Case Report of Succesful Multidisiplinary Treatment for Patient with Metastatic Lung Cancer and Relapsed/Refractory Chronic Lymphatic Leukemia/Small Lymphocytic Lymphoma

Introduction: Croatian National Cancer Registry of Croatian Institute for Public Health reported that in year 2020 lung cancer was the second most common cancer site diagnosed in men with 16% and the third most common in women with 10% incidence among all cancer sites. Unfortunatelly lung cancer has the highest mortality in both men and women. Haematological malignancies had 7% share in all malignancies in both male and female cances cases. In 2020 190 newly diagnosed cases of lymphatic leukemia in men and 128 cases in women were reporeted, meaning 1.5 and 1.2% of all malignancies, respectively. Chronic lymphatic leukemia (CLL) is an advanced age disease and incidence increases with age. Impaired immunity, T and B cell dysfunction in CLL, chromosomal aberations, long-term immunosuppressive therapy and genetic factors can all cause secondary malignancies. Co- occurence of solid tumors and CLL is very rare. Although patiens with CLL have an increased risk of developing second primary malignancies including lung carcinoma, the data about their clinical outcomes are lacking. Parekh et al. retrospectively analyzed patients with simultaneous CLL and lung carcinoma over a 20-year period, and they found that ~2% of patients with CLL actually developed lung carcinoma. The authors claimed that up to 38% of patients will also develop a third neoplasm more likely of the skin (melanoma and basal cell carcinoma), larynx (laryngeal carcinoma) or colon. Currently there are no specific guidelines for concurrent CLL and non-small cell lung carcinoma (NSCLC) treatment. Usually, when the tumors are diagnosed simultaneously, treatment is based to target the most aggressive malignancy, as the clinical outcomes depend on the response of the tumor with the poorest prognosis. For this reason, a multidisciplinary approach is mandatory. Case report: A patient with history of coronary heart disease, myocardial infarction and paroxysmal atrial fibrillation was diagnosed in 2019 (at the age of 71) with B chronic lymphocytic leukemia with bulky tumor (inguinal lymph nodes 8x5 cm), stage B according to Binet, intermediate risk. He was treated with 6 cycles of chemoimmunotherapy (rituximab/cyclofosfamid/fludarabine). In 10/2019 remission was confirmed, but MSCT described tumor in the posterior segment of upper right lung lobe measuring 20x17 mm and bilateral metastases up to 11 mm. Bronchoscopy and biopsy were performed, and EGFR neg, ALK neg, ROS 1 neg, PD-L1>50% adenocarcinoma was confirmed. He was referred to Clinical Hospital Center Osijek where monotherapy with pembrolizumab in a standard dose of 200 mg intravenously was started in 01/2020. Partial remission was confirmed in October 2020. Immunotherapy was discontinued due to development of pneumonitis, dysphagia and severe weight loss (20kg), but without radiologically confirmed disease progression. At that time he was referred to our hospital for further treatment. Gastroscopy has shown erosive gastritis with active duodenal ulcus, Forrest III. Supportive therapy and proton pump inhibitor were introduced. After complete regression of pneumonitis, improvement of general condition and resolution of dysphagia, no signs of lung cancer progression were found and pembrolizumab was reintroduced in 12/2021. Hypothyroidism was diagnosed in 01/2021 and levothyroxine replacement ther apy was started. In 03/2021 he underwent surgical removal of basal cell carcinoma of skin on the right temporal region with lobe reconstruction. From 02/2021, when pembrolizumab was reintroduced, regression in tumor size was continously confirmed with complete recovery of general condition. He was hospitalized for COVID 19 infection in 09/2021, and due to complications pembrolizumab was discontinued till 11/2021. Lung cancer immunotherapy proceeded till 11/2022, when Multidisciplinary team decided to finish pembrolizumab because of CLL relapse. CLL was in remission till August 2022 when due to B symptoms, lymphcytosis, anemia and generalized lymphadenopathy, hematological workup including biopsy of cervical lymph node was performed and CLL/SLL relapse was confirmed. Initially chlorambucil was introduced, but disease was refractory. Based on cytogenetic test results (IGHV unmutated, negative TP53) and due to cardiovascular comorbidity (contraindication for BTK inhibitors) venetoclax and rituximab were started in 01/2023. After just 1 cycle of treatment normal blood count as well as regression of B symptoms and peripheral lymphadenopathy occured, indicating the probability of complete disease remission. In our patient with metastatic lung adenocarcinoma excellent disease control is achieved during 41 month of treatment in first line setting. Furthermore, relapsed/refractory CLL/SLL is currently in confirmed remission. Conclusion(s): Successful treatment of patients with multiple primary malignancies is based on multidisciplinarity, early recognition and management of side effects, treatment of comorbidities with the aim of prolonging life, controlling symptoms of disease and preserving quality of life.

