Short-Term Oral Corticosteroid Use Tied to Higher Risks of GI Bleeds, Sepsis, Heart Failure

Study Authors: Tsung-Chieh Yao, Ya-Wen Huang, et al.; Beth I. Wallace, Akbar K. Waljee

Target Audience and Goal Statement: Primary care physicians, rheumatologists, pulmonologists, dermatologists, gastroenterologists, cardiologists

The goal of this study was to examine the associations between oral corticosteroid bursts and severe adverse events among adults in Taiwan.

Question Addressed:

  • What were the associations between steroid bursts and severe adverse events, specifically gastrointestinal (GI) bleeding, sepsis, and heart failure?

Study Synopsis and Perspective:

It has long been known that long-term use of corticosteroids can be both effective and toxic. Long-term use is associated with adverse effects such as infections, GI bleeding/ulcers, cardiovascular disease (CVD), Cushing syndrome, diabetes and metabolic syndromes, cataracts, glaucoma, and osteoporosis. Most clinical practice guidelines caution against long-term steroid use unless medically necessary.

Action Points

  • In a retrospective cohort study and self-controlled case series, prescriptions for oral steroid bursts were found to be associated with increased risks for gastrointestinal bleeding, sepsis, and heart failure within the first month after initiation, despite a median exposure of just 3 days.
  • Note that the risks were highest 5 to 30 days after exposure, and attenuated during the subsequent 31 to 90 days.

Instead, clinical practice guidelines recommend steroid bursts for inflammatory ailments such as asthma, inflammatory bowel disease, and rheumatoid arthritis. Waljee and colleagues noted in 2017 that they are most commonly used for upper respiratory infections, suggesting that many people are receiving steroids in the real world.

In a retrospective cohort study and self-controlled case series, prescriptions for oral steroid bursts — defined as short courses of oral corticosteroids for 14 or fewer days — were found to be associated with increased risks for GI bleeding, sepsis, and heart failure within the first month after initiation, despite a median exposure of just 3 days, according to Tsung-Chieh Yao, MD, PhD, of Chang Gung Memorial Hospital in Taoyuan, and colleagues.

The risks were highest 5 to 30 days after exposure, and attenuated during the subsequent 31 to 90 days, they reported in Annals of Internal Medicine.

The self-controlled case series was based on national medical claims records. Included were adults, ages 20-64, covered by Taiwan’s National Health Insurance in 2013-2015.

Out of a population of more than 15.8 million, study authors identified 2,623,327 people who received a steroid burst during the study period. These individuals were age 38 on average, and 55.3% were women. About 85% had no baseline comorbid conditions.

The most common indications for the steroid burst were skin disorders and respiratory tract infections.

The incidence rates among patients prescribed steroid bursts were 27.1 per 1,000 person-years for GI bleeding (incidence rate ratio [IRR] 1.80, 95% CI 1.75-1.84), 1.5 per 1,000 person-years for sepsis (IRR 1.99, 95% CI 1.70-2.32), and 1.3 per 1,000 person-years for heart failure (IRR 2.37, 95% CI 2.13-2.63).

Absolute risk elevations were similar in patients with and without comorbid conditions, meaning that the potential for harm was not limited to those at high risk for these adverse events.

The study authors acknowledged that they could not adjust for disease severity and major lifestyle factors such as alcohol use, smoking, and body mass index; because these factors were static, the effect could be eliminated using the self-controlled case series design. Their reliance on prescription data also meant they could not tell if patients actually complied with oral corticosteroid therapy. Furthermore, the exclusion of the elderly and younger populations also left room for underestimation of the risks of steroid bursts, they said.

Source References: Annals of Internal Medicine 2020; DOI: 10.7326/M20-0432

Editorial: Annals of Internal Medicine 2020; DOI: 10.7326/M20-4234

Study Highlights and Explanation of Findings:

Over the 3-year study period, steroid bursts were commonly prescribed to adults. Such prescriptions were written for common conditions, including skin disorders and upper respiratory tract infections. The highest risks for GI bleeding, sepsis, and heart failure occurred within the first month after receipt of the steroid burst, and this risk was attenuated during the subsequent 31 to 90 days.

