Heart rate variability and adrenal size provide clues to sudden cardiac death in hospitalized COVID-19 patients.

PURPOSE: To examine the association between a measure of heart rate variability and sudden cardiac death (SCD) in COVID-19 patients. METHODS: Patients with SARS-COV-2 infection admitted to Columbia University Irving Medical Center who died between 4/25/2020 and 7/14/2020 and had an autopsy were examined for root mean square of successive differences (RMSSD), organ weights, and evidence of SCD. RESULTS: Thirty COVID-19 patients were included and 12 had SCD. The RMSSD over 7 days without vs with SCD was median 0.0129 (IQR 0.0074-0.026) versus 0.0098 (IQR 0.0056-0.0197), p < 0.0001. The total adjusted adrenal weight of the non-SCD group was 0.40 g/kg (IQR 0.35-0.55) versus 0.25 g/kg (IQR 0.21-0.31) in the SCD group, p = 0.0007. CONCLUSIONS: Hospitalized patients with COVID-19 who experienced SCD had lower parasympathetic activity (RMSSD) and smaller sized adrenal glands. Further research is required to replicate these findings.

Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19.

SARS-CoV-2, the virus responsible for COVID-19, uses angiotensin converting enzyme 2 (ACE2) as its primary cell-surface receptor. ACE2 is a key enzyme in the counter-regulatory pathway of the broader renin-angiotensin system (RAS) that has been implicated in a broad array of human pathology. The RAS is composed of two competing pathways that work in opposition to each other: the "conventional" arm involving angiotensin converting enzyme (ACE) generating angiotensin-2 and the more recently identified ACE2 pathway that generates angiotensin (1-7). Following the original SARS pandemic, additional studies suggested that coronaviral binding to ACE2 resulted in downregulation of the membrane-bound enzyme. Given the similarities between the two viruses, many have posited a similar process with SARS-CoV-2. Proponents of this ACE2 deficiency model argue that downregulation of ACE2 limits its enzymatic function, thereby skewing the delicate balance between the two competing arms of the RAS. In this review we critically examine this model. The available data remain incomplete but are consistent with the possibility that the broad multisystem dysfunction of COVID-19 is due in large part to functional ACE2 deficiency leading to angiotensin imbalance with consequent immune dysregulation and endothelial cell dysfunction.

Post-acute COVID-19 syndrome.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.

Extrapulmonary manifestations of COVID-19.

Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

Ectopic ACTH Syndrome Emerging 5 Years after the Diagnosis of Neuroendocrine Tumor.

Ectopic ACTH syndrome (EAS) arising years after the diagnosis of a neuroendocrine tumor (NET) is exceedingly rare. We describe a case of EAS occurring five years after the diagnosis of a metastatic lung NET in a 61-year-old woman. She presented with severe hypokalemia but was not overtly Cushingoid on exam. Serum cortisol was 61mcg/dL after an overnight 1mg dexamethasone suppression test (<1.8mcg/dL) and urinary free cortisol was 7544 mcg/24h (<45mcg/24h), establishing the diagnosis of Cushing's syndrome. Plasma levels of peptides which have been associated with EAS, Agouti-related peptide (AgRP) and the ACTH precursors POMC (31-kDa) and pro-ACTH (22-kDa), were elevated. Metyrapone was initiated, but hypercortisolism persisted and the patient succumbed to pneumonia shortly after presentation. Retrospective examination of biopsy tissues showed rare ACTH immunoreactivity at the time of initial diagnosis, followed by staining in a greater proportion of cells as the disease progressed, consistent with EAS arising years after the diagnosis of NET. Given the increase in mortality associated with EAS, this unusual case highlights the importance of early detection and raises the possibility that early immunohistochemical stains for ACTH and measurements of ACTH precursors may facilitate the identification of NETs at high risk for EAS.

OUTCOME OF IMPLEMENTATION OF A MULTIDISCIPLINARY TEAM APPROACH TO THE CARE OF PATIENTS AFTER TRANSSPHENOIDAL SURGERY.

OBJECTIVE: Transsphenoidal surgery (TS) for sellar lesions is an established and safe procedure, but complications can occur, particularly involving the neuroendocrine system. We hypothesized that postoperative care of TS patients would be optimized when performed by a coordinated team including a pituitary neurosurgeon, endocrinologists, and a specialty nurse. METHODS: We implemented a formalized, multidisciplinary team approach and standardized postoperative protocols for the care of adult patients undergoing TS by a single surgeon (J.N.B.) at our institution beginning in July 2009. We retrospectively compared the outcomes of 214 consecutive TS-treated cases: 113 cases prior to and 101 following the initiation of the team approach and protocol implementation. Outcomes assessed included the incidence of neurosurgical and endocrine complications, length of stay (LOS), and rates of hospital readmission and unscheduled clinical visits. RESULTS: The median LOS decreased from 3 days preteam to 2 days postteam (P<.01). Discharge occurred on postoperative day 2 in 46% of the preteam group patients compared to 69% of the postteam group (P<.01). Rates of early postoperative diabetes insipidus (DI) and readmissions within 30 days for syndrome of inappropriate antidiuretic hormone (SIADH) or other complications did not differ between groups. CONCLUSION: Implementation of a multidisciplinary team approach was associated with a reduction of LOS. Despite earlier discharge, postoperative outcomes were not compromised. The endocrinologist is central to the success of this team approach, which could be successfully applied to care of patients undergoing TS, as well as other types of endocrine surgery at other centers.

