Rescue and rehabilitation of maned wolf (Chrysocyon brachyurus) in Paraguay: Case description.

The maned wolf, Chrysocyon brachyurus, is the largest South American canid, with a natural distribution that stretches across Peru, Bolivia, Brazil, Argentina, Paraguay and Uruguay. The present study reports the case of a rescued specimen of maned wolf that underwent a rehabilitation process in Paraguay, starting in October 2020 with its rescue, and finalising in May 2021 with the reintroduction. Herein, we document findings regarding the general management, biometrics, feeding and environmental enrichment; chemical immobilisation and monitoring; haematology, blood biochemistry and specific serology-relevant pathogens; skin examination and bone marrow cytology; orthopaedic, ophthalmological and dental evaluation; abdominal and cardiac ultrasonography; radiology and copro-parasitology. Main findings include the feeding habits of the individual and enrichment opportunities. The animal weighed 7 kg on arrival, with an estimated age of 5 months, and 18 kg on reintroduction, with an estimated age of 1 year. The animal tested negative to serologic tests for Brucella canis, Dirofilaria, canine distemper, Toxoplasmosis and canine parvovirus. Leptospira testing showed antibodies against L. grippotyphosa on both samplings, L. wolffi and L. ictero on the first sampling, and L. pomona on the second sampling. Abdominal organs were examined and measured through ultrasound evaluation and kidneys showed no alterations. Echocardiography showed preserved mitral, tricuspid and aortic valve flows, but turbulent pulmonary valve flow. Copro-parasitology reported the presence of Lagochilascaris sp. and Balantidium sp. All the information gathered aided in diagnosing the health status of the individual, and the response to environmental enrichment helped assess the behaviour, which led to the suggestion of reintroducing the animal. These data constitute the first published health check of a maned wolf in Paraguay, which can contribute to the species' conservation in the country. The protocol presented in this study can serve as a basis for developing an action plan for the maned wolf in Paraguay.

Therapeutic Plasma Exchange Versus FcRn Inhibition in Autoimmune Disease.

Therapeutic plasma exchange (TPE or PLEX) is used in a broad range of autoimmune diseases, with the goal of removing autoantibodies from the circulation. A newer approach for the selective removal of immunoglobulin G (IgG) antibodies is the use of therapeutic molecules targeting the neonatal Fc receptor (FcRn). FcRn regulates IgG recycling, and its inhibition results in a marked decrease in circulating autoantibodies of the IgG subtype. The difference between FcRn inhibition and PLEX is often questioned. With anti-FcRn monoclonal antibodies (mAbs) and fragments only recently entering this space, limited data are available regarding long-term efficacy and safety. However, the biology of FcRn is well understood, and mounting evidence regarding the efficacy, safety, and potential differences among compounds in development is available, allowing us to compare against nonselective plasma protein depletion methods such as PLEX. FcRn inhibitors may have distinct advantages and disadvantages over PLEX in certain scenarios. Use of PLEX is preferred over FcRn inhibition where removal of antibodies other than IgG or when concomitant repletion of missing plasma proteins is needed for therapeutic benefit. Also, FcRn targeting has not yet been studied for use in acute flares or crisis states of IgG-mediated diseases. Compared with PLEX, FcRn inhibition is associated with less invasive access requirements, more specific removal of IgG versus other immunoglobulins without a broad impact on circulating proteins, and any impacts on other therapeutic drug levels are restricted to other mAbs. In addition, the degree of IgG reduction is similar with FcRn inhibitors compared with that afforded by PLEX. Here we describe the scientific literature regarding the use of PLEX and FcRn inhibitors in autoimmune diseases and provide an expert discussion around the potential benefits of these options in varying clinical conditions and scenarios.

Burden of Atopic Dermatitis in Pediatric Patients: An International Cross-sectional Study.

