclusions: Our results suggest that hypocortisolism, predominantly caused by pituitary disruption, may emerge after SARS-CoV-2 infection and should be considered in patients with a history of COVID-19 pneumonia with or without clinical hypocortisolism.

The immunogenicity of the ChAdOx1 nCoV-19 vaccination in participants with underlying comorbidity diseases: A prospective cohort study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) increases mortality rates in older adults and those with comorbidities. Individuals with certain comorbidities may have a poor immune response and require early booster vaccines. We aimed to assess the immune response after two doses of ChAdOx1 nCoV-19 vaccine, at 84-day intervals, in participants with the following comorbidities; diabetes mellitus; obesity; cardiovascular disease; chronic kidney disease; rheumatological disease; cirrhosis; hematological disease; hematological malignancy; or solid malignancy. The study was conducted at Chulabhorn Hospital in Thailand, with healthy healthcare workers serving as the control group. Of the 769 participants, 352 were in the healthy cohort and 417 were in the comorbidity cohort, all received at least one dose of vaccine. Anti-RBD total antibody levels were evaluated on Day 0, Day 84, and Day 112. The results at Day 112 (4 weeks after the second dose) showed that individuals with comorbidities had a poor immune response compared to healthy individuals, especially those with hematological malignancy and solid malignancy. The geometric mean concentration (GMC) of anti-RBD antibody in the comorbidity cohort was significantly lower than that in the healthy cohort: 433.66 BAU/ml (95% CI 334.62-562.01) versus 1096.14 BAU/ml (95% CI 1010.26-1189.33), respectively. The geometric mean ratio (GMR) between the two cohorts was 0.40 (95% CI 0.30-0.52, p < .001). This study concluded that individuals with comorbidities, particularly hematological and solid malignancies, had poor immune responses and may require an early booster vaccine to prevent infection and death.

Dynamics of anti-RBD (anti-receptor binding domain) levels in diabetes patients following the ChAdOx1 nCoV-19 vaccine (AZD1222) in the Thai population.

The ChAdOx1 nCoV-19 vaccine (AZD1222) was used in Thailand during the early outbreak of coronavirus disease 2019 (COVID-19). A previous study showed a low immune response in diabetes patients after the first dose of the AZD1222 vaccine. Furthermore, humoral immune responses after the second vaccination were inconsistent. This study evaluated the immunogenicity following the first and second doses of the AZD1222 vaccine in people with type 2 diabetes (T2D) compared with the general population of Thailand. This was a prospective, single-center cohort study. 59 adults with T2D and 118 age- and sex-matched healthcare personnel were eligible. The participants received two doses of AZD1222 12 weeks apart. Antibodies against the receptor-binding domain (anti-RBD) of the SARS-CoV-2 spike protein, using an automated electrochemiluminesence immunoassay (ECLIA), were measured at baseline, 8 and 12 weeks after the first dose of vaccine, and 4 weeks after the second dose of vaccine. The anti-RBD levels were reported as the geometric mean concentration (GMC) and compared between groups using the geometric mean ratio (GMR). A total of 177 participants were included: The average age of 59 T2D patients was 60.1 years (SD: 11.4), and 31 (52.5%) of them were female. The GMC of anti-RBD 8 and 12 weeks after the first vaccination were significantly lower in T2D (week 8 60; 17.05 BAU/mL, 95% confidence interval [CI] 11.1-26.19, P = 0.035, week 12; 24.68 BAU/mL, 95% CI 16.4-37.0, P = 0.002) than in those without diabetes (week 8; 29.79 BAU/mL, 95% CI 22.07-40.42, week 12; 50.67 BAU/mL, 95% CI 40.62-63.20). However, there was no difference in the GMC of anti-RBD 4 weeks after the second vaccination among groups (T2D; 687.95 BAU/mL, 95% CI 462.7-1022.7, Normal; 697.95 BAU/mL, 95% CI 583.7-834.5, P = 0.947). In both groups, the GMC of anti-RBD was persistently high without decline 12 weeks after the first vaccination. Albuminuria was a major factor related to low humoral immune responses in T2D patients after the second dose of AZD122 vaccine (the GMR was 0.29, 95% CI 0.08-0.98, P = 0.047) whereas the HbA1C level and age were not. Immunogenicity in T2D cases was lower than in the normal population after the first dose of the AZD1222 vaccine. The two doses of AZD122 vaccine induced immunity in T2D equal to that of normal individuals in Thailand. People with diabetes should be boosted as soon as possible to induce adequate immunity to prevent COVID-19 infection.

