Sleep disturbance in the critically ill has received much attention over recent years as this is a common result of intensive care unit (ICU) admission. Disruptions in sleep not only can, at a minimum, cause distress and lower patient satisfaction, but also inhibit recovery from illness and increase morbidity.^1,2 Several studies have been conducted highlighting the altered sleep patterns of critically ill patients; although total sleep time may seem normal (7-9 hours), patients can experience multiple awakenings per hour, more time in light sleep (stages 1 and 2), and less time in restorative sleep (stages 3 and 4, [REM]rapid eye movement).^2-5

There are several hypothesized physiologic detriments that contribute to slower ICU recovery with sleep deprivation. Research in noncritically ill subjects suggests that sleep deprivation contributes to hypoventilation and potentially prolonged time on the ventilator.^6-9 Cardiovascular morbidity may be adversely affected by inflammatory cytokine release seen in sleep disruption.^10,11 Studies of noncritically ill patients also suggest that immune response is impaired, potentially protracting infection recovery.^12,13 Finally, although not directly investigated, sleep deprivation may contribute to ICU delirium, an independent adverse effect (AE) associated with increased mortality and worse long-term outcomes.^14-16

The Society of Critical Care Medicine (SCCM) recently updated its consensus guidelines for the management of pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS) in adult patients.¹⁷ These guidelines offer limited interventions to promote sleep in ICU patients based on available evidence and steer the clinician toward minimizing exacerbating factors. Although factors that affect sleep patterns are multifactorial, such as noise levels, pain, mechanical ventilation, and inflammatory mediators, medication therapy is a known modifiable risk factor for sleep disturbance in critically ill patients.² This focused review will specifically evaluate the effects of steroids on sleep deprivation, psychosis, delirium, and what is known about these effects in a critically ill population.

To include articles relevant to a critically ill population, a systematic search of MEDLINE and PubMed from 1966 to 2019 was performed using the following Medical Subject Headings (MeSH) terms: delirium/etiology, psychoses, substance-induced/etiology, sleep-wake disorders/chemically induced, neurocognitive disorders/chemically induced, dyssomnias/drug effects plus glucocorticoids/adverse effects, adrenal cortex hormones/adverse effects, prednisone/adverse effects, methylprednisolone/adverse effects, and hydrocortisone/adverse effects. The initial search produced 285 articles. Case reports, reviews, letters, and articles pertaining to primary care or palliative populations were excluded, leaving 8 relevant articles for inclusion (Table 1).^18-25

ICU Steroid Use

Steroids are commonly used in the ICU and affect nearly every critically ill population. Common indications for steroids in the ICU include anaphylaxis, airway edema, septic shock, asthma and COPD exacerbations, pneumocystis pneumonia, adrenal crisis, antiemetic treatment, elevated intracranial pressure from tumors, autoimmune disorders, and stress doses needed for chronic steroid users before invasive procedures.²⁶ Whether divided into glucocorticoid or mineralocorticoid subgroups, corticosteroids offer therapeutic benefit from their pharmacologic similarity to endogenously produced cortisol, which includes anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.

Steroid receptors are present in most human tissue, and in varying degrees of binding affinity produce a wide variety of effects. After passive diffusion across cell membranes, steroid-receptor activation binds to various DNA sites, called glucocorticoid regulatory elements, which either stimulates or inhibits transcription of multiple nearby genes.

At the cellular level, corticosteroids inhibit the release of arachidonic acid through upstream production of lipocortin peptides and antagonism of phospholipase A₂. This action decreases subsequent inflammatory mediators, including kinins, histamine, liposomal enzymes, and prostaglandins. Steroids also inhibit NF-κB, which further decreases expression of proinflammatory genes while promoting interleukin-10 and its anti-inflammatory properties. Antiproliferative effects of steroids are seen by triggering cell apoptosis and inhibition of fibroblast proliferation.^27,28

By binding to mineralocorticoid receptors, steroids cause sodium retention coupled with hydrogen and potassium excretion in the distal renal tubule. Steroids also promote vasoconstriction by upregulating the production and sensitivity of β receptors in the endothelium while suppressing the production of vasodilators. Although rarely used for these physiologic effects, steroids also are involved in a number of metabolic pathways, including calcium regulation, gluconeogenesis, protein metabolism, and fat distribution. Given the similar structure to cortisol, exogenous steroids depress the hypothalamic-pituitary axis (HPA) and decrease the release of adrenocorticotropic hormone (ACTH). Tapering doses of steroid regimens is often required to allow natural androgen and cortisol synthesis and prevent steroid withdrawal.^27,28

The potency of various exogenous steroids closely parallels their ability to retain sodium (Table 2). Prolonged activation of steroid receptors can have numerous systemic AEs, including unwanted neurocognitive effects (Table 3). Insomnia and psychosis are commonly described in corticosteroid clinical trials, and in one meta-analysis, both are associated with high costs per episode per year.²⁹

Steroid-Induced Sleep Disruption and Psychosis

Sleep disruption caused by exogenous administration of steroids is thought to trigger other psychostimulant effects, such as mood swings, nervousness, psychoses, and delirium.³⁰ Similarly, the SCCM PADIS guidelines included an ungraded statement: “although an association between sleep quality and delirium occurrence exists in critically ill adults, a cause-effect relationship has not been established.”¹⁷ For this review, these AEs will be discussed as related events.

The medical literature proposes 3 pathways primarily responsible for neurocognitive AEs of steroids: behavior changes through modification of the HPA axis, changes in natural sleep-wake cycles, and hyperarousal caused by modification in neuroinhibitory pathways (Figure).

HPA Axis Modification

Under either physical or psychological stress, neural circuits in the brain release corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), and arginine vasopressin, which go on to activate the sympathetic nervous system and the HPA axis. CRH from the hypothalamus goes on to stimulate ACTH release from the pituitary. ACTH then stimulates cortisol secretion from the adrenal glands. Circulating cortisol feeds into several structures of the brain, including the pituitary, hippocampus, and amygdala. Steroid-receptor complexes alter gene transcription in the central nervous system (CNS), affecting the production of neurotransmitters (eg, dopamine, serotonin) and neuropeptides (eg, somatostatin, β-endorphin). Feedback inhibition ensues, with downregulation of the HPA axis, which prevents depletion of endogenous production of steroids.³¹ DHEA has protective effects against excessive cortisol activity, but DHEA secretion declines with prolonged cortisol exposure. Exogenous steroids may have different effects than endogenous steroids, and neurocognitive sequelae stem from disruption and imbalance of these physiologic mechanisms.^32,33

Steroid receptors are densely located in behavior centers in the brain: the amygdala, septum, and hippocampus. Pharmacologic changes in gene expression alter norepinephrine and serotonin levels in the brain as well as their receptors.³² Prolonged exposure to exogenous steroids has been shown to decrease amygdala and hippocampal volumes.^34,35 Furthermore, prolonged corticosteroid exposure has been shown to decrease the number of steroid receptors in the hippocampus, pituitary gland, and amygdala.³⁶ In a somewhat paradoxical finding, the production of CNS proinflammatory cytokines like interleuken-1β and tumor necrosis factor α has been seen after steroid administration, suggesting alternate gene signaling in the CNS.³⁷ Although not proven conclusively, it is felt that these physiologic changes and hyperactivity of the HPA axis are predominantly responsible for changes in behavior, mood, memory, and eventually psychosis in steroid-treated patients.^33,38

Finally, alterations in cognition and behavior may be related to steroid-induced changes in CNS carbohydrate, protein, and lipid metabolism with subsequent cellular neurotoxicity.^32,38 Glucose uptake into the hippocampus is decreased with steroid exposure. Additionally, breakdown of metabolic compounds to produce energy can be destructive if left unchecked for prolonged periods. DHEA, growth hormone, and testosterone work to repair catabolic damage produced by cortisol, known as anabolic balance. A low anabolic balance (low DHEA levels to high cortisol levels) leads to a cascade of dysregulation in brain activity.³⁹

Changes in Natural Sleep-Wake Cycles

Natural sleep pathways are also affected by steroids. The sleep-wake cycle is primarily regulated in the hypothalamus with circadian release of melatonin from the pineal gland. Melatonin release is highest at night, where it promotes sleep onset and continuity. Upstream, tryptophan is an amino acid that serves as a precursor to serotonin and melatonin.⁴⁰ Both endogenous and exogenous corticosteroids decrease serum melatonin levels with a markedly diminished circadian rhythm secretion.^41,42Demish and colleagues found a significant decrease in mean (SD) nocturnal melatonin plasma levels after the evening administration of oral dexamethasone 1 mg in 11 healthy volunteers: 127 (42) pg/mL before vs 73 (38) pg/mL after; P < .01.⁴² This result is likely due to decreased cellular metabolism and melatonin synthesis in the pineal gland. Of note, melatonin has neuroprotective affects, and the administration of melatonin has been shown to reverse some steroid-induced neurotoxicities in animal models.⁴³

Steroids also reduce the uptake of tryptophan into the brain.³³ Additionally, in animal models, dexamethasone administration caused a significant decrease in the gene expression of tryptophan hydroxylase, which is part of the multistep pathway in synthesizing serotonin from L-tryptophan. These effects upstream could inhibit the biosynthetic capacity of both melatonin and serotonin.⁴⁴

A third pathway investigated in sleep regulation are the orexin neuropeptides. Orexins are produced in the hypothalamus and stimulate daytime wake activity in monoaminergic and cholinergic neurons. Subsequently, orexin receptor antagonists are a newer class of drugs aimed at mitigating nighttime hyperarousal and sleep disruption. Orexin overexpression may be a causal factor in steroid-induced sleep disturbance. However, this effect was specifically evaluated in a recent study in children with acute lymphoblastic leukemia, which showed that cerebral spinal fluid orexin levels (SD) were not significantly different from baseline after dexamethasone administration: 574 (26.6) pg/mL vs 580 (126.1) pg/mL; P = .8.⁴⁵

Hyperarousal State

Finally, a hyperarousal state is thought to be produced by nongenomic changes to natural neuroinhibitory regulation seen with nonclassical steroid production called neurosteroids. Animal studies revealed that high levels of steroids were found in the CNS long after adrenalectomy, suggesting CNS de novo synthesis.⁴⁶ In addition to altering gene expression at classic intercellular steroid receptors, neurosteroids can alter neurotransmission by direct interaction on ion-gated membranes and other receptors on the cell surface. Restlessness and insomnia could be due to γ-aminobutyric acid type A (GABA_A) receptor modulation in the CNS where neuroactive steroids slow the rate of recovery of GABA_A and potentially inhibit postsynaptic GABAergic transmission. It also is hypothesized that neuroactive steroids have excitatory action at nicotinic acetylcholine, 5HT₃ receptors, and through increasing the fractional open time of the N-methyl-D-aspartate -activated channels.⁴⁷ Allopregnanolone and DHEA are neurosteroids that act as GABA_A agonists and have neuroprotective effects with anxiolytic, antidepressant, and antiaggressive properties.

Neurosteroids are synthesized from cholesterol in the hippocampus. Neurosteroids are upregulated in response to stress by CNS cortisol effects on various enzyme expressions.⁴⁷ Whether exogenous steroid administration affects this biosynthesis vs the stress response in the HPA axis itself is not fully elucidated. Monteleone and colleagues found that dexamethasone 1 mg given orally significantly reduced cortisol and DHEA and allopregnanolone levels in both healthy volunteers and anorexia nervosa patients.⁴⁸ Similarly, Genazzani and colleagues demonstrated that oral dexamethasone administration (0.5 mg every 6 hours) caused significant reductions in both serum allopregnanolone and DHEA levels.⁴⁹

Outcomes Studies

The majority of reported data in steroid-induced insomnia and psychosis is in noncritically ill populations. In a randomized, prospective crossover study of healthy volunteers, dexamethasone administration (3 mg every 8 hours for 48 hours) resulted in significant changes in sleep patterns measured with polysomnography. Compared with placebo, steroid treatment showed significantly longer percentage (SD) of stage 0/awake times (11.7% [11.4] vs 2.9% [1.8]; P < .05); longer percentage (SD) of REM sleep latency (363.8 [74.5] minutes vs 202.8 [79.6] minutes; P < .01), and a reduced number (SD) of REM periods (3.8 [2.6] vs 9.7 [3.6]; P < .01).⁵⁰ Insomnia was one of the most commonly self-reported AEs (> 60%) in a survey of 2,446 chronic steroid users, and the incidence increased as steroid doses increased.⁵¹

A prospective, open-label study of 240 patients with cancer demonstrated significant sleep disruptions using the Pittsburgh Sleep Quality Index with the use of high-dose steroids in chemotherapy.⁵² Naber and colleagues evaluated 50 previously healthy patients taking methylprednisolone 119 mg (41 mg/d) for retinitis and uveitis.⁵³ They reported 26% to 34% of subjects experienced hypomanic syndrome based on a semistructured interview examination. Symptoms developed within 3 days and persisted for the 8-day course of therapy. Brown and colleagues prospectively evaluated 32 asthmatic patients prescribed bursts of prednisone > 40 mg daily. They observed significantly increased scores in the Young Mania Rating Scale within 3 to 7 days of starting therapy, which dissipated to baseline after stopping therapy.⁵⁴

Despite a high reported incidence of neurologic AEs, outcomes in critically ill populations are mixed. Study methods are varied, and many were largely observational. No prospective, randomized studies exist to date specifically aimed and powered to evaluate the effects of steroids on sleep disturbances or delirium in a critically ill population. Furthermore, sleep quality is difficult to measure in this population, and self-reporting often is not an option. In critical care trials, if AEs such as insomnia, delirium, or psychosis are recorded at all, there is heterogeneity in the definitions, and these AEs are generally poorly defined (eg, psychiatric or neurologic disorder not otherwise specified), making pooled analysis of this outcome difficult.⁵⁵

One of the largest observational studies in hospitalized patients was through the Boston Collaborative Drug Surveillance Program. A total of 718 consecutively enrolled inpatients who received prednisone were monitored for acute reactions. Psychiatric AEs were rare (1.3%) with low doses (< 40 mg/d), more prevalent (4.6%) with higher doses (41-80 mg/d), and most prevalent (18.4%) with the highest doses (> 80 mg/d), suggesting CNS AEs are dose dependent.¹⁸ A single-center, retrospective review of 755 psychiatric consults in hospitalized patients revealed that 54% of manic patients were due to corticosteroid administration.¹⁹ In a prospective observational study of 206 consecutive ICU admissions, steroid administration was an independent risk factor for development of ICU delirium, using the Confusion Assessment Method-ICU (CAM-ICU) at a single center (odds ratio [OR], 2.8; 95% CI, 1.05-7.28).²⁵

Two studies in hospitalized oncology patients found conflicting results using the Nursing Delirium Screening Scale (Nu-DESC). One did not find a significant association between delirium and dexamethasone equivalent doses > 15 mg, while the second found an increased hazard ratio (HR) for a positive Nu-DESC score (HR, 2.67; 95% CI, 1.18-6.03).^20,21 Similarly, conflicting results were found in 2 studies using first-order Markov models. In one prospective cohort study, 520 consecutive mechanically ventilated patients in 13 ICUs were monitored for the transition to delirium (CAM-ICU positive) from nondelirium states. Steroid administration was significantly associated with transitioning to delirium (OR, 1.52; 95% CI, 1.05-2.21).²² This conflicts with a similar study by Wolters and colleagues, which monitored 1,112 ICU patients who were given a median prednisone equivalent of 50 mg (interquartile range, 25-75 mg). Steroid administration was not significantly associated with the transition to delirium from an awake without delirium state (OR, 1.08; 95% CI, 0.89-1.32; adjusted OR, 1.00; 95% CI, 0.99-1.01 per 10-mg increase in prednisone equivalent).²³

Mitigating Effects

Although steroid therapy often cannot be altered in the critically ill population, research showed that steroid overuse is common in ICUs.^56,57 Minimizing dosage and duration are important ways clinicians can mitigate unwanted effects. CNS AEs seen with steroids often can be reversed once therapy is discontinued. Avoiding split-dose administration has been proposed given the natural diurnal production of cortisol.⁵⁸ A review by Flaherty discusses the importance of avoiding pharmacologic agents in hospitalized older patients if possible due to known risks (falls, dependency, hip fractures, rebound insomnia, and risk of delirium) and provides a HELP ME SLEEP nomogram for nonpharmacologic interventions in hospitalized patients (Table 4).⁵⁹

Historically, lithium has been recommended for steroid-induced mania with chronic steroid use; however, given the large volume and electrolyte shifts seen in critically ill patients, this may not be a viable option. Antidepressants, especially tricyclics, should generally be avoided in steroid-induced psychosis as these may exacerbate symptoms. If symptoms are severe, either typical (haloperidol) or atypical (olanzapine, quetiapine, risperidone) antipsychotics have been used with success.⁶⁰ Given the known depletion of serum melatonin levels, melatonin supplements are an attractive and relatively safe option for steroid-induced insomnia; however, there are no robust studies specifically aimed at this intervention for this population.

Conclusions

With known, multimodal foci driving sleep impairment in ICU patients, PADIS guidelines recommend myriad interventions for improvement. Recommendations include noise and light reduction with earplugs and/or eyeshades to improve sleep quality. Nocturnal assist-control ventilation may improve sleep quality in ventilated patients. Finally, the development of institutional protocols for promoting sleep quality in ICU patients is recommended.¹⁷

Sleep disturbance in the critically ill has received much attention over recent years as this is a common result of intensive care unit (ICU) admission. Disruptions in sleep not only can, at a minimum, cause distress and lower patient satisfaction, but also inhibit recovery from illness and increase morbidity.^1,2 Several studies have been conducted highlighting the altered sleep patterns of critically ill patients; although total sleep time may seem normal (7-9 hours), patients can experience multiple awakenings per hour, more time in light sleep (stages 1 and 2), and less time in restorative sleep (stages 3 and 4, [REM]rapid eye movement).^2-5

There are several hypothesized physiologic detriments that contribute to slower ICU recovery with sleep deprivation. Research in noncritically ill subjects suggests that sleep deprivation contributes to hypoventilation and potentially prolonged time on the ventilator.^6-9 Cardiovascular morbidity may be adversely affected by inflammatory cytokine release seen in sleep disruption.^10,11 Studies of noncritically ill patients also suggest that immune response is impaired, potentially protracting infection recovery.^12,13 Finally, although not directly investigated, sleep deprivation may contribute to ICU delirium, an independent adverse effect (AE) associated with increased mortality and worse long-term outcomes.^14-16

The Society of Critical Care Medicine (SCCM) recently updated its consensus guidelines for the management of pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS) in adult patients.¹⁷ These guidelines offer limited interventions to promote sleep in ICU patients based on available evidence and steer the clinician toward minimizing exacerbating factors. Although factors that affect sleep patterns are multifactorial, such as noise levels, pain, mechanical ventilation, and inflammatory mediators, medication therapy is a known modifiable risk factor for sleep disturbance in critically ill patients.² This focused review will specifically evaluate the effects of steroids on sleep deprivation, psychosis, delirium, and what is known about these effects in a critically ill population.

To include articles relevant to a critically ill population, a systematic search of MEDLINE and PubMed from 1966 to 2019 was performed using the following Medical Subject Headings (MeSH) terms: delirium/etiology, psychoses, substance-induced/etiology, sleep-wake disorders/chemically induced, neurocognitive disorders/chemically induced, dyssomnias/drug effects plus glucocorticoids/adverse effects, adrenal cortex hormones/adverse effects, prednisone/adverse effects, methylprednisolone/adverse effects, and hydrocortisone/adverse effects. The initial search produced 285 articles. Case reports, reviews, letters, and articles pertaining to primary care or palliative populations were excluded, leaving 8 relevant articles for inclusion (Table 1).^18-25

ICU Steroid Use

Steroids are commonly used in the ICU and affect nearly every critically ill population. Common indications for steroids in the ICU include anaphylaxis, airway edema, septic shock, asthma and COPD exacerbations, pneumocystis pneumonia, adrenal crisis, antiemetic treatment, elevated intracranial pressure from tumors, autoimmune disorders, and stress doses needed for chronic steroid users before invasive procedures.²⁶ Whether divided into glucocorticoid or mineralocorticoid subgroups, corticosteroids offer therapeutic benefit from their pharmacologic similarity to endogenously produced cortisol, which includes anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.

Steroid receptors are present in most human tissue, and in varying degrees of binding affinity produce a wide variety of effects. After passive diffusion across cell membranes, steroid-receptor activation binds to various DNA sites, called glucocorticoid regulatory elements, which either stimulates or inhibits transcription of multiple nearby genes.