Thyroid Eye Disease Following COVID-19 Infection in a Patient with a History of Graves' Disease

Introduction: Autoimmune and inflammatory thyroid diseases have been reported following SARS-CoV-2 infection or vaccination, but thyroid eye disease (TED) post-COVID-19 infection is less common. We describe a case of TED following SAR-CoV-2 infection in a patient with a history of Graves' disease. Case Description: A 59-year-old female with history of Graves' disease status post radioiodine ablation therapy in 2002. She developed post-ablative hypothyroidism which has been stable on levothyroxine 88 mcg daily. In January 2021, the patient's husband and daughter were diagnosed with COVID-19 infection. A few days later, the patient developed an upper respiratory tract infection associated with loss of sense of smell and taste consistent with COVID-19 infection. Three days later, she developed bilateral watery eyes which progressed to eye redness, eyelid fullness, retraction, and pain with eye movement over 1-month duration. Her eye examination was significant for severe periocular soft tissue swelling, lagophthalmos and bilateral exophthalmos. The laboratory workup was consistent with normal TSH 0.388 mIU/L (0.358-3.740 mIU/L) and positive TSI 1.01 (0.0-0.55). The patient was referred to an Ophthalmologist for evaluation of TED. He noted bilateral exophthalmos, no restrictive ocular dysmotility or compressive optic neuropathy (clinical activity score 4/7 points). CT scan of orbit showed findings compatible with thyroid orbitopathy. Based on clinical activity score of 4, treatment with Teprotumumab was recommended pending insurance approval. Discussion(s): Many cases of new-onset Graves' hyperthyroidism have been reported after COVID-19, with only a few associated with TED. Our patient has been in remission for 20 years before she developed COVID-19 infection with occurence of TED.This suggests that COVID-19 infection may have played a role. SARS-CoV-2 may act through several mechanisms, including breakdown of central and peripheral tolerance, molecular mimicry between viral and self-antigens, stimulation of inflammasome with release of type I interferon. In our patient, treatment with Teprotumumab was indicated due to Graves' orbitopathy clinical activity score greater than or equal to 3. In conclusion, it is very uncommon for TED to present after COVID-19 infection. Our case reinforces the speculative hypothesis that SARS-CoV-2 virus could have triggered an autoimmune response against eye antigens. There is a need for increased awareness about the link between COVID-19 and autoimmunity to help better define the management of patients.Copyright © 2023

BREAKTHROUGH HIV-1 INFECTION IN SETTING OF LONG-ACTING CABOTEGRAVIR FOR PrEP

Background: Long-acting cabotegravir (CAB-LA) is highly effective as HIV PrEP and superior to daily oral F/TDF in sexually active adults. We report a 28-yearold gender diverse patient assigned male at birth who acquired HIV-1 91 days after transitioning from F/TAF to CAB-LA despite on-time dosing. Method(s): Electronic medical records were reviewed to assess patient history and CAB-LA administration details. Plasma 4th generation HIV-1/2 Ag/Ab combination immunoassay and HIV-1 RNA quantitative PCR were performed at each injection visit. Result(s): Patient was on daily F/TAF for ten months prior to CAB-LA with acceptable adherence, missing 1 dose per week. Their medical history included hypothyroidism on levothyroxine and unconfirmed hypogonadism with illicit use of IM testosterone cypionate complicated by significantly elevated total testosterone levels. They were sexually active with cisgender men, endorsing condomless oral and anal sex with one primary partner and 20-30 unique partners per month. In the past 6 months, patient was diagnosed with syphilis and mpox. Patient was given 600mg of CAB-LA into their left gluteal medius on Day 0, 27, and 91. Day 0 and 27, plasma HIV 1/2 Ag/Ab was non-reactive and HIV-1 RNA PCR was not detected. Patient reported flu-like illness on Day 76 with positive SARS-COV-2 PCR;they completed a five-day course of nirmatrelvirritonavir with rapid resolution of symptoms. At the third injection of 600mg CAB-LA on Day 91, their plasma HIV 1/2 Ag/Ab was non-reactive but the HIV-1 RNA PCR test was detected at 1.48log c/mL. On repeat testing on Day 100, plasma HIV 1/2 Ag/Ab was reactive with HIV-1 Ab detected on differentiation assay and HIV-1 RNA PCR was detected at 1.30 log c/mL. Patient's primary partner was living with HIV resistant to NRTIs (65R, 118I) and INSTIs (92G) with undetectable plasma HIV-1 RNA for the past 24 months. Patient's viremia was below the threshold to perform standard HIV-1 sequencing;HIV-1 DNA qualitative PCR and HIV-1 proviral DNA resistance testing are currently pending. Patient ultimately started on F/TAF/DRV/COBI and DTG on Day 112. Conclusion(s): This patient's history suggests HIV-1 infection despite on-time and appropriate CAB-LA injections. To our knowledge, this is the first case of CAB-LA PrEP failure outside the setting of a clinical trial and highlights the diagnostic and management challenges that may arise with such breakthrough infections in the real world.

New-Onset Thyroid Eye Disease After COVID-19 Infection in Patient with Graves' Disease Post-Radioactive Iodine Treatment