“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the researchers wrote. Notably, one corticosteroid that fits the bill is dexamethasone — a medication that holds promise for the treatment of critically ill COVID-19 patients, although it is not generally prescribed orally for these patients.

Based on preliminary results, the NIH’s COVID-19 treatment guidelines panel recommended the use of “dexamethasone (at a dose of 6 mg per day for up to 10 days) in patients with COVID-19 who are mechanically ventilated and in patients with COVID-19 who require supplemental oxygen but who are not mechanically ventilated.” In addition, they recommend “against using dexamethasone in patients with COVID-19 who do not require supplemental oxygen.”

“We are now learning that bursts as short as 3 days may increase risk for serious AEs [adverse events], even in young and healthy people. As providers, we must reflect on how and why we prescribe corticosteroids to develop strategies that prevent avoidable harms,” wrote Beth Wallace, MD, and Akbar Waljee, MD, both of the VA Ann Arbor Healthcare System and Michigan Medicine.

On the basis of the reported risk differences in the study, Wallace and Waljee calculated that one million patients exposed to corticosteroid bursts experienced 41,200 GI bleeding events, 400 cases of sepsis, and 4,000 cases of new heart failure per year that were directly attributed to this brief treatment.

“Although many providers already avoid corticosteroids in elderly patients and those with comorbid conditions, prescribing short bursts to ‘low-risk’ patients has generally been viewed as innocuous, even in cases where the benefit is unclear. However, Yao and colleagues provide evidence that this practice may risk serious harm, making it difficult to justify in cases where corticosteroid use lacks evidence of meaningful benefit,” they wrote in an accompanying editorial.

“Medication-related risks for AEs can, of course, be outweighed by major treatment benefit. However, this study and prior work show that corticosteroid bursts are frequently prescribed for self-limited conditions, where evidence of benefit is lacking,” Wallace and Waljee noted.

“As we reflect on how to respond to these findings, it is useful to note the many parallels between use of corticosteroid bursts and that of other short-term medications, such as antibiotics and opiates. All of these treatments have well-defined indications but can cause net harm when used — as they frequently are — when evidence of benefit is low,” they emphasized.

Last Updated August 07, 2020
Reviewed by Dori F. Zaleznik, MD Associate Clinical Professor of Medicine (Retired), Harvard Medical School, Boston

From https://www.medpagetoday.org/primarycare/generalprimarycare/87959?xid=nl_mpt_DHE_2020-08-08&eun=g1406328d0r&utm_term=NL_Daily_DHE_dual-gmail-definition&vpass=1

Smart, Soft Contact Lens For Wireless Immunosensing of Cortisol

Abstract

Despite various approaches to immunoassay and chromatography for monitoring cortisol concentrations, conventional methods require bulky external equipment, which limits their use as mobile health care systems. Here, we describe a human pilot trial of a soft, smart contact lens for real-time detection of the cortisol concentration in tears using a smartphone. A cortisol sensor formed using a graphene field-effect transistor can measure cortisol concentration with a detection limit of 10 pg/ml, which is low enough to detect the cortisol concentration in human tears. In addition, this soft contact lens only requires the integration of this cortisol sensor with transparent antennas and wireless communication circuits to make a smartphone the only device needed to operate the lens remotely without obstructing the wearer’s view. Furthermore, in vivo tests using live rabbits and the human pilot experiment confirmed the good biocompatibility and reliability of this lens as a noninvasive, mobile health care solution.