At the cellular level, corticosteroids inhibit the release of arachidonic acid through upstream production of lipocortin peptides and antagonism of phospholipase A₂. This action decreases subsequent inflammatory mediators, including kinins, histamine, liposomal enzymes, and prostaglandins. Steroids also inhibit NF-κB, which further decreases expression of proinflammatory genes while promoting interleukin-10 and its anti-inflammatory properties. Antiproliferative effects of steroids are seen by triggering cell apoptosis and inhibition of fibroblast proliferation.^27,28

By binding to mineralocorticoid receptors, steroids cause sodium retention coupled with hydrogen and potassium excretion in the distal renal tubule. Steroids also promote vasoconstriction by upregulating the production and sensitivity of β receptors in the endothelium while suppressing the production of vasodilators. Although rarely used for these physiologic effects, steroids also are involved in a number of metabolic pathways, including calcium regulation, gluconeogenesis, protein metabolism, and fat distribution. Given the similar structure to cortisol, exogenous steroids depress the hypothalamic-pituitary axis (HPA) and decrease the release of adrenocorticotropic hormone (ACTH). Tapering doses of steroid regimens is often required to allow natural androgen and cortisol synthesis and prevent steroid withdrawal.^27,28

The potency of various exogenous steroids closely parallels their ability to retain sodium (Table 2). Prolonged activation of steroid receptors can have numerous systemic AEs, including unwanted neurocognitive effects (Table 3). Insomnia and psychosis are commonly described in corticosteroid clinical trials, and in one meta-analysis, both are associated with high costs per episode per year.²⁹

Steroid-Induced Sleep Disruption and Psychosis

Sleep disruption caused by exogenous administration of steroids is thought to trigger other psychostimulant effects, such as mood swings, nervousness, psychoses, and delirium.³⁰ Similarly, the SCCM PADIS guidelines included an ungraded statement: “although an association between sleep quality and delirium occurrence exists in critically ill adults, a cause-effect relationship has not been established.”¹⁷ For this review, these AEs will be discussed as related events.

The medical literature proposes 3 pathways primarily responsible for neurocognitive AEs of steroids: behavior changes through modification of the HPA axis, changes in natural sleep-wake cycles, and hyperarousal caused by modification in neuroinhibitory pathways (Figure).

HPA Axis Modification

Under either physical or psychological stress, neural circuits in the brain release corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), and arginine vasopressin, which go on to activate the sympathetic nervous system and the HPA axis. CRH from the hypothalamus goes on to stimulate ACTH release from the pituitary. ACTH then stimulates cortisol secretion from the adrenal glands. Circulating cortisol feeds into several structures of the brain, including the pituitary, hippocampus, and amygdala. Steroid-receptor complexes alter gene transcription in the central nervous system (CNS), affecting the production of neurotransmitters (eg, dopamine, serotonin) and neuropeptides (eg, somatostatin, β-endorphin). Feedback inhibition ensues, with downregulation of the HPA axis, which prevents depletion of endogenous production of steroids.³¹ DHEA has protective effects against excessive cortisol activity, but DHEA secretion declines with prolonged cortisol exposure. Exogenous steroids may have different effects than endogenous steroids, and neurocognitive sequelae stem from disruption and imbalance of these physiologic mechanisms.^32,33

Steroid receptors are densely located in behavior centers in the brain: the amygdala, septum, and hippocampus. Pharmacologic changes in gene expression alter norepinephrine and serotonin levels in the brain as well as their receptors.³² Prolonged exposure to exogenous steroids has been shown to decrease amygdala and hippocampal volumes.^34,35 Furthermore, prolonged corticosteroid exposure has been shown to decrease the number of steroid receptors in the hippocampus, pituitary gland, and amygdala.³⁶ In a somewhat paradoxical finding, the production of CNS proinflammatory cytokines like interleuken-1β and tumor necrosis factor α has been seen after steroid administration, suggesting alternate gene signaling in the CNS.³⁷ Although not proven conclusively, it is felt that these physiologic changes and hyperactivity of the HPA axis are predominantly responsible for changes in behavior, mood, memory, and eventually psychosis in steroid-treated patients.^33,38

Finally, alterations in cognition and behavior may be related to steroid-induced changes in CNS carbohydrate, protein, and lipid metabolism with subsequent cellular neurotoxicity.^32,38 Glucose uptake into the hippocampus is decreased with steroid exposure. Additionally, breakdown of metabolic compounds to produce energy can be destructive if left unchecked for prolonged periods. DHEA, growth hormone, and testosterone work to repair catabolic damage produced by cortisol, known as anabolic balance. A low anabolic balance (low DHEA levels to high cortisol levels) leads to a cascade of dysregulation in brain activity.³⁹

Changes in Natural Sleep-Wake Cycles

Natural sleep pathways are also affected by steroids. The sleep-wake cycle is primarily regulated in the hypothalamus with circadian release of melatonin from the pineal gland. Melatonin release is highest at night, where it promotes sleep onset and continuity. Upstream, tryptophan is an amino acid that serves as a precursor to serotonin and melatonin.⁴⁰ Both endogenous and exogenous corticosteroids decrease serum melatonin levels with a markedly diminished circadian rhythm secretion.^41,42Demish and colleagues found a significant decrease in mean (SD) nocturnal melatonin plasma levels after the evening administration of oral dexamethasone 1 mg in 11 healthy volunteers: 127 (42) pg/mL before vs 73 (38) pg/mL after; P < .01.⁴² This result is likely due to decreased cellular metabolism and melatonin synthesis in the pineal gland. Of note, melatonin has neuroprotective affects, and the administration of melatonin has been shown to reverse some steroid-induced neurotoxicities in animal models.⁴³

Steroids also reduce the uptake of tryptophan into the brain.³³ Additionally, in animal models, dexamethasone administration caused a significant decrease in the gene expression of tryptophan hydroxylase, which is part of the multistep pathway in synthesizing serotonin from L-tryptophan. These effects upstream could inhibit the biosynthetic capacity of both melatonin and serotonin.⁴⁴

A third pathway investigated in sleep regulation are the orexin neuropeptides. Orexins are produced in the hypothalamus and stimulate daytime wake activity in monoaminergic and cholinergic neurons. Subsequently, orexin receptor antagonists are a newer class of drugs aimed at mitigating nighttime hyperarousal and sleep disruption. Orexin overexpression may be a causal factor in steroid-induced sleep disturbance. However, this effect was specifically evaluated in a recent study in children with acute lymphoblastic leukemia, which showed that cerebral spinal fluid orexin levels (SD) were not significantly different from baseline after dexamethasone administration: 574 (26.6) pg/mL vs 580 (126.1) pg/mL; P = .8.⁴⁵

Hyperarousal State

Finally, a hyperarousal state is thought to be produced by nongenomic changes to natural neuroinhibitory regulation seen with nonclassical steroid production called neurosteroids. Animal studies revealed that high levels of steroids were found in the CNS long after adrenalectomy, suggesting CNS de novo synthesis.⁴⁶ In addition to altering gene expression at classic intercellular steroid receptors, neurosteroids can alter neurotransmission by direct interaction on ion-gated membranes and other receptors on the cell surface. Restlessness and insomnia could be due to γ-aminobutyric acid type A (GABA_A) receptor modulation in the CNS where neuroactive steroids slow the rate of recovery of GABA_A and potentially inhibit postsynaptic GABAergic transmission. It also is hypothesized that neuroactive steroids have excitatory action at nicotinic acetylcholine, 5HT₃ receptors, and through increasing the fractional open time of the N-methyl-D-aspartate -activated channels.⁴⁷ Allopregnanolone and DHEA are neurosteroids that act as GABA_A agonists and have neuroprotective effects with anxiolytic, antidepressant, and antiaggressive properties.

Neurosteroids are synthesized from cholesterol in the hippocampus. Neurosteroids are upregulated in response to stress by CNS cortisol effects on various enzyme expressions.⁴⁷ Whether exogenous steroid administration affects this biosynthesis vs the stress response in the HPA axis itself is not fully elucidated. Monteleone and colleagues found that dexamethasone 1 mg given orally significantly reduced cortisol and DHEA and allopregnanolone levels in both healthy volunteers and anorexia nervosa patients.⁴⁸ Similarly, Genazzani and colleagues demonstrated that oral dexamethasone administration (0.5 mg every 6 hours) caused significant reductions in both serum allopregnanolone and DHEA levels.⁴⁹

Outcomes Studies

The majority of reported data in steroid-induced insomnia and psychosis is in noncritically ill populations. In a randomized, prospective crossover study of healthy volunteers, dexamethasone administration (3 mg every 8 hours for 48 hours) resulted in significant changes in sleep patterns measured with polysomnography. Compared with placebo, steroid treatment showed significantly longer percentage (SD) of stage 0/awake times (11.7% [11.4] vs 2.9% [1.8]; P < .05); longer percentage (SD) of REM sleep latency (363.8 [74.5] minutes vs 202.8 [79.6] minutes; P < .01), and a reduced number (SD) of REM periods (3.8 [2.6] vs 9.7 [3.6]; P < .01).⁵⁰ Insomnia was one of the most commonly self-reported AEs (> 60%) in a survey of 2,446 chronic steroid users, and the incidence increased as steroid doses increased.⁵¹

A prospective, open-label study of 240 patients with cancer demonstrated significant sleep disruptions using the Pittsburgh Sleep Quality Index with the use of high-dose steroids in chemotherapy.⁵² Naber and colleagues evaluated 50 previously healthy patients taking methylprednisolone 119 mg (41 mg/d) for retinitis and uveitis.⁵³ They reported 26% to 34% of subjects experienced hypomanic syndrome based on a semistructured interview examination. Symptoms developed within 3 days and persisted for the 8-day course of therapy. Brown and colleagues prospectively evaluated 32 asthmatic patients prescribed bursts of prednisone > 40 mg daily. They observed significantly increased scores in the Young Mania Rating Scale within 3 to 7 days of starting therapy, which dissipated to baseline after stopping therapy.⁵⁴

Despite a high reported incidence of neurologic AEs, outcomes in critically ill populations are mixed. Study methods are varied, and many were largely observational. No prospective, randomized studies exist to date specifically aimed and powered to evaluate the effects of steroids on sleep disturbances or delirium in a critically ill population. Furthermore, sleep quality is difficult to measure in this population, and self-reporting often is not an option. In critical care trials, if AEs such as insomnia, delirium, or psychosis are recorded at all, there is heterogeneity in the definitions, and these AEs are generally poorly defined (eg, psychiatric or neurologic disorder not otherwise specified), making pooled analysis of this outcome difficult.⁵⁵

One of the largest observational studies in hospitalized patients was through the Boston Collaborative Drug Surveillance Program. A total of 718 consecutively enrolled inpatients who received prednisone were monitored for acute reactions. Psychiatric AEs were rare (1.3%) with low doses (< 40 mg/d), more prevalent (4.6%) with higher doses (41-80 mg/d), and most prevalent (18.4%) with the highest doses (> 80 mg/d), suggesting CNS AEs are dose dependent.¹⁸ A single-center, retrospective review of 755 psychiatric consults in hospitalized patients revealed that 54% of manic patients were due to corticosteroid administration.¹⁹ In a prospective observational study of 206 consecutive ICU admissions, steroid administration was an independent risk factor for development of ICU delirium, using the Confusion Assessment Method-ICU (CAM-ICU) at a single center (odds ratio [OR], 2.8; 95% CI, 1.05-7.28).²⁵

Two studies in hospitalized oncology patients found conflicting results using the Nursing Delirium Screening Scale (Nu-DESC). One did not find a significant association between delirium and dexamethasone equivalent doses > 15 mg, while the second found an increased hazard ratio (HR) for a positive Nu-DESC score (HR, 2.67; 95% CI, 1.18-6.03).^20,21 Similarly, conflicting results were found in 2 studies using first-order Markov models. In one prospective cohort study, 520 consecutive mechanically ventilated patients in 13 ICUs were monitored for the transition to delirium (CAM-ICU positive) from nondelirium states. Steroid administration was significantly associated with transitioning to delirium (OR, 1.52; 95% CI, 1.05-2.21).²² This conflicts with a similar study by Wolters and colleagues, which monitored 1,112 ICU patients who were given a median prednisone equivalent of 50 mg (interquartile range, 25-75 mg). Steroid administration was not significantly associated with the transition to delirium from an awake without delirium state (OR, 1.08; 95% CI, 0.89-1.32; adjusted OR, 1.00; 95% CI, 0.99-1.01 per 10-mg increase in prednisone equivalent).²³

Mitigating Effects

Although steroid therapy often cannot be altered in the critically ill population, research showed that steroid overuse is common in ICUs.^56,57 Minimizing dosage and duration are important ways clinicians can mitigate unwanted effects. CNS AEs seen with steroids often can be reversed once therapy is discontinued. Avoiding split-dose administration has been proposed given the natural diurnal production of cortisol.⁵⁸ A review by Flaherty discusses the importance of avoiding pharmacologic agents in hospitalized older patients if possible due to known risks (falls, dependency, hip fractures, rebound insomnia, and risk of delirium) and provides a HELP ME SLEEP nomogram for nonpharmacologic interventions in hospitalized patients (Table 4).⁵⁹

Historically, lithium has been recommended for steroid-induced mania with chronic steroid use; however, given the large volume and electrolyte shifts seen in critically ill patients, this may not be a viable option. Antidepressants, especially tricyclics, should generally be avoided in steroid-induced psychosis as these may exacerbate symptoms. If symptoms are severe, either typical (haloperidol) or atypical (olanzapine, quetiapine, risperidone) antipsychotics have been used with success.⁶⁰ Given the known depletion of serum melatonin levels, melatonin supplements are an attractive and relatively safe option for steroid-induced insomnia; however, there are no robust studies specifically aimed at this intervention for this population.

Conclusions

With known, multimodal foci driving sleep impairment in ICU patients, PADIS guidelines recommend myriad interventions for improvement. Recommendations include noise and light reduction with earplugs and/or eyeshades to improve sleep quality. Nocturnal assist-control ventilation may improve sleep quality in ventilated patients. Finally, the development of institutional protocols for promoting sleep quality in ICU patients is recommended.¹⁷

Sleep disturbance in the critically ill has received much attention over recent years as this is a common result of intensive care unit (ICU) admission. Disruptions in sleep not only can, at a minimum, cause distress and lower patient satisfaction, but also inhibit recovery from illness and increase morbidity.^1,2 Several studies have been conducted highlighting the altered sleep patterns of critically ill patients; although total sleep time may seem normal (7-9 hours), patients can experience multiple awakenings per hour, more time in light sleep (stages 1 and 2), and less time in restorative sleep (stages 3 and 4, [REM]rapid eye movement).^2-5

There are several hypothesized physiologic detriments that contribute to slower ICU recovery with sleep deprivation. Research in noncritically ill subjects suggests that sleep deprivation contributes to hypoventilation and potentially prolonged time on the ventilator.^6-9 Cardiovascular morbidity may be adversely affected by inflammatory cytokine release seen in sleep disruption.^10,11 Studies of noncritically ill patients also suggest that immune response is impaired, potentially protracting infection recovery.^12,13 Finally, although not directly investigated, sleep deprivation may contribute to ICU delirium, an independent adverse effect (AE) associated with increased mortality and worse long-term outcomes.^14-16

The Society of Critical Care Medicine (SCCM) recently updated its consensus guidelines for the management of pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS) in adult patients.¹⁷ These guidelines offer limited interventions to promote sleep in ICU patients based on available evidence and steer the clinician toward minimizing exacerbating factors. Although factors that affect sleep patterns are multifactorial, such as noise levels, pain, mechanical ventilation, and inflammatory mediators, medication therapy is a known modifiable risk factor for sleep disturbance in critically ill patients.² This focused review will specifically evaluate the effects of steroids on sleep deprivation, psychosis, delirium, and what is known about these effects in a critically ill population.

To include articles relevant to a critically ill population, a systematic search of MEDLINE and PubMed from 1966 to 2019 was performed using the following Medical Subject Headings (MeSH) terms: delirium/etiology, psychoses, substance-induced/etiology, sleep-wake disorders/chemically induced, neurocognitive disorders/chemically induced, dyssomnias/drug effects plus glucocorticoids/adverse effects, adrenal cortex hormones/adverse effects, prednisone/adverse effects, methylprednisolone/adverse effects, and hydrocortisone/adverse effects. The initial search produced 285 articles. Case reports, reviews, letters, and articles pertaining to primary care or palliative populations were excluded, leaving 8 relevant articles for inclusion (Table 1).^18-25

ICU Steroid Use

Steroids are commonly used in the ICU and affect nearly every critically ill population. Common indications for steroids in the ICU include anaphylaxis, airway edema, septic shock, asthma and COPD exacerbations, pneumocystis pneumonia, adrenal crisis, antiemetic treatment, elevated intracranial pressure from tumors, autoimmune disorders, and stress doses needed for chronic steroid users before invasive procedures.²⁶ Whether divided into glucocorticoid or mineralocorticoid subgroups, corticosteroids offer therapeutic benefit from their pharmacologic similarity to endogenously produced cortisol, which includes anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.

Steroid receptors are present in most human tissue, and in varying degrees of binding affinity produce a wide variety of effects. After passive diffusion across cell membranes, steroid-receptor activation binds to various DNA sites, called glucocorticoid regulatory elements, which either stimulates or inhibits transcription of multiple nearby genes.

At the cellular level, corticosteroids inhibit the release of arachidonic acid through upstream production of lipocortin peptides and antagonism of phospholipase A₂. This action decreases subsequent inflammatory mediators, including kinins, histamine, liposomal enzymes, and prostaglandins. Steroids also inhibit NF-κB, which further decreases expression of proinflammatory genes while promoting interleukin-10 and its anti-inflammatory properties. Antiproliferative effects of steroids are seen by triggering cell apoptosis and inhibition of fibroblast proliferation.^27,28

By binding to mineralocorticoid receptors, steroids cause sodium retention coupled with hydrogen and potassium excretion in the distal renal tubule. Steroids also promote vasoconstriction by upregulating the production and sensitivity of β receptors in the endothelium while suppressing the production of vasodilators. Although rarely used for these physiologic effects, steroids also are involved in a number of metabolic pathways, including calcium regulation, gluconeogenesis, protein metabolism, and fat distribution. Given the similar structure to cortisol, exogenous steroids depress the hypothalamic-pituitary axis (HPA) and decrease the release of adrenocorticotropic hormone (ACTH). Tapering doses of steroid regimens is often required to allow natural androgen and cortisol synthesis and prevent steroid withdrawal.^27,28

The potency of various exogenous steroids closely parallels their ability to retain sodium (Table 2). Prolonged activation of steroid receptors can have numerous systemic AEs, including unwanted neurocognitive effects (Table 3). Insomnia and psychosis are commonly described in corticosteroid clinical trials, and in one meta-analysis, both are associated with high costs per episode per year.²⁹

Steroid-Induced Sleep Disruption and Psychosis

Sleep disruption caused by exogenous administration of steroids is thought to trigger other psychostimulant effects, such as mood swings, nervousness, psychoses, and delirium.³⁰ Similarly, the SCCM PADIS guidelines included an ungraded statement: “although an association between sleep quality and delirium occurrence exists in critically ill adults, a cause-effect relationship has not been established.”¹⁷ For this review, these AEs will be discussed as related events.

The medical literature proposes 3 pathways primarily responsible for neurocognitive AEs of steroids: behavior changes through modification of the HPA axis, changes in natural sleep-wake cycles, and hyperarousal caused by modification in neuroinhibitory pathways (Figure).