Gaps in the Care of Subjects with Familial Hypercholesterolemia: Insights from the Thai Familial Hypercholesterolemia Registry.

AIMS: Familial hypercholesterolemia (FH) is currently underdiagnosed and undertreated. The establishment of a FH registry could facilitate a deeper understanding of this disease. We described the clinical characteristics of subjects with FH from the Thai FH Registry, compared our data with the regional and global data, and identified gaps in the care of these subjects. METHODS: A multicenter, nationwide prospective FH registry was established in Thailand. Our data were compared with those of the European Atherosclerosis Society-FH Studies Collaboration. Multiple logistic regression analyses were performed for variables associated with lipid-lowering medication (LLM) use and the attainment of low-density lipoprotein-cholesterol (LDL-C) goal. RESULTS: The study includes 472 subjects with FH (mean age at FH diagnosis: 46±12 years, 61.4% women). A history of premature coronary artery disease was found in 12%. The percentage of LLM use in subjects with a Dutch Lipid Clinic Network score of ≥ 6 (probable or definite FH) in our registry (64%) was slightly lower than the regional data but higher than the global data. Among those who received statins, 25.2% and 6.4% achieved LDL-C levels of ＜100 mg/dL and ＜70 mg/dL, respectively. Women with FH were less likely to achieve LDL-C ＜70 mg/dL (adjusted odds ratio: 0.22, 95% confidence interval: 0.06-0.71, p=0.012). CONCLUSIONS: FH in Thailand was diagnosed late, and treatment was inadequate for the majority of subjects. Women with FH were less likely to achieve LDL-C goals. Our insights could potentially help raise awareness and narrow the gap in patient care.

Immunogenicity and reactogenicity of heterologous prime-boost vaccination with inactivated COVID-19 and ChAdOx1 nCoV-19 (AZD1222) vaccines, a quasi-experimental study.

The global supply of COVID-19 vaccines has been limited, and concerns have arisen about vaccine supply chain disruptions in developing countries. Heterologous prime-boost vaccination, which involves using different vaccines for the first and second doses, has been proposed to enhance the immune response. We aimed to compare the immunogenicity and safety of a heterologous prime-boost vaccination using an inactivated COVID-19 vaccine and AZD1222 vaccine with that of a homologous vaccination using AZD1222. This pilot involved 164 healthy volunteers without prior SARS-CoV-2 infection aged 18 years or older assigned to receive either the heterologous or homologous vaccination. The results showed that the heterologous approach was safe and well-tolerated, although the reactogenicity of the heterologous approach was higher. At 4 weeks after receiving the booster dose, the heterologous approach elicited a non-inferior immune response compared to the homologous approach in neutralizing antibody and cell-mediated immune response. The percentage of inhibition was 83.88 (79.72-88.03) in the heterologous and 79.88 (75.50-84.25) in the homologous group, a mean difference of 4.60 (-1.67-10.88). The geometric mean of interferon-gamma was 1072.53 mIU/mL (799.29-1439.18) in the heterologous group and 867.67 mIU/mL (671.94-1120.40) in the homologous group, a GMR of 1.24 (0.82-1.85). However, the binding antibody test of the heterologous group was inferior to the homologous group. Our findings suggest that the use of heterologous prime-boost vaccination with different types of COVID-19 vaccines is a viable strategy, especially in settings where vaccine supply is limited or where vaccine distribution is challenging.