BACKGROUND: Few large-scale international studies broadly characterized the burden of atopic dermatitis (AD) across age groups among children and adolescents. OBJECTIVE: To better characterize the AD burden in pediatric subjects by disease severity. METHODS: This cross-sectional, web-based survey of pediatric subjects (6 months to <18 years old) was conducted in 18 countries representing North America, Latin America, Europe, Middle East/Eurasia, and East Asia. Subjects with diagnosed AD were identified based on the International Study of Asthma and Allergies in Childhood criteria and self-/parent-report of ever being told by a physician that they/their child had eczema. AD severity was assessed using Patient Oriented Eczema Measure and Patient Global Assessment. Outcomes included measures of itch, skin pain, sleep, health-related quality-of-life (HRQoL), missed school days, and atopic comorbidities. RESULTS: The survey included 1489 children 6 months to < 6 years; 2898 children 6 to < 12 years; and 3078 adolescents 12 to < 18 years diagnosed with AD. Although the burden of mild AD was substantial, pediatric subjects with moderate or severe AD had more itch, skin pain, sleep problems, and impaired HRQoL, and missed more school days relative to those with mild AD; greater burden was observed among severe relative to moderate AD. At least one atopic comorbidity was present in 92·5% of all respondents. CONCLUSIONS: These results highlight the burden of AD in pediatric subjects especially those with moderate-to-severe disease, and suggest the need for assessments that include the impact of AD on function and daily life.

Identification of Clinically Significant Cytokine Signature Clusters in Patients With Septic Shock.

OBJECTIVES: To identify cytokine signature clusters in patients with septic shock. DESIGN: Prospective observational cohort study. SETTING: Single academic center in the United States. PATIENTS: Adult (≥ 18 yr old) patients admitted to the medical ICU with septic shock requiring vasoactive medication support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fourteen patients with septic shock completed cytokine measurement at time of enrollment (t 1 ) and 24 hours later (t 2 ). Unsupervised random forest analysis of the change in cytokines over time, defined as delta (t 2 -t 1 ), identified three clusters with distinct cytokine profiles. Patients in cluster 1 had the lowest initial levels of circulating cytokines that decreased over time. Patients in cluster 2 and cluster 3 had higher initial levels that decreased over time in cluster 2 and increased in cluster 3. Patients in clusters 2 and 3 had higher mortality compared with cluster 1 (clusters 1-3: 11% vs 31%; odds ratio [OR], 3.56 [1.10-14.23] vs 54% OR, 9.23 [2.89-37.22]). Cluster 3 was independently associated with in-hospital mortality (hazard ratio, 5.24; p = 0.005) in multivariable analysis. There were no significant differences in initial clinical severity scoring or steroid use between the clusters. Analysis of either t 1 or t 2 cytokine measurements alone or in combination did not reveal clusters with clear clinical significance. CONCLUSIONS: Longitudinal measurement of cytokine profiles at initiation of vasoactive medications and 24 hours later revealed three distinct cytokine signature clusters that correlated with clinical outcomes.

Aortic Dissection From an Intra-aortic Balloon Pump: A Dangerous Complication to Keep in Mind.

Despite the benefits of the intra-aortic balloon pump (IABP) being a subject of debate, it remains a widely available and easy-to-use mechanical circulatory support device. Nonetheless, its use is not exempt from complications. Aortic dissection from IABP is an infrequent but deathly complication. We describe a case in which early recognition of the condition led to control through an endovascular approach. A 57-year-old male was admitted for acute decompensated heart failure requiring intravenous inotropic agents. While undergoing assessment for a heart transplant, he developed cardiogenic shock requiring initiation of mechanical circulatory support with an IABP. A few hours after device implantation, the patient developed acute tearing chest pain and was found to have an acute dissection in the descending thoracic aorta. Prompt liaison with the endovascular team led to a thoracic endovascular aortic repair to control the extent of the lesion.

Real-world treatment utilization and economic implications of lupus nephritis disease activity in the United States.