HPA Axis Modification

Under either physical or psychological stress, neural circuits in the brain release corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), and arginine vasopressin, which go on to activate the sympathetic nervous system and the HPA axis. CRH from the hypothalamus goes on to stimulate ACTH release from the pituitary. ACTH then stimulates cortisol secretion from the adrenal glands. Circulating cortisol feeds into several structures of the brain, including the pituitary, hippocampus, and amygdala. Steroid-receptor complexes alter gene transcription in the central nervous system (CNS), affecting the production of neurotransmitters (eg, dopamine, serotonin) and neuropeptides (eg, somatostatin, β-endorphin). Feedback inhibition ensues, with downregulation of the HPA axis, which prevents depletion of endogenous production of steroids.³¹ DHEA has protective effects against excessive cortisol activity, but DHEA secretion declines with prolonged cortisol exposure. Exogenous steroids may have different effects than endogenous steroids, and neurocognitive sequelae stem from disruption and imbalance of these physiologic mechanisms.^32,33

Steroid receptors are densely located in behavior centers in the brain: the amygdala, septum, and hippocampus. Pharmacologic changes in gene expression alter norepinephrine and serotonin levels in the brain as well as their receptors.³² Prolonged exposure to exogenous steroids has been shown to decrease amygdala and hippocampal volumes.^34,35 Furthermore, prolonged corticosteroid exposure has been shown to decrease the number of steroid receptors in the hippocampus, pituitary gland, and amygdala.³⁶ In a somewhat paradoxical finding, the production of CNS proinflammatory cytokines like interleuken-1β and tumor necrosis factor α has been seen after steroid administration, suggesting alternate gene signaling in the CNS.³⁷ Although not proven conclusively, it is felt that these physiologic changes and hyperactivity of the HPA axis are predominantly responsible for changes in behavior, mood, memory, and eventually psychosis in steroid-treated patients.^33,38

Finally, alterations in cognition and behavior may be related to steroid-induced changes in CNS carbohydrate, protein, and lipid metabolism with subsequent cellular neurotoxicity.^32,38 Glucose uptake into the hippocampus is decreased with steroid exposure. Additionally, breakdown of metabolic compounds to produce energy can be destructive if left unchecked for prolonged periods. DHEA, growth hormone, and testosterone work to repair catabolic damage produced by cortisol, known as anabolic balance. A low anabolic balance (low DHEA levels to high cortisol levels) leads to a cascade of dysregulation in brain activity.³⁹

Changes in Natural Sleep-Wake Cycles

Natural sleep pathways are also affected by steroids. The sleep-wake cycle is primarily regulated in the hypothalamus with circadian release of melatonin from the pineal gland. Melatonin release is highest at night, where it promotes sleep onset and continuity. Upstream, tryptophan is an amino acid that serves as a precursor to serotonin and melatonin.⁴⁰ Both endogenous and exogenous corticosteroids decrease serum melatonin levels with a markedly diminished circadian rhythm secretion.^41,42Demish and colleagues found a significant decrease in mean (SD) nocturnal melatonin plasma levels after the evening administration of oral dexamethasone 1 mg in 11 healthy volunteers: 127 (42) pg/mL before vs 73 (38) pg/mL after; P < .01.⁴² This result is likely due to decreased cellular metabolism and melatonin synthesis in the pineal gland. Of note, melatonin has neuroprotective affects, and the administration of melatonin has been shown to reverse some steroid-induced neurotoxicities in animal models.⁴³

Steroids also reduce the uptake of tryptophan into the brain.³³ Additionally, in animal models, dexamethasone administration caused a significant decrease in the gene expression of tryptophan hydroxylase, which is part of the multistep pathway in synthesizing serotonin from L-tryptophan. These effects upstream could inhibit the biosynthetic capacity of both melatonin and serotonin.⁴⁴

A third pathway investigated in sleep regulation are the orexin neuropeptides. Orexins are produced in the hypothalamus and stimulate daytime wake activity in monoaminergic and cholinergic neurons. Subsequently, orexin receptor antagonists are a newer class of drugs aimed at mitigating nighttime hyperarousal and sleep disruption. Orexin overexpression may be a causal factor in steroid-induced sleep disturbance. However, this effect was specifically evaluated in a recent study in children with acute lymphoblastic leukemia, which showed that cerebral spinal fluid orexin levels (SD) were not significantly different from baseline after dexamethasone administration: 574 (26.6) pg/mL vs 580 (126.1) pg/mL; P = .8.⁴⁵

Hyperarousal State

Finally, a hyperarousal state is thought to be produced by nongenomic changes to natural neuroinhibitory regulation seen with nonclassical steroid production called neurosteroids. Animal studies revealed that high levels of steroids were found in the CNS long after adrenalectomy, suggesting CNS de novo synthesis.⁴⁶ In addition to altering gene expression at classic intercellular steroid receptors, neurosteroids can alter neurotransmission by direct interaction on ion-gated membranes and other receptors on the cell surface. Restlessness and insomnia could be due to γ-aminobutyric acid type A (GABA_A) receptor modulation in the CNS where neuroactive steroids slow the rate of recovery of GABA_A and potentially inhibit postsynaptic GABAergic transmission. It also is hypothesized that neuroactive steroids have excitatory action at nicotinic acetylcholine, 5HT₃ receptors, and through increasing the fractional open time of the N-methyl-D-aspartate -activated channels.⁴⁷ Allopregnanolone and DHEA are neurosteroids that act as GABA_A agonists and have neuroprotective effects with anxiolytic, antidepressant, and antiaggressive properties.

Neurosteroids are synthesized from cholesterol in the hippocampus. Neurosteroids are upregulated in response to stress by CNS cortisol effects on various enzyme expressions.⁴⁷ Whether exogenous steroid administration affects this biosynthesis vs the stress response in the HPA axis itself is not fully elucidated. Monteleone and colleagues found that dexamethasone 1 mg given orally significantly reduced cortisol and DHEA and allopregnanolone levels in both healthy volunteers and anorexia nervosa patients.⁴⁸ Similarly, Genazzani and colleagues demonstrated that oral dexamethasone administration (0.5 mg every 6 hours) caused significant reductions in both serum allopregnanolone and DHEA levels.⁴⁹

Outcomes Studies

The majority of reported data in steroid-induced insomnia and psychosis is in noncritically ill populations. In a randomized, prospective crossover study of healthy volunteers, dexamethasone administration (3 mg every 8 hours for 48 hours) resulted in significant changes in sleep patterns measured with polysomnography. Compared with placebo, steroid treatment showed significantly longer percentage (SD) of stage 0/awake times (11.7% [11.4] vs 2.9% [1.8]; P < .05); longer percentage (SD) of REM sleep latency (363.8 [74.5] minutes vs 202.8 [79.6] minutes; P < .01), and a reduced number (SD) of REM periods (3.8 [2.6] vs 9.7 [3.6]; P < .01).⁵⁰ Insomnia was one of the most commonly self-reported AEs (> 60%) in a survey of 2,446 chronic steroid users, and the incidence increased as steroid doses increased.⁵¹

A prospective, open-label study of 240 patients with cancer demonstrated significant sleep disruptions using the Pittsburgh Sleep Quality Index with the use of high-dose steroids in chemotherapy.⁵² Naber and colleagues evaluated 50 previously healthy patients taking methylprednisolone 119 mg (41 mg/d) for retinitis and uveitis.⁵³ They reported 26% to 34% of subjects experienced hypomanic syndrome based on a semistructured interview examination. Symptoms developed within 3 days and persisted for the 8-day course of therapy. Brown and colleagues prospectively evaluated 32 asthmatic patients prescribed bursts of prednisone > 40 mg daily. They observed significantly increased scores in the Young Mania Rating Scale within 3 to 7 days of starting therapy, which dissipated to baseline after stopping therapy.⁵⁴

Despite a high reported incidence of neurologic AEs, outcomes in critically ill populations are mixed. Study methods are varied, and many were largely observational. No prospective, randomized studies exist to date specifically aimed and powered to evaluate the effects of steroids on sleep disturbances or delirium in a critically ill population. Furthermore, sleep quality is difficult to measure in this population, and self-reporting often is not an option. In critical care trials, if AEs such as insomnia, delirium, or psychosis are recorded at all, there is heterogeneity in the definitions, and these AEs are generally poorly defined (eg, psychiatric or neurologic disorder not otherwise specified), making pooled analysis of this outcome difficult.⁵⁵

One of the largest observational studies in hospitalized patients was through the Boston Collaborative Drug Surveillance Program. A total of 718 consecutively enrolled inpatients who received prednisone were monitored for acute reactions. Psychiatric AEs were rare (1.3%) with low doses (< 40 mg/d), more prevalent (4.6%) with higher doses (41-80 mg/d), and most prevalent (18.4%) with the highest doses (> 80 mg/d), suggesting CNS AEs are dose dependent.¹⁸ A single-center, retrospective review of 755 psychiatric consults in hospitalized patients revealed that 54% of manic patients were due to corticosteroid administration.¹⁹ In a prospective observational study of 206 consecutive ICU admissions, steroid administration was an independent risk factor for development of ICU delirium, using the Confusion Assessment Method-ICU (CAM-ICU) at a single center (odds ratio [OR], 2.8; 95% CI, 1.05-7.28).²⁵

Two studies in hospitalized oncology patients found conflicting results using the Nursing Delirium Screening Scale (Nu-DESC). One did not find a significant association between delirium and dexamethasone equivalent doses > 15 mg, while the second found an increased hazard ratio (HR) for a positive Nu-DESC score (HR, 2.67; 95% CI, 1.18-6.03).^20,21 Similarly, conflicting results were found in 2 studies using first-order Markov models. In one prospective cohort study, 520 consecutive mechanically ventilated patients in 13 ICUs were monitored for the transition to delirium (CAM-ICU positive) from nondelirium states. Steroid administration was significantly associated with transitioning to delirium (OR, 1.52; 95% CI, 1.05-2.21).²² This conflicts with a similar study by Wolters and colleagues, which monitored 1,112 ICU patients who were given a median prednisone equivalent of 50 mg (interquartile range, 25-75 mg). Steroid administration was not significantly associated with the transition to delirium from an awake without delirium state (OR, 1.08; 95% CI, 0.89-1.32; adjusted OR, 1.00; 95% CI, 0.99-1.01 per 10-mg increase in prednisone equivalent).²³

Mitigating Effects

Although steroid therapy often cannot be altered in the critically ill population, research showed that steroid overuse is common in ICUs.^56,57 Minimizing dosage and duration are important ways clinicians can mitigate unwanted effects. CNS AEs seen with steroids often can be reversed once therapy is discontinued. Avoiding split-dose administration has been proposed given the natural diurnal production of cortisol.⁵⁸ A review by Flaherty discusses the importance of avoiding pharmacologic agents in hospitalized older patients if possible due to known risks (falls, dependency, hip fractures, rebound insomnia, and risk of delirium) and provides a HELP ME SLEEP nomogram for nonpharmacologic interventions in hospitalized patients (Table 4).⁵⁹

Historically, lithium has been recommended for steroid-induced mania with chronic steroid use; however, given the large volume and electrolyte shifts seen in critically ill patients, this may not be a viable option. Antidepressants, especially tricyclics, should generally be avoided in steroid-induced psychosis as these may exacerbate symptoms. If symptoms are severe, either typical (haloperidol) or atypical (olanzapine, quetiapine, risperidone) antipsychotics have been used with success.⁶⁰ Given the known depletion of serum melatonin levels, melatonin supplements are an attractive and relatively safe option for steroid-induced insomnia; however, there are no robust studies specifically aimed at this intervention for this population.

Conclusions

With known, multimodal foci driving sleep impairment in ICU patients, PADIS guidelines recommend myriad interventions for improvement. Recommendations include noise and light reduction with earplugs and/or eyeshades to improve sleep quality. Nocturnal assist-control ventilation may improve sleep quality in ventilated patients. Finally, the development of institutional protocols for promoting sleep quality in ICU patients is recommended.¹⁷

To the Editor: COVID-19 is a pandemic caused by the virus SARS-CoV-2. Serious complications of COVID-19 are characterized by acute respiratory distress syndrome (ARDS), pneumonia and rapidly progressing to multiorgan dysfunction syndrome (MODS).

The pathophysiology of COVID-19 is not fully understood yet and neither vaccine nor clearly effective antiviral treatment is available at this time. Based on the endothelial pathogenesis of viral sepsis, which includes ARDS as seen in severe acute respiratory syndrome (SARS) due to SARS-CoV and Middle East respiratory syndrome due to MERS-CoV,^1,2 we believe COVID-19-associated ARDS is also caused by endotheliopathy-associated vascular microthrombotic disease (EA-VMTD), which also involves multiorgan dysfunction syndrome (MODS) that has been reported as the cause of death.³ We suspect these complications are secondary to disequilibrium state (for various reasons^4,5) between insufficient ADAMTS13 and excessive exocytosis of ultra large von Willebrand factor multimers (ULVWF) from Weibel-Palade bodies present in endothelial cells due to COVID-19-induced endotheliopathy.

Endothelial-derived ULVWF multimers anchored to the endothelial surface of the vascular wall recruit platelets and initiate microthrombogenesis within the microvasculature, leading to large microthrombi strings composed of platelet and eULVWF complexes like “beads-on-a-string structures”⁶ where platelets firmly adhere to eULVWF, instead of roll on eULVWF strings.⁴ Platelets, once adhered to eULVWF strings, are rapidly activated causing platelet aggregation and also recruit leukocytes in a P-selectin dependent manner.⁴ These aggregates grow until they become sufficiently large and can no longer be held onto the eULVWF strings against the force of blood flow and released from endothelial cells into the circulation.⁴ It appears to us that in COVID-19 microthrombotic disease, large amounts of circulating complexes of endothelial-derived ULVWF decorated-platelet microthrombi strings are filtered in the microvasculature (embolism) or develops in the microvasculature in situ causing microthrombotic occlusion. During our data search, we have come across several articles published by Chang, including on endotheliopathy causing vascular microthrombotic disease based on a novel concept of “TTP-like syndrome”⁷

The genesis of EA-VMTD in TTP like syndrome is suspected to be triggered by complement activation and terminal complement complex (C5b-9, membrane attack complex, MAC) may play a key role in producing endotheliopathy.⁷ Magro and colleagues reported that COVID-19 patients have demonstrated generalized thrombotic microvascular injury involving the lungs and skin showing intense complement activation and C5b-9 deposition in the tissue.⁸ Also, recent pathology reports of COVID-19 diseased lungs showed extensive platelet-rich clotting with adherent mononuclear cells and extensive fibrin clotting,⁹ which appear consistent with involvement of NETosis.¹⁰ In another case report from Switzerland, a patient with severe COVID-19 had massive elevation of VWF antigen and activity (555% and 520%, respectively) and increased Factor VIII clotting activity (369%).¹¹ These findings support vascular endotheliopathy causing exocytosis of ULVWF and associated increase in Factor VIII causing microthrombotic disease/embolism.

COVID-19 clinical syndrome appears very much consistent with EA-VMTD presenting with ARDS and MODS as well as micro-macro-thrombotic complications, including peripheral ischemia/gangrene involving fingers and toes and skin necrosis.^8,12

We believe that an appropriate therapy may not be anticoagulation but should include antimicrothrombotic therapy targeting endotheliopathy and primary hemostasis in the early stages of the disease (platelet adhesion, activation, and aggregation; especially eULVWF) like recombinant CD59 (membrane attack complex inhibition factor [MACIF]), recombinant ADAMTS13, glycoprotein IIb/IIIa receptor blocker, therapeutic plasma exchange, and perhaps anticomplement therapy (in selected cases) and others; these need to be validated in clinical trials prior to clinical application.

Of note, ADAMTS13 is a zinc containing protease. We noted that zinc and calcium concentrations play a significant role (in vitro) in ADAMTS13 activity in citrated plasma and recombinant ADAMTS13 activity with no added chelators (recombinant ADAMTS13 activity can enhance up to 200-fold); whereas in high zinc concentrations, ADAMTS13 gets deactivated.¹³ We suggest this finding merits an urgent clinical trial since it appears to us as the best possible cost-effective treatment for COVID-19 microthrombotic complications.

In this view of clinical pathophysiology of sepsis in COVID-19, we would like to enlighten the relationship between endothelial pathogenesis of coronaviral sepsis and vascular microthrombotic disease and would urge the medical community to immediately explore appropriate therapeutic options.

N. Varatharajah, MD

Suganthi Rajah, MD

Virginia, US

To the Editor: COVID-19 is a pandemic caused by the virus SARS-CoV-2. Serious complications of COVID-19 are characterized by acute respiratory distress syndrome (ARDS), pneumonia and rapidly progressing to multiorgan dysfunction syndrome (MODS).

The pathophysiology of COVID-19 is not fully understood yet and neither vaccine nor clearly effective antiviral treatment is available at this time. Based on the endothelial pathogenesis of viral sepsis, which includes ARDS as seen in severe acute respiratory syndrome (SARS) due to SARS-CoV and Middle East respiratory syndrome due to MERS-CoV,^1,2 we believe COVID-19-associated ARDS is also caused by endotheliopathy-associated vascular microthrombotic disease (EA-VMTD), which also involves multiorgan dysfunction syndrome (MODS) that has been reported as the cause of death.³ We suspect these complications are secondary to disequilibrium state (for various reasons^4,5) between insufficient ADAMTS13 and excessive exocytosis of ultra large von Willebrand factor multimers (ULVWF) from Weibel-Palade bodies present in endothelial cells due to COVID-19-induced endotheliopathy.

Endothelial-derived ULVWF multimers anchored to the endothelial surface of the vascular wall recruit platelets and initiate microthrombogenesis within the microvasculature, leading to large microthrombi strings composed of platelet and eULVWF complexes like “beads-on-a-string structures”⁶ where platelets firmly adhere to eULVWF, instead of roll on eULVWF strings.⁴ Platelets, once adhered to eULVWF strings, are rapidly activated causing platelet aggregation and also recruit leukocytes in a P-selectin dependent manner.⁴ These aggregates grow until they become sufficiently large and can no longer be held onto the eULVWF strings against the force of blood flow and released from endothelial cells into the circulation.⁴ It appears to us that in COVID-19 microthrombotic disease, large amounts of circulating complexes of endothelial-derived ULVWF decorated-platelet microthrombi strings are filtered in the microvasculature (embolism) or develops in the microvasculature in situ causing microthrombotic occlusion. During our data search, we have come across several articles published by Chang, including on endotheliopathy causing vascular microthrombotic disease based on a novel concept of “TTP-like syndrome”⁷

The genesis of EA-VMTD in TTP like syndrome is suspected to be triggered by complement activation and terminal complement complex (C5b-9, membrane attack complex, MAC) may play a key role in producing endotheliopathy.⁷ Magro and colleagues reported that COVID-19 patients have demonstrated generalized thrombotic microvascular injury involving the lungs and skin showing intense complement activation and C5b-9 deposition in the tissue.⁸ Also, recent pathology reports of COVID-19 diseased lungs showed extensive platelet-rich clotting with adherent mononuclear cells and extensive fibrin clotting,⁹ which appear consistent with involvement of NETosis.¹⁰ In another case report from Switzerland, a patient with severe COVID-19 had massive elevation of VWF antigen and activity (555% and 520%, respectively) and increased Factor VIII clotting activity (369%).¹¹ These findings support vascular endotheliopathy causing exocytosis of ULVWF and associated increase in Factor VIII causing microthrombotic disease/embolism.

COVID-19 clinical syndrome appears very much consistent with EA-VMTD presenting with ARDS and MODS as well as micro-macro-thrombotic complications, including peripheral ischemia/gangrene involving fingers and toes and skin necrosis.^8,12

We believe that an appropriate therapy may not be anticoagulation but should include antimicrothrombotic therapy targeting endotheliopathy and primary hemostasis in the early stages of the disease (platelet adhesion, activation, and aggregation; especially eULVWF) like recombinant CD59 (membrane attack complex inhibition factor [MACIF]), recombinant ADAMTS13, glycoprotein IIb/IIIa receptor blocker, therapeutic plasma exchange, and perhaps anticomplement therapy (in selected cases) and others; these need to be validated in clinical trials prior to clinical application.

Of note, ADAMTS13 is a zinc containing protease. We noted that zinc and calcium concentrations play a significant role (in vitro) in ADAMTS13 activity in citrated plasma and recombinant ADAMTS13 activity with no added chelators (recombinant ADAMTS13 activity can enhance up to 200-fold); whereas in high zinc concentrations, ADAMTS13 gets deactivated.¹³ We suggest this finding merits an urgent clinical trial since it appears to us as the best possible cost-effective treatment for COVID-19 microthrombotic complications.

In this view of clinical pathophysiology of sepsis in COVID-19, we would like to enlighten the relationship between endothelial pathogenesis of coronaviral sepsis and vascular microthrombotic disease and would urge the medical community to immediately explore appropriate therapeutic options.

N. Varatharajah, MD

Suganthi Rajah, MD

Virginia, US

To the Editor: COVID-19 is a pandemic caused by the virus SARS-CoV-2. Serious complications of COVID-19 are characterized by acute respiratory distress syndrome (ARDS), pneumonia and rapidly progressing to multiorgan dysfunction syndrome (MODS).

The pathophysiology of COVID-19 is not fully understood yet and neither vaccine nor clearly effective antiviral treatment is available at this time. Based on the endothelial pathogenesis of viral sepsis, which includes ARDS as seen in severe acute respiratory syndrome (SARS) due to SARS-CoV and Middle East respiratory syndrome due to MERS-CoV,^1,2 we believe COVID-19-associated ARDS is also caused by endotheliopathy-associated vascular microthrombotic disease (EA-VMTD), which also involves multiorgan dysfunction syndrome (MODS) that has been reported as the cause of death.³ We suspect these complications are secondary to disequilibrium state (for various reasons^4,5) between insufficient ADAMTS13 and excessive exocytosis of ultra large von Willebrand factor multimers (ULVWF) from Weibel-Palade bodies present in endothelial cells due to COVID-19-induced endotheliopathy.