Introduction: Coronavirus disease 2019 (COVID-19) has been associated with dysregulation of the immune system and abnormal thyroid function. The aim of this novel case report is to inform physicians of the possibility that COVID-19 infection may precipitate thyroid eye disease (TED) in patients with Graves' Disease (GD) even after treatment with radioactive iodine (RAI). Case Description: In this report, we describe a patient with GD treated with RAI who developed TED after COVID-19 infection. The patient was initially diagnosed with GD in 2018. A thyroid uptake scan (I-123) was consistent with GD with moderately elevated uptake. She was initially managed with methimazole and atenolol and was eventually treated with RAI (16.32 millicurie I-131) in February 2021. She had post-ablative hypothyroidism managed with levothyroxine. The patient contracted COVID-19 in January 2022. In February 2022, the patient started experiencing eye irritation, dryness, protrusion of eyes, eyelid swelling, and visual disturbances. Thyroid stimulating hormone (TSH) receptor auto-antibodies (7.33 IU/L, normal < /=1.00 IU/L) and thyroid stimulating immunoglobulin (4.30 IU/L, normal < /=1.00 IU/L) were elevated. TSH was normal (2.180 mIU/L, normal 0.270 - 4.200 mIU/L) on levothyroxine 125 mcg daily. She was later diagnosed with TED. Discussion(s): GD is an autoimmune thyroid disorder related to the presence of TSH receptor-stimulating antibodies and is often associated with ocular symptoms. Activation of an autoimmune response during COVID-19 infection, may induce onset or relapse of GD. A study using the national health insurance service database in South Korea noted an increase in the incidence of subacute thyroiditis in 2020 in association with the COVID-19 pandemic. TED is usually seen in patients with GD. Radioactive iodine is widely used in the treatment of GD and has been associated with development or worsening of TED. There are published cases of TED occurring in patients with GD after receiving COVID-19 vaccine. It is thought that the inflammatory syndrome induced by the adjuvants could induce molecular mimicry, which could trigger TED. In most cases this adverse effect was transient, lasting a few months after treatment. There have been case reports of TED occurring after 3 to 21 days of COVID-19 vaccination in patients with controlled GD. Symptoms improved in 4-8 months. Development of TED in patients with GD who have been treated with RAI typically occurs soon after RAI therapy. For TED to occur in a GD patient 11 months after receiving RAI therapy is unusual. COVID-19 infection appears to have been the trigger for this patient's eye disease. This is highly unusual and has not been published to our knowledge.Copyright © 2023

Hyponatremia in Empty Sella Syndrome: Is it a Covid Sequelae?

The symptoms associated with empty sella syndrome (ESS) include headache, giddiness, vomiting, visual field deficits, and endocrine problems, as well as the radiological appearance of an enlarged sella turcica. This case report highlights a 45-year-old female who had a COVID-19 infection 2 months back and presented with chronic headache, giddiness, and lethargy having persistent hyponatremia later diagnosed as empty sella syndrome on brain magnetic resonance imaging. In this case, we tried to correlate all of these clinical and radiological features as COVID-19 sequelae due to post-Covid hypothalamic-pituitary axis dysfunction.Copyright © 2023 Authors. All rights reserved.

Transverse myelitis 48 hours after the administration of an mRNA COVID 19 vaccine

Background Vaccinations against SARS-CoV-2 have been a topic of political, social, and medical intrigue since the declaration of the COVID-19 pandemic in early 2020. The vaccine side effects have been relatively mild to date, with few observed systemic effects. Case presentation A 69-year-old previously healthy female presented with symptoms of asymmetric bilateral lower and upper extremity weakness 2 days after vaccination with the Pfizer-BioNTech mRNA vaccine. MRI of the cervical spine revealed a non-compressive myelitis extending from C3-4 to T2-3. Common known causes of transverse myelitis were ruled out by diagnostic techniques. Conclusions Transverse myelitis is a rare autoimmune disorder that has been shown to have a temporal association with vaccination in the past. With a progressively partisan societal view on vaccinations, it is important for clinicians to remain vigilant on documenting potential associations without encouraging fear of causation.Copyright © 2021 The Author(s)

A contrasting diagnosis: iododerma

An 86-year-old woman presented to the emergency department with acute shortness of breath. She was treated with intravenous furosemide for acute-on-chronic heart failure. Her past medical history included atrial fibrillation, hypertension, diverticulosis and hypothyroidism. Rivaroxaban and levothyroxine were her only long-term medications. On day 5 of hospital admission, she developed painful haemorrhagic and purulent bullae on her dorsal hands, head and neck. These evolved to large suppurative, vegetative plaques over a 72 h period and she developed additional lesions on her trunk, upper back and thighs. The patient had routine blood tests, which showed a raised C-reactive protein at 260 mg L-1, and an acute kidney injury with a glomerular filtration rate of 54 mL-1 min-1. She had a negative COVID-19 swab, and swabs from the lesions for bacterial culture and viral polymerase chain reaction were negative. She had a normal serum protein electrophoresis, immunoglobulin, antinuclear antibody and antineutrophil cytoplasmic antibody. She had computed tomography of her chest 24 h prior to the onset of her lesions, which showed mild bilateral pleural effusions in keeping with fluid overload secondary to heart failure. A biopsy taken from her hand showed orthokeratosis and parakeratosis, and there was bulla formation subepidermally. There was a dense neutrophilic infiltrate with microabscess formation with scattered eosinophils and lymphocytes. There was no evidence of vasculitis. Direct immunofluorescence was negative and a tissue culture for atypical mycobacteria was negative. The patient was commenced on high-dose intravenous methylprednisolone at 500 mg for 3 days followed by 40 mg prednisolone orally for 1 week, but there was a limited response. Our initial differential was Sweet syndrome or pyoderma vegetans;however, the patient had no fevers and no risk factors (malignancy, inflammatory disease, infection, etc.). She also had no response to high-dose oral prednisolone. Given the timing of her CT examination in relation to her acute dermatosis and the use of radioiodine for contrast, we assessed the patient's serum iodine and urine iodine. These were both high at 1.02 mmol L-1 (reference interval 0.32- 0.63) and 3.46 mmol L-1 (reference interval 0.0-2.43), respectively. A diagnosis of iododerma was made. The patient's eruption slowly resolved and at 12 weeks there was evidence of postinflammatory skin changes only. Her urine and serum iodine were rechecked, and both had normalized. In the last 20 years there have been approximately 20 case reports of iododerma. Most have been following iodine contrast use in patients with abnormal kidney function, like our patient. Most describe an acneiform eruption that subsequently evolves to vegetative plaques (Chalela JG, Aguilar L. Iododerma from contrast material. N Engl J Med 2016;374: 2477). Iododerma is largely a diagnosis of exclusion, but histopathology and urine and serum iodine levels can help support diagnosis.