BACKGROUND: Lupus nephritis (LN) is a common and severe complication of systemic lupus erythematosus (SLE), with approximately 40% of patients with SLE developing LN. Even with treatment, 10%-30% of patients will progress to end-stage renal disease (ESRD). Although many studies have assessed the clinical value of low disease activity in LN, the economic implications are less defined. OBJECTIVE: To evaluate treatment utilization and health care costs associated with active disease, low disease activity, and ESRD in patients with LN. METHODS: A retrospective analysis of Optum pharmacy and medical claims data from 2015 to 2019 was performed and included patients with a diagnosis of SLE (International Classification of Diseases, Ninth Revision or Tenth Revision codes 710.0 or M32, respectively) and additional prespecified criteria for LN. Total health care payer costs for medical and pharmacy services and treatment utilization for commonly prescribed medications were determined for periods of low disease activity, active disease, or ESRD. RESULTS: A total of 21,251 patients (mean age 60.3 years; 87% female; 55% White patients and 18% Black patients) with a mean follow-up period of 30.6 months were included; the majority of patients had active disease (67.3%), followed by low disease activity (51.3%), and ESRD (10.5%). Glucocorticoids were used 2 times more often and mycophenolate mofetil was used 4 times more often in patients with active disease vs low disease activity. Glucocorticoids, mycophenolate mofetil, and tacrolimus were more commonly used in patients with ESRD vs those with low disease activity. Mean medical costs were $4,777 per month in active disease and $18,084 per month in ESRD vs $2,523 per month in low disease activity. CONCLUSIONS: Treatment burden and costs are high for patients with active disease and ESRD in LN. Treatments that allow patients to achieve and maintain low disease activity may help improve patient outcomes and reduce medication use and overall health care costs. DISCLOSURES: Maria Dall'Era and Kenneth Kalunian are consultants of Aurinia Pharmaceuticals. Eric Turowski, Vanessa Birardi, Neil Solomons, Simrat Randhawa, and Paola Mina-Osorio are employees and stockholders of Aurinia Pharmaceuticals. Michael Eaddy is a former employee of Xcenda, LLC. Augustina Ogbonnaya and Eileen Farrelly are employees of Xcenda, LLC, which was contracted by Aurinia Pharmaceuticals to assist in the conduct of this study and the writing of this manuscript. Aurinia Pharmaceuticals provided funding for this study and the preparation of the manuscript. Aurinia Pharmaceuticals had a role in writing the report and decision to submit for publication.

Comparison of stationary and nonstationary estimation of return period for sewer design in Antioquia (Colombia).

Estimating the probability of occurrence of extreme hydrologic events is a fundamental input in the design of hydraulic infrastructure. The classical approach to this problem has been to fit parametric probability functions to annual maxima streamflow data and use them to calculate the risk of failure. An underlying assumption of this approach is the stationarity of the time series. However, the stationarity of streamflows may not hold due to the effect of land cover change and climate change on rainfall runoff processes on watersheds. This study assesses the effect of considering non-stationarity in the estimation of design peak flows at 33 gauging stations in the state of Antioquia, Colombia. Particularly, the effect of non-stationarity in the mean of Gumbel-distributed peak flows is evaluated. This study focuses on the 5-yr and 10-yr return period annual flood flows, which are customary in the design of type sewerage systems. The results show similar behaviours for both return periods. All gauge stations show an asymptotically tendency in the risk of failure to 100% as the project lifetime tends to 30 years. In general, 71.4% of gauging stations show that the estimated risk of failure is larger when non-stationary conditions are assumed, relative to assuming stationary conditions, and that the magnitude of the difference increases for larger return periods. The rest of gauging stations shows the opposite behaviour. Our results support the use of a probability model that includes non-stationary in the mean, and they suggest that a model that also includes non-stationary in the variance could be important.

Immunomodulatory fecal metabolites are associated with mortality in COVID-19 patients with respiratory failure.

Respiratory failure and mortality from COVID-19 result from virus- and inflammation-induced lung tissue damage. The intestinal microbiome and associated metabolites are implicated in immune responses to respiratory viral infections, however their impact on progression of severe COVID-19 remains unclear. We prospectively enrolled 71 patients with COVID-19 associated critical illness, collected fecal specimens within 3 days of medical intensive care unit admission, defined microbiome compositions by shotgun metagenomic sequencing, and quantified microbiota-derived metabolites (NCT #04552834). Of the 71 patients, 39 survived and 32 died. Mortality was associated with increased representation of Proteobacteria in the fecal microbiota and decreased concentrations of fecal secondary bile acids and desaminotyrosine (DAT). A microbiome metabolic profile (MMP) that accounts for fecal secondary bile acids and desaminotyrosine concentrations was independently associated with progression of respiratory failure leading to mechanical ventilation. Our findings demonstrate that fecal microbiota composition and microbiota-derived metabolite concentrations can predict the trajectory of respiratory function and death in patients with severe SARS-Cov-2 infection and suggest that the gut-lung axis plays an important role in the recovery from COVID-19.

The Family Impact of Atopic Dermatitis in the Pediatric Population: Results from an International Cross-sectional Study.