Endothelial-derived ULVWF multimers anchored to the endothelial surface of the vascular wall recruit platelets and initiate microthrombogenesis within the microvasculature, leading to large microthrombi strings composed of platelet and eULVWF complexes like “beads-on-a-string structures”⁶ where platelets firmly adhere to eULVWF, instead of roll on eULVWF strings.⁴ Platelets, once adhered to eULVWF strings, are rapidly activated causing platelet aggregation and also recruit leukocytes in a P-selectin dependent manner.⁴ These aggregates grow until they become sufficiently large and can no longer be held onto the eULVWF strings against the force of blood flow and released from endothelial cells into the circulation.⁴ It appears to us that in COVID-19 microthrombotic disease, large amounts of circulating complexes of endothelial-derived ULVWF decorated-platelet microthrombi strings are filtered in the microvasculature (embolism) or develops in the microvasculature in situ causing microthrombotic occlusion. During our data search, we have come across several articles published by Chang, including on endotheliopathy causing vascular microthrombotic disease based on a novel concept of “TTP-like syndrome”⁷

The genesis of EA-VMTD in TTP like syndrome is suspected to be triggered by complement activation and terminal complement complex (C5b-9, membrane attack complex, MAC) may play a key role in producing endotheliopathy.⁷ Magro and colleagues reported that COVID-19 patients have demonstrated generalized thrombotic microvascular injury involving the lungs and skin showing intense complement activation and C5b-9 deposition in the tissue.⁸ Also, recent pathology reports of COVID-19 diseased lungs showed extensive platelet-rich clotting with adherent mononuclear cells and extensive fibrin clotting,⁹ which appear consistent with involvement of NETosis.¹⁰ In another case report from Switzerland, a patient with severe COVID-19 had massive elevation of VWF antigen and activity (555% and 520%, respectively) and increased Factor VIII clotting activity (369%).¹¹ These findings support vascular endotheliopathy causing exocytosis of ULVWF and associated increase in Factor VIII causing microthrombotic disease/embolism.

COVID-19 clinical syndrome appears very much consistent with EA-VMTD presenting with ARDS and MODS as well as micro-macro-thrombotic complications, including peripheral ischemia/gangrene involving fingers and toes and skin necrosis.^8,12

We believe that an appropriate therapy may not be anticoagulation but should include antimicrothrombotic therapy targeting endotheliopathy and primary hemostasis in the early stages of the disease (platelet adhesion, activation, and aggregation; especially eULVWF) like recombinant CD59 (membrane attack complex inhibition factor [MACIF]), recombinant ADAMTS13, glycoprotein IIb/IIIa receptor blocker, therapeutic plasma exchange, and perhaps anticomplement therapy (in selected cases) and others; these need to be validated in clinical trials prior to clinical application.

Of note, ADAMTS13 is a zinc containing protease. We noted that zinc and calcium concentrations play a significant role (in vitro) in ADAMTS13 activity in citrated plasma and recombinant ADAMTS13 activity with no added chelators (recombinant ADAMTS13 activity can enhance up to 200-fold); whereas in high zinc concentrations, ADAMTS13 gets deactivated.¹³ We suggest this finding merits an urgent clinical trial since it appears to us as the best possible cost-effective treatment for COVID-19 microthrombotic complications.

In this view of clinical pathophysiology of sepsis in COVID-19, we would like to enlighten the relationship between endothelial pathogenesis of coronaviral sepsis and vascular microthrombotic disease and would urge the medical community to immediately explore appropriate therapeutic options.

N. Varatharajah, MD

Suganthi Rajah, MD

Virginia, US

For health care professionals, especially those in the epicenters of the pandemic, among the most distressing aspects of this first wave of COVID-19 has been the absence of any drug to treat the virus. The practitioners on the frontlines have confronted repeated surges of critically ill and dying patients without any effective treatment to offer, resulting in feelings of hopelessness, guilt, moral distress, depression, and in some tragic cases, suicide.²

On May 12th, the Centers of Disease Control and Prevention (CDC) released additional guidance on the antiviral medications that are the subject of this essay. The CDC may have updated its treatment guidelines in part to try and bring a measure of clinical reasoning and scientific order into the impassioned and politicized chaos that surrounded hydrocloroquine and remdesivir in the media.³

In this fourth installment of my series on pandemic ethics, we examine the desperate race for hope in the form of drug treatments for COVID-19. The race has been run faster than any in history thanks to biotechnology, genetic engineering, and artificial intelligence, although many experts believe it will still be a marathon rather than a sprint to a vaccine.⁴

The first editorial in this series provided a primer of the key differences between public health ethics and clinical ethics. Another crucial distinction is the far more pervasive and powerful influence of nonmedical factors in decision making, including political agendas, economic motives, journalistic hyperbole, and cultural biases and orientations. These competing interests make it even more challenging for scientists of integrity and health care institutions that are trying to uphold core values to make principled judgments about what is best for critically ill patients and the demoralized staff caring for them. In the remainder of this column, I will trace the dynamics of these forces as they impact the use of 2 drugs in federal practice: hydroxychloroquine and remdesivir.

The trajectory of hydroxychloroquine has been a political and medical roller-coaster since the pandemic hit, as is evident in its US Department of Veterans Affairs (VA) ride. Various media outlets have reported that beginning about March 26, 2020, VA placed orders for up to $400,000 of the antimalarial drug hydroxychloroquine to be given to veterans hospitalized with COVID-19.⁵ The same day the VA Office of Inspector General (OIG) issued a report critical of VA pandemic readiness and its availability of hydroxychloroquine.⁶

The VA strongly refuted the report, objecting to the premise of the OIG investigation, which was to determine whether VA facilities had on hand a 14-day supply of chloroquine or hydroxychloroquine. “This is both inaccurate and irresponsible.” Noting that the drugs were still under investigation, the VA insisted that “No conclusions have been made on their effectiveness. To insist that a 14 days’ supply of these drugs is appropriate or not appropriate displays this dangerous lack of expertise on COVID-19 and Pandemic response.”⁶

In April, National Institutes of Health-sponsored researchers released data that hydroxychloroquine actually increased mortality among VA patients with COVID-19,⁷ leading veterans’ groups and the Senate minority leader to demand that VA cease to use hydroxychloroquine for COVID-19.⁸ As recently as May 15, the Associated Press reported that top VA officials have defended their use of the medication and stated they will not stop administering the medication for this indication.⁹ And VA is not alone, many other health care institutions are still prescribing hydroxychloroquine even amid scientific controversy about its putative benefits. In response to the growing awareness of the potential harms of the drug, the World Health Organization on May 25 announced it was halting all hydroxychloroquine trials.¹⁰ Why then do some physicians and health care providers continue to prescribe it? Because when nothing else stands between the patient and certain death even if there are known risks and uncertain benefits, some in health care feel morally obliged to use their best clinical judgment to help a patient.

Remdesivir’s fortunes both scientific and monetary also rose and fell on the tide of mixed results from studies. Military Times reported on March 10, 2020, that the US Army Medical Research and Development Command had made an agreement with Gilead Sciences, the manufacturer of remdesivir, to provide the medication to COVID-19-positive service members.¹¹ The antiviral had failed against Ebola and hepatitis but showed some efficacy for Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). On April 15, the Secretary of the Army announced that 2 COVID-19-positive soldiers had recovered after being given remdesivir.¹² In late April, the National Institute of Allergy and Infectious Diseases reported that in the scientific gold standard randomized placebo-controlled trial, remdesivir did speed the recovery of patients with advanced COVID-19. With the publication of the study in the prestigious New England Journal of Medicine on May 22, 2020, clearly the Army had bet on the right horse.¹³

This column has not been about quack cures and patent medicines that greed and ignorance breed in almost every American public health crisis—although these are by no means absent in this pandemic. This is about the serious endeavor of the top scientists and physicians in the country and, indeed, the world to discover a new medication or to repurpose an older pharmaceutical that is effective in the battle against COVID-19. The pressure on scientists and physicians to find a magic bullet in the battle against such an implacable enemy is unprecedented and unimaginable and can easily lead to sloppy science and ethical erosion.

In a utopia, pharmaceutical and vaccine research would be a matter of the discoveries of basic science trialed in the proof of concept of clinical care on a methodical, deliberate, and exacting timetable that balanced burdens and benefits.

In our current dystopia, science and medicine are only one of the many considerations affecting drug and vaccine development. As scientists and health care practitioners, we all experience a therapeutic imperative that we must heed with both caution and courage. Without caution we risk causing more harm than the disease we are fighting. Without courage we lose hope, the most potent antidote of all.

For health care professionals, especially those in the epicenters of the pandemic, among the most distressing aspects of this first wave of COVID-19 has been the absence of any drug to treat the virus. The practitioners on the frontlines have confronted repeated surges of critically ill and dying patients without any effective treatment to offer, resulting in feelings of hopelessness, guilt, moral distress, depression, and in some tragic cases, suicide.²

On May 12th, the Centers of Disease Control and Prevention (CDC) released additional guidance on the antiviral medications that are the subject of this essay. The CDC may have updated its treatment guidelines in part to try and bring a measure of clinical reasoning and scientific order into the impassioned and politicized chaos that surrounded hydrocloroquine and remdesivir in the media.³

In this fourth installment of my series on pandemic ethics, we examine the desperate race for hope in the form of drug treatments for COVID-19. The race has been run faster than any in history thanks to biotechnology, genetic engineering, and artificial intelligence, although many experts believe it will still be a marathon rather than a sprint to a vaccine.⁴

The first editorial in this series provided a primer of the key differences between public health ethics and clinical ethics. Another crucial distinction is the far more pervasive and powerful influence of nonmedical factors in decision making, including political agendas, economic motives, journalistic hyperbole, and cultural biases and orientations. These competing interests make it even more challenging for scientists of integrity and health care institutions that are trying to uphold core values to make principled judgments about what is best for critically ill patients and the demoralized staff caring for them. In the remainder of this column, I will trace the dynamics of these forces as they impact the use of 2 drugs in federal practice: hydroxychloroquine and remdesivir.

The trajectory of hydroxychloroquine has been a political and medical roller-coaster since the pandemic hit, as is evident in its US Department of Veterans Affairs (VA) ride. Various media outlets have reported that beginning about March 26, 2020, VA placed orders for up to $400,000 of the antimalarial drug hydroxychloroquine to be given to veterans hospitalized with COVID-19.⁵ The same day the VA Office of Inspector General (OIG) issued a report critical of VA pandemic readiness and its availability of hydroxychloroquine.⁶

The VA strongly refuted the report, objecting to the premise of the OIG investigation, which was to determine whether VA facilities had on hand a 14-day supply of chloroquine or hydroxychloroquine. “This is both inaccurate and irresponsible.” Noting that the drugs were still under investigation, the VA insisted that “No conclusions have been made on their effectiveness. To insist that a 14 days’ supply of these drugs is appropriate or not appropriate displays this dangerous lack of expertise on COVID-19 and Pandemic response.”⁶

In April, National Institutes of Health-sponsored researchers released data that hydroxychloroquine actually increased mortality among VA patients with COVID-19,⁷ leading veterans’ groups and the Senate minority leader to demand that VA cease to use hydroxychloroquine for COVID-19.⁸ As recently as May 15, the Associated Press reported that top VA officials have defended their use of the medication and stated they will not stop administering the medication for this indication.⁹ And VA is not alone, many other health care institutions are still prescribing hydroxychloroquine even amid scientific controversy about its putative benefits. In response to the growing awareness of the potential harms of the drug, the World Health Organization on May 25 announced it was halting all hydroxychloroquine trials.¹⁰ Why then do some physicians and health care providers continue to prescribe it? Because when nothing else stands between the patient and certain death even if there are known risks and uncertain benefits, some in health care feel morally obliged to use their best clinical judgment to help a patient.

Remdesivir’s fortunes both scientific and monetary also rose and fell on the tide of mixed results from studies. Military Times reported on March 10, 2020, that the US Army Medical Research and Development Command had made an agreement with Gilead Sciences, the manufacturer of remdesivir, to provide the medication to COVID-19-positive service members.¹¹ The antiviral had failed against Ebola and hepatitis but showed some efficacy for Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). On April 15, the Secretary of the Army announced that 2 COVID-19-positive soldiers had recovered after being given remdesivir.¹² In late April, the National Institute of Allergy and Infectious Diseases reported that in the scientific gold standard randomized placebo-controlled trial, remdesivir did speed the recovery of patients with advanced COVID-19. With the publication of the study in the prestigious New England Journal of Medicine on May 22, 2020, clearly the Army had bet on the right horse.¹³

This column has not been about quack cures and patent medicines that greed and ignorance breed in almost every American public health crisis—although these are by no means absent in this pandemic. This is about the serious endeavor of the top scientists and physicians in the country and, indeed, the world to discover a new medication or to repurpose an older pharmaceutical that is effective in the battle against COVID-19. The pressure on scientists and physicians to find a magic bullet in the battle against such an implacable enemy is unprecedented and unimaginable and can easily lead to sloppy science and ethical erosion.

In a utopia, pharmaceutical and vaccine research would be a matter of the discoveries of basic science trialed in the proof of concept of clinical care on a methodical, deliberate, and exacting timetable that balanced burdens and benefits.

In our current dystopia, science and medicine are only one of the many considerations affecting drug and vaccine development. As scientists and health care practitioners, we all experience a therapeutic imperative that we must heed with both caution and courage. Without caution we risk causing more harm than the disease we are fighting. Without courage we lose hope, the most potent antidote of all.

For health care professionals, especially those in the epicenters of the pandemic, among the most distressing aspects of this first wave of COVID-19 has been the absence of any drug to treat the virus. The practitioners on the frontlines have confronted repeated surges of critically ill and dying patients without any effective treatment to offer, resulting in feelings of hopelessness, guilt, moral distress, depression, and in some tragic cases, suicide.²

On May 12th, the Centers of Disease Control and Prevention (CDC) released additional guidance on the antiviral medications that are the subject of this essay. The CDC may have updated its treatment guidelines in part to try and bring a measure of clinical reasoning and scientific order into the impassioned and politicized chaos that surrounded hydrocloroquine and remdesivir in the media.³

In this fourth installment of my series on pandemic ethics, we examine the desperate race for hope in the form of drug treatments for COVID-19. The race has been run faster than any in history thanks to biotechnology, genetic engineering, and artificial intelligence, although many experts believe it will still be a marathon rather than a sprint to a vaccine.⁴

The first editorial in this series provided a primer of the key differences between public health ethics and clinical ethics. Another crucial distinction is the far more pervasive and powerful influence of nonmedical factors in decision making, including political agendas, economic motives, journalistic hyperbole, and cultural biases and orientations. These competing interests make it even more challenging for scientists of integrity and health care institutions that are trying to uphold core values to make principled judgments about what is best for critically ill patients and the demoralized staff caring for them. In the remainder of this column, I will trace the dynamics of these forces as they impact the use of 2 drugs in federal practice: hydroxychloroquine and remdesivir.

The trajectory of hydroxychloroquine has been a political and medical roller-coaster since the pandemic hit, as is evident in its US Department of Veterans Affairs (VA) ride. Various media outlets have reported that beginning about March 26, 2020, VA placed orders for up to $400,000 of the antimalarial drug hydroxychloroquine to be given to veterans hospitalized with COVID-19.⁵ The same day the VA Office of Inspector General (OIG) issued a report critical of VA pandemic readiness and its availability of hydroxychloroquine.⁶

The VA strongly refuted the report, objecting to the premise of the OIG investigation, which was to determine whether VA facilities had on hand a 14-day supply of chloroquine or hydroxychloroquine. “This is both inaccurate and irresponsible.” Noting that the drugs were still under investigation, the VA insisted that “No conclusions have been made on their effectiveness. To insist that a 14 days’ supply of these drugs is appropriate or not appropriate displays this dangerous lack of expertise on COVID-19 and Pandemic response.”⁶

In April, National Institutes of Health-sponsored researchers released data that hydroxychloroquine actually increased mortality among VA patients with COVID-19,⁷ leading veterans’ groups and the Senate minority leader to demand that VA cease to use hydroxychloroquine for COVID-19.⁸ As recently as May 15, the Associated Press reported that top VA officials have defended their use of the medication and stated they will not stop administering the medication for this indication.⁹ And VA is not alone, many other health care institutions are still prescribing hydroxychloroquine even amid scientific controversy about its putative benefits. In response to the growing awareness of the potential harms of the drug, the World Health Organization on May 25 announced it was halting all hydroxychloroquine trials.¹⁰ Why then do some physicians and health care providers continue to prescribe it? Because when nothing else stands between the patient and certain death even if there are known risks and uncertain benefits, some in health care feel morally obliged to use their best clinical judgment to help a patient.

Remdesivir’s fortunes both scientific and monetary also rose and fell on the tide of mixed results from studies. Military Times reported on March 10, 2020, that the US Army Medical Research and Development Command had made an agreement with Gilead Sciences, the manufacturer of remdesivir, to provide the medication to COVID-19-positive service members.¹¹ The antiviral had failed against Ebola and hepatitis but showed some efficacy for Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). On April 15, the Secretary of the Army announced that 2 COVID-19-positive soldiers had recovered after being given remdesivir.¹² In late April, the National Institute of Allergy and Infectious Diseases reported that in the scientific gold standard randomized placebo-controlled trial, remdesivir did speed the recovery of patients with advanced COVID-19. With the publication of the study in the prestigious New England Journal of Medicine on May 22, 2020, clearly the Army had bet on the right horse.¹³

This column has not been about quack cures and patent medicines that greed and ignorance breed in almost every American public health crisis—although these are by no means absent in this pandemic. This is about the serious endeavor of the top scientists and physicians in the country and, indeed, the world to discover a new medication or to repurpose an older pharmaceutical that is effective in the battle against COVID-19. The pressure on scientists and physicians to find a magic bullet in the battle against such an implacable enemy is unprecedented and unimaginable and can easily lead to sloppy science and ethical erosion.

In a utopia, pharmaceutical and vaccine research would be a matter of the discoveries of basic science trialed in the proof of concept of clinical care on a methodical, deliberate, and exacting timetable that balanced burdens and benefits.

In our current dystopia, science and medicine are only one of the many considerations affecting drug and vaccine development. As scientists and health care practitioners, we all experience a therapeutic imperative that we must heed with both caution and courage. Without caution we risk causing more harm than the disease we are fighting. Without courage we lose hope, the most potent antidote of all.

The Diagnosis: Bullous Leukocytoclastic Vasculitis  

Histopathology with hematoxylin and eosin (H&E) stain showed a perivascular neutrophilic infiltrate, karyorrhexis, red blood cell extravasation, and fibrin deposition in the vessel wall (quiz images). Direct immunofluorescence (DIF) showed fibrin surrounding the vasculature, consistent with vasculitis. The clinical and histopathological evaluation supported the diagnosis of bullous leukocytoclastic vasculitis (LCV). The patient had a full LCV workup including antinuclear antibody, rheumatoid factor, hepatitis B and hepatitis C screening, erythrocyte sedimentation rate, C-reactive protein, and C3/C4/total complement level, which were all within reference range. The patient denied that she had taken any medications prior to the onset of the rash. She was started on a 12-day prednisone taper starting at 60 mg, and the rash resolved in 1 week.  

Although the incidence of LCV is estimated to be 30 cases per million individuals per year,¹ bullous LCV is a rarer entity with only a few cases reported in the literature.^2,3 As in our patient's case, up to 50% of LCV cases are idiopathic or the etiology cannot be determined despite laboratory workup and medication review. Other cases can be secondary to medication, infection, collagen vascular disease, or malignancy.³ Despite the exact pathogenesis of bullous LCV being unknown,⁴ it likely is related to a type III hypersensitivity reaction with immune complex deposition in postcapillary venules leading to endothelial injury, activation of the complement cascade, and development of intraepidermal or subepidermal blister formation depending on location of inflammation and edema.² Clinically, an intraepidermal split would be more flaccid, similar to pemphigus vulgaris, while a subepidermal split, as in our patient, would be taut bullae. The subepidermal split more commonly is seen in bullous LCV.²  

Leukocytoclastic vasculitis on H&E staining characteristically has a perivascular inflammatory infiltrate, neutrophilic fragments called leukocytoclasis, and blood extravasation.³ Extravasated blood presents clinically as petechiae. In this case, the petechiae helped distinguish this entity from the differential diagnosis. Furthermore, DIF would be helpful in distinguishing bullous diseases such as bullous pemphigoid (BP) and pemphigus vulgaris from LCV.² Direct immunofluorescence in bullous LCV would have fibrinogen surrounding the vasculature without C3 and IgG deposition (intraepidermal or subepidermal).  

Mild cases of LCV often resolve with supportive measures including elevation of the legs, ice packs applied to the affected area, and removal of the inciting drug or event.⁴ In the few cases reported in the literature, bullous LCV presented more diffusely than classic LCV with bullous lesions on the forearms and the lower extremities. Oral steroids are efficacious for extensive bullous LCV.⁴ 

The differential diagnosis of bullous LCV includes bullous diseases with subepidermal split including BP and linear IgA bullous dermatosis (LABD). Bullous pemphigoid is an autoimmune subepidermal blistering disease typically affecting patients older than 60 years.⁵ The pathogenesis of BP is related to development of autoantibodies directed against hemidesmosome components, bullous pemphigoid antigen (BPAG) 1 or BPAG2.⁵ Bullous pemphigoid presents clinically as widespread, generally pruritic, erythematous, urticarial plaques with bullae. Histologically, BP characteristically has a subepidermal split with superficial dermal edema and eosinophils at the dermoepidermal junction (Figure 1). Direct immunofluorescence confirms the diagnosis with IgG and C3 deposition in an n-serrated pattern at the dermoepidermal junction.⁶ Bullous pemphigoid can be distinguished from bullous LCV by the older age of presentation, DIF findings, and the absence of purpura.  

