Pressure Injury Data Reconciliation in a Randomized Controlled Trial.

OBJECTIVE: To advance pressure injury (PrI) research in individuals with spinal cord injury (SCI) by describing lessons learned and recommendations for future research, ultimately promoting PrI prevention and more effective wound care. This paper describes the detailed procedures undertaken to collect and reconcile PrI data and summarizes the types of discrepancies identified. DESIGN: Secondary analyses of PrI data collected between 2009 and 2014 in a randomized controlled trial (parent study). SETTING: Participants in the parent study were recruited from a large rehabilitation center in the Los Angeles area that serves primarily individuals with limited resources. PARTICIPANTS: 232 participants with SCI and a history of 1 or more medically serious PrI (MSPrI) in the previous 5 years. INTERVENTIONS: Participants in the parent study were randomized to a 12-month PrI prevention intervention led by an occupational therapist, or to usual care. MAIN OUTCOME MEASURES: Relations among PrI characteristics, data sources (phone interviews, skin checks, paper and electronic medical records [MRs]), and treatment condition, and sensitivity of 6 different data sources in detecting MSPrIs. RESULTS: The majority (62%) of MSPrIs were in the pelvic region. MRs detected 82% of the MSPrIs overall, making it the most sensitive data source, and scheduled skin checks were the second-most sensitive data source, finding 37% of the MSPrIs. CONCLUSIONS: MR review is the preferred method for ascertaining MSPrIs in clinical trials of interventions designed to reduce the incidence of these injuries. When multiple sources of information are used, careful reconciliation of reports is necessary to ensure accuracy.

Development of a decision support tool to prevent community acquired pressure injuries for use in the spinal cord injury clinic using the delphi technique.

STUDY DESIGN: Delphi Technique. OBJECTIVES: Describe the development of a decision support tool to prevent community-acquired pressure injuries (CAPrIs) in individuals with spinal cord injury (SCI) for use in SCI clinics, called the Community-Acquired Pressure Injury Prevention-Field Implementation Tool (CAPP-FIT). SETTING: Veteran Health Administration Hospital, Chicago, Illinois, USA. METHODS: Concept mapping of current pressure injury (PrI) guidelines and qualitative research describing risks, actions, and resources needed to prevent CAPrIs associated with SCI were used to develop 40 veteran checklist items (Items) along with 37 associated provider actions (Actions) for the tool. The Delphi technique was used to refine Items and Actions with a panel of interprofessional SCI providers (n = 15), veterans with SCI (n = 4), and caregivers (n = 3) to determine consensus on a 4-point Likert scale (strongly agree-strongly disagree) for each Item and Action. A 75% agreement was set for responses rated as strongly agree or agree. RESULTS: Panelists were 60% female, 62% White, 33% veterans with SCI or caregivers, 33% wound care certified with a mean age of 59 years. Two survey rounds were required for consensus for 41 Item and 38 Action CAPP-FIT. Response rate was 95% for both rounds. Delphi round 1 showed all but two Actions affirming agreement above 75%. Substantive comments from panelists required revision to 5 Items and 9 Actions and one additional Item/Actions related to coping, meeting threshold percent agreement in Round 2. CONCLUSIONS: The CAPP-FIT could become a useful tool for Veterans living with SCI, caregivers, and SCI providers.

Using Technology to Detect Erythema Across Skin Tones.

OBJECTIVE: To examine the effectiveness of the ColorMeter DSM III (ColorMeter; Cortex Technology) at grouping individuals by skin tone and measuring erythema/skin discoloration after erythema induction across skin tones. METHODS: This pre/post experimental study induced erythema on a convenience sample of 61 healthy adults. Skin tone at baseline was measured using the ColorMeter, Munsell Soil Color Chart 5YR (Munsell), and Pantone SkinTone Guide (Pantone) and compared with the Eumelanin Human Skin Colour Scale (Eumelanin Scale) groupings. Erythema and melanin values on the arm immediately and after recovery time were compared with baseline values. Melanin was measured at five body regions on the face and arm. RESULTS: Participants were predominantly women (64% [n = 39] women, 36% [n = 22] men) and young (mean, 28.8 ± 14.3 years); 5% (n = 3) were Hispanic, 26% (n = 16) Asian, 29% (n = 18) Black, 38% (n = 23) White, and 7% (n = 4) identified with more than one race. ColorMeter lightness (L*) and melanin measures were strongly correlated with both Munsell and Pantone values. Munsell skin tone groups were not aligned with Eumelanin Scale groupings. Most participants were in the Eumelanin intermediate-low group, and this changed depending on which body location melanin value was used. The change in erythema from baseline did not differ significantly across skin tone groups at the ulnar head, but on the forearm at the delayed time point, significant differences existed between light and both medium and dark skin tone groups (P = .001; 95% CI, 0.04-0.37). CONCLUSIONS: The ColorMeter provides an effective objective measure of skin tone and erythema/discoloration across various skin tones and may improve on current standards for detection. The proposed Eumelanin Scale-Modified provides additional sensitivity for persons with medium skin tones.