Was Covid Era a Blessing in Disguise for the Patient?

Background and Aims: In the Covid era, Continuous blood glucose monitoring(CGM) was used more frequently and it proved to be quite a helpful and accurate tool for glycemic regulation. Method(s): 75 yrs old Saudi gentleman, had Type 2 diabetes >30yrs, Hypertension, Primary Hypothyroidism, dyslipidemia, mixed polyneuropathy, Iron deficiency anemia, and benign prostatic hypertrophy. In March,2020 his BP and blood glucose readings were high at home. He had a past history of subdural hematoma with hydrocephalus(staus post-shunting). He was on Glargine, oral hypoglycemic agents, anti-hypertensives, Levothyroxine, Atorvastatin, Aspirin, iron fumarate, calcium carbonate and cholecalciferol. Fully conscious, and co-operative, of average built and height.BP 170/70 mmHg, pulse 93/m, RR 18/ m,O2sat 100%, afebrile, BMI 24.96 kg/m2. Fundoscopy normal. He had dry feet and impaired monofilament and vibration testing. Result(s): Hb% 13.1g/dl(12.6 before),MCV 93.8fl,S.Ferritin 10.5ug/l(30-400),Vit.B12 270 pmol/l(145-637),HbA1c 8%(6.4 in Feb.2020).The renal, liver and thyroid functions-intact. Albumin creatinine ratio 12.23mg/g(0-30). Nerve conduction study-mixed polyneuropathy. He continued to follow-up physically even during the Covid crisis due to the elevated SMBG and BP values. Gliclazide & antihypertensive doses were optimized and Glargine was started.On patient's follow-up in August, 2020, time in range had improved to 80%(33% in June,2020),average glucose was 147 mg/dl(200 before), glucose variability was 27.8%(28.9), hypoglycemia (54-79mg/dl) was 1%(0). On last follow-up on 27.06.2022 his HbA1c had climbed up to 8.3%(7.3 in September, 2021). He was compliant to the diabetes regime, but had stopped using the Libre sensor. Conclusion(s): The case signifies the advantage of a meticulous CGM usage during the Covid pandemic, that resulted in a reasonable glycemic control.

Unusual case of Obesity and Hypoventilation in Childhood

Objectives Childhood obesity can be monogenic or polygenic in etiology and is associated with significant morbidities. Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation, and neural crest tumor (ROHHHAD[NET]) syndrome, is a rare autonomic and respiratory pediatric disorder presenting with rapid weight gain in early childhood, hypothalamic-pituitary dysfunction, central hypoventilation, and an association with neural crest tumors. Methods A 6-year-old Asian girl with abnormal weight gain since the age of 3 years, presented to the pediatrician's office due to pulse oximeter readings in the 60s at home. Parents were monitoring saturations at home as a way of screening for COVID-19 infection. The pediatrician confirmed hypoxemia and transferred the patient to the Children's Medical Center emergency department on oxygen via EMS. She had occasional snoring and nighttime cough, but no history of respiratory distress, or signs of infection. There was no hyperphagia, neonatal hypoglycemia, or developmental or behavioral concerns. On examination her body weight was 30 kg (+1.56 SD) and height was 113 cm (-1.46 SD) with a body mass index (BMI) of 23.4 kg/m2 (+2.33 SD). No acanthosis nigricans, cushingoid features, or respiratory distress were noted on examination. In the intensive care unit, she was diagnosed with central hypoventilation requiring mechanical ventilation. Her laboratory work-up revealed central hypothyroidism (low Free T4 of 0.64 ng/dl, TSH 1.553 microIU/L). Other anterior pituitary hormones were normal (adrenocorticotropic hormone, 16.3 pg/mL;cortisol, 10.7 mug/dL;prolactin, 9.95 ng/ml;Insulin-like growth factor-1, 83 ng/mL;and IGF binding protein 3, 3.02 mg/L). Genetic investigations revealed no known mutations in the PHOX2B gene, making a diagnosis of central hypoventilation syndrome unlikely. Results Rapid onset weight gain around 3 years of age, central hypoventilation, and anterior pituitary hormone deficiency in our patient with negative PHOX2B is consistent with a clinical diagnosis of ROHHHAD[NET]. Our patient was started on levothyroxine;received tracheostomy for mechanical ventilation;and gastrostomy for pharyngeal dysphagia. She is doing well, goes to school, and is tolerating trials off the ventilator during the day. Conclusions ROHHAD is an important differential to consider for any child with rapid and early obesity and hypoventilation as early diagnosis is critical in improving the clinical management and the prognosis.

SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARSCoV- 2) VACCINE-INDUCED THYROID DYSFUNCTION: A TALE OF TWO PATIENTS