Linear IgA bullous dermatosis represents a rare subepidermal vesiculobullous disease occurring in patients in their 60s.⁷ Clinically, this entity presents as tense bullae often located on the periphery of an urticarial plaque, classically called the "string of pearls sign." Histologically, LABD also presents with subepidermal split; however, neutrophils are the predominant cell type vs eosinophils in BP (Figure 2).⁷ Direct immunofluorescence is specific with a linear deposition of IgA at the dermoepidermal junction. Linear IgA bullous dermatosis most commonly is induced by vancomycin. Unlike bullous LCV, the bullae of LABD have an annular peripheral pattern on an erythematous base and lack purpura.  

Stasis dermatitis is inflammation of the dermis due to venous insufficiency that often is present in the bilateral lower extremities. The disorder affects approximately 7% of adults older than 50 years, but it also can occur in younger patients.⁸ The pathophysiology of stasis dermatitis is caused by edema, which leads to extracellular fluid, plasma proteins, macrophages, and erythrocytes passing into the interstitial space. Patients with stasis dermatitis present with scaly erythematous papules and plaques or edematous blisters on the lower extremities. Diagnosis usually can be made clinically; however, a skin biopsy also can be helpful. Hematoxylin and eosin shows a pauci-inflammatory subepidermal bulla with fibrin (Figure 3).⁸ The overlying epidermis is intact. The dermis has cannon ball angiomatosis, red blood cell extravasation, and fibrosis typical of stasis dermatitis. Stasis dermatitis with bullae is cell poor and lacks the perivascular inflammatory infiltrate and neutrophilic fragments that often are present in LCV, making the 2 entities distinguishable. 

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) lies on a spectrum of severe cutaneous drug reactions involving the skin and mucous membranes. Cutaneous involvement typically begins on the trunk and face and later can involve the palms and soles.⁹ Similar drugs have been implicated in bullous LCV and SJS/TEN, including nonsteroidal anti-inflammatory drugs and antibiotics. Histologically, SJS/TEN has full-thickness epidermal necrolysis, vacuolar interface, and keratinocyte apoptosis (Figure 4).⁹ The clinical presentation of sloughing of skin with positive Nikolsky sign, oral involvement, and H&E and DIF findings can help differentiate this entity from bullous LCV.  

The Diagnosis: Bullous Leukocytoclastic Vasculitis  

Histopathology with hematoxylin and eosin (H&E) stain showed a perivascular neutrophilic infiltrate, karyorrhexis, red blood cell extravasation, and fibrin deposition in the vessel wall (quiz images). Direct immunofluorescence (DIF) showed fibrin surrounding the vasculature, consistent with vasculitis. The clinical and histopathological evaluation supported the diagnosis of bullous leukocytoclastic vasculitis (LCV). The patient had a full LCV workup including antinuclear antibody, rheumatoid factor, hepatitis B and hepatitis C screening, erythrocyte sedimentation rate, C-reactive protein, and C3/C4/total complement level, which were all within reference range. The patient denied that she had taken any medications prior to the onset of the rash. She was started on a 12-day prednisone taper starting at 60 mg, and the rash resolved in 1 week.  

Although the incidence of LCV is estimated to be 30 cases per million individuals per year,¹ bullous LCV is a rarer entity with only a few cases reported in the literature.^2,3 As in our patient's case, up to 50% of LCV cases are idiopathic or the etiology cannot be determined despite laboratory workup and medication review. Other cases can be secondary to medication, infection, collagen vascular disease, or malignancy.³ Despite the exact pathogenesis of bullous LCV being unknown,⁴ it likely is related to a type III hypersensitivity reaction with immune complex deposition in postcapillary venules leading to endothelial injury, activation of the complement cascade, and development of intraepidermal or subepidermal blister formation depending on location of inflammation and edema.² Clinically, an intraepidermal split would be more flaccid, similar to pemphigus vulgaris, while a subepidermal split, as in our patient, would be taut bullae. The subepidermal split more commonly is seen in bullous LCV.²  

Leukocytoclastic vasculitis on H&E staining characteristically has a perivascular inflammatory infiltrate, neutrophilic fragments called leukocytoclasis, and blood extravasation.³ Extravasated blood presents clinically as petechiae. In this case, the petechiae helped distinguish this entity from the differential diagnosis. Furthermore, DIF would be helpful in distinguishing bullous diseases such as bullous pemphigoid (BP) and pemphigus vulgaris from LCV.² Direct immunofluorescence in bullous LCV would have fibrinogen surrounding the vasculature without C3 and IgG deposition (intraepidermal or subepidermal).  

Mild cases of LCV often resolve with supportive measures including elevation of the legs, ice packs applied to the affected area, and removal of the inciting drug or event.⁴ In the few cases reported in the literature, bullous LCV presented more diffusely than classic LCV with bullous lesions on the forearms and the lower extremities. Oral steroids are efficacious for extensive bullous LCV.⁴ 

The differential diagnosis of bullous LCV includes bullous diseases with subepidermal split including BP and linear IgA bullous dermatosis (LABD). Bullous pemphigoid is an autoimmune subepidermal blistering disease typically affecting patients older than 60 years.⁵ The pathogenesis of BP is related to development of autoantibodies directed against hemidesmosome components, bullous pemphigoid antigen (BPAG) 1 or BPAG2.⁵ Bullous pemphigoid presents clinically as widespread, generally pruritic, erythematous, urticarial plaques with bullae. Histologically, BP characteristically has a subepidermal split with superficial dermal edema and eosinophils at the dermoepidermal junction (Figure 1). Direct immunofluorescence confirms the diagnosis with IgG and C3 deposition in an n-serrated pattern at the dermoepidermal junction.⁶ Bullous pemphigoid can be distinguished from bullous LCV by the older age of presentation, DIF findings, and the absence of purpura.  

Linear IgA bullous dermatosis represents a rare subepidermal vesiculobullous disease occurring in patients in their 60s.⁷ Clinically, this entity presents as tense bullae often located on the periphery of an urticarial plaque, classically called the "string of pearls sign." Histologically, LABD also presents with subepidermal split; however, neutrophils are the predominant cell type vs eosinophils in BP (Figure 2).⁷ Direct immunofluorescence is specific with a linear deposition of IgA at the dermoepidermal junction. Linear IgA bullous dermatosis most commonly is induced by vancomycin. Unlike bullous LCV, the bullae of LABD have an annular peripheral pattern on an erythematous base and lack purpura.  

Stasis dermatitis is inflammation of the dermis due to venous insufficiency that often is present in the bilateral lower extremities. The disorder affects approximately 7% of adults older than 50 years, but it also can occur in younger patients.⁸ The pathophysiology of stasis dermatitis is caused by edema, which leads to extracellular fluid, plasma proteins, macrophages, and erythrocytes passing into the interstitial space. Patients with stasis dermatitis present with scaly erythematous papules and plaques or edematous blisters on the lower extremities. Diagnosis usually can be made clinically; however, a skin biopsy also can be helpful. Hematoxylin and eosin shows a pauci-inflammatory subepidermal bulla with fibrin (Figure 3).⁸ The overlying epidermis is intact. The dermis has cannon ball angiomatosis, red blood cell extravasation, and fibrosis typical of stasis dermatitis. Stasis dermatitis with bullae is cell poor and lacks the perivascular inflammatory infiltrate and neutrophilic fragments that often are present in LCV, making the 2 entities distinguishable. 

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) lies on a spectrum of severe cutaneous drug reactions involving the skin and mucous membranes. Cutaneous involvement typically begins on the trunk and face and later can involve the palms and soles.⁹ Similar drugs have been implicated in bullous LCV and SJS/TEN, including nonsteroidal anti-inflammatory drugs and antibiotics. Histologically, SJS/TEN has full-thickness epidermal necrolysis, vacuolar interface, and keratinocyte apoptosis (Figure 4).⁹ The clinical presentation of sloughing of skin with positive Nikolsky sign, oral involvement, and H&E and DIF findings can help differentiate this entity from bullous LCV.  

The Diagnosis: Bullous Leukocytoclastic Vasculitis  

Histopathology with hematoxylin and eosin (H&E) stain showed a perivascular neutrophilic infiltrate, karyorrhexis, red blood cell extravasation, and fibrin deposition in the vessel wall (quiz images). Direct immunofluorescence (DIF) showed fibrin surrounding the vasculature, consistent with vasculitis. The clinical and histopathological evaluation supported the diagnosis of bullous leukocytoclastic vasculitis (LCV). The patient had a full LCV workup including antinuclear antibody, rheumatoid factor, hepatitis B and hepatitis C screening, erythrocyte sedimentation rate, C-reactive protein, and C3/C4/total complement level, which were all within reference range. The patient denied that she had taken any medications prior to the onset of the rash. She was started on a 12-day prednisone taper starting at 60 mg, and the rash resolved in 1 week.  

Although the incidence of LCV is estimated to be 30 cases per million individuals per year,¹ bullous LCV is a rarer entity with only a few cases reported in the literature.^2,3 As in our patient's case, up to 50% of LCV cases are idiopathic or the etiology cannot be determined despite laboratory workup and medication review. Other cases can be secondary to medication, infection, collagen vascular disease, or malignancy.³ Despite the exact pathogenesis of bullous LCV being unknown,⁴ it likely is related to a type III hypersensitivity reaction with immune complex deposition in postcapillary venules leading to endothelial injury, activation of the complement cascade, and development of intraepidermal or subepidermal blister formation depending on location of inflammation and edema.² Clinically, an intraepidermal split would be more flaccid, similar to pemphigus vulgaris, while a subepidermal split, as in our patient, would be taut bullae. The subepidermal split more commonly is seen in bullous LCV.²  

Leukocytoclastic vasculitis on H&E staining characteristically has a perivascular inflammatory infiltrate, neutrophilic fragments called leukocytoclasis, and blood extravasation.³ Extravasated blood presents clinically as petechiae. In this case, the petechiae helped distinguish this entity from the differential diagnosis. Furthermore, DIF would be helpful in distinguishing bullous diseases such as bullous pemphigoid (BP) and pemphigus vulgaris from LCV.² Direct immunofluorescence in bullous LCV would have fibrinogen surrounding the vasculature without C3 and IgG deposition (intraepidermal or subepidermal).  

Mild cases of LCV often resolve with supportive measures including elevation of the legs, ice packs applied to the affected area, and removal of the inciting drug or event.⁴ In the few cases reported in the literature, bullous LCV presented more diffusely than classic LCV with bullous lesions on the forearms and the lower extremities. Oral steroids are efficacious for extensive bullous LCV.⁴ 

The differential diagnosis of bullous LCV includes bullous diseases with subepidermal split including BP and linear IgA bullous dermatosis (LABD). Bullous pemphigoid is an autoimmune subepidermal blistering disease typically affecting patients older than 60 years.⁵ The pathogenesis of BP is related to development of autoantibodies directed against hemidesmosome components, bullous pemphigoid antigen (BPAG) 1 or BPAG2.⁵ Bullous pemphigoid presents clinically as widespread, generally pruritic, erythematous, urticarial plaques with bullae. Histologically, BP characteristically has a subepidermal split with superficial dermal edema and eosinophils at the dermoepidermal junction (Figure 1). Direct immunofluorescence confirms the diagnosis with IgG and C3 deposition in an n-serrated pattern at the dermoepidermal junction.⁶ Bullous pemphigoid can be distinguished from bullous LCV by the older age of presentation, DIF findings, and the absence of purpura.  

Linear IgA bullous dermatosis represents a rare subepidermal vesiculobullous disease occurring in patients in their 60s.⁷ Clinically, this entity presents as tense bullae often located on the periphery of an urticarial plaque, classically called the "string of pearls sign." Histologically, LABD also presents with subepidermal split; however, neutrophils are the predominant cell type vs eosinophils in BP (Figure 2).⁷ Direct immunofluorescence is specific with a linear deposition of IgA at the dermoepidermal junction. Linear IgA bullous dermatosis most commonly is induced by vancomycin. Unlike bullous LCV, the bullae of LABD have an annular peripheral pattern on an erythematous base and lack purpura.  

Stasis dermatitis is inflammation of the dermis due to venous insufficiency that often is present in the bilateral lower extremities. The disorder affects approximately 7% of adults older than 50 years, but it also can occur in younger patients.⁸ The pathophysiology of stasis dermatitis is caused by edema, which leads to extracellular fluid, plasma proteins, macrophages, and erythrocytes passing into the interstitial space. Patients with stasis dermatitis present with scaly erythematous papules and plaques or edematous blisters on the lower extremities. Diagnosis usually can be made clinically; however, a skin biopsy also can be helpful. Hematoxylin and eosin shows a pauci-inflammatory subepidermal bulla with fibrin (Figure 3).⁸ The overlying epidermis is intact. The dermis has cannon ball angiomatosis, red blood cell extravasation, and fibrosis typical of stasis dermatitis. Stasis dermatitis with bullae is cell poor and lacks the perivascular inflammatory infiltrate and neutrophilic fragments that often are present in LCV, making the 2 entities distinguishable. 

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) lies on a spectrum of severe cutaneous drug reactions involving the skin and mucous membranes. Cutaneous involvement typically begins on the trunk and face and later can involve the palms and soles.⁹ Similar drugs have been implicated in bullous LCV and SJS/TEN, including nonsteroidal anti-inflammatory drugs and antibiotics. Histologically, SJS/TEN has full-thickness epidermal necrolysis, vacuolar interface, and keratinocyte apoptosis (Figure 4).⁹ The clinical presentation of sloughing of skin with positive Nikolsky sign, oral involvement, and H&E and DIF findings can help differentiate this entity from bullous LCV.  

A quality initiative to restrict the use of Foley catheters in middle-aged and geriatric trauma patients with hip fracture reduced the risk of urinary tract infections (UTI) and led to earlier discharge, findings from a study revealed. The results of the study were reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled because of COVID-19.

“We reduced the use of Foley catheters in our target population by more than 50%, which led to a decrease in the rate of hospital-acquired UTI and positively affected other perioperative outcomes,” reported Sanjit R. Konda, MD, an orthopedic surgeon with New York University Langone Health.

The quality initiative was introduced about 2 years ago specifically to reduce the risk of UTI in older patients admitted for femur or hip fractures. Previously at the level 1 trauma center where this quality initiative was introduced, placement of Foley catheters in these types of patients had been routine.

After the policy change, Foley catheters were only offered to these trauma patients 55 years of age or older when more than three episodes or urinary retention had been documented with a bladder scan. Urinary retention was defined as a volume of at least 600 mL.

When outcomes in 184 patients treated in the 15 months after the policy change were compared with 393 treated in the prior 38 months, Foley catheter use was substantially and significantly reduced (43.5% vs. 95.5%; P < .001), Dr. Konda said in an interview.

Although the lower rate of UTI following the policy change fell short of statistical significance (10.33% vs. 14.5%; P = .167), the policy change was associated with a decreased time to surgery (33.27 vs. 38.54 hours; P = .001), shorter length of stay (6.89 vs. 8.34 days; P < .001), and higher rate of home discharge (22.8% vs. 15.6%; P = .038).

When those who avoided a Foley catheter were compared with those who did not after the policy change, there was a significant reduction in UTI (4.81% vs. 17.4%; P = .014). In addition, patients who avoided a Foley catheter had a decreased time to surgery (P = .014), shorter length of stay (P < .001) and an almost 900% greater likelihood of home discharge (odds ratio, 9.9; P < .001).

“This quality initiative does increase the number of bladder scans required, meaning more work for nurses, but the program was developed in collaboration with our nursing staff, who were supportive of the goals,” Dr. Konda reported.

Reducing the incidence of UTI is an important initiative because the Centers for Medicare & Medicaid Services and other third-party payers employ this as a quality metric, according to Dr. Konda. This explains why hospital administrators generally embrace effective strategies to reduce UTI rates.

The improvement in outcomes, including the reduction in UTIs and length of stay, has cost implications, which will be evaluated in a future analysis, according to Dr. Konda.

Although this quality initiative was undertaken in a level 1 trauma center, Dr. Konda believes the same principles can be applied to other settings.

Jennifer A. Meddings, MD, an associate professor of medicine at the University of Michigan, Ann Arbor, agreed. Active in the evaluation of strategies to reduce hospital-acquired complications, Dr. Meddings published a study of procedural appropriateness ratings to guide strategies for improving the likelihood that catheters are employed only when needed (BMJ Qual Saf. 2019;28:56-66).

“In addition to avoiding UTI, reducing unnecessary placement of Foley catheters also eliminates the risk of trauma to the urinary tract,” Dr. Meddings said. This is a complication that is not well appreciated because the trauma is not always documented, according to Dr. Meddings, who believes increased risk of both UTI and urinary tract trauma should discourage use of Foley catheters when there is not a specific indication.

Although there are criteria other than excess bladder volume to determine when to consider a Foley catheter, Dr. Meddings encourages any systematic approach that increases the likelihood that catheters are not placed unnecessarily. She emphasized that a hip fracture by itself “is not a criterion for catheterization.”

Dr. Konda reported a financial relationship with Stryker.
 

A quality initiative to restrict the use of Foley catheters in middle-aged and geriatric trauma patients with hip fracture reduced the risk of urinary tract infections (UTI) and led to earlier discharge, findings from a study revealed. The results of the study were reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled because of COVID-19.

“We reduced the use of Foley catheters in our target population by more than 50%, which led to a decrease in the rate of hospital-acquired UTI and positively affected other perioperative outcomes,” reported Sanjit R. Konda, MD, an orthopedic surgeon with New York University Langone Health.

The quality initiative was introduced about 2 years ago specifically to reduce the risk of UTI in older patients admitted for femur or hip fractures. Previously at the level 1 trauma center where this quality initiative was introduced, placement of Foley catheters in these types of patients had been routine.

After the policy change, Foley catheters were only offered to these trauma patients 55 years of age or older when more than three episodes or urinary retention had been documented with a bladder scan. Urinary retention was defined as a volume of at least 600 mL.

When outcomes in 184 patients treated in the 15 months after the policy change were compared with 393 treated in the prior 38 months, Foley catheter use was substantially and significantly reduced (43.5% vs. 95.5%; P < .001), Dr. Konda said in an interview.

Although the lower rate of UTI following the policy change fell short of statistical significance (10.33% vs. 14.5%; P = .167), the policy change was associated with a decreased time to surgery (33.27 vs. 38.54 hours; P = .001), shorter length of stay (6.89 vs. 8.34 days; P < .001), and higher rate of home discharge (22.8% vs. 15.6%; P = .038).

When those who avoided a Foley catheter were compared with those who did not after the policy change, there was a significant reduction in UTI (4.81% vs. 17.4%; P = .014). In addition, patients who avoided a Foley catheter had a decreased time to surgery (P = .014), shorter length of stay (P < .001) and an almost 900% greater likelihood of home discharge (odds ratio, 9.9; P < .001).

“This quality initiative does increase the number of bladder scans required, meaning more work for nurses, but the program was developed in collaboration with our nursing staff, who were supportive of the goals,” Dr. Konda reported.

Reducing the incidence of UTI is an important initiative because the Centers for Medicare & Medicaid Services and other third-party payers employ this as a quality metric, according to Dr. Konda. This explains why hospital administrators generally embrace effective strategies to reduce UTI rates.

The improvement in outcomes, including the reduction in UTIs and length of stay, has cost implications, which will be evaluated in a future analysis, according to Dr. Konda.

Although this quality initiative was undertaken in a level 1 trauma center, Dr. Konda believes the same principles can be applied to other settings.

Jennifer A. Meddings, MD, an associate professor of medicine at the University of Michigan, Ann Arbor, agreed. Active in the evaluation of strategies to reduce hospital-acquired complications, Dr. Meddings published a study of procedural appropriateness ratings to guide strategies for improving the likelihood that catheters are employed only when needed (BMJ Qual Saf. 2019;28:56-66).

“In addition to avoiding UTI, reducing unnecessary placement of Foley catheters also eliminates the risk of trauma to the urinary tract,” Dr. Meddings said. This is a complication that is not well appreciated because the trauma is not always documented, according to Dr. Meddings, who believes increased risk of both UTI and urinary tract trauma should discourage use of Foley catheters when there is not a specific indication.

Although there are criteria other than excess bladder volume to determine when to consider a Foley catheter, Dr. Meddings encourages any systematic approach that increases the likelihood that catheters are not placed unnecessarily. She emphasized that a hip fracture by itself “is not a criterion for catheterization.”

Dr. Konda reported a financial relationship with Stryker.
 

A quality initiative to restrict the use of Foley catheters in middle-aged and geriatric trauma patients with hip fracture reduced the risk of urinary tract infections (UTI) and led to earlier discharge, findings from a study revealed. The results of the study were reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled because of COVID-19.

“We reduced the use of Foley catheters in our target population by more than 50%, which led to a decrease in the rate of hospital-acquired UTI and positively affected other perioperative outcomes,” reported Sanjit R. Konda, MD, an orthopedic surgeon with New York University Langone Health.

The quality initiative was introduced about 2 years ago specifically to reduce the risk of UTI in older patients admitted for femur or hip fractures. Previously at the level 1 trauma center where this quality initiative was introduced, placement of Foley catheters in these types of patients had been routine.