Barriers to the Success of Recreational Groups for Persons With Dementia.

BACKGROUND: This paper describes barriers to engagement in the context of group activities attended by nursing home residents with dementia. OBJECTIVE: The goal is to clarify the presence and types of barriers to group activities for persons with dementia. METHODS: Therapeutic recreation staff (TRs) who conducted the group activities, and trained research observers (ROs) independently identified barriers occurring during group activity sessions through ratings and open-ended comments, which were analyzed via a mixed-method approach. RESULTS: Barriers were related to specific participant, environmental, and group session characteristics. Most frequently noted barriers were participant-related, pertaining to apathy and challenging behavior. Noise was the most frequent environmental barrier. Overall, ROs reported more barriers than TRs, yet TRs reported the barrier of inappropriate topic more frequently than ROs. CONCLUSIONS: The study suggests that the number and specific types of barriers are associated with negative engagement outcomes. Insight into these barriers is the first step toward addressing them and minimizing their effects.

Bid from the Association for the Advancement of Wound Care.

The Association for the Advancement of Wound Care sets out its bid for the WUWHS 2026 Congress to be held in Chicago, Illinois, US.

Developing a decision support tool to prevent community-acquired pressure injuries in spinal cord injury in ambulatory care: A nurse-led protocol for mix methods research.

BACKGROUND: There is a lack of formal guidelines and decision support tools to prevent community-acquired pressure injuries (CAPrIs) in Veterans with spinal cord injury (SCI). PURPOSE: In this article we present our research protocol that describes our plans to create and test a decision support tool to prevent CAPrIs in SCI. METHODS: In Aim 1, we identified mental-models of CAPrI prevention from the perspectives of Veterans (using photovoice, guided tours), and Veterans Health Administration SCI providers (using interviews), and triangulation to compare the two mental-models. This led to a decision support tool developed and validated using Delphi approaches in Aim 2 and will be followed by tool automation and system redesign for pilot implementation in Aim 3. FINDINGS: The nurse-led research protocol provides a map to systematically explore, address and translate research into evidence-based practice. DISCUSSION: Refinement of the protocol will guide future research and implementation.

Anatomical variability of sub-epidermal moisture and its clinical implications.

BACKGROUND: Technologies have been developed to monitor changes in dermal oedema, indicative of the early signs of pressure ulcers. However, there is limited information on the effects of regional differences in tissue morphology on these sub-epidermal moisture (SEM) parameters. This study was designed to investigate the absolute SEM readings across different anatomical sites using a commercial device. METHODS: Twenty-four healthy participants were recruited to evaluate basal SEM values at different bony prominences, sampled by an experienced operator. RESULTS: Distinct differences were observed in unloaded SEM values across different anatomical sites, notably between the upper and lower extremities. A high degree of variability was observed in particular sites, such as the heels. Moreover, SEM values at certain locations revealed significant relationships with age, BMI and gender (p < 0.05). CONCLUSION: The study revealed a high level of variability between and within anatomical sites in a healthy cohort of participants. Determining the changes in local skin and sub-dermal tissue status using SEM may require consideration of both site specific and individual demographic factors, with further research needed in cohorts at risk of pressure ulcers.

Natural History of Pressure Injury Among Ethnically/Racially Diverse Nursing Home Residents: The Pressure Ulcer Detection Study.

The current observational study provides descriptive data on 270 pressure injuries (PrIs) among 142 racially/ethnically diverse nursing home (NH) residents over 16 weeks. Weekly assessments were conducted with the Bates-Jensen Wound Assessment Tool. NH data were obtained from public government websites. NH, resident, and PrI characteristics across race/ethnicity groups were compared using analysis of variance and chi-square. Participants were 62% female and 89% functionally dependent. More Black and Asian individuals had peripheral vascular disease. More Black individuals had persistent trunk and Stage 4 PrIs. Black and Hispanic individuals had normal skin color surrounding PrIs. More Asian individuals had PrIs surrounded by purple/red discolored skin. More Black individuals' heel PrIs were unstageable, necrotic, and showed no granulation. Black and Hispanic individuals exhibited more deep tissue injury. No NH or prevention differences existed. Health disparities found validate administrative data results. Differences in PrI characteristics should be further examined among diverse NH residents. [Journal of Gerontological Nursing, 47(3), 37-46.].