OBJECTIVE: To evaluate the impact of atopic dermatitis on families of pediatric patients. STUDY DESIGN: This cross-sectional, web-based survey of children/adolescents (6 months to <18 years old) with atopic dermatitis and their parents and caregivers was conducted in 18 countries encompassing North America, Latin America, Europe, Middle East/Eurasia, and East Asia. Children and adolescents with atopic dermatitis and their parents and caregivers were identified by the International Study of Asthma and Allergies in Childhood criteria and ever being told by a physician that they had "eczema". Atopic dermatitis severity was assessed using the Patient-Oriented Eczema Measure and the Patient Global Assessment. Atopic dermatitis impact on families' lives was evaluated using the Dermatitis Family Impact questionnaire and stand-alone questions on hours of atopic dermatitis-related care (past week) and missed work days (past 4 weeks) owing to their child's atopic dermatitis. RESULTS: A total of 7465 pairs of pediatric participants with atopic dermatitis and their parents or caregivers were surveyed. Across age groups, the Dermatitis Family Impact questionnaire total score for all regions ranged from 7.1 to 8.6, 13.2 to 14.9, and 17.0 to 17.2 for Patient-Oriented Eczema Measure mild, moderate, and severe atopic dermatitis, respectively. Subscale scores showed that greater atopic dermatitis severity had a greater impact on all family life domains, including sleep and tiredness. No specific patterns or trends were observed across age groups. Time spent on childcare and missed work days increased with atopic dermatitis severity. CONCLUSIONS: Across pediatric age groups and geographic regions, greater atopic dermatitis severity was associated with a greater negative impact on physical, emotional, social, and economic components of family life.

Immediate Effect of Mechanical Ventilation Mode and Sedative Infusion on Measured Diaphragm Thickness.

Rationale: In patients who are mechanically ventilated, diaphragm thinning on ultrasound is thought to correlate with diaphragm atrophy and has been associated with prolonged intubation. Factors other than atrophy, however, may cause changes in diaphragm thickness, which may confound studies examining changes in diaphragm thickness over time. Objectives: To determine if changes in the mode of mechanical ventilation or an interruption of sedatives have immediate effects on diaphragm thickness measurements in adult patients in the intensive care unit who are mechanically ventilated. Methods: Adult patients receiving invasive mechanical ventilation for less than 48 hours were included. Diaphragm thickness was measured at end-expiration and peak inspiration using ultrasound while patients were receiving both volume assist-control and pressure-support modes in a randomized crossover fashion. In patients receiving sedatives, additional measurements were taken after an interruption of sedatives. Measurements were compared between modes and on assist-control before and after an interruption of sedatives. Results: Of 85 patients enrolled, 66 had measurements on assist-control and spontaneous modes, and 40 had measurements before and after an interruption of sedatives. End-expiratory diaphragm thickness increased by a median of 0.08 mm after an interruption of sedatives (95% confidence interval [CI], 0.002 mm to 0.164 mm; P = 0.017), corresponding to a median increase of 6.5%. No difference was seen when comparing measurements taken on volume assist-control and pressure support (median difference, 0 mm; 95% CI, -0.07 mm to 0.08 mm; P = 0.98). Conclusions: End-expiratory diaphragm thickness increased by 6.5% after an interruption of sedatives. The effect of sedatives on measured diaphragm thickness should be considered in future studies examining changes in diaphragm thickness over time. Clinical trial registered with Clinicaltrials.gov (NCT04319939).

Prevalence of type 2 inflammatory diseases in pediatric patients with atopic dermatitis: Real-world evidence.

BACKGROUND: Patients with atopic dermatitis (AD) are considered at increased risk of developing other type 2 inflammatory diseases. However, real-world evidence based on large commercially insured pediatric populations in the United States is scarce. OBJECTIVE: To use a large claims database (IBM MarketScan 2013-2017) in the United States to assess prevalence and incidence of type 2 inflammatory diseases in pediatric patients with AD. METHODS: Pediatric patients with AD were matched 1:1 to patients without AD. Prevalence was assessed for conjunctivitis, rhinitis, urticaria, asthma, eosinophilic esophagitis, and chronic rhinosinusitis/nasal polyps at the 12 months' post-index date (the first AD diagnosis date for patients with AD; a randomly selected outpatient visit for control patients). The incidence of other type 2 inflammatory diseases post-index was assessed among patients 0-2 years of age. RESULTS: A total of 244,776 AD and matched non-AD patients were selected. The prevalence and incidence of type 2 inflammatory diseases were higher among patients with AD. Overall, the prevalence more than doubled for asthma, eosinophilic esophagitis, urticaria, and rhinitis, and increased with AD severity. LIMITATIONS: AD identification was based on billing diagnoses; the observation period was only 12 months; and the study was limited to commercially insured patients. CONCLUSION: The burden of type 2 inflammatory diseases in pediatric patients with AD is substantial, highlighting the need to optimize management of AD and its numerous associated morbidities.