Introduction SARS-CoV-2 vaccine has been the main pillar in battling the coronavirus disease 2019 (COVID-19) pandemic. However, the current vast scale of SARS-CoV-2 vaccination programme has led to inevitable reports of various adverse reactions, one of which include thyroid dysfunction. CASES We describe two patients who manifested hyperthyroidism following BNT162b2 mRNA-based COVID-19 vaccine boosters. Patient 1, a previously euthyroid 46-year-old female, has an eight-year history of type 1 diabetes mellitus. She developed palpitations of increasing severity about two weeks after her COVID-19 booster vaccine on 20th January 2022. She had weight loss of 4 kg and experienced menstrual irregularities in the subsequent three months. Examination revealed tachycardia (112 beats per minute, regular) and bilateral fine tremors of the hands. There was no goitre or neck tenderness. Blood investigations showed overt hyperthyroidism with positive thyroid autoantibodies, consistent with Graves' disease. Treatment with carbimazole led to marked symptomatic improvement. Patient 2, a 38-year-old female with a six-year history of Hashimoto thyroiditis, was clinically and biochemically euthyroid while taking levothyroxine 100 mcg daily prior to her COVID-19 booster vaccine on 5th January 2022. Five weeks following the vaccine, her thyroid function test during her endocrine clinic appointment showed overt hyperthyroidism, which was confirmed by a second blood sample ten days later. There was neither a change in levothyroxine dose nor any additional supplement intake. She was otherwise asymptomatic. Levothyroxine was then withheld. She regained her baseline hypothyroid state two weeks later, during which levothyroxine was resumed. Conclusion SARS-CoV-2 vaccine-induced thyroid dysfunction can affect both euthyroid and hypothyroid patients. A history of recent COVID-19 vaccination should be included in the clinical evaluation of a newly diagnosed hyperthyroid patient or unexplained hyperthyroidism in a long-standing hypothyroid patient.

NEW-ONSET THYROID EYE DISEASE AFTER COVID-19 VACCINATION: A CASE REPORT

Introduction The relationship between autoimmunity and SARS-CoV-2 vaccine has explained how thyroid dysfunction developed following vaccination but the onset of thyroid eye disease (TED) is scarcely described. We report a case of Graves' disease (GD) who developed TED after three weeks of BNT162B2 SARS-CoV-2 vaccine (Pfizer-BioNTech) injection. CASE A 54-year-old non-smoking male presented with newonset bilateral eyes redness, proptosis, and diplopia three weeks after receiving the second dose of mRNA BNT162B2 SARS-CoV-2 vaccine. He was diagnosed with GD without TED in 2003 and underwent radioactive iodine ablation in 2020. He subsequently developed hypothyroidism and was started on levothyroxine with stable thyroid function test throughout clinic visits. There were no recent stressful events including COVID-19 infection. On examination, he has bilateral exophthalmos, chemosis, conjunctival injection, swollen eyelids and caruncles, with intact vision. Blood tests revealed normal TSH, free T4, and T3, but elevated TSH-receptor antibodies of 3.60 IU/L (<1.75) and antithyroid peroxidase (TPO) antibodies of >600 IU/ml (0-34). MRI orbit showed bilateral extraocular muscle enlargement and proptosis. Intravenous methylprednisolone was given weekly for 12 weeks. There was significant improvement concerning congestive symptoms and diplopia after the third dose of methylprednisolone. Thyroid eye disease is the extrathyroidal manifestation of GD resulting from the autoimmune and inflammatory process. The temporal relationship of the onset of TED after mRNA SARS-CoV-2 vaccination in our case was suggestive, and there were no other inciting events identified. The postulated mechanisms include immune reactivation, molecular mimicry between the SARS-CoV-2 spike proteins and thyroid proteins, and the autoimmune/ inflammatory syndrome induced by adjuvants present in the mRNA vaccine. Conclusion Patients with autoimmune thyroiditis should be monitored closely after SARS-CoV-2 vaccine as they may develop TED and require treatment.

Bullous pemphigoid onset following Pfizer-BioNTech COVID-19 vaccine (COMIRNATY®): coincidence or a new emerging adverse effect?

We report the case of a 61-year-old man referred to the dermatology clinic with a new onset of itchy rash with blisters within 2 weeks following the first dose of the Pfizer-BioNTech COVID-19 vaccine (COMIRNATY®). After the second dose of the same vaccine within 72 h, he developed a widespread rash with tense blisters with oral mucosal involvement. His medical history included obesity (body mass index 47.8 kg m-2), type 2 diabetes mellitus, hypertension and hypothyroidism. His regular medications included alogliptin (established for 3 years) and levothyroxine. There were no recent changes or additions to his drugs reported. On examination, he had extensive erythematous plaques with tense bullae and oral ulcers. Skin anti-epi basement membrane antibodies were positive, and anti-epidermal intercellular antibodies were negative. We considered the diagnosis of bullous pemphigoid (BP) on the clinical picture and indirect immunofluorescence studies. Topical treatment started with 50: 50 white soft paraffin, clobetasol propionate ointment and systemic oral prednisolone with doxycycline with reasonable disease control within 4 weeks. We were faced with a diagnostic conundrum. We postulated two possibilities: new-onset BP coincidental and unrelated to vaccination or BP secondary to the vaccine as suggested by the time-dose relationship. As the patient was established on alogliptin for 3 years, we considered it unlikely this drug had contributed to the disease onset. Case reports are now emerging of BP following vaccination with other COVID- 19 vaccines. This phenomenon has implications for future inoculation with the booster vaccine, requiring careful consideration and discussion with our patients. This case is registered on the Yellow Card scheme (Pérez-López I, Moyano- Bueno D, Ruiz-Villaverde R. Bullous pemphigoid and COVID-19 vaccine. Med Clin (Engl Ed) 2021;157: e333-4;Agharbi F, Eljazouly M, Basri G et al. Bullous pemphigoid induced by the AstraZeneca COVID-19 vaccine. Ann Dermatol Venereol 2022;149: 56-7).