Subepidermal Moisture and Pressure Injury in a Pediatric Population: A Prospective Observational Study.

PURPOSE: To describe relationships between subepidermal moisture (SEM) and visual skin assessment of pressure injury (PI) in children. DESIGN: Prospective descriptive study. SUBJECTS AND SETTING: Twenty-four participants aged 8 to 16 years recruited from a pediatric orthopedic unit in a children's hospital in Ireland. METHODS: Subepidermal moisture measured with the SEM scanner (Bruin Biometrics, Los Angeles, California) ranged from 0 to 7 picoFarads [pF], and visual observation of trunk and heels occurred daily for 3 days after admission to the unit and/or after surgery. Skin was assessed for discoloration categorized as blanchable erythema, stage 1 PI, or deep tissue injury (DTI). Any open wound PI was classified as stage 2, 3, 4, or unstageable. Demographic, medical, and pain data were collected. Chi-square test, t tests, analysis of variance, and regression were used to describe data and examine relationships. RESULTS: Participants were pediatric patients; 100% (n = 24) were white, 62% (n = 15) were female, 8 to 16 years of age (mean = 12.5 ± 2.5 years), and 29% (n = 7) had fractures and 71% (n = 17) surgery diagnoses. Blanchable erythema incidence was 21% (n = 5) and stage 1 PI incidence was 42% (n = 10); nearly all at heels. Deep tissue injury incidence was 4% (one sacral DTI). Stage 2 or greater PI incidence was 4% (one heel stage 2 PI). For skin that was assessed as normal in this pediatric population, SEM for trunk was 2.65 to 2.76 pF and for heels 2.37 to 2.41 pF. Subepidermal moisture for blanchable erythema and stage 1 PI was higher (range, 3.2-3.7 pF) and significant at trochanters and heels (left trochanter: P = .003; right trochanter: P = .02; right and left heels: P = .000). Nominal regression, controlling for participant and assessment day, showed SEM a predictor of erythema and stage 1 PI at heels. We also found that SEM was higher with pain (significant at sacrum and heels). CONCLUSIONS: In this pediatric population, SEM values over skin assessed as normal are lower than SEM values reported for normal skin in adults, 2.37 to 2.76 pF. Subepidermal moisture was significantly higher for blanchable erythema and stage 1 PI at trochanters and heels, and with the presence of pain at sacrum and heels. We recommend that SEM should be examined for detecting PIs in pediatric populations; SEM and pain should be explored in larger pediatric and adult populations.

Reliability of the Bates-Jensen wound assessment tool for pressure injury assessment: The pressure ulcer detection study.

The Bates-Jensen Wound Assessment Tool (BWAT) is used to assess wound healing in clinical practice. The purpose of this study was to evaluate BWAT use among nursing home residents with pressure injury. Findings and reliability estimates from the BWAT related to pressure injury characteristics (stage, anatomic location) and natural history (resolved, persisted) among 142 ethnically and racially diverse residents are reported. In this prospective 16-week study, 305 pressure injuries among 142 participants (34% prevalence) are described by stage, anatomic location, and BWAT scores. Visual and subepidermal moisture assessments were obtained from sacrum, buttock, ischial, and heel ulcers weekly. Participants were 14% Asian, 28% Black, 18% Hispanic, 40% White with a mean age of 78 ± 14 years, and were 62% female; 80% functionally dependent (bed mobility extensive/total assistance) and at risk (Braden Scale score 14 ± 2.7). The reliability coefficient for BWAT score (all participants, all anatomic locations) was high (r = 0.90; p < 0.0001; n = 1,161 observations). Weighted Kappas for characteristics ranging from 0.46 (skin color surrounding wound) to 0.79 (undermining) were consistent for all participants. BWAT scores showed strongest agreement coefficients for stage 4 pressure injury (r = 0.69), pressure injuries among Asian and White ethnicity/racial groups (r = 0.89, and r = 0.91, respectively), and sacrum anatomic location (r = 0.92) indicating scores are better correlated to fair skin tones. Lower agreement coefficients were demonstrated for stage 2 pressure injury (r = 0.38) and pressure injuries among African American and Hispanic ethnicity/racial groups (r = 0.88 and 0.87, respectively). BWAT scores were significantly different by pressure injury stage (F = 496.7, df = 6, p < 0.001) and anatomic location (F = 33.76, df = 8, p < 0.001). BWAT score correlated with pressure injury natural history (ulcer resolved 18.4 ± 7.4, ulcer persisted 24.9 ± 10.0; F = 70.11, df = 2, p < 0.001), but not with comorbidities. The BWAT provides reliable, objective data for assessing pressure injury healing progress.