INTRODUCTION

The steroid hormone, cortisol, which is known as a stress hormone, is secreted by the adrenal gland when people are stressed psychologically or physically (1). This secretion occurs when the adrenal gland is stimulated by adrenocorticotropic hormone, which is secreted by the pituitary gland when it is stimulated by the corticotropin-releasing hormone secreted by the hypothalamus. This serial cortisol secretion system is referred to as a hypothalamus–pituitary gland–adrenal gland axis, which is affected by chronic stress, resulting in abnormal secretion of cortisol (23). The accumulation of cortisol caused by the abnormal secretion of cortisol increases the concentrations of fat and amino acid, which can result in diverse severe diseases (e.g., Cushing’s disease, autoimmune disease, cardiovascular complications, and type 2 diabetes) and neurological disorders (such as depression and anxiety disorders) (27). In contrast, abnormally low cortisol levels can lead to Addison’s disease, which results in hypercholesterolemia, weight loss, and chronic fatigue (8). In addition, it was recently reported that plasma cortisol can be correlated to the prognosis of traumatic brain injury (9). Furthermore, the extent of cortisol secretion varies from person to person, and it changes continuously (1011). Thus, developing health care systems for real-time monitoring of the cortisol level has been explored extensively over the past decade as the key to the quantitative analysis of stress levels. Although various efforts have led to the development of cortisol sensors that can measure the concentration of cortisol in blood, saliva, sweat, hair, urine, and interstitial fluid (1217), the accurate measurement of cortisol concentrations has been limited because of the difficulties associated with the transportation and storage of cortisol as well as the instability of the biologically active cortisol in these body fluids at room temperature. In addition, these conventional sensing methods require bulky equipment for the extraction and analysis of these body fluids, which is not suitable for mobile health care systems (1218). Therefore, the development of noninvasive and wearable sensors that can monitor cortisol concentration accurately is highly desirable for a smart health care solution. For example, the immunoassay method, which uses an antigen-antibody binding reaction, has been used extensively for electrochemical cortisol immunosensors using saliva and interstitial fluid, except tears (121419). However, these immunosensors still require the use of bulky impedance analyzers for the analysis of the Nyquist plot from electrochemical impedance spectroscopy. Although the cyclic voltammetry (CV) technique can be used as an alternative approach for sensing cortisol, additional bulky electrochemical instruments still are necessary for analyzing the CV curves (131419). Recently, wearable forms of cortisol sensors that use sweat were developed (15), but they still required bulky measurement equipment (1516). Therefore, portable and smart sensors that can monitor the accurate concentration of cortisol in real time are highly desirable for use in mobile health care.

Among the various body fluids, tears, in particular, contain important biomarkers, including cortisol (2021). Thus, the integration of biosensors with contact lenses is a potentially attractive candidate for the noninvasive and real-time monitoring of these biomarkers from tears (2225). However, an approach for fabricating a smart contact lens for sensing the cortisol in tears has not been demonstrated previously. Thus, here, we present an extraordinary approach for the formation of a smart, soft contact lens that enables remote, real-time monitoring of the cortisol level in the wearer’s tears using mobile phones. This smart, soft contact lens is composed of a cortisol sensor, a wireless antenna, capacitors, resistors, and integrated circuit chips that use stretchable interconnects without obstructing the wearer’s view. The components of this device (except the antenna) were protected from mechanical deformations by locating each of the components on discrete, rigid islands and by embedding these islands inside an elastic layer. A graphene field-effect transistor (FET; with the binding of monoclonal antibody) was used as this cortisol immunosensor, which exhibited a sufficiently low detection limit, i.e., 10 pg/ml, for its sensing of cortisol in human tears in which the cortisol concentration ranges from 1 to 40 ng/ml (26). This sensor was integrated with a near-field communication (NFC) chip and antenna inside the soft contact lens for the real-time wireless transmission of the data to the user’s mobile device (e.g., a smart phone or a smart watch). The antenna occupies a relatively large area of this soft lens, so it requires its high stretchability, good transparency, and low resistance for operating a standard NFC chip at 13.56 MHz. In our approach, the hybrid random networks of ultralong silver nanofibers (AgNFs) and fine silver nanowires (AgNWs) enabled high transparency and good stretchability of this antenna and its low sheet resistance for reliable standard NFCs (at 13.56 MHz) inside this smart contact lens. Thus, the fully integrated system of this smart contact lens provided wireless and battery-free operation for the simultaneous detection and transmission of the cortisol concentration from tears to a mobile phone using standard NFC. In addition, a human pilot trial and in vivo tests conducted using live rabbits demonstrated the biocompatibility of this lens, and its safety against inflammation and thermal/electromagnetic field radiation suggests its substantial usability as a noninvasive, mobile health care solution.