TREATMENT SUCCESS IN A RESISTANT CASE OF INSOMNIA WITH AN IRREGULAR CIRCADIAN RHYTHM DISORDER

Introduction: A 19-year-old non-verbal male with history of CHARGE syndrome, severe autism, intellectual disability, coloboma with blindness OD and severely imparied vision OS, deafness, self-injurious and aggressive behavior, Tetralogy of Fallot status post repair, pulmonary valve replacement, hypertension, hypothyroidism, megacolon, gastrostomy tube dependence, eosinophilic esophagitis and chronic kidney disease with an irregular sleep cycle who has failed multiple medications for insomnia has shown treatment success with suvorexant. Report of Cases: This patient's sleep schedule ranges from 1.5 to 5 hour segments at various times of day or night including naps at school with occasional longer periods of sleep up to 10 hours and longer periods of wakefulness up to 22 hours who has been treated with the following medications: trazodone, clonidine, hydroxyzine, diphenhydramine, quetiapine, gabapentin, mirtazapine, eszopiclone, melatonin and ramelteon. His behavioral problems have been treated with olanzapine. He continued to be aggressive and difficult to direct. His parents reported exhaustion. Then, suvorexant 5mg was added at bedtime while the following sleep medications were continued: gabapentin total daily dose of 1500mg (300mg in morning and 3pm;900mg at bedtime, 300mg one hour later if still awake), ramelteon 8mg, mirtazapine 7.5mg and olanzapine 10mg at bedtime and bid prn aggressive behavior. He also takes the following daily medications: bisacodyl, polyethylene glycol, simethicone, hyoscyamine, cholecalciferol, aspirin, levothyroxine, hypoallergenic nutritional formula, starch and albuterol prn. With the addition of suvorexant 5mg, he had been able to get 9.5 hours of consolidated sleep at night with improvement in his behavior until he contracted Covid-19 and regressed. The suvorexant dose was increased to 10mg which again improved his insomnia and behavior. Conclusion: Various medications have either not worked at all or have worked suboptimally for insomnia in this medically complex patient who has an irregular Circadian rhythm disorder. Adding an orexin receptor antagonist as a novel mechanism to his regimen has shown promise. At this time, this patient has been stable for one month with suvorexant 10mg at bedtime after regression on the 5mg dose that coincided with a Covid-19 infection. We are proceeding with cautious optimism.

A Novel Solution of Levothyroxine Results in Clinically Similar Maximum and Extent of Exposure Whether Taken 30 or just 15 Minutes Before a High-Fat High-Caloric Breakfast

Objective: Levothyroxine is essential for the treatment of hypothyroidism, but unfortunately its absorption when taken as a tablet has been shown to be significantly decreased with coffee or food ingestion, particularly if containing calcium or magnesium. Tablets and soft-gel formulations of levothyroxine are therefore recommended to be taken at least 30 minutes before meals, an inconvenience for patients in the morning. Tirosint-Sol® is a novel solution of levothyroxine that has been shown to result in an approximate 30 minutes faster absorption process than tablets or soft gel formulations. The objective of this trial was to investigate whether Tirosint-Sol® could be administered as late as 15 minutes before a high-fat, high-caloric meal, in comparison to 30 minutes. Methods: Thirthy-six (thirty-three completers, 24 males and 9 females) healthy volunteers participating in the randomized study took a 600 mcg Levothyroxine dose of Tirosint-Sol® after a 10-hour fast, 15 or 30 minutes before a high-fat high-caloric “FDA type” breakfast. Serum samples were taken at three different times at baseline, and at 0.5, 1, 1.5, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48 and at 72 hours after dosing. The washout period was at least 35 days. Serum concentrations of Levothyroxine were measured using a validated LC-MS method. Results: Median tmax was unchanged between the two groups at 1.5 h. The three subjects that did not complete the trial did so because of not showing up for COVID19 testing, vomiting within 6 hours after dosing, and not finishing the breakfast. The geometric mean ratios and confidence intervals for the baseline adjusted maximum (Cmax, 85%, CI: 80-90%) and extent of exposure (AUC0-72, 92%, CI: 87-97%) were within the recognized equivalence boundaries of 80 to 125%, indicating an absence of meaningful clinical difference between dosing at 15 or 30 minutes before a meal. There were no differences in adverse events between groups. Discussion/Conclusion: The data of this randomized study indicate that the absorption profile of Tirosint-Sol® is clinically equivalent when administered 30 or 15 minutes before a high-fat high-caloric breakfast.

Adrenal Insufficiency: A Unique Presentation of Multicentric Castleman Disease with Human Herpes Virus 8 Positivity and Concomitant Kaposi Sarcoma