Langerhans Cell Histiocytosis: Diagnosis on Thyroid Aspirate and Review of the Literature.

Thyroid gland involvement by Langerhans cell histiocytosis is extremely rare. A 35-year-old woman with a history of a suprasellar mass previously diagnosed as a ganglioglioma and complicated by diabetes insipidus, hypogonadotropic hypogonadism, and central hypothyroidism presented with acute onset of neck enlargement. On ultrasound examination, almost the entire thyroid appeared replaced by abnormal lobulated hypoechoic tissue with increased vascularity. Fine needle aspiration (FNA) of the thyroid was performed and revealed singly scattered and loosely cohesive large cells with abundant cytoplasm, including some with irregular nuclear contours and nuclear grooves. No thyroid follicular cells were noted. Based on the cytomorphologic findings and ancillary studies (immunohistochemistry and flow cytometry analysis) a cytological diagnosis of "positive for neoplastic cells" with features suggestive of monocytic/histiocytic origin, possibly Langerhans cell histiocytosis (LCH) was rendered. Following FNA, the patient underwent an incisional thyroid biopsy that confirmed the cytological impression of LCH. In light of the new diagnosis of LCH, the prior suprasellar mass biopsy slides were re-reviewed and rare cells suspicious for LCH were observed. Appropriate treatment for systemic LCH was initiated successfully. This case demonstrates that the presence of enlarged and loosely cohesive cells, especially those with irregular nuclear contours, in thyroid FNA specimens should raise suspicion for LCH. The diagnosis of LCH in FNA specimens is challenging. Additional material should be allocated for ancillary studies to confirm the morphological impression. In our case, not only was the thyroid FNA crucial in diagnosing LCH, but instrumental in initiating a thorough diagnostic work-up for multisystem involvement and thus unmasking the true etiology of the patient's suprasellar mass and associated endocrinopathies.

Epithelioid pituicytoma.

BACKGROUND: Pituicytomas are rare tumors of the sellar region that are derived from specialized glial cells called pituicytes. They characteristically exhibit spindle-cell features and fascicular or storiform patterns of growth. No other histological variants of this tumor have been described. CASE DESCRIPTION: Here we report a diagnostically challenging case of pituicytoma in a 42-year-old man with a sellar mass arising from the pituitary stalk. On histological examination, the tumor displayed an epithelioid histoarchitecture with no characteristic spindle-cell or fascicular growth features. Strong immunopositivity for the pituicyte marker thyroid transcription factor-1 within tumor cells proved essential for diagnosing this unusual pituicytoma variant. CONCLUSION: Pituicytomas may display epithelioid rather than fascicular or storiform histoarchitecture. Epithelioid pituicytoma variants may be diagnosed in cases such as ours in which both the clinical findings and immunohistochemical analysis suggest a tumor derived from pituicytes.

Postoperative assessment of the patient after transsphenoidal pituitary surgery.

While most transsphenoidal pituitary surgery is accomplished without complication, monitoring is required postoperatively for a set of disorders that are specific to this surgery. Postoperative assessments are tailored to the early and later postoperative periods. In the early period, which spans the first few weeks after surgery, both monitoring of anterior and posterior pituitary function and managing neurosurgical issues are the focus of care. Potential disruption of pituitary-adrenal function is covered with perioperative glucocorticoids. Various strategies exist for ensuring the integrity of this axis, but typically this is done by measuring a morning cortisol on the 2nd or 3rd postoperative days. Patients with levels <10 microg/l should continue therapy with reassessment in the later postoperative period. Monitoring for water imbalances, which are due to deficiency or excess of ADH (DI or SIADH, respectively), is accomplished by continuous accounting of fluid intake, urine output and specific gravities coupled with daily serum electrolyte measurements. DI is characterized by excess volumes of inappropriately dilute urine, which can lead to hypernatremia. Most patients maintain adequate fluid intake and euvolemia, but desmopressin therapy is required for some. SIADH, which peaks in incidence on 7th postoperative day, presents with hyponatremia that can be severe and symptomatic. Management consists of fluid restriction. Neurosurgical monitoring is primarily for disturbances in vision or neurological function, and although uncommon, for CSF leak and infections such as meningitis. In the later postoperative period, the adrenal, thyroid and gonadal axes are assessed. New persistent hypopituitarism is rare when transsphenoidal surgery is performed by an experienced surgeon. Various strategies are available for assessing each axis and for providing replacement therapy in patients with deficiencies. Long term monitoring with assessments of visual, neurological and pituitary function coupled with pituitary imaging is necessary for all patients who have undergone surgery, irrespective of the hormone status of their tumors.