Bedside estimates of dead space using end-tidal CO2 are independently associated with mortality in ARDS.

PURPOSE: In acute respiratory distress syndrome (ARDS), dead space fraction has been independently associated with mortality. We hypothesized that early measurement of the difference between arterial and end-tidal CO2 (arterial-ET difference), a surrogate for dead space fraction, would predict mortality in mechanically ventilated patients with ARDS. METHODS: We performed two separate exploratory analyses. We first used publicly available databases from the ALTA, EDEN, and OMEGA ARDS Network trials (N = 124) as a derivation cohort to test our hypothesis. We then performed a separate retrospective analysis of patients with ARDS using University of Chicago patients (N = 302) as a validation cohort. RESULTS: The ARDS Network derivation cohort demonstrated arterial-ET difference, vasopressor requirement, age, and APACHE III to be associated with mortality by univariable analysis. By multivariable analysis, only the arterial-ET difference remained significant (P = 0.047). In a separate analysis, the modified Enghoff equation ((PaCO2-PETCO2)/PaCO2) was used in place of the arterial-ET difference and did not alter the results. The University of Chicago cohort found arterial-ET difference, age, ventilator mode, vasopressor requirement, and APACHE II to be associated with mortality in a univariate analysis. By multivariable analysis, the arterial-ET difference continued to be predictive of mortality (P = 0.031). In the validation cohort, substitution of the arterial-ET difference for the modified Enghoff equation showed similar results. CONCLUSION: Arterial to end-tidal CO2 (ETCO2) difference is an independent predictor of mortality in patients with ARDS.

Effect of Dupilumab on Laboratory Parameters in Adolescents with Atopic Dermatitis: Results from a Randomized, Placebo-Controlled, Phase 3 Clinical Trial.

BACKGROUND: Laboratory testing is typically required for patients with atopic dermatitis (AD) treated with systemic immunosuppressants. A previous analysis of laboratory outcomes in randomized, double-blinded, placebo-controlled clinical trials of dupilumab in adults with moderate-to-severe AD found no clinically important changes in hematologic, serum chemistry, and urinalysis parameters, supporting the use of dupilumab without routine laboratory monitoring. OBJECTIVE: The aim was to assess laboratory results in adolescents with moderate-to-severe AD treated with dupilumab in a phase 3, randomized, double-blind, placebo-controlled trial. METHODS: Adolescents aged ≥ 12 to < 18 years with moderate-to-severe AD were randomized 1:1:1 to subcutaneous dupilumab 200/300 mg every 2 weeks (q2w) (200 mg for patients < 60 kg at baseline; 300 mg for patients ≥ 60 kg at baseline); dupilumab 300 mg every 4 weeks (q4w); or placebo for 16 weeks. Laboratory evaluations included hematology, serum chemistry, and urinalysis parameters. RESULTS: Of 251 patients enrolled in the study, 250 received treatment and were included in the analysis. 4.7%, 2.4%, and 4.8% of patients receiving placebo, dupilumab 200/300 mg q2w, and dupilumab 300 mg q4w, respectively, had laboratory abnormalities reported as treatment-emergent adverse events, none of which prompted discontinuation of study treatment or study withdrawal. Mean eosinophil counts were elevated at baseline in all treatment groups. Patients in both dupilumab regimens, but not the placebo group, showed mild transient increases in mean eosinophil counts above baseline that returned to near-baseline values by week 16. Mean levels of lactate dehydrogenase trended towards the upper limit of normal at baseline and decreased with treatment; greater decreases were seen in dupilumab-treated patients than placebo-treated patients. There were no meaningful changes in other laboratory parameters, and none of the laboratory abnormalities were clinically significant. CONCLUSION: No clinically meaningful changes in laboratory parameters were seen in adolescents, similar to that observed in adults. The findings of this study indicate no routine laboratory monitoring is required in this population prior to or during dupilumab treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03054428. Video abstract: Effect of Dupilumab on Laboratory Parameters in Adolescents with Atopic Dermatitis: Results from a Randomized Placebo-Controlled Phase 3 Clinical Trial (MP4 175137 KB).