Introduction: Multicentric Castleman Disease (MCD) is a lymphoproliferative disorder involving multiple lymph nodes and can be associated with human herpes 8 virus (HHV-8). Hyaline vascular (HV) MCD is rare, occurring in < 10% of cases. MCD with concomitant HIV negative Kaposi Sarcoma (KS) is also uncommon and can peculiarly present with adrenal insufficiency. Case Description: 53-year-old male with biopsy proven diagnosis of HHV-8 positive KS was transferred to our institution with persistent hypotension requiring pressor support. He described a two-week history of night sweats, 20 Ib weight & appetite loss, fatigue, muscles aches, and subjective fevers. Vitals: BP: 99/50 mmHg, HR: 90 bpm, RR: 19 and T: 103oF. Physical exam revealed multiple violaceous, non-blanching plaques on his body, tender inguinal & axillary lymphadenopathy, and bilateral lower extremity edema. Initial labs: Na: 137 mmol/L, K: 3.6 mmol/L, WBC: 5.6 k/uL, Hg: 7.1 gm/dL, Hct: 21%, Plt: 91 k/uL, AM cortisol: 12.5 mcg/dL (5.3-22.5), ACTH < 1 pg/mL, TSH: 7.5 uIU/mL, FTF: 0.63 ng/dL, PRL: 7 ng/mL, Total testosterone: 20 ng/dL, FSH: 4.2 mIU/mL, LH: 8.3 mIU/mL, IGF-1: 77 ng/mL (64-218), ESR >85 mm/hr (< 20), and CRP: 76 mg/dL (< 3). HIV and COVID-19 tests were negative. He was started on oral Levothyroxine and IV Hydrocortisone with significant improvement in his BP leading to discontinuation of pressor support. CT chest/abdomen/pelvis showed diffuse lymphadenopathy consistent with KS with normal adrenal glands. Left axillary lymph node biopsy revealed HV MCD. Additional labs;IL-6: 11.5 pg/mL (< 2), IgG4: 45 mg/dL (1-123), normal CD4 count, renin and aldosterone levels. 21 alpha hydroxylase antibody, T-spot, extensive autoimmune and infectious work-up were negative. Pituitary MRI could not be obtained due to a metal object behind his right orbit. Head CT was negative for pituitary abnormality. He failed his ACTH stimulation test with cortisol level: 13 mcg/dL at 90 minutes (baseline ACTH was not obtained). Thus, he was discharged on physiological oral Hydrocortisone upon clinical improvement. He began chemotherapy 1 week post discharge, however he succumbed to his disseminated and aggressive disease 20 days later. Discussion: MCD with concomitant KS is a rare and rapidly progressive disease which can cause death within weeks. IL-6 overproduction is thought to be associated with its symptom progression. Worse clinical outcomes are correlated with HIV or HHV-8 positivity. It can uncommonly be associated with either primary or secondary adrenal insufficiency requiring prompt evaluation and treatment with systemic steroids to prevent development of adrenal crisis.

Hashimoto's encephalopathy in a patient with severe hypothyroidism

Introduction: Hashimoto's encephalopathy (HE) manifests itself with neuro-psychiatric disorders, which can reach coma;HE usually occurs in euthyroid, being less frequent states of thyroid dysfunction. We present the case of a patient with HE and severe hypothyroidism. Case Description: A 71-year-old woman;history of rheumatoid arthritis, hypertension and cerebral infarction without sequelae. The family referred a 3-week history of illness characterized by disorientation and "jerking" movements, she progressed to drowsiness with left hemiparesis, focal epileptic seizures and myoclonus. The brain CT showed atrophy and left frontal malacia;diagnosed status epilepticus and cerebral infarction, indicating phenytoin. During hospitalization she was added valproic acid and levetiracetam, without improvement. Brain MRI showed cerebral atrophy and periventricular leukoaraiosis. The study of the CSF: hyperproteinorraquia;EEG: diffuse slowing and periodic lateralized discharges in the right hemisphere. They request an endocrinology evaluation for TSH: > 75uIU/ml, Free T4: 0.31ng/dl, we expand with Anti-TPO > 1000 and Anti-thyroglobulin > 3000, and we indicate treatment for severe hypothyroidism with levothyroxine for nasogastric tube and intravenous hydrocortisone for 5 days and with minimal recovery from sensory disorder. After the withdrawal of hydrocortisone, she developed drowsiness and intensified myoclonus despite an improvement in the blood concentration of thyroid hormones. Having excluded infectious, metabolic and paraneoplastic etiology of encephalopathy, with the presence of elevated antithyroid antibodies in blood and CSF, the diagnosis of Hashimoto's encephalopathy was raised, receiving methylprednisolone (1 g/day for 5 days), then human immunoglobulin (25g for 5 days) Faced with poor response, she received 5 sessions of plasmapheresis with favorable clinical and paraclinical evolution. After overcoming hospital infection by COVID-19, she was discharged at 3 months. In the follow-up, cognitive deterioration, partial dependence, without epileptic seizures or myoclonus were reported. Discussion: HE is rare, with variable clinical presentation. HE has a good response to corticosteroids, although it sometimes requires other interventions. The alteration of thyroid function itself can be confusing at the time of diagnosis. Severe hypothyroidism can present neurological complications such as seizures, dementia, or psychosis;but it differs from HE in that manifestations improve when thyroxine is replaced.

Panhypopituitarism Induced by COVID-19 Infection

Introduction: Coronavirus disease 2019 (COVID-19) infection has led to multiple endocrinopathies. We present a case of panhypopituitarism induced by COVID -19 infection. Case Description: 76 yo male with history of type 2 diabetes, hypertension, and 1.5 cm stable, nonfunctioning, pituitary macroadenoma diagnosed in 2017 had multiple admissions for altered mental status and hyponatremia following COVID-19 infection in April 2020. Workup revealed low free T4 0.60 ng/dL (0.8-1.8), low random cortisol 1.8 mcg/dL(2.9-19.4), high prolactin 33.5 ng/mL (2-18), low total testosterone < 10 ng/dl (175-781), SHBG 32.7 nmol/L (13.3-89.5), and low gonadotropins. While hospitalized, he was diagnosed with pan-hypopituitarism and started on glucocorticoids and levothyroxine. Repeat MRI pituitary done after discharge, documented stability of the macroadenoma without hemorrhage. To date, the patient remains on glucocorticoid replacement and thyroid hormone replacement in stable state. Discussion: Hypopituitarism from any etiology has an incidence of 4.2 per 100,000. Hormone replacement therapy remains the mainstay of treatment. This case represents a patient who had unexplained recurrent hyponatremia after COVID-19 infection and later diagnosed with pan-hypopituitarism. Given the continued pandemic, more endocrinopathies related to the COVID-19 infection have been reported. We have data for other viral infections, such as SARS and Dengue, documenting pituitary dysfunction. Review of literature documents SARS infection leading to post infectious hypophysitis with resulting secondary hypocortisolism and hypothyroidism. The cause was thought to be virus binding to pituitary angiotensin-converting enzyme 2 (ACE2) receptors. There is also data supporting COVID-19 infection leading to pituitary apoplexy and hypophysitis, though the number of cases reported is limited. The pathophysiology is thought to be the COVID 19 virus binding to pituitary ACE2 receptors for which it has a 10-20-fold higher affinity. Furthermore, the hypothalamus also expresses ACE2 receptors making it a target for the virus. The binding leads to cellular destruction and autoimmune collateral damage. Hypothalamic pituitary dysfunction could be due to direct effect of virus. The virus can also lead to reversible hypophysitis.