Are minority children the last to benefit from a new technology? Technology diffusion and inhaled corticosteriods for asthma.

BACKGROUND: Racial and ethnic disparities in health and health care have been well documented, but few studies have addressed how disparities may change over time. OBJECTIVE: We sought to determine the change in relative rates over time of corticosteroid metered dose inhaler (MDI) use in minority and nonminority populations with asthma. DESIGN AND SETTING: We used a cross-sectional survey for 5 periods of 2 years' each (1989-1990, 1991-1992, 1993-1994, 1995-1996, 1997-1998) using the National Ambulatory Medical Care Surveys (NAMCS). PARTICIPANTS: A total of 3671 visits by adults and children with asthma to U.S. office-based physicians comprised our sample. MAIN OUTCOME MEASURE: We sought to measure differences in inhaled corticosteroid use for minority and nonminority adults and children controlling for gender, specialty, U.S. region, and type of insurance. RESULTS: Minority patients with asthma were less than half as likely as nonminority patients to have had a steroid MDI prescribed during 1989-1990. By 1995-1996, minority and nonminority patients with asthma were equally likely to have had a steroid MDI prescribed. Although differences between black and white patients resolved, differences between white and Hispanic patients persisted even after adjusting for insurance. Children initially were less likely than adults with asthma to have steroid MDI prescribed, and this difference persisted. Minority children had the greatest delay in adoption of steroid MDIs. CONCLUSION: Steroid MDIs diffused into minority and nonminority adult and child populations at different rates.

Trends in medication use for osteoarthritis treatment.

OBJECTIVE: To investigate recent national trends in nonsteroidal antiinflammatory drug (NSAID) and acetaminophen use for osteoarthritis (OA). METHODS: Using data from the 1989-98 National Ambulatory Medical Care Survey, a representative sample of US office based physician visits, we assessed 4471 visits by patients 45 years or older with a diagnosis of OA. We examined cross sectional and longitudinal patterns of OA pharmacotherapy. The independent effects of patient and physician characteristics on NSAID and acetaminophen use were examined using multiple logistic regression analysis. RESULTS: Pharmacological treatment for OA (either NSAID, acetaminophen, or both) has steadily decreased from 49% of visits (1989-91) to 46% (1992-94) to 40% (1995-98) (p = 0.001). Reduced NSAID use over this time period (46% to 33%; p = 0.001) was partially offset by a modest increase in acetaminophen use (5% to 10%; p = 0.001). Among individual NSAID, ibuprofen (5.7% of OA visits), nabumetone (4.9%), naproxen (4.6%), and aspirin (4.4%) were the most frequently reported in 1995-98. For patient visits in 1995-98, 45 to 59-year-olds (38%) received NSAID more often than 60 to 74-year-olds (34%) or patients older than 75 (28%; p = 0.029). Other possible predictors of OA therapy included patient race and physician specialty. CONCLUSION: The decline in the use of NSAID from 1989 to 1998, especially among elderly patients, and the frequent selection of safer medications may reflect awareness of the literature citing the risks of nonsteroidals for OA. However, variations in prescribing patterns among different patient populations and the modest use of acetaminophen, despite evidence supporting its efficacy, suggest that better assimilation of the literature into medical practice is needed to optimize OA therapy.

National Patterns of Depression Treatment in Primary Care.

BACKGROUND: While past studies suggest that primary care physicians underdiagnose and undertreat depression, little is known about recent national patterns of depression treatment. METHOD: Using the 1995 and 1996 National Ambulatory Medical Care Surveys, we analyzed 1322 primary care office visits by patients reported to have depression. Rates of psychotherapy/mental health counseling, antidepressant use, and benzodiazepine use were assessed. Independent predictors of depression therapy were examined using multiple logistic regression. Where instructive, we compared the practices of primary care physicians with those of psychiatrists (2418 depression visits). RESULTS: Primary care physicians reported depression in 7.8% of their office visits. For these depression visits, antidepressants (42%) were the most common form of treatment, followed by psychotherapy/mental health counseling (28%) and benzodiazepines (21%). Among specific antidepressants, selective serotonin reuptake inhibitors were most often prescribed by primary care physicians (26% of depression visits). Rates of antidepressant and benzodiazepine use varied significantly by primary care specialty. In addition, geographic region and health insurance status influenced the likelihood of receiving benzodiazepines. In their depression visits, psychiatrists reported psychotherapy/mental health counseling (88%) most frequently, followed by antidepressants (64%) and benzodiazepines (25%). CONCLUSION: The predominant use of selective serotonin reuptake inhibitors suggests that primary care physicians have begun to adopt new therapeutic strategies for depression. The modest rate of antidepressant therapy for a clinical population specifically identified by primary care physicians as having depression may indicate undertreatment of depression in primary care settings. Furthermore, high rates of benzodiazepine use are inconsistent with treatment guidelines, and variations in treatment patterns suggest that nonclinical factors influence depression management.