RESULTS

Cortisol immunosensor

A graphene FET sensor was fabricated by binding the cortisol monoclonal antibody (C-Mab) to the surface of graphene for the immunosensing of cortisol. Here, graphene acts as a transducer that converts the interaction between cortisol and C-Mab into electrical signals. Figure 1A shows the immobilization process of C-Mab to graphene. Immobilization proceeds through amide bonding of the C-Mab onto the carboxyl group of the graphene surface via the EDC [1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride]/NHS (N-hydroxysulfosuccinimide) coupling reaction. A chemical vapor deposition–synthesized graphene layer was transferred onto a desired substrate and exposed to ultraviolet ozone (UVO) to activate the surface of the graphene with the carboxylate group. Figure S1 shows the contact angle between this surface of the graphene and a droplet of deionized (DI) water. Longer exposure time to UVO can decrease the hydrophobicity of graphene with decreasing the contact angle. Table S1 shows the increase in the electrical resistance of graphene that resulted from this UVO treatment. In our experiment, 2 min of exposure time to UVO decreased the contact angle from 70° to 38° without increasing the resistance of the graphene notably. UVO exposure times longer than this threshold time degraded the resistance of the graphene excessively, so the time of exposure of our samples to UVO was limited to 2 min. Figure S2A illustrates the process of immobilizing C-Mab through the EDC/NHS coupling reaction. This two-step coupling reaction of EDC and NHS can mediate the amide bonding between the carboxylate group of the UVO-exposed graphene and the amine group of the protein (12172728). Here, EDC forms reactive O-acylisourea ester, thereby making the surface unstable. This O-acylisourea ester reacts with the NHS to form amine-reactive NHS ester with the surface still remaining semistable. Then, C-Mab with the amine group reacts with the amine-reactive NHS ester, thereby forming stable amide bonding that can immobilize C-Mab to the NHS on the surface of the graphene. Figure S2B shows the Fourier transform infrared (FTIR) spectroscopy spectra of the DI water after the cortisol sensor had been immersed for 24 hours. The spectra of the DI water in which the sensor was immersed were not significantly different from those of the pristine DI water. However, the C-Mab solution that had a concentration of 1 μg/ml had a significant peak intensity in the range of 3000 to 2800 cm−1, representing the N-H bonding in the C-Mab. These results indicated that C-Mab formed stable bonding on the carboxylated graphene and was negligibly detached by exposure to water.

From https://advances.sciencemag.org/content/6/28/eabb2891

Estrogen receptor α plays an important role in Cushing’s syndrome during pregnancy

Abstract

Cushing’s syndrome (CS) during pregnancy is very rare with a few cases reported in the literature.

Of great interest, some cases of CS during pregnancy spontaneously resolve after delivery. Most studies suggest that aberrant luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor (LHCGR) seems to play a critical role in the pathogenesis of CS during pregnancy.

However, not all women during pregnancy are observed cortisol hypersecretion. Moreover, some cases of adrenal tumors or macronodular hyperplasia with LHCGR expressed, have no response to hCG or LH.

Therefore, alternative pathogenic mechanisms are indicated. It has been recently reported that estrogen binding to estrogen receptor α (ERα) could enhance the adrenocortical adenocarcinoma (ACC) cell proliferation.

Herein, we hypothesize that ERα is probably involved in CS development during pregnancy.

Better understanding of the possible mechanism of ERα on cortisol production and adrenocortical tumorigenesis will contribute to the diagnosis and treatment of CS during pregnancy.