Atopic dermatitis in the pediatric population: A cross-sectional, international epidemiologic study.

BACKGROUND: Little is known on the current global prevalence of atopic dermatitis (AD) in the pediatric population. OBJECTIVE: To estimate the real-world global prevalence of AD in the pediatric population and by disease severity. METHODS: This international, cross-sectional, web-based survey of children and adolescents (6 months to <18 years old) was conducted in the following 18 countries: North America (Canada, United States), Latin America (Argentina, Brazil, Columbia, Mexico), Europe (France, Germany, Italy, Spain, United Kingdom), Middle East and Eurasia (Israel, Saudi Arabia, Turkey, United Arab Emirates, Russia), and East Asia (Japan, Taiwan). Prevalence was determined using the following 2 definitions: (1) diagnosed as having AD according to the International Study of Asthma and Allergies in Childhood (ISAAC) criteria and self- or parent-report of ever being told by a physician that they or their child child had AD (eczema); and (2) reported AD based on the ISAAC criteria only. Severity was assessed using the Patient Global Assessment (PtGA) and Patient-Oriented Eczema Measure (POEM). RESULTS: Among 65,661 responders, the 12-month diagnosed AD prevalence (ISAAC plus self-reported diagnosis) ranged from 2.7% to 20.1% across countries; reported AD (ISAAC only) was 13.5% to 41.9%. Severe AD evaluated with both PtGA and POEM was generally less than 15%; more subjects rated AD as mild on PtGA than suggested by POEM. No trends in prevalence were observed based on age or sex; prevalence was generally lower in rural residential settings than urban or suburban. CONCLUSION: This global survey in 18 countries revealed that AD affects a substantial proportion of the pediatric population. Although prevalence and severity varied across age groups and countries, less than 15% had severe AD.

Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma.

BACKGROUND: Conjunctivitis is a known comorbidity of atopic dermatitis. Dupilumab clinical trials for moderate-to-severe atopic dermatitis in adults showed a higher conjunctivitis incidence for dupilumab-treated patients than placebo-treated patients, whereas trials for uncontrolled asthma reported lower rates for both dupilumab and placebo. OBJECTIVE: The objective of this study was to evaluate the incidence and severity of conjunctivitis in dupilumab clinical trials in adolescents with moderate-to-severe atopic dermatitis or uncontrolled asthma. METHODS: We evaluated the incidence of conjunctivitis in adolescents (aged 12 to < 18 years) in three phase III trials. Ocular events were diagnosed and treated based on patient-reported symptoms and an external eye examination by study investigators, in most cases without an ophthalmologic referral. In LIBERTY AD ADOL (16-week, randomized, placebo-controlled, double-blinded trial), adolescents with moderate-to-severe atopic dermatitis were randomized to subcutaneous placebo, dupilumab 300 mg every 4 weeks, or dupilumab every 2 weeks (200 mg, patients < 60 kg at baseline; 300 mg, ≥ 60 kg at baseline). In LIBERTY AD PED-OLE (open-label extension), pediatric patients from previous dupilumab atopic dermatitis trials received dupilumab 2 mg/kg or 4 mg/kg weekly (up to 300 mg) or 300 mg every 4 weeks. In LIBERTY ASTHMA QUEST (randomized, double-blinded, placebo-controlled trial), patients with uncontrolled moderate-to-severe asthma were randomized to 52 weeks of add-on therapy with dupilumab 200 or 300 mg every 2 weeks or matched-volume placebo. RESULTS: In ADOL, more dupilumab-treated (17/165; 10.3%) than placebo-treated patients (4/85; 4.7%) reported one or more conjunctivitis event. All events were mild to moderate in severity; 12 (7.3%) dupilumab-treated and 4 (4.7%) placebo-treated patients received treatment. Most patients with conjunctivitis (dupilumab, 12/17; placebo, 4/4) recovered/resolved during the treatment period. The risk of conjunctivitis showed no relationship with dupilumab serum concentration. In PED-OLE, 12/275 adolescents (4.4%) reported one or more conjunctivitis event. Most conjunctivitis events were mild to moderate. Ten patients received treatment for conjunctivitis. Ten patients recovered/resolved during the study. In QUEST, similar low proportions of dupilumab-treated (2/68, 2.9%) and placebo-treated (1/39, 2.6%) adolescents reported one or more conjunctivitis event. All events were mild to moderate. One dupilumab-treated patient received treatment for conjunctivitis. All cases recovered/resolved during the study. No patients in these trials discontinued study treatment temporarily or permanently because of conjunctivitis. In ADOL, one case of unspecified viral keratitis (specific viral etiology not known) in the dupilumab 300-mg every 4 weeks group and one case of allergic blepharitis in the placebo group were reported; both events resolved during the treatment period, and neither led to treatment discontinuation. CONCLUSIONS: Dupilumab-treated adolescents in atopic dermatitis trials had a higher incidence of conjunctivitis than placebo-treated patients, whereas overall rates of conjunctivitis among adolescents in the asthma trial were lower than in atopic dermatitis trials and were similar for dupilumab- and placebo-treated patients. Most events were mild to moderate, most recovered/resolved, and none prompted study withdrawal. These results are similar to those reported in adult trials and support a drug-disease interaction. CLINICALTRIALS. GOV IDENTIFIERS: NCT03054428, NCT02612454, NCT02414854. Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma (MP4 18453 kb).