After the policy change, Foley catheters were only offered to these trauma patients 55 years of age or older when more than three episodes or urinary retention had been documented with a bladder scan. Urinary retention was defined as a volume of at least 600 mL.

When outcomes in 184 patients treated in the 15 months after the policy change were compared with 393 treated in the prior 38 months, Foley catheter use was substantially and significantly reduced (43.5% vs. 95.5%; P < .001), Dr. Konda said in an interview.

Although the lower rate of UTI following the policy change fell short of statistical significance (10.33% vs. 14.5%; P = .167), the policy change was associated with a decreased time to surgery (33.27 vs. 38.54 hours; P = .001), shorter length of stay (6.89 vs. 8.34 days; P < .001), and higher rate of home discharge (22.8% vs. 15.6%; P = .038).

When those who avoided a Foley catheter were compared with those who did not after the policy change, there was a significant reduction in UTI (4.81% vs. 17.4%; P = .014). In addition, patients who avoided a Foley catheter had a decreased time to surgery (P = .014), shorter length of stay (P < .001) and an almost 900% greater likelihood of home discharge (odds ratio, 9.9; P < .001).

“This quality initiative does increase the number of bladder scans required, meaning more work for nurses, but the program was developed in collaboration with our nursing staff, who were supportive of the goals,” Dr. Konda reported.

Reducing the incidence of UTI is an important initiative because the Centers for Medicare & Medicaid Services and other third-party payers employ this as a quality metric, according to Dr. Konda. This explains why hospital administrators generally embrace effective strategies to reduce UTI rates.

The improvement in outcomes, including the reduction in UTIs and length of stay, has cost implications, which will be evaluated in a future analysis, according to Dr. Konda.

Although this quality initiative was undertaken in a level 1 trauma center, Dr. Konda believes the same principles can be applied to other settings.

Jennifer A. Meddings, MD, an associate professor of medicine at the University of Michigan, Ann Arbor, agreed. Active in the evaluation of strategies to reduce hospital-acquired complications, Dr. Meddings published a study of procedural appropriateness ratings to guide strategies for improving the likelihood that catheters are employed only when needed (BMJ Qual Saf. 2019;28:56-66).

“In addition to avoiding UTI, reducing unnecessary placement of Foley catheters also eliminates the risk of trauma to the urinary tract,” Dr. Meddings said. This is a complication that is not well appreciated because the trauma is not always documented, according to Dr. Meddings, who believes increased risk of both UTI and urinary tract trauma should discourage use of Foley catheters when there is not a specific indication.

Although there are criteria other than excess bladder volume to determine when to consider a Foley catheter, Dr. Meddings encourages any systematic approach that increases the likelihood that catheters are not placed unnecessarily. She emphasized that a hip fracture by itself “is not a criterion for catheterization.”

Dr. Konda reported a financial relationship with Stryker.
 

A disease risk index is now available for pediatric patients with acute myeloid leukemia or acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation.

The model, which was developed and validated using data from more than 2,000 patients, stratifies probabilities of leukemia-free survival (LFS) into four risk groups for acute myeloid leukemia (AML) and three risk groups for acute lymphoblastic leukemia (ALL), reported lead author Muna Qayed, MD, of Emory University, Atlanta, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“The outcome of stem cell transplantation for hematologic malignancy is influenced by disease type, cytogenetics, and disease status at transplantation,” Dr. Qayed said. “In adults, these attributes were used to develop the disease risk index, or DRI, that can stratify patients for overall survival for purposes such as prognostication or clinical trial entry.”

But no such model exists for pediatric patients, Dr. Qayed said, noting that the adult DRI was found to be inaccurate when applied to children.

“[T]he [adult] DRI did not differentiate [pediatric] patients by overall survival,” Dr. Qayed said. “Therefore, knowing that pediatric AML and ALL differ biologically from adult leukemia, and further, treatment strategies differ between adults and children, we aimed to develop a pediatric-specific DRI.”

This involved analysis of data from 1,135 children with AML and 1,228 children with ALL who underwent transplantation between 2008 and 2017. All patients had myeloablative conditioning, and 75% received an unrelated donor graft. Haploidentical transplants were excluded because of small sample size.

Analyses were conducted in AML and ALL cohorts, with patients in each population randomized to training and validation subgroups in a 1:1 ratio. The primary outcome was LFS. Cox regression models were used to identify significant characteristics, which were then integrated into a prognostic scoring system for the training groups. These scoring systems were then tested in the validation subgroups. Maximum likelihood was used to identify age cutoffs, which were 3 years for AML and 2 years for ALL.

In both cohorts, disease status at transplantation was characterized by complete remission and minimal residual disease status.

In the AML cohort, approximately one-third of patients were in first complete remission with negative minimal residual disease. Risk was stratified into four groups, including good, intermediate, high, and very high risk, with respective 5-year LFS probabilities of 81%, 56%, 44%, and 21%. Independent predictors of poorer outcome included unfavorable cytogenetics, first or second complete remission with minimal residual disease positivity, relapse at transplantation, and age less than 3 years.

In the ALL cohort, risk was stratified into three risk tiers: good, intermediate, and high, with 5-year LFS probabilities of 68%, 50%, and 15%, respectively. Independent predictors of poorer outcome included age less than 2 years, relapse at transplantation, and second complete remission regardless of minimal residual disease status.

The models for each disease also predicted overall survival.

For AML, hazard ratios, ascending from good to very-high-risk tiers, were 1.00, 3.52, 4.67, and 8.62. For ALL risk tiers, ascending hazard ratios were 1.00, 2.16, and 3.86.

“In summary, the pediatric disease risk index validated for leukemia-free survival and overall survival successfully stratifies children with acute leukemia at the time of transplantation,” Dr. Qayed said.

She concluded her presentation by highlighting the practicality and relevance of the new scoring system.

“The components included in the scoring system used information that is readily available pretransplantation, lending support to the deliverability of the prognostic scoring system,” Dr. Qayed said. “It can further be used for improved interpretation of multicenter data and in clinical trials for risk stratification.”

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., first emphasized the clinical importance of an accurate disease risk index for pediatric patients.

“When going into transplant, the No. 1 question that all parents will ask is: ‘Will my child be cured?’ ” she said.

According to Dr. Shah, the risk model developed by Dr. Qayed and colleagues is built on a strong foundation, including adequate sample size, comprehensive disease characterization, exclusion of patients that did not undergo myeloablative conditioning, and use of minimal residual disease status.

Still, more work is needed, Dr. Shah said.

“This DRI will need to be prospectively tested and compared to other established risk factors. For instance, minimal residual disease alone can be further stratified and has a significant role in establishing risk for posttransplant relapse. And the development of acute graft-versus-host disease also plays an important role in posttransplant relapse.”

Dr. Shah went on to outline potential areas of improvement.

“[F]uture directions for this study could include incorporation of early posttransplant events like graft-versus-host disease, potential stratification of the minimal residual disease results among those patients in complete remission, and potential application of this DRI to the adolescent and young adult population, which may have slight variation even from the adult DRI.”The study was funded by the National Institutes of Health. The investigators disclosed no conflicts of interest

SOURCE: Qayed M et al. ASCO 2020, Abstract 7503.

A disease risk index is now available for pediatric patients with acute myeloid leukemia or acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation.

The model, which was developed and validated using data from more than 2,000 patients, stratifies probabilities of leukemia-free survival (LFS) into four risk groups for acute myeloid leukemia (AML) and three risk groups for acute lymphoblastic leukemia (ALL), reported lead author Muna Qayed, MD, of Emory University, Atlanta, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“The outcome of stem cell transplantation for hematologic malignancy is influenced by disease type, cytogenetics, and disease status at transplantation,” Dr. Qayed said. “In adults, these attributes were used to develop the disease risk index, or DRI, that can stratify patients for overall survival for purposes such as prognostication or clinical trial entry.”

But no such model exists for pediatric patients, Dr. Qayed said, noting that the adult DRI was found to be inaccurate when applied to children.

“[T]he [adult] DRI did not differentiate [pediatric] patients by overall survival,” Dr. Qayed said. “Therefore, knowing that pediatric AML and ALL differ biologically from adult leukemia, and further, treatment strategies differ between adults and children, we aimed to develop a pediatric-specific DRI.”

This involved analysis of data from 1,135 children with AML and 1,228 children with ALL who underwent transplantation between 2008 and 2017. All patients had myeloablative conditioning, and 75% received an unrelated donor graft. Haploidentical transplants were excluded because of small sample size.

Analyses were conducted in AML and ALL cohorts, with patients in each population randomized to training and validation subgroups in a 1:1 ratio. The primary outcome was LFS. Cox regression models were used to identify significant characteristics, which were then integrated into a prognostic scoring system for the training groups. These scoring systems were then tested in the validation subgroups. Maximum likelihood was used to identify age cutoffs, which were 3 years for AML and 2 years for ALL.

In both cohorts, disease status at transplantation was characterized by complete remission and minimal residual disease status.

In the AML cohort, approximately one-third of patients were in first complete remission with negative minimal residual disease. Risk was stratified into four groups, including good, intermediate, high, and very high risk, with respective 5-year LFS probabilities of 81%, 56%, 44%, and 21%. Independent predictors of poorer outcome included unfavorable cytogenetics, first or second complete remission with minimal residual disease positivity, relapse at transplantation, and age less than 3 years.

In the ALL cohort, risk was stratified into three risk tiers: good, intermediate, and high, with 5-year LFS probabilities of 68%, 50%, and 15%, respectively. Independent predictors of poorer outcome included age less than 2 years, relapse at transplantation, and second complete remission regardless of minimal residual disease status.

The models for each disease also predicted overall survival.

For AML, hazard ratios, ascending from good to very-high-risk tiers, were 1.00, 3.52, 4.67, and 8.62. For ALL risk tiers, ascending hazard ratios were 1.00, 2.16, and 3.86.

“In summary, the pediatric disease risk index validated for leukemia-free survival and overall survival successfully stratifies children with acute leukemia at the time of transplantation,” Dr. Qayed said.

She concluded her presentation by highlighting the practicality and relevance of the new scoring system.

“The components included in the scoring system used information that is readily available pretransplantation, lending support to the deliverability of the prognostic scoring system,” Dr. Qayed said. “It can further be used for improved interpretation of multicenter data and in clinical trials for risk stratification.”

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., first emphasized the clinical importance of an accurate disease risk index for pediatric patients.

“When going into transplant, the No. 1 question that all parents will ask is: ‘Will my child be cured?’ ” she said.

According to Dr. Shah, the risk model developed by Dr. Qayed and colleagues is built on a strong foundation, including adequate sample size, comprehensive disease characterization, exclusion of patients that did not undergo myeloablative conditioning, and use of minimal residual disease status.

Still, more work is needed, Dr. Shah said.

“This DRI will need to be prospectively tested and compared to other established risk factors. For instance, minimal residual disease alone can be further stratified and has a significant role in establishing risk for posttransplant relapse. And the development of acute graft-versus-host disease also plays an important role in posttransplant relapse.”

Dr. Shah went on to outline potential areas of improvement.

“[F]uture directions for this study could include incorporation of early posttransplant events like graft-versus-host disease, potential stratification of the minimal residual disease results among those patients in complete remission, and potential application of this DRI to the adolescent and young adult population, which may have slight variation even from the adult DRI.”The study was funded by the National Institutes of Health. The investigators disclosed no conflicts of interest

SOURCE: Qayed M et al. ASCO 2020, Abstract 7503.

A disease risk index is now available for pediatric patients with acute myeloid leukemia or acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation.

The model, which was developed and validated using data from more than 2,000 patients, stratifies probabilities of leukemia-free survival (LFS) into four risk groups for acute myeloid leukemia (AML) and three risk groups for acute lymphoblastic leukemia (ALL), reported lead author Muna Qayed, MD, of Emory University, Atlanta, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“The outcome of stem cell transplantation for hematologic malignancy is influenced by disease type, cytogenetics, and disease status at transplantation,” Dr. Qayed said. “In adults, these attributes were used to develop the disease risk index, or DRI, that can stratify patients for overall survival for purposes such as prognostication or clinical trial entry.”

But no such model exists for pediatric patients, Dr. Qayed said, noting that the adult DRI was found to be inaccurate when applied to children.

“[T]he [adult] DRI did not differentiate [pediatric] patients by overall survival,” Dr. Qayed said. “Therefore, knowing that pediatric AML and ALL differ biologically from adult leukemia, and further, treatment strategies differ between adults and children, we aimed to develop a pediatric-specific DRI.”

This involved analysis of data from 1,135 children with AML and 1,228 children with ALL who underwent transplantation between 2008 and 2017. All patients had myeloablative conditioning, and 75% received an unrelated donor graft. Haploidentical transplants were excluded because of small sample size.

Analyses were conducted in AML and ALL cohorts, with patients in each population randomized to training and validation subgroups in a 1:1 ratio. The primary outcome was LFS. Cox regression models were used to identify significant characteristics, which were then integrated into a prognostic scoring system for the training groups. These scoring systems were then tested in the validation subgroups. Maximum likelihood was used to identify age cutoffs, which were 3 years for AML and 2 years for ALL.

In both cohorts, disease status at transplantation was characterized by complete remission and minimal residual disease status.

In the AML cohort, approximately one-third of patients were in first complete remission with negative minimal residual disease. Risk was stratified into four groups, including good, intermediate, high, and very high risk, with respective 5-year LFS probabilities of 81%, 56%, 44%, and 21%. Independent predictors of poorer outcome included unfavorable cytogenetics, first or second complete remission with minimal residual disease positivity, relapse at transplantation, and age less than 3 years.

In the ALL cohort, risk was stratified into three risk tiers: good, intermediate, and high, with 5-year LFS probabilities of 68%, 50%, and 15%, respectively. Independent predictors of poorer outcome included age less than 2 years, relapse at transplantation, and second complete remission regardless of minimal residual disease status.

The models for each disease also predicted overall survival.

For AML, hazard ratios, ascending from good to very-high-risk tiers, were 1.00, 3.52, 4.67, and 8.62. For ALL risk tiers, ascending hazard ratios were 1.00, 2.16, and 3.86.

“In summary, the pediatric disease risk index validated for leukemia-free survival and overall survival successfully stratifies children with acute leukemia at the time of transplantation,” Dr. Qayed said.

She concluded her presentation by highlighting the practicality and relevance of the new scoring system.

“The components included in the scoring system used information that is readily available pretransplantation, lending support to the deliverability of the prognostic scoring system,” Dr. Qayed said. “It can further be used for improved interpretation of multicenter data and in clinical trials for risk stratification.”

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., first emphasized the clinical importance of an accurate disease risk index for pediatric patients.

“When going into transplant, the No. 1 question that all parents will ask is: ‘Will my child be cured?’ ” she said.

According to Dr. Shah, the risk model developed by Dr. Qayed and colleagues is built on a strong foundation, including adequate sample size, comprehensive disease characterization, exclusion of patients that did not undergo myeloablative conditioning, and use of minimal residual disease status.

Still, more work is needed, Dr. Shah said.

“This DRI will need to be prospectively tested and compared to other established risk factors. For instance, minimal residual disease alone can be further stratified and has a significant role in establishing risk for posttransplant relapse. And the development of acute graft-versus-host disease also plays an important role in posttransplant relapse.”

Dr. Shah went on to outline potential areas of improvement.

“[F]uture directions for this study could include incorporation of early posttransplant events like graft-versus-host disease, potential stratification of the minimal residual disease results among those patients in complete remission, and potential application of this DRI to the adolescent and young adult population, which may have slight variation even from the adult DRI.”The study was funded by the National Institutes of Health. The investigators disclosed no conflicts of interest

SOURCE: Qayed M et al. ASCO 2020, Abstract 7503.

Adding a tumor necrosis factor inhibitor to the treatment regimen of patients with psoriatic arthritis who failed to reach minimal disease activity on methotrexate monotherapy after 4 or more weeks had more than triple the rate of minimal disease activity after 16 weeks, compared with patients who had their methotrexate dosage escalated but received no second drug, in a multicenter, randomized study with 245 patients.

After 16 weeks, 42% of 123 patients with psoriatic arthritis (PsA) treated with methotrexate and the tumor necrosis factor (TNF) inhibitor adalimumab achieved minimal disease activity, compared with 13% of 122 patients randomized to receive escalated methotrexate monotherapy to their maximally tolerated dosage or to a maximum of 25 mg/week, Laura C. Coates, MBChB, PhD, reported at the annual European Congress of Rheumatology, held online this year due to COVID-19.

The findings are “supportive of the EULAR recommendations” for managing patients with PsA, said Dr. Coates, a rheumatologist at the University of Oxford (England). The EULAR recommendations call for starting a biologic disease-modifying antirheumatic drug (bDMARD) in patients with PsA and peripheral arthritis and “inadequate response to at least one [conventional synthetic] DMARD,” such as methotrexate (Ann Rheum Dis. 2019 Jun;79[6]:700-12). “A proportion of patients treated with methotrexate do well, but for those struggling on methotrexate, these results support use of a TNF inhibitor. It’s a balance of cost and benefit. If TNF inhibitors were as cheap as methotrexate, I suspect that would be first line more frequently,” Dr. Coates said in an interview. In contrast, the PsA management recommendations from the American College of Rheumatology make treatment with a TNF inhibitor first line, before starting with what these guidelines call an oral small molecule, the same as a conventional synthetic DMARD such as methotrexate (Arthritis Rheumatol. 2019 Jan;71[1]:5-32).

The results seen in the CONTROL study with adalimumab would likely be similar using a different TNF inhibitor or an agent that’s an adalimumab biosimilar, Dr. Coates said. The only patients with PsA and not achieving minimal disease activity on methotrexate monotherapy who should not then receive add-on treatment with a TNF inhibitor are those known to have a safety exclusion for this drug class or patients for whom the incremental cost poses a barrier, she added. In addition, patients with more substantial skin involvement may get greater benefit from a different class of bDMARD, such as a drug that inhibits interleukin-17 or IL-12 and -23 as recommended by the EULAR panel.

“We still get very good results with a TNF inhibitor for psoriasis, but in patients with severe psoriasis there is an argument to use a different drug,” Dr. Coates acknowledged. Skin responses with an IL-17 inhibitor or an IL-12/23 inhibitor “are far better” than with a TNF inhibitor, said Dr. Landewé. He also added the caution that longer-term use of adalimumab “may induce aggravation of PsA in a significant number of patients.”

CONTROL was sponsored by AbbVie, the company that markets adalimumab (Humira). Dr. Coates has been a consultant to AbbVie, as well as to Amgen, Biogen, Boehringer Ingelheim, Celgene, Jansen, Novartis, Pfizer, and UCB. Dr. Landewé has been a consultant to AbbVie, as well as to Eli Lilly, Novartis, Pfizer, and UCB.

mzoler@mdedge.com

SOURCE: Coates LC et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:33, Abstract OP0050.

Adding a tumor necrosis factor inhibitor to the treatment regimen of patients with psoriatic arthritis who failed to reach minimal disease activity on methotrexate monotherapy after 4 or more weeks had more than triple the rate of minimal disease activity after 16 weeks, compared with patients who had their methotrexate dosage escalated but received no second drug, in a multicenter, randomized study with 245 patients.

After 16 weeks, 42% of 123 patients with psoriatic arthritis (PsA) treated with methotrexate and the tumor necrosis factor (TNF) inhibitor adalimumab achieved minimal disease activity, compared with 13% of 122 patients randomized to receive escalated methotrexate monotherapy to their maximally tolerated dosage or to a maximum of 25 mg/week, Laura C. Coates, MBChB, PhD, reported at the annual European Congress of Rheumatology, held online this year due to COVID-19.

The findings are “supportive of the EULAR recommendations” for managing patients with PsA, said Dr. Coates, a rheumatologist at the University of Oxford (England). The EULAR recommendations call for starting a biologic disease-modifying antirheumatic drug (bDMARD) in patients with PsA and peripheral arthritis and “inadequate response to at least one [conventional synthetic] DMARD,” such as methotrexate (Ann Rheum Dis. 2019 Jun;79[6]:700-12). “A proportion of patients treated with methotrexate do well, but for those struggling on methotrexate, these results support use of a TNF inhibitor. It’s a balance of cost and benefit. If TNF inhibitors were as cheap as methotrexate, I suspect that would be first line more frequently,” Dr. Coates said in an interview. In contrast, the PsA management recommendations from the American College of Rheumatology make treatment with a TNF inhibitor first line, before starting with what these guidelines call an oral small molecule, the same as a conventional synthetic DMARD such as methotrexate (Arthritis Rheumatol. 2019 Jan;71[1]:5-32).

The results seen in the CONTROL study with adalimumab would likely be similar using a different TNF inhibitor or an agent that’s an adalimumab biosimilar, Dr. Coates said. The only patients with PsA and not achieving minimal disease activity on methotrexate monotherapy who should not then receive add-on treatment with a TNF inhibitor are those known to have a safety exclusion for this drug class or patients for whom the incremental cost poses a barrier, she added. In addition, patients with more substantial skin involvement may get greater benefit from a different class of bDMARD, such as a drug that inhibits interleukin-17 or IL-12 and -23 as recommended by the EULAR panel.