Read the entire article here: https://www.sciencedirect.com/science/article/pii/S0306987720303893?via%3Dihub

AACE Position Statement: Coronavirus (COVID-19) and People with Adrenal Insufficiency and Cushing’s Syndrome

With the novel COVID-19 virus continuing to spread, it is crucial to adhere to the advice from experts and the Centers for Disease Control and Prevention (CDC) to help reduce risk of infection for individuals and the population at large. This is particularly important for people with adrenal insufficiency and people with uncontrolled Cushing’s Syndrome.

Studies have reported that individuals with adrenal insufficiency have an increased rate of respiratory infection-related deaths, possibly due to impaired immune function. As such, people with adrenal insufficiency should observe the following recommendations:

  • Maintain social distancing to reduce the risk of contracting COVID-19
  • Continue taking medications as prescribed
  • Ensure appropriate supplies for oral and injectable steroids at home, ideally a 90-day preparation
    • In the case of hydrocortisone shortages, ask your pharmacist and physician about replacement with different strengths of hydrocortisone tablets that might be available. Hydrocortisone (or brand name Cortef) tablets have 5 mg, 10 mg or 20 mg strength
  • In cases of acute illness, increase the hydrocortisone dose per instructions and call the physician’s office for more details
    • Follow sick day rules for increasing oral glucocorticoids or injectables per your physician’s recommendations
      • In general, patients should double their usual glucocorticoid dose in times of acute illness
      • In case of inability to take oral glucocorticoids, contact your physician for alternative medicines and regimens
  • If experiencing fever, cough, shortness of breath or other symptoms, call both the COVID-19 hotline (check your state government website for contact information) and your primary care physician or endocrinologist
  • Monitor symptoms and contact your physician immediately following signs of illness
  • Acquire a medical alert bracelet/necklace in case of an emergency

Individuals with uncontrolled Cushing’s Syndrome of any origin are at higher risk of infection in general. Although information on people with Cushing’s Syndrome and COVID-19 is scarce, given the rarity of the condition, those with Cushing’s Syndrome should strictly adhere to CDC recommendations:

  • Maintain social distancing to reduce the risk of contracting COVID-19
  • If experiencing fever, cough, shortness of breath or other symptoms, call both the COVID-19 hotline (check your state government website for contact information) and your primary care physician or endocrinologist

In addition, people with either condition should continue to follow the general guidelines at these times:

  • Stay home as much as possible to reduce your risk of being exposed
    • When you do go out in public, avoid crowds and limit close contact with others
    • Avoid non-essential travel
  • Wash your hands with soap and water regularly, for at least 20 seconds, especially before eating or drinking and after using the restroom and blowing your nose, coughing or sneezing
  • If soap and water are not readily available, use an alcohol-based sanitizer with at least 60% alcohol
  • Cover your nose and mouth when coughing or sneezing with a tissue or a flexed elbow, then throw the tissue in the trash
  • Avoid touching your eyes, mouth or nose when possible

From https://www.aace.com/recent-news-and-updates/aace-position-statement-coronavirus-covid-19-and-people-adrenal

Update on Coronavirus (COVID-19)

Along with all of you, NADF is monitoring this outbreak by paying close attention to CDC and FDA updates. We have also asked our Medical Advisor to help answer your important questions as they come up.

We asked Medical Director Paul Margulies, MD, FACE, FACP to help us with this question:

Question: Does Adrenal Insufficiency cause us to have a weakened immune system and therefore make us more susceptible?

Response: Individuals with adrenal insufficiency on replacement doses of glucocorticoids do not have a suppressed immune system. The autoimmune mechanism that causes Addison’s disease does not cause an immune deficiency that would make one more likely to get an infection. The problem is with the individual’s ability to deal with the stress of an infection once it develops. Those with adrenal insufficiency fall into that category. When sick with a viral infection, they can have a more serious illness, and certainly require stress dose steroids to help to respond to the illness. If someone with adrenal insufficiency contracts the coronavirus, it is more likely to lead to the need for supportive care, including hospitalization.

This information from the CDC Website provides important information regarding Prevention & Treatment.  You can find this information here: https://www.cdc.gov/coronavirus/2019-ncov/about/prevention-treatment.html

 

From https://www.nadf.us/

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