Immune Response to CoronaVac and Its Safety in Patients with Type 2 Diabetes Compared with Healthcare Workers.

BACKGROUND: Vaccines for SARS-CoV-2 have been critical for preventing disease. Previous research showed patients with diabetes have impaired immunity. This study aimed to determine the immunity to coronavirus after CoronaVac by comparing patients with type 2 diabetes (T2D) and healthcare workers (HCW). MATERIALS AND METHODS: A prospective cohort study evaluated immune responses and safety after two doses of CoronaVac in T2D and HCW groups at Chulabhorn Hospital. The levels of total antibodies against the receptor-binding domain (anti-RBD) of the SARS-CoV-2 spike protein at baseline and 4 weeks after vaccination were collected. The level of anti-RBD concentrations was reported as geometric mean concentration (GMC) and compared between groups using the geometric mean ratio (GMR). RESULTS: 81 participants were included; 27 had T2D and 54 were HCW. After complete vaccination, anti-RBD concentrations were not significantly different between T2D (57.68 binding antibody units (BAU)/mL, 95% confidence interval (CI) = 29.08; 114.44) and HCW (72.49 BAU/mL, 95% CI = 55.77; 94.22) groups. Subgroup analysis showed the GMC of anti-RBD was significantly lower in T2D patients with dyslipidaemia (50.04 BAU/mL) than in T2D patients without dyslipidaemia (341.64 BAU/mL). CONCLUSIONS: The immune response at 4 weeks after two doses of CoronaVac did not significantly differ between patients with T2D and HCW.

Reactogenicity, immunogenicity, and humoral immune response dynamics after the third dose of heterologous COVID-19 vaccines in participants fully vaccinated with inactivated vaccine.

INTRODUCTION: Immunogenicity after the CoronaVac vaccine remains uncertain, especially regarding infections with the coronavirus variants of concern and waning immunity. METHODS: This was a single-center, open-label clinical trial designed to assess the immunogenicity and safety of BBIBP-CorV, AZD1222, or BNT162b2 as the third vaccination. The key eligible criteria were individuals at least 18 years old who were fully vaccinated with two doses of CoronaVac vaccine for 2-4 months. The primary endpoint was the ratio of the geometric mean concentration (GMC) of the total anti-receptor binding domain (RBD) antibody post-vaccination compared with that pre-vaccination. The secondary endpoint was reactogenicity within 7 days. RESULTS: Forty-one participants received AZD1222, 40 received BBIBP-CorV, and 40 received BNT162b2. The GMC of anti-RBD antibody at 2 weeks post-vaccination was 31,138.67 binding antibody units (BAU)/mL for BNT162b2, 6,412.10 BAU/mL for AZD1222, and 1,092.7 BAU/mL for BBIBP-CorV. Compared with pre-vaccination, the ratio of anti-RBD concentration was 690.24 for BNT162b2, 130.02 for AZD1222, and 17.79 for BBIBP-CorV. No potentially life-threatening adverse reaction were observed within 7 days. CONCLUSION: A third vaccination with the heterologous vaccine, BBIBP-CorV, AZD1222, or BNT162b2, can elicit a robust immune response, without serious adverse events in participants fully vaccinated with the CoronaVac vaccine.

Desmopressin Stimulation Test in a Pregnant Patient with Cushing's Disease.