“We still get very good results with a TNF inhibitor for psoriasis, but in patients with severe psoriasis there is an argument to use a different drug,” Dr. Coates acknowledged. Skin responses with an IL-17 inhibitor or an IL-12/23 inhibitor “are far better” than with a TNF inhibitor, said Dr. Landewé. He also added the caution that longer-term use of adalimumab “may induce aggravation of PsA in a significant number of patients.”

CONTROL was sponsored by AbbVie, the company that markets adalimumab (Humira). Dr. Coates has been a consultant to AbbVie, as well as to Amgen, Biogen, Boehringer Ingelheim, Celgene, Jansen, Novartis, Pfizer, and UCB. Dr. Landewé has been a consultant to AbbVie, as well as to Eli Lilly, Novartis, Pfizer, and UCB.

mzoler@mdedge.com

SOURCE: Coates LC et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:33, Abstract OP0050.

Adding a tumor necrosis factor inhibitor to the treatment regimen of patients with psoriatic arthritis who failed to reach minimal disease activity on methotrexate monotherapy after 4 or more weeks had more than triple the rate of minimal disease activity after 16 weeks, compared with patients who had their methotrexate dosage escalated but received no second drug, in a multicenter, randomized study with 245 patients.

After 16 weeks, 42% of 123 patients with psoriatic arthritis (PsA) treated with methotrexate and the tumor necrosis factor (TNF) inhibitor adalimumab achieved minimal disease activity, compared with 13% of 122 patients randomized to receive escalated methotrexate monotherapy to their maximally tolerated dosage or to a maximum of 25 mg/week, Laura C. Coates, MBChB, PhD, reported at the annual European Congress of Rheumatology, held online this year due to COVID-19.

The findings are “supportive of the EULAR recommendations” for managing patients with PsA, said Dr. Coates, a rheumatologist at the University of Oxford (England). The EULAR recommendations call for starting a biologic disease-modifying antirheumatic drug (bDMARD) in patients with PsA and peripheral arthritis and “inadequate response to at least one [conventional synthetic] DMARD,” such as methotrexate (Ann Rheum Dis. 2019 Jun;79[6]:700-12). “A proportion of patients treated with methotrexate do well, but for those struggling on methotrexate, these results support use of a TNF inhibitor. It’s a balance of cost and benefit. If TNF inhibitors were as cheap as methotrexate, I suspect that would be first line more frequently,” Dr. Coates said in an interview. In contrast, the PsA management recommendations from the American College of Rheumatology make treatment with a TNF inhibitor first line, before starting with what these guidelines call an oral small molecule, the same as a conventional synthetic DMARD such as methotrexate (Arthritis Rheumatol. 2019 Jan;71[1]:5-32).

The results seen in the CONTROL study with adalimumab would likely be similar using a different TNF inhibitor or an agent that’s an adalimumab biosimilar, Dr. Coates said. The only patients with PsA and not achieving minimal disease activity on methotrexate monotherapy who should not then receive add-on treatment with a TNF inhibitor are those known to have a safety exclusion for this drug class or patients for whom the incremental cost poses a barrier, she added. In addition, patients with more substantial skin involvement may get greater benefit from a different class of bDMARD, such as a drug that inhibits interleukin-17 or IL-12 and -23 as recommended by the EULAR panel.

“We still get very good results with a TNF inhibitor for psoriasis, but in patients with severe psoriasis there is an argument to use a different drug,” Dr. Coates acknowledged. Skin responses with an IL-17 inhibitor or an IL-12/23 inhibitor “are far better” than with a TNF inhibitor, said Dr. Landewé. He also added the caution that longer-term use of adalimumab “may induce aggravation of PsA in a significant number of patients.”

CONTROL was sponsored by AbbVie, the company that markets adalimumab (Humira). Dr. Coates has been a consultant to AbbVie, as well as to Amgen, Biogen, Boehringer Ingelheim, Celgene, Jansen, Novartis, Pfizer, and UCB. Dr. Landewé has been a consultant to AbbVie, as well as to Eli Lilly, Novartis, Pfizer, and UCB.

mzoler@mdedge.com

SOURCE: Coates LC et al. Ann Rheum Dis. 2020 Jun;79[suppl 1]:33, Abstract OP0050.

Early signs of neurodegeneration appeared in young adult carriers of the Huntington’s disease gene mutation approximately 24 years before the clinical onset of symptoms, according to a study published in the June Lancet Neurology. The data come from the Huntington’s disease Young Adult Study (HD-YAS) conducted in the United Kingdom.

The genetic cause of Huntington’s disease provides a potential target for biomarker treatment, wrote joint first authors Rachael I. Scahill, PhD, and Paul Zeun, BMBS, of University College London and colleagues.

“A detailed characterization of the premanifest period in Huntington’s disease is crucial for disease staging, informing the optimum time to initiate treatments, and identifying biomarkers for future trials in people with premanifest Huntington’s disease (preHD),” they said.

Identifying biomarkers of pre-Huntington’s disease

For their study, the researchers recruited 64 young adults with presymptomatic Huntington’s disease (preHD) and 67 controls, with an average age of 29 years. Brain imaging was conducted between Aug. 2, 2017, and April 25, 2019. Individuals with preexisting measurable cognitive and psychiatric disorders were excluded.

The researchers found no significant evidence of cognitive or psychiatric impairment in the preHD group at 23.6 years from the predicted onset of symptoms. The preHD group showed smaller putamen volumes, compared with controls, but this difference had no apparent relation to the timing of symptom onset, the researchers said.

Brain imaging revealed elevations in the CSF mutant huntingtin, neurofilament light protein (NfL), YKL-40, and plasma NfL among individuals with preHD, compared with controls. Of these, CSF NfL showed the highest effect size of measures in the study and showed a significant increasing association with estimated years to the onset of clinical symptoms of HD carriers. Overall, 53% of individuals with preHD had CSF NfL values in the normal range, and 47% had elevated values, compared with controls.

“NfL is therefore a potential candidate to provide a measure of disease progression in early preHD and might eventually be used as a marker of response to treatment in future preventive trials,” the researchers said.

The study findings were limited by several factors including potential underpowering to detect associations with age and CAG gene segment repeats, the researchers noted.

However, “By identifying a cohort of individuals with preHD and no detectable functional impairment but who begin to exhibit subtle elevations in select biological measures of neurodegeneration, we have highlighted a crucial point early in the disease process,” they concluded.

“Intervening at this stage might offer the prospect of delaying or preventing further neurodegeneration while function is intact, giving gene carriers many more years of life without impairment,” they added.

What is the best window for treatment?

The study is “particularly important since the absence of any subclinical symptoms in preHD individuals far from onset shows that the abnormal developmental aspect of Huntington’s disease has no substantial effect on adults’ clinical pattern,” wrote Anne-Catherine Bachoud-Lévi, MD, of Université Paris Est, Créteil, France, in an accompanying comment.

“The most robust findings of [the study] are the sensitiveness of NfL, compared with mutant huntingtin in CSF of individuals with preHD, and that degenerative rather than developmental disorders are clinically relevant,” she said. However, potential limitations to the study include the exclusion absence of language and calculation as part of the cognitive assessments, she noted. “Ideally, more sensitive cognitive tasks including these domains should be designed for preHD participants.”

In addition, the risks versus benefits of any long-term treatment must be considered, Dr. Bachoud-Lévi noted.

“The best window for treatment should instead target the time when a detectable subclinical slope of cognitive performance allows for predicting disease onset within a few years,” she said. “Turning to machine learning methodology, such as that in oncology, might also permit combining the best window and the best disease-modifying therapy for individuals with preHD,” she added.

The study was supported by the Wellcome Trust, CHDI Foundation. The researchers had no financial conflicts to disclose. Dr. Bachoud-Lévi disclosed grants and personal fees from Roche, and grants from the French Ministry of Health and Direction de la Recherche Clinique.

SOURCES: Scahill RI et al. Lancet Neurol. 2020 June;19:502-12; Bachoud-Lévi A-C. Lancet Neurol. 2020 June;19:473-5.

Early signs of neurodegeneration appeared in young adult carriers of the Huntington’s disease gene mutation approximately 24 years before the clinical onset of symptoms, according to a study published in the June Lancet Neurology. The data come from the Huntington’s disease Young Adult Study (HD-YAS) conducted in the United Kingdom.

The genetic cause of Huntington’s disease provides a potential target for biomarker treatment, wrote joint first authors Rachael I. Scahill, PhD, and Paul Zeun, BMBS, of University College London and colleagues.

“A detailed characterization of the premanifest period in Huntington’s disease is crucial for disease staging, informing the optimum time to initiate treatments, and identifying biomarkers for future trials in people with premanifest Huntington’s disease (preHD),” they said.

Identifying biomarkers of pre-Huntington’s disease

For their study, the researchers recruited 64 young adults with presymptomatic Huntington’s disease (preHD) and 67 controls, with an average age of 29 years. Brain imaging was conducted between Aug. 2, 2017, and April 25, 2019. Individuals with preexisting measurable cognitive and psychiatric disorders were excluded.

The researchers found no significant evidence of cognitive or psychiatric impairment in the preHD group at 23.6 years from the predicted onset of symptoms. The preHD group showed smaller putamen volumes, compared with controls, but this difference had no apparent relation to the timing of symptom onset, the researchers said.

Brain imaging revealed elevations in the CSF mutant huntingtin, neurofilament light protein (NfL), YKL-40, and plasma NfL among individuals with preHD, compared with controls. Of these, CSF NfL showed the highest effect size of measures in the study and showed a significant increasing association with estimated years to the onset of clinical symptoms of HD carriers. Overall, 53% of individuals with preHD had CSF NfL values in the normal range, and 47% had elevated values, compared with controls.

“NfL is therefore a potential candidate to provide a measure of disease progression in early preHD and might eventually be used as a marker of response to treatment in future preventive trials,” the researchers said.

The study findings were limited by several factors including potential underpowering to detect associations with age and CAG gene segment repeats, the researchers noted.

However, “By identifying a cohort of individuals with preHD and no detectable functional impairment but who begin to exhibit subtle elevations in select biological measures of neurodegeneration, we have highlighted a crucial point early in the disease process,” they concluded.

“Intervening at this stage might offer the prospect of delaying or preventing further neurodegeneration while function is intact, giving gene carriers many more years of life without impairment,” they added.

What is the best window for treatment?

The study is “particularly important since the absence of any subclinical symptoms in preHD individuals far from onset shows that the abnormal developmental aspect of Huntington’s disease has no substantial effect on adults’ clinical pattern,” wrote Anne-Catherine Bachoud-Lévi, MD, of Université Paris Est, Créteil, France, in an accompanying comment.

“The most robust findings of [the study] are the sensitiveness of NfL, compared with mutant huntingtin in CSF of individuals with preHD, and that degenerative rather than developmental disorders are clinically relevant,” she said. However, potential limitations to the study include the exclusion absence of language and calculation as part of the cognitive assessments, she noted. “Ideally, more sensitive cognitive tasks including these domains should be designed for preHD participants.”

In addition, the risks versus benefits of any long-term treatment must be considered, Dr. Bachoud-Lévi noted.

“The best window for treatment should instead target the time when a detectable subclinical slope of cognitive performance allows for predicting disease onset within a few years,” she said. “Turning to machine learning methodology, such as that in oncology, might also permit combining the best window and the best disease-modifying therapy for individuals with preHD,” she added.

The study was supported by the Wellcome Trust, CHDI Foundation. The researchers had no financial conflicts to disclose. Dr. Bachoud-Lévi disclosed grants and personal fees from Roche, and grants from the French Ministry of Health and Direction de la Recherche Clinique.

SOURCES: Scahill RI et al. Lancet Neurol. 2020 June;19:502-12; Bachoud-Lévi A-C. Lancet Neurol. 2020 June;19:473-5.

Early signs of neurodegeneration appeared in young adult carriers of the Huntington’s disease gene mutation approximately 24 years before the clinical onset of symptoms, according to a study published in the June Lancet Neurology. The data come from the Huntington’s disease Young Adult Study (HD-YAS) conducted in the United Kingdom.

The genetic cause of Huntington’s disease provides a potential target for biomarker treatment, wrote joint first authors Rachael I. Scahill, PhD, and Paul Zeun, BMBS, of University College London and colleagues.

“A detailed characterization of the premanifest period in Huntington’s disease is crucial for disease staging, informing the optimum time to initiate treatments, and identifying biomarkers for future trials in people with premanifest Huntington’s disease (preHD),” they said.

Identifying biomarkers of pre-Huntington’s disease

For their study, the researchers recruited 64 young adults with presymptomatic Huntington’s disease (preHD) and 67 controls, with an average age of 29 years. Brain imaging was conducted between Aug. 2, 2017, and April 25, 2019. Individuals with preexisting measurable cognitive and psychiatric disorders were excluded.

The researchers found no significant evidence of cognitive or psychiatric impairment in the preHD group at 23.6 years from the predicted onset of symptoms. The preHD group showed smaller putamen volumes, compared with controls, but this difference had no apparent relation to the timing of symptom onset, the researchers said.

Brain imaging revealed elevations in the CSF mutant huntingtin, neurofilament light protein (NfL), YKL-40, and plasma NfL among individuals with preHD, compared with controls. Of these, CSF NfL showed the highest effect size of measures in the study and showed a significant increasing association with estimated years to the onset of clinical symptoms of HD carriers. Overall, 53% of individuals with preHD had CSF NfL values in the normal range, and 47% had elevated values, compared with controls.

“NfL is therefore a potential candidate to provide a measure of disease progression in early preHD and might eventually be used as a marker of response to treatment in future preventive trials,” the researchers said.

The study findings were limited by several factors including potential underpowering to detect associations with age and CAG gene segment repeats, the researchers noted.

However, “By identifying a cohort of individuals with preHD and no detectable functional impairment but who begin to exhibit subtle elevations in select biological measures of neurodegeneration, we have highlighted a crucial point early in the disease process,” they concluded.

“Intervening at this stage might offer the prospect of delaying or preventing further neurodegeneration while function is intact, giving gene carriers many more years of life without impairment,” they added.

What is the best window for treatment?

The study is “particularly important since the absence of any subclinical symptoms in preHD individuals far from onset shows that the abnormal developmental aspect of Huntington’s disease has no substantial effect on adults’ clinical pattern,” wrote Anne-Catherine Bachoud-Lévi, MD, of Université Paris Est, Créteil, France, in an accompanying comment.

“The most robust findings of [the study] are the sensitiveness of NfL, compared with mutant huntingtin in CSF of individuals with preHD, and that degenerative rather than developmental disorders are clinically relevant,” she said. However, potential limitations to the study include the exclusion absence of language and calculation as part of the cognitive assessments, she noted. “Ideally, more sensitive cognitive tasks including these domains should be designed for preHD participants.”

In addition, the risks versus benefits of any long-term treatment must be considered, Dr. Bachoud-Lévi noted.

“The best window for treatment should instead target the time when a detectable subclinical slope of cognitive performance allows for predicting disease onset within a few years,” she said. “Turning to machine learning methodology, such as that in oncology, might also permit combining the best window and the best disease-modifying therapy for individuals with preHD,” she added.

The study was supported by the Wellcome Trust, CHDI Foundation. The researchers had no financial conflicts to disclose. Dr. Bachoud-Lévi disclosed grants and personal fees from Roche, and grants from the French Ministry of Health and Direction de la Recherche Clinique.

SOURCES: Scahill RI et al. Lancet Neurol. 2020 June;19:502-12; Bachoud-Lévi A-C. Lancet Neurol. 2020 June;19:473-5.

Patients with rheumatoid arthritis (RA) who are treated with Janus kinase (JAK) inhibitors had the highest risk of developing herpes zoster among newer disease-modifying antirheumatic drugs (DMARDs), according to data released from the German biologics registry.

These are believed to be the first European data on the risk of herpes zoster with JAK inhibitors and showed that the crude incidence rate of herpes zoster per 1,000 patient-years was 24.9 with JAK inhibitors, compared with just 5.8 for controls taking conventional synthetic (cs) DMARDs.

The risk of herpes zoster was also increased with other biologic (b) and targeted synthetic (ts) DMARDs that were assessed, with crude rates per 1,000 patient-years of 10.4 for monoclonal tumor necrosis factor inhibitors (TNFi), 10.5 for B-cell targeted therapies, 9.4 for T-cell costimulation modulators, 9.0 for soluble TNF receptors, and 8.5 for interleukin (IL)-6 inhibitors.

Overall, JAK inhibitor treatment was associated with a fivefold higher risk of herpes zoster (hazard ratio, 5.0; P < .0001), compared with the control csDMARD population after adjustment using an inverse probability weights (IPW) method.

“The general risk of herpes zoster is [twofold] higher in patients with rheumatoid arthritis when you compare it with the general population,” said Anja Strangfeld, MD of the German Research Center, Berlin, and one of the three RABBIT [Rheumatoide Arthritis: Biobachtung der Biologika-Therapie] principal investigators.

“If you think of all the treatments that RA patients get, then the risk is further increased with bDMARD and [JAK inhibitor] treatments,” she added in an interview. While the risk was highest with JAK inhibitors, “we also saw that monoclonal TNF antibodies as well as all the other biologic DMARD treatments have a higher risk of herpes zoster in RA patients, compared to csDMARD therapy,” Dr. Strangfeld said.

Adjusted IPW HR for the other RA treatments showed an increased herpes zoster risk for all but the soluble TNF receptor agents, at 1.6 for IL-6 inhibitors (P = .0045) and monoclonal TNFi antibodies (P = .0003), and 1.7 for B-cell targeted therapies (P = .00026) and T-cell costimulation modulators (P = .0048).

Dr. Strangfeld presented these data during the annual European Congress of Rheumatology, held online this year due to COVID-19. The analysis included 12,470 patients with RA enrolled in RABBIT from 2007 onward and who had been treated with monoclonal TNF inhibitor antibodies, cell-targeted therapies, and tsDMARDs such as JAK inhibitors. In all, at the data cutoff at the end of April 2019, 452 cases of herpes zoster were recorded in 433 patients, of which 52 cases were serious.

“The reactivation of the varicella zoster virus causing the herpes zoster is triggered by a decline of cellular immunity. This can be due to aging or immune suppression of any kind,” Dr. Strangfeld said in her presentation.

“The Cox regression [analysis] revealed that higher age and intake of glucocorticoids were associated with an increased risk of herpes zoster,” she reported, with a dose dependent increase with glucocorticoids. IPW HR for age per 10 years was 1.3 (P < .0001) and 1.9 (P = .0022) for higher doses of glucocorticoids (>10 vs. 0 mg/day).

Commenting on the study, rheumatologist and epidemiologist Loreto Carmona, MD, PhD, said: “This is a very interesting study. The results are confident and precise. The frequency of herpes zoster infection [based on crude incidence rate estimates] is very high. However, we must focus on the [multivariable with IPW] analysis after taking into account baseline risk.”

Dr. Carmona, who is the chair of the congress’s Abstract Selection Committee and is the scientific director of the Instituto de Salud Musculoesquelética in Madrid, added: “Having a disease with high levels of activity or a disease refractory to treatments [both of which were very likely used in creating the IPW] levels off the risk a bit. Also, because RA by itself, glucocorticoids, and age all increase the risk. Still, jakinibs [JAK inhibitors] stand out as the treatment related to higher risk of herpes zoster infection.”

Dr. Strangfeld and fellow RABBIT investigators have previously looked at the risk of herpes zoster in patients treated with anti–TNF-alpha agents (JAMA. 2009;301[7]:737-44). They found that monoclonal anti–TNF-alpha agents may be associated with increased risk of herpes zoster, which is now confirmed by the current analysis. The reason for looking at herpes zoster risk again is that since that first analysis, many more therapies have become available for RA during the past 10 years, notably the tsDMARDs.

Herpes zoster may not always be a serious event, Dr. Strangfeld said in the interview, “but it diminishes your quality of life; it can also be associated with pain and may be followed by postherpetic neuralgia, which is very painful.” With new herpes zoster vaccinations available, it is now possible to vaccinate patients more easily. “This is advisable for all kinds of treatments,” she said.

“What we found was quite in agreement with the data that we know from the U.S., from the observational studies, for example from the Corrona database,” Dr. Strangfeld stated. The key finding is that the risk of herpes zoster is increased to some level, almost regardless of which drug is chosen, she said. “This gives a clear message that systematic herpes zoster vaccination should be done in patients with RA,” she suggested.

The German biologics registry RABBIT is supported by a joint unconditional grant from AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Hexal, Lilly, Merck Sharp & Dohme, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Strangfeld has received speaker fees from AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, Sanofi-Aventis, and UCB. Dr. Carmona had no relevant conflicts of interest to disclose.

SOURCE: Strangfeld A et al. Ann Rheum Dis. 2020;79[suppl 1]:150. Abstract OP0238.