Effects of variations in access to care for children with atopic dermatitis.

BACKGROUND: An estimated 50% of children in the US are Medicaid-insured. Some of these patients have poor health literacy and limited access to medications and specialty care. These factors affect treatment utilization for pediatric patients with atopic dermatitis (AD), the most common inflammatory skin disease in children. This study assesses and compares treatment patterns and healthcare resource utilization (HCRU) between large cohorts of Medicaid and commercially insured children with AD. METHODS: Pediatric patients with AD were identified from 2 large US healthcare claims databases (2011-2016). Included patients had continuous health plan eligibility for ≥6 months before and ≥12 months after the first AD diagnosis (index date). Patients with an autoimmune disease diagnosis within 6 months of the index date were excluded. Treatment patterns and all-cause and AD-related HCRU during the observation period were compared between commercially and Medicaid-insured children. RESULTS: A minority of children were evaluated by a dermatology or allergy/immunology specialist. Several significant differences were observed between commercially and Medicaid-insured children with AD. Disparities detected for Medicaid-insured children included: comparatively fewer received specialist care, emergency department and urgent care center utilization was higher, a greater proportion had asthma and non-atopic morbidities, high- potency topical corticosteroids and calcineurin inhibitors were less often prescribed, and prescriptions for antihistamines were more than three times higher, despite similar rates of comorbid asthma and allergies among antihistamine users. Treatment patterns also varied substantially across physician specialties. CONCLUSIONS: Results suggest barriers in accessing specialty care for all children with AD and significant differences in management between commercially and Medicaid-insured children. These disparities in treatment and access to specialty care may contribute to poor AD control, especially in Medicaid-insured patients.

Temperature Trajectory Subphenotypes Correlate With Immune Responses in Patients With Sepsis.

OBJECTIVES: We recently found that distinct body temperature trajectories of infected patients correlated with survival. Understanding the relationship between the temperature trajectories and the host immune response to infection could allow us to immunophenotype patients at the bedside using temperature. The objective was to identify whether temperature trajectories have consistent associations with specific cytokine responses in two distinct cohorts of infected patients. DESIGN: Prospective observational study. SETTING: Large academic medical center between 2013 and 2019. SUBJECTS: Two cohorts of infected patients: 1) patients in the ICU with septic shock and 2) hospitalized patients with Staphylococcus aureus bacteremia. INTERVENTIONS: Clinical data (including body temperature) and plasma cytokine concentrations were measured. Patients were classified into four temperature trajectory subphenotypes using their temperature measurements in the first 72 hours from the onset of infection. Log-transformed cytokine levels were standardized to the mean and compared with the subphenotypes in both cohorts. MEASUREMENTS AND MAIN RESULTS: The cohorts consisted of 120 patients with septic shock (cohort 1) and 88 patients with S. aureus bacteremia (cohort 2). Patients from both cohorts were classified into one of four previously validated temperature subphenotypes: "hyperthermic, slow resolvers" (n = 19 cohort 1; n = 13 cohort 2), "hyperthermic, fast resolvers" (n = 18 C1; n = 24 C2), "normothermic" (n = 54 C1; n = 31 C2), and "hypothermic" (n = 29 C1; n = 20 C2). Both "hyperthermic, slow resolvers" and "hyperthermic, fast resolvers" had high levels of G-CSF, CCL2, and interleukin-10 compared with the "hypothermic" group when controlling for cohort and timing of cytokine measurement (p < 0.05). In contrast to the "hyperthermic, slow resolvers," the "hyperthermic, fast resolvers" showed significant decreases in the levels of several cytokines over a 24-hour period, including interleukin-1RA, interleukin-6, interleukin-8, G-CSF, and M-CSF (p < 0.001). CONCLUSIONS: Temperature trajectory subphenotypes are associated with consistent cytokine profiles in two distinct cohorts of infected patients. These subphenotypes could play a role in the bedside identification of cytokine profiles in patients with sepsis.