Objective: Hypothalamic-pituitary-adrenal axis stimulation during pregnancy complicates the investigation of Cushing's syndrome (CS). Our objective was to present the case of a pregnant patient with CS caused by a pituitary tumor in whom the desmopressin stimulation test helped in the diagnosis and led to appropriate management. Case Report: A 27-year-old woman with 9-week gestation presented with a 2-month history of proximal myopathy. She had high blood pressure, wide purplish striae, and a 1-year history of hypertension and dysglycemia. The 8 am cortisol level was 32.4 µg/dL (normal, 5-18 µg/dL), late-night salivary cortisol level was 0.7 µg/dL (11 pm, normal, <0.4 µg/dL), 24-hour urinary free cortisol levels were 237.6 µg/d (normal, 21.0-143.0 µg/d), and adrenocorticotropic hormone (ACTH) levels were 44.0 pg/mL (8 am, normal, 0-46.0 pg/mL). Nongadolinium-enhanced pituitary magnetic resonance imaging revealed no obvious lesion. The desmopressin stimulation test showed a 70% increase in ACTH levels from baseline after desmopressin administration. Pituitary magnetic resonance imaging with gadolinium revealed an 8 × 8 × 7-mm3 pituitary adenoma. Transsphenoidal surgery was performed, which revealed the presence of ACTH-positive tumor cells. After tumor removal, the patient carried on pregnancy uneventfully. Discussion: During pregnancy, ACTH levels may not be an accurate marker to help in the differential diagnosis of CS. Moreover, nongadolinium pituitary imaging might not detect small pituitary lesions. Conclusion: In the present case, the desmopressin stimulation test suggested the diagnosis of Cushing's disease, which subsequently led to successful treatment. This suggests that the desmopressin test serves as a useful test for diagnosing Cushing's disease in pregnant individuals.

Antibody levels in people with diabetes after one dose of the ChAdOx1 nCoV-19 (AZD1222) vaccine.

Patients with diabetes and coexistent coronavirus disease 2019 (COVID-19) have a higher risk of COVID-19 complications. Therefore, it is critical that sustained and effective immunogenicity against COVID-19 is achieved in such patients. This study evaluates the antibody response for 56 days after the first dose of the AZD1222 vaccine in subjects with and without diabetes to assess the potential risk of delaying the second dose. This study included 282 people who received one dose of AZD1222. The geometric mean concentration of antibodies specific for severe acute respiratory syndrome coronavirus 2 IgG at 56 days was significantly (P < 0.001) lower in people with type 2 diabetes mellitus (T2D; 15.13 BAU/mL, 95% confidence interval [CI] = 10.7-21.4) than in those without diabetes (40.20 BAU/mL, 95% CI = 33.43-48.36), as confirmed by a geometric mean ratio of 0.37 (95% CI = 0.25-0.54). Weaker immune responses were also observed in diabetic patients ≥ 65 years old (10.09 BAU/mL, 95% CI = 6.09-16.71) compared with their younger counterparts (22.31 BAU/mL, 95% CI = 13.98-35.59, P = 0.034). People with T2D had weaker antibody responses than those without diabetes after the first dose of AZD1222. Older age was associated with weaker antibody responses in elderly patients with diabetes.

Safety and Immunogenicity of the BBIBP-CorV Vaccine in Adolescents Aged 12 to 17 Years in the Thai Population: An Immunobridging Study.

Adolescents can develop a severe form of Coronavirus disease 2019 (COVID-19), especially with underlying comorbidities. No study has examined the efficacy or effectiveness of inactivated COVID-19 vaccines in adolescents. This single-center, prospective cohort study was performed to evaluate the safety and effectiveness of an inactivated COVID-19 vaccine in adolescents using the immunobridging approach at Chulabhorn Hospital. The key eligibility criterion was a healthy clinical condition or stable pre-existing comorbidity. The anti-receptor-binding domain (anti-RBD) antibody concentration at 4 weeks after dose 2 of the vaccine was compared between participants aged 12 to 17 years and those aged 18 to 30 years. Safety profiles included adverse events within 7 days after each dose of the vaccine and any adverse events through 1 month after dose 2 of the vaccine. In the adolescent and adult cohorts, the geometric mean concentration of anti-RBD antibody was 102.9 binding antibody unit (BAU)/mL (95% CI, 91.0−116.4) and 36.9 BAU/mL (95% CI, 30.9−44.0), respectively. The geometric mean ratio of the adolescent cohort was 2.79 (95% CI, 2.25−3.46, p < 0.0001) compared with the adult cohort, meeting the non-inferiority criterion. The reactogenicity was slightly lower in the adolescent than in the adult cohort. No serious adverse events occurred. The inactivated COVID-19 vaccine appears safe and effective in adolescents.