Patients with rheumatoid arthritis (RA) who are treated with Janus kinase (JAK) inhibitors had the highest risk of developing herpes zoster among newer disease-modifying antirheumatic drugs (DMARDs), according to data released from the German biologics registry.

These are believed to be the first European data on the risk of herpes zoster with JAK inhibitors and showed that the crude incidence rate of herpes zoster per 1,000 patient-years was 24.9 with JAK inhibitors, compared with just 5.8 for controls taking conventional synthetic (cs) DMARDs.

The risk of herpes zoster was also increased with other biologic (b) and targeted synthetic (ts) DMARDs that were assessed, with crude rates per 1,000 patient-years of 10.4 for monoclonal tumor necrosis factor inhibitors (TNFi), 10.5 for B-cell targeted therapies, 9.4 for T-cell costimulation modulators, 9.0 for soluble TNF receptors, and 8.5 for interleukin (IL)-6 inhibitors.

Overall, JAK inhibitor treatment was associated with a fivefold higher risk of herpes zoster (hazard ratio, 5.0; P < .0001), compared with the control csDMARD population after adjustment using an inverse probability weights (IPW) method.

“The general risk of herpes zoster is [twofold] higher in patients with rheumatoid arthritis when you compare it with the general population,” said Anja Strangfeld, MD of the German Research Center, Berlin, and one of the three RABBIT [Rheumatoide Arthritis: Biobachtung der Biologika-Therapie] principal investigators.

“If you think of all the treatments that RA patients get, then the risk is further increased with bDMARD and [JAK inhibitor] treatments,” she added in an interview. While the risk was highest with JAK inhibitors, “we also saw that monoclonal TNF antibodies as well as all the other biologic DMARD treatments have a higher risk of herpes zoster in RA patients, compared to csDMARD therapy,” Dr. Strangfeld said.

Adjusted IPW HR for the other RA treatments showed an increased herpes zoster risk for all but the soluble TNF receptor agents, at 1.6 for IL-6 inhibitors (P = .0045) and monoclonal TNFi antibodies (P = .0003), and 1.7 for B-cell targeted therapies (P = .00026) and T-cell costimulation modulators (P = .0048).

Dr. Strangfeld presented these data during the annual European Congress of Rheumatology, held online this year due to COVID-19. The analysis included 12,470 patients with RA enrolled in RABBIT from 2007 onward and who had been treated with monoclonal TNF inhibitor antibodies, cell-targeted therapies, and tsDMARDs such as JAK inhibitors. In all, at the data cutoff at the end of April 2019, 452 cases of herpes zoster were recorded in 433 patients, of which 52 cases were serious.

“The reactivation of the varicella zoster virus causing the herpes zoster is triggered by a decline of cellular immunity. This can be due to aging or immune suppression of any kind,” Dr. Strangfeld said in her presentation.

“The Cox regression [analysis] revealed that higher age and intake of glucocorticoids were associated with an increased risk of herpes zoster,” she reported, with a dose dependent increase with glucocorticoids. IPW HR for age per 10 years was 1.3 (P < .0001) and 1.9 (P = .0022) for higher doses of glucocorticoids (>10 vs. 0 mg/day).

Commenting on the study, rheumatologist and epidemiologist Loreto Carmona, MD, PhD, said: “This is a very interesting study. The results are confident and precise. The frequency of herpes zoster infection [based on crude incidence rate estimates] is very high. However, we must focus on the [multivariable with IPW] analysis after taking into account baseline risk.”

Dr. Carmona, who is the chair of the congress’s Abstract Selection Committee and is the scientific director of the Instituto de Salud Musculoesquelética in Madrid, added: “Having a disease with high levels of activity or a disease refractory to treatments [both of which were very likely used in creating the IPW] levels off the risk a bit. Also, because RA by itself, glucocorticoids, and age all increase the risk. Still, jakinibs [JAK inhibitors] stand out as the treatment related to higher risk of herpes zoster infection.”

Dr. Strangfeld and fellow RABBIT investigators have previously looked at the risk of herpes zoster in patients treated with anti–TNF-alpha agents (JAMA. 2009;301[7]:737-44). They found that monoclonal anti–TNF-alpha agents may be associated with increased risk of herpes zoster, which is now confirmed by the current analysis. The reason for looking at herpes zoster risk again is that since that first analysis, many more therapies have become available for RA during the past 10 years, notably the tsDMARDs.

Herpes zoster may not always be a serious event, Dr. Strangfeld said in the interview, “but it diminishes your quality of life; it can also be associated with pain and may be followed by postherpetic neuralgia, which is very painful.” With new herpes zoster vaccinations available, it is now possible to vaccinate patients more easily. “This is advisable for all kinds of treatments,” she said.

“What we found was quite in agreement with the data that we know from the U.S., from the observational studies, for example from the Corrona database,” Dr. Strangfeld stated. The key finding is that the risk of herpes zoster is increased to some level, almost regardless of which drug is chosen, she said. “This gives a clear message that systematic herpes zoster vaccination should be done in patients with RA,” she suggested.

The German biologics registry RABBIT is supported by a joint unconditional grant from AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Hexal, Lilly, Merck Sharp & Dohme, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Strangfeld has received speaker fees from AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, Sanofi-Aventis, and UCB. Dr. Carmona had no relevant conflicts of interest to disclose.

SOURCE: Strangfeld A et al. Ann Rheum Dis. 2020;79[suppl 1]:150. Abstract OP0238.

Patients with rheumatoid arthritis (RA) who are treated with Janus kinase (JAK) inhibitors had the highest risk of developing herpes zoster among newer disease-modifying antirheumatic drugs (DMARDs), according to data released from the German biologics registry.

These are believed to be the first European data on the risk of herpes zoster with JAK inhibitors and showed that the crude incidence rate of herpes zoster per 1,000 patient-years was 24.9 with JAK inhibitors, compared with just 5.8 for controls taking conventional synthetic (cs) DMARDs.

The risk of herpes zoster was also increased with other biologic (b) and targeted synthetic (ts) DMARDs that were assessed, with crude rates per 1,000 patient-years of 10.4 for monoclonal tumor necrosis factor inhibitors (TNFi), 10.5 for B-cell targeted therapies, 9.4 for T-cell costimulation modulators, 9.0 for soluble TNF receptors, and 8.5 for interleukin (IL)-6 inhibitors.

Overall, JAK inhibitor treatment was associated with a fivefold higher risk of herpes zoster (hazard ratio, 5.0; P < .0001), compared with the control csDMARD population after adjustment using an inverse probability weights (IPW) method.

“The general risk of herpes zoster is [twofold] higher in patients with rheumatoid arthritis when you compare it with the general population,” said Anja Strangfeld, MD of the German Research Center, Berlin, and one of the three RABBIT [Rheumatoide Arthritis: Biobachtung der Biologika-Therapie] principal investigators.

“If you think of all the treatments that RA patients get, then the risk is further increased with bDMARD and [JAK inhibitor] treatments,” she added in an interview. While the risk was highest with JAK inhibitors, “we also saw that monoclonal TNF antibodies as well as all the other biologic DMARD treatments have a higher risk of herpes zoster in RA patients, compared to csDMARD therapy,” Dr. Strangfeld said.

Adjusted IPW HR for the other RA treatments showed an increased herpes zoster risk for all but the soluble TNF receptor agents, at 1.6 for IL-6 inhibitors (P = .0045) and monoclonal TNFi antibodies (P = .0003), and 1.7 for B-cell targeted therapies (P = .00026) and T-cell costimulation modulators (P = .0048).

Dr. Strangfeld presented these data during the annual European Congress of Rheumatology, held online this year due to COVID-19. The analysis included 12,470 patients with RA enrolled in RABBIT from 2007 onward and who had been treated with monoclonal TNF inhibitor antibodies, cell-targeted therapies, and tsDMARDs such as JAK inhibitors. In all, at the data cutoff at the end of April 2019, 452 cases of herpes zoster were recorded in 433 patients, of which 52 cases were serious.

“The reactivation of the varicella zoster virus causing the herpes zoster is triggered by a decline of cellular immunity. This can be due to aging or immune suppression of any kind,” Dr. Strangfeld said in her presentation.

“The Cox regression [analysis] revealed that higher age and intake of glucocorticoids were associated with an increased risk of herpes zoster,” she reported, with a dose dependent increase with glucocorticoids. IPW HR for age per 10 years was 1.3 (P < .0001) and 1.9 (P = .0022) for higher doses of glucocorticoids (>10 vs. 0 mg/day).

Commenting on the study, rheumatologist and epidemiologist Loreto Carmona, MD, PhD, said: “This is a very interesting study. The results are confident and precise. The frequency of herpes zoster infection [based on crude incidence rate estimates] is very high. However, we must focus on the [multivariable with IPW] analysis after taking into account baseline risk.”

Dr. Carmona, who is the chair of the congress’s Abstract Selection Committee and is the scientific director of the Instituto de Salud Musculoesquelética in Madrid, added: “Having a disease with high levels of activity or a disease refractory to treatments [both of which were very likely used in creating the IPW] levels off the risk a bit. Also, because RA by itself, glucocorticoids, and age all increase the risk. Still, jakinibs [JAK inhibitors] stand out as the treatment related to higher risk of herpes zoster infection.”

Dr. Strangfeld and fellow RABBIT investigators have previously looked at the risk of herpes zoster in patients treated with anti–TNF-alpha agents (JAMA. 2009;301[7]:737-44). They found that monoclonal anti–TNF-alpha agents may be associated with increased risk of herpes zoster, which is now confirmed by the current analysis. The reason for looking at herpes zoster risk again is that since that first analysis, many more therapies have become available for RA during the past 10 years, notably the tsDMARDs.

Herpes zoster may not always be a serious event, Dr. Strangfeld said in the interview, “but it diminishes your quality of life; it can also be associated with pain and may be followed by postherpetic neuralgia, which is very painful.” With new herpes zoster vaccinations available, it is now possible to vaccinate patients more easily. “This is advisable for all kinds of treatments,” she said.

“What we found was quite in agreement with the data that we know from the U.S., from the observational studies, for example from the Corrona database,” Dr. Strangfeld stated. The key finding is that the risk of herpes zoster is increased to some level, almost regardless of which drug is chosen, she said. “This gives a clear message that systematic herpes zoster vaccination should be done in patients with RA,” she suggested.

The German biologics registry RABBIT is supported by a joint unconditional grant from AbbVie, Amgen, Bristol-Myers Squibb, Celltrion, Hexal, Lilly, Merck Sharp & Dohme, Mylan, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB. Dr. Strangfeld has received speaker fees from AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, Sanofi-Aventis, and UCB. Dr. Carmona had no relevant conflicts of interest to disclose.

SOURCE: Strangfeld A et al. Ann Rheum Dis. 2020;79[suppl 1]:150. Abstract OP0238.

Here are the stories our MDedge editors across specialties think you need to know about today:

#WhiteCoats4BlackLives stands up to racism

Participants in the growing #WhiteCoats4BlackLives protest against racism say it is a chance to use their status as trusted messengers, show themselves as allies of people of color, and demonstrate that they are familiar with how racism has contributed to health disparities.

The medical student-run group WhiteCoats4BlackLives has helped organize ongoing, large-scale events at hospitals, medical campuses, and city centers nationwide.“It’s important to use our platform for good,” said Danielle Verghese, MD, a first-year internal medicine resident at Thomas Jefferson University Hospital in Philadelphia, who helped recruit a small group of students, residents, and pharmacy school students to take part in a kneel-in late last month in a city park.

“As a doctor, most people in society regard me with a certain amount of respect and may listen if I say something,” Dr. Verghese said.

Read more.
 

A conversation on race

In this special episode of the Psychcast podast, host Lorenzo Norris, MD, and fourth-year psychiatry resident Brandon C. Newsome, MD, discuss race relations as physicians in the wake of the death of George Floyd. The pair discuss what their patients are experiencing and what they’re experiencing as black physicians.

“Racism – whether or not you witness it, whether or not you utilize it, whether or not you are the subject of it – affects and hurts us all,” Dr. Norris says. “We all have to start to own that. You can’t just stay siloed, because it is going to affect you.” Listen here.
 

Two journals retract studies on HCQ

The Lancet has retracted a highly cited study that suggested hydroxychloroquine (HCQ) may cause more harm than benefit in patients with COVID-19. Hours later, the New England Journal of Medicine announced that it had retracted a second article by some of the same authors, also on heart disease and COVID-19.

Three authors of the Lancet article wrote in a letter that the action came after concerns were raised about the integrity of the data, and about how the analysis was conducted by Chicago-based Surgisphere Corp and study coauthor Sapan Desai, MD, Surgisphere’s founder and CEO. The authors asked for an independent third-party review of Surgisphere to evaluate the integrity of the trial elements and to replicate the analyses in the article.

“Our independent peer reviewers informed us that Surgisphere would not transfer the full dataset, client contracts, and the full ISO audit report to their servers for analysis, as such transfer would violate client agreements and confidentiality requirements,” the authors wrote, leading them to request a retraction of the paper.

In a similar note, the authors requested that the New England Journal of Medicine retract the earlier article as well.

Both journals had already published “Expression of Concern” notices about the articles. The expression of concern followed an open letter, endorsed by more than 200 scientists, ethicists, and clinicians and posted on May 28, questioning the data and ethics of the study.

Read more.

FDA approves antibiotic to treat pneumonia

The Food and Drug Administration has approved Recarbrio (imipenem-cilastatin and relebactam) for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia in people aged 18 years and older.

Approval for Recarbrio was based on results of a randomized, controlled clinical trial of 535 hospitalized adults with hospital-acquired and ventilator-associated bacterial pneumonia who received either Recarbrio or piperacillin-tazobactam. After 28 days, 16% of patients who received Recarbrio and 21% of patients who received piperacillin-tazobactam had died.

“As a public health agency, the FDA addresses the threat of antimicrobial-resistant infections by facilitating the development of safe and effective new treatments. These efforts provide more options to fight serious bacterial infections and get new, safe and effective therapies to patients as soon as possible,” said Sumathi Nambiar, MD, MPH, of the agency’s Center for Drug Evaluation and Research.

Read more.

For more on COVID-19, visit our Resource Center. All of our latest news is available on MDedge.com.

Here are the stories our MDedge editors across specialties think you need to know about today:

#WhiteCoats4BlackLives stands up to racism

Participants in the growing #WhiteCoats4BlackLives protest against racism say it is a chance to use their status as trusted messengers, show themselves as allies of people of color, and demonstrate that they are familiar with how racism has contributed to health disparities.

The medical student-run group WhiteCoats4BlackLives has helped organize ongoing, large-scale events at hospitals, medical campuses, and city centers nationwide.“It’s important to use our platform for good,” said Danielle Verghese, MD, a first-year internal medicine resident at Thomas Jefferson University Hospital in Philadelphia, who helped recruit a small group of students, residents, and pharmacy school students to take part in a kneel-in late last month in a city park.

“As a doctor, most people in society regard me with a certain amount of respect and may listen if I say something,” Dr. Verghese said.

Read more.
 

A conversation on race

In this special episode of the Psychcast podast, host Lorenzo Norris, MD, and fourth-year psychiatry resident Brandon C. Newsome, MD, discuss race relations as physicians in the wake of the death of George Floyd. The pair discuss what their patients are experiencing and what they’re experiencing as black physicians.

“Racism – whether or not you witness it, whether or not you utilize it, whether or not you are the subject of it – affects and hurts us all,” Dr. Norris says. “We all have to start to own that. You can’t just stay siloed, because it is going to affect you.” Listen here.
 

Two journals retract studies on HCQ

The Lancet has retracted a highly cited study that suggested hydroxychloroquine (HCQ) may cause more harm than benefit in patients with COVID-19. Hours later, the New England Journal of Medicine announced that it had retracted a second article by some of the same authors, also on heart disease and COVID-19.

Three authors of the Lancet article wrote in a letter that the action came after concerns were raised about the integrity of the data, and about how the analysis was conducted by Chicago-based Surgisphere Corp and study coauthor Sapan Desai, MD, Surgisphere’s founder and CEO. The authors asked for an independent third-party review of Surgisphere to evaluate the integrity of the trial elements and to replicate the analyses in the article.

“Our independent peer reviewers informed us that Surgisphere would not transfer the full dataset, client contracts, and the full ISO audit report to their servers for analysis, as such transfer would violate client agreements and confidentiality requirements,” the authors wrote, leading them to request a retraction of the paper.

In a similar note, the authors requested that the New England Journal of Medicine retract the earlier article as well.

Both journals had already published “Expression of Concern” notices about the articles. The expression of concern followed an open letter, endorsed by more than 200 scientists, ethicists, and clinicians and posted on May 28, questioning the data and ethics of the study.

Read more.

FDA approves antibiotic to treat pneumonia

The Food and Drug Administration has approved Recarbrio (imipenem-cilastatin and relebactam) for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia in people aged 18 years and older.

Approval for Recarbrio was based on results of a randomized, controlled clinical trial of 535 hospitalized adults with hospital-acquired and ventilator-associated bacterial pneumonia who received either Recarbrio or piperacillin-tazobactam. After 28 days, 16% of patients who received Recarbrio and 21% of patients who received piperacillin-tazobactam had died.

“As a public health agency, the FDA addresses the threat of antimicrobial-resistant infections by facilitating the development of safe and effective new treatments. These efforts provide more options to fight serious bacterial infections and get new, safe and effective therapies to patients as soon as possible,” said Sumathi Nambiar, MD, MPH, of the agency’s Center for Drug Evaluation and Research.

Read more.

For more on COVID-19, visit our Resource Center. All of our latest news is available on MDedge.com.

Here are the stories our MDedge editors across specialties think you need to know about today:

#WhiteCoats4BlackLives stands up to racism

Participants in the growing #WhiteCoats4BlackLives protest against racism say it is a chance to use their status as trusted messengers, show themselves as allies of people of color, and demonstrate that they are familiar with how racism has contributed to health disparities.

The medical student-run group WhiteCoats4BlackLives has helped organize ongoing, large-scale events at hospitals, medical campuses, and city centers nationwide.“It’s important to use our platform for good,” said Danielle Verghese, MD, a first-year internal medicine resident at Thomas Jefferson University Hospital in Philadelphia, who helped recruit a small group of students, residents, and pharmacy school students to take part in a kneel-in late last month in a city park.

“As a doctor, most people in society regard me with a certain amount of respect and may listen if I say something,” Dr. Verghese said.

Read more.
 

A conversation on race

In this special episode of the Psychcast podast, host Lorenzo Norris, MD, and fourth-year psychiatry resident Brandon C. Newsome, MD, discuss race relations as physicians in the wake of the death of George Floyd. The pair discuss what their patients are experiencing and what they’re experiencing as black physicians.

“Racism – whether or not you witness it, whether or not you utilize it, whether or not you are the subject of it – affects and hurts us all,” Dr. Norris says. “We all have to start to own that. You can’t just stay siloed, because it is going to affect you.” Listen here.
 

Two journals retract studies on HCQ

The Lancet has retracted a highly cited study that suggested hydroxychloroquine (HCQ) may cause more harm than benefit in patients with COVID-19. Hours later, the New England Journal of Medicine announced that it had retracted a second article by some of the same authors, also on heart disease and COVID-19.

Three authors of the Lancet article wrote in a letter that the action came after concerns were raised about the integrity of the data, and about how the analysis was conducted by Chicago-based Surgisphere Corp and study coauthor Sapan Desai, MD, Surgisphere’s founder and CEO. The authors asked for an independent third-party review of Surgisphere to evaluate the integrity of the trial elements and to replicate the analyses in the article.

“Our independent peer reviewers informed us that Surgisphere would not transfer the full dataset, client contracts, and the full ISO audit report to their servers for analysis, as such transfer would violate client agreements and confidentiality requirements,” the authors wrote, leading them to request a retraction of the paper.

In a similar note, the authors requested that the New England Journal of Medicine retract the earlier article as well.

Both journals had already published “Expression of Concern” notices about the articles. The expression of concern followed an open letter, endorsed by more than 200 scientists, ethicists, and clinicians and posted on May 28, questioning the data and ethics of the study.

Read more.

FDA approves antibiotic to treat pneumonia

The Food and Drug Administration has approved Recarbrio (imipenem-cilastatin and relebactam) for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia in people aged 18 years and older.

Approval for Recarbrio was based on results of a randomized, controlled clinical trial of 535 hospitalized adults with hospital-acquired and ventilator-associated bacterial pneumonia who received either Recarbrio or piperacillin-tazobactam. After 28 days, 16% of patients who received Recarbrio and 21% of patients who received piperacillin-tazobactam had died.

“As a public health agency, the FDA addresses the threat of antimicrobial-resistant infections by facilitating the development of safe and effective new treatments. These efforts provide more options to fight serious bacterial infections and get new, safe and effective therapies to patients as soon as possible,” said Sumathi Nambiar, MD, MPH, of the agency’s Center for Drug Evaluation and Research.

Read more.

For more on COVID-19, visit our Resource Center. All of our latest news is available on MDedge.com.