Protocol for a prospective, observational, longitudinal study in paediatric patients with moderate-to-severe atopic dermatitis (PEDISTAD): study objectives, design and methodology.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease often associated with atopic comorbidities and has significant impact on children and their families. There is a lack of robust and longitudinal long-term data on disease characteristics and typical clinical practice with currently available treatments in children with moderate-to-severe AD. Hence, an observational study is needed to evaluate AD characteristics and progression in paediatric patients with moderate-to-severe AD. METHODS AND ANALYSIS: Pediatric Study in Atopic Dermatitis (PEDISTAD) is a prospective, observational, longitudinal study in paediatric patients with moderate-to-severe AD who are currently receiving systemic or topical treatment and whose disease is not adequately controlled by topical prescription therapies or for whom those therapies are not medically advisable. 1300 children at 100-150 sites in approximately 20 countries worldwide will be enrolled and followed for 5 years. AD therapy is at the discretion of the investigator. Data collected will include: AD disease characteristics and comorbidities; current therapy for AD and initiation of new treatments/changes in current treatment; patient-reported/caregiver-reported outcomes; days missed from school/work for the patient/caregiver; healthcare professional visits; safety and biomarkers. ETHICS AND DISSEMINATION: This study is conducted in accordance with the principles established by the 18th World Medical Assembly and all subsequent amendments and the guidelines for Good Epidemiology Practice. Each individual country assures that ethics approval has been received and local regulatory requirements are met. Ethics approval has been obtained in all countries currently participating in PEDISTAD. Study data will be disseminated in manuscripts submitted to peer-reviewed medical journals as well as in abstracts submitted to congresses and in the resulting posters and presentations. TRIAL REGISTRATION NUMBER: NCT03687359; pre-results.

Treatment patterns of pediatric patients with atopic dermatitis: A claims data analysis.

BACKGROUND: Real-world evidence on treatment patterns of pediatric patients with atopic dermatitis (AD) is sparse. OBJECTIVE: To assess current treatment patterns in pediatric AD patients. METHODS: Retrospective observational analysis of commercial insurance and Medicaid administrative claims data (January 2011-December 2016) for pediatric AD patients, stratified by age and provider type. RESULTS: The analytic sample comprised 607,258 pediatric AD patients. Median observation period was 30.3 months. Overall, 78.6% were prescribed ≥1 AD medication; 86.7% were prescribed topical corticosteroids, and 5.4% were prescribed a calcineurin inhibitor. Systemic corticosteroids (SCSs) were prescribed for 24.4% of patients, 51.8% of whom did not have asthma or allergic comorbidities. Of the 46.6% prescribed an antihistamine and 16.2% prescribed montelukast, 62.0% and 41.3%, respectively, did not have asthma or allergic comorbidities. Systemic immunosuppressants were rarely prescribed (<0.5%). Higher potency topical corticosteroid and SCS use increased with age. Treatment patterns varied by provider type; specialists were more likely to prescribe higher potency topicals and/or systemics, regardless of patient age. A minority of patients were treated by or referred to a specialist. LIMITATIONS: Identification of AD patients relied on billing diagnoses; the disease severity was proxied by the treatment prescribed. CONCLUSION: Results indicate that SCSs, despite known risks, and other medications with disproven efficacy in AD are frequently prescribed, suggesting a need for safer and more effective alternatives.