Persistence of immunogenicity, contributing factors of an immune response, and reactogenicities after a single dose of the ChAdOx1 (AZD1222) COVID-19 vaccine in the Thai population.

INTRODUCTION: Due to the vaccine's short supply and the efficacy of a single dose of the ChAdOx1 (AZD1222) vaccine, many governments delayed the interval between prime and boost dose from 4 to 8-12 weeks. However, the waning of immune response in this period is a concern. This study evaluated the durability, contributing factors of anti-RBD antibody concentration, and reactogenicities after the single dose of AZD1222 vaccine in the Thai population. METHODS: This was a single-center, prospective cohort study at Chulabhorn Hospital, Bangkok, Thailand. Individuals 18 years or older who were negative for anti-SARS-CoV-2 antibody were eligible. Anti- receptor-binding domain antibody concentrations were tested at least three weeks after the first vaccination and immediately before the second dose of vaccine. Information on reactogenicities was obtained via a questionnaire sent by a short message service. RESULTS: Anti-RBD Antibody concentration at 2 and 3 months post-vaccination were significantly higher than at 1 months post-vaccination (20.14 BAU/mL (95%CI; 16.37, 24.77) at 1 month, 48.08 BAU/mL (95%CI; 42.76, 54.08) at 2 month, and 65.01 BAU/mL (95%CI; 58.88,71.61) at 3 month). Adverse events occurred in approximately 60% of participants. Factors influencing vaccine immunogenicity include age, sex, the time elapsed from the first dose of vaccine, and underlying disease with diabetes and hematologic disease. CONCLUSION: A single dose of AZD1222 could elicit immune responses that did not decline within three months in Thai individuals. These data support the public health strategy of a delay between the prime and boost dose of AZD1222 of 4 to 12 weeks.

Immunogenicity and reactogenicity after heterologous prime-boost vaccination with CoronaVac and ChAdox1 nCov-19 (AZD1222) vaccines.

Mass vaccination with a safe and effective vaccine may be the best way to control the COVID-19 pandemic. Heterologous prime-boost vaccination with the CoronaVac and AZD1222 vaccines may increase the immunogenicity elicited by either vaccine alone. This study sought to compare the immunogenicity of a heterologous CoronaVac and AZD1222 prime-boost with a homologous CoronaVac prime-boost. From July 13 to September 2, 2021, 88 participants were enrolled in the study. Half (n = 44) of the participants were assigned to the AZD1222/CoronaVac cohort and half were assigned to the CoronaVac/AZD1222 cohort. Both cohorts had a prime-boost interval of 4 weeks. A control group of 136 health care personnel who received the homologous CoronaVac/CoronaVac prime-boost was matched by age and sex to the experimental cohorts. The primary endpoint was the geometric mean ratio (GMR) of the anti-receptor binding domain (RBD) antibody concentration 4 weeks after the booster dose was administered. The CoronaVac/CoronaVac cohort served as the reference group. Baseline age and sex were similar, and the median age was 42.5 years. The GMR was 2.58 (95% confidence interval [CI] 1.80-3.71) and 8.69 (95% CI 6.05-12.47) in the AZD1222/CoronaVac and CoronaVac/AZD1222 cohorts, respectively. Reactogenicity was similar following prime and booster doses with the same vaccine. Findings indicated that the heterologous CoronaVac and AZD1222 prime-boost combination elicited a more robust immune response than the homologous CoronaVac prime-boost. While both heterologous prime-boost combinations showed similar reactogenicity, the immunogenicity of the CoronaVac/AZD1222 cohort was higher, indicating that the order of prime-boost vaccine administration was important.

Immunogenicity and safety of an intradermal fractional third dose of ChAdOx1 nCoV-19/AZD1222 vaccine compared with those of a standard intramuscular third dose in volunteers who previously received two doses of CoronaVac: A randomized controlled trial.