A Rare case of Pituitary Apoplexy associated with COVID infection presenting with Central Diabetes Insipidus

Introduction: Pituitary apoplexy (PA) is rare and occurs in up to 20% of patients with a non-functioning pituitary adenoma. It can occur de novo or can be precipitated by surgery, head trauma, anticoagulant therapy, and pregnancy among others. Incidence of persistent Diabetes Insipidus (DI) is only about 2% in such patients. Limited literature exists on the association of PA and COVID infection. We present a case of PA and subsequent central DI in a patient with a pituitary adenoma and severe COVID-19 pneumonia. Case Description: A 64-year-old male with a history of a non-functioning pituitary macroadenoma (2 cm) of 5 months duration, primary hypothyroidism, and acute myeloid leukemia on chemotherapy presented to the emergency department with one day of headache, fever, and cough. He was diagnosed with COVID-19 pneumonia and started on dexamethasone, broad spectrum antibiotics and supplemental oxygen. Sudden loss of peripheral vision in his left eye with a persistent headache and altered mental status led to plain computed tomography that revealed a hyperattenuating suprasellar mass compressing the optic chiasm. MRI brain showed a T2 hypointense acutely hemorrhagic suprasellar mass compressing the infundibulum and the optic chiasm indicative of PA. Labs showed thrombocytopenia with platelet count 55,000/mcL (130-400), low AM cortisol 3 mcg/dL, normal prolactin 10 ng/mL, normal thyroid function and preserved somatotrophic axis. In addition, the patient developed polyuria with a urine output of up to 8 liters in a 24-hour period, acute hypernatremia (sodium 172 mmol/L), urine specific gravity < 1.005 and serum osmolality 360 mOsm/kg (275-295 mOsm/kg). Conservative management with stress dose hydrocortisone and desmopressin was the first line of therapy. Levothyroxine was continued at home dose. After resolution of COVID-19 pneumonia and improvement in electrolyte disarray, the patient underwent pituitary decompression surgery in 3 weeks with subsequent resolution of DI post-operatively. He was discharged home on hydrocortisone (20 mg total daily dose) and levothyroxine with close endocrinology follow up. Discussion: Association of COVID infection and PA has been reported in 10 patients in the literature so far. Although the exact mechanism is unknown, SARS-CoV-2 neural invasion via cerebral ACE-2 expression can lead to oxidative stress and thrombogenesis, ultimately predisposing to neural hemorrhage. Thrombocytopenia secondary to chemotherapy can be a contributing factor in our patient. DI is rare and usually resolves after decompression surgery. Further research focusing on the association and pathophysiology of COVID-19 with PA in those without precipitating factors are needed.

Euglycemic diabetic ketoacidosis in a young adult associated with the use of SGLT2 inhibitors

Introduction: In 2015, the FDA warned the risk of euglycemic diabetic ketoacidosis (eDKA) as an adverse effect of SGLT-2 inhibitors (SGLT2i), with a frequency of < 0.1%. We present the case of a patient with type 2 diabetes mellitus (T2D) who developed eDKA with empagliflozin. Case Description: A 34-year-old man with a history of obesity, hypothyroidism and T2D 5 years ago, with regular medication of metformin 850mg bid and levothyroxine 100ug/d. He was admitted to the emergency room due to dyspnea, abdominal pain, vomiting, and drowsiness. He reported that from 4 days before his admission, he took the combination of empagliflozin/metformin 12.5/1000mg bid due to blood glucose of 385mg/dL. Analytical: leukocytes: 12940 x mm3, hemoglobin: 16,5 g/dL, platelets: 219000 x mm3, sodium: 130 mmol/L, potassium: 4,29 mmol/L, glucose: 179 mg/dl, creatinine: 0,89 mg/dl, urea : 22,1 mg/dl, test for COVID-19 (-);arterial blood gases test: pH 7,13;pC02 13;HCO3 4,2;Gap Anion: 13,8;Lactate: 1,2;Osm: 269. Ketonuria: 4+. With the diagnosis of eDKA he was managed in emergency with EV hydration, EV bicarbonate, and EV infusion of insulin. In the Endocrinology service: A1c: 9.4%, C-peptide: 6.72ng/ml, cGFR (CKD-EPI): 119 mL/min/1.73 m2, LDL: 30 mg/dL, HDL: 33 mg/dL, triglycerides: 148 mg/dl. He was discharged with nutritional medical therapy, NPH-insulin: 40UI/d, metformin 850 tid. In follow-up by teleconsultation, home self-monitoring showed capillary blood glucose between 80-130mg/dL. Discussion: the eDKA due to SGLT2i is uncommon in patients with T2D;factors that were identified in some of the reports as possible triggers for ketoacidosis were certain serious illnesses, a reduced intake of food and fluids, and a reduced insulin dose. The remission time for eDKA is similar to other cases reported in the literature. In view of the increased use of these drugs and the risk of eDKA in patients with T2D, we must consider this adverse effect when prescribing some iSGLT2.