INTRODUCTION: The CoronaVac vaccine is widely used in Thailand to combat the coronavirus disease 2019 (COVID-19) pandemic. The limited immunogenicity of this vaccine is a concern, especially because of expanding delta variant outbreaks. A third boost may enhance antiviral immune responses. METHODS: This non-inferiority randomized controlled trial evaluated the immunogenicity and safety of an intradermal (ID) fractional third dose of AZD1222 vaccine compared with those of a standard intramuscular (IM) third dose. Participants were enrolled from August 9, 2021 to August 13, 2021 at Chulabhorn Hospital, Bangkok, Thailand. The eligibility criteria were age 18 years or older and prior two-dose Coronavac vaccination completed at least 2 months previously. Participants were randomly assigned to one of three groups by block randomization: (i) standard dose by IM administration (IM), (ii) 20% of the standard dose ID (ID1), or (iii) 40% of the standard dose ID (ID2). The primary endpoint was the geometric mean ratio of anti-receptor binding domain antibody in the ID1/ID2 vs. the IM groups 14 days post-vaccination. RESULTS: A total of 125 participants were randomized (IM, n = 41; ID1, n = 41; and ID2, n = 43). One participant was lost to follow-up by day 14 post-vaccination in the ID1 group. The geometric mean ratio (95% confidence interval) of anti-receptor binding domain antibody was 0.94 (0.80-1.09) in the ID1 group and 1.28 (0.95-1.74) in the ID2 group. Immunogenicity in both ID groups met the non-inferiority criteria. Local adverse events were more common in the ID groups than in the IM group but were mostly mild to moderate in severity. CONCLUSION: An ID fractional third dose of AZD1222 was non-inferior to a standard IM third dose among individuals previously vaccinated with CoronaVac. Adverse events associated with the ID fractional third dose included mild to moderate local site reactions. This vaccination strategy may help conserve vaccine supply.

Pembrolizumab- and ipilimumab-induced diabetic ketoacidosis and isolated adrenocorticotropic hormone deficiency: a case report.

BACKGROUND: Several human monoclonal antibodies directed against immune checkpoints, including T lymphocyte antigen 4 and programmed cell death protein 1, have been implemented for cancer treatment in order to promote effector T cell response to tumors. Despite the antitumor activity of these agents, a significant number of patients demonstrated immune-related adverse events that affected the functions of multiple organs, including the endocrine system. We report the first case of immune checkpoint inhibitor-induced simultaneous diabetic ketoacidosis and isolated adrenocorticotropic hormone deficiency following combination treatment with immune checkpoint inhibitors. CASE PRESENTATION: A 70-year-old Thai man with no previous history of diabetes mellitus was diagnosed with stage IVB non-small cell lung with pleural and liver metastases. After 14 weeks of combination treatment with pembrolizumab and ipilimumab, he presented with fatigue, nausea, and vomiting. Laboratory investigation revealed random plasma glucose 794 mg/dl, serum ketone 6.3 mmol/L, bicarbonate 13 mmol/L, and high anion gap 24 mmol/L. New-onset diabetes mellitus and diabetic ketoacidosis were diagnosed. Insulin therapy was initiated a favorable outcome within 10 hours. Despite improvement of hyperglycemia, the patient had persistent nausea and hyponatremia. Further investigation revealed cortisol 0.8 µg/dl and adrenocorticotropic hormone 21.7 pg/ml. His other pituitary hormone levels were normal, except for mild elevation of gonadotropin hormone. Magnetic resonance imaging of the pituitary showed a normal pituitary gland. Isolated adrenocorticotropic hormone deficiency was diagnosed, and corticosteroid replacement therapy was administered, resulting in an improvement of his symptoms. CONCLUSION: Our patient developed new-onset diabetes mellitus, diabetic ketoacidosis, and isolated adrenocorticotropic hormone deficiency during cancer treatment with pembrolizumab and ipilimumab. The present case highlights the need for physicians to be aware that immune-related adverse events can occur in multiple organs at the same time.