Subepidermal moisture detection of heel pressure injury: The pressure ulcer detection study outcomes.

We examined subepidermal moisture (SEM) and visual skin assessment of heel pressure injury (PrI) among 417 nursing home residents in 19 facilities over 16 weeks. Participants were older (mean age 77 years), 58% were female, over half were ethnic minorities (29% African American, 12% Asian American, 21% Hispanic), and at risk for PrI (mean Braden Scale Risk score = 15.6). Blinded concurrent visual assessments and SEM measurements were obtained at heels weekly. Visual skin damage was categorised as normal, erythema, stage 1 PrI, deep tissue injury (DTI) or stage 2 or greater PrI. PrI incidence was 76%. Off-loading occurred with pillows (76% of residents) rather than heel boots (21%) and often for those with DTI (91%). Subepidermal moisture was measured with a device where higher readings indicate greater moisture (range: 0-70 tissue dielectric constant), with normal skin values significantly different from values in the presence of skin damage. Subepidermal moisture was associated with concurrent damage and damage 1 week later in generalised multinomial logistic models adjusting for age, diabetes and function. Subepidermal moisture detected DTI and differentiated those that resolved, remained and deteriorated over 16 weeks. Subepidermal moisture may be an objective method for detecting PrI.

Subepidermal moisture detection of pressure induced tissue damage on the trunk: The pressure ulcer detection study outcomes.

We examined the relationship between subepidermal moisture measured using surface electrical capacitance and visual skin assessment of pressure ulcers at the trunk location (sacral, ischial tuberosities) in 417 nursing home residents residing in 19 facilities. Participants were on average older (mean age of 77 years), 58% were female, over half were ethnic minorities (29% African American, 12% Asian American, and 21% Hispanic), and at risk for pressure ulcers (mean score for Braden Scale for Predicting Pressure Ulcer Risk of 15.6). Concurrent visual assessments and subepidermal moisture were obtained at the sacrum and right and left ischium weekly for 16 weeks. Visual assessment was categorized as normal, erythema, stage 1 pressure ulcer, Deep Tissue Injury or stage 2+ pressure ulcer using the National Pressure Ulcer Advisory Panel 2009 classification system. Incidence of any skin damage was 52%. Subepidermal moisture was measured with a dermal phase meter where higher readings indicate greater moisture (range: 0-70 tissue dielectric constant), with values increasing significantly with the presence of skin damage. Elevated subepidermal moisture values co-occurred with concurrent skin damage in generalized multinomial logistic models (to control for repeated observations) at the sacrum, adjusting for age and risk. Higher subepidermal moisture values were associated with visual damage 1 week later using similar models. Threshold values for subepidermal moisture were compared to visual ratings to predict skin damage 1 week later. Subepidermal moisture of 39 tissue dielectric constant units predicted 41% of future skin damage while visual ratings predicted 27%. Thus, this method of detecting early skin damage holds promise for clinicians, especially as it is objective and equally valid for all groups of patients.

Difficulty in Identifying Factors Responsible for Pressure Ulcer Healing in Veterans With Spinal Cord Injury.

OBJECTIVE: To identify characteristics associated with pressure ulcer (PrU) healing for individuals with spinal cord injury (SCI). DESIGN: Secondary analysis of a large clinical trial's data for healing PrUs in individuals with SCI; prospective Delphi process was conducted with SCI and/or PrU experts. SETTING: Spinal cord injury centers. PARTICIPANTS: There were 629 screening and 162 treatment participants (N=791); 185 SCI clinicians/national PrU/wound care experts participated in the Delphi process. INTERVENTIONS: None. MAIN OUTCOME MEASURE: PrU healing of 50% and 100% at weeks 4 and 12. RESULTS: Poisson regression models using the top Delphi-recommended factors found that only ulcer stage consistently predicted 50% and 100% healing at weeks 4 and 12. Additionally, ischial/perineal location was associated with 33% higher likelihood of 50% healing at week 4. Patient noncompliance with treatment recommendations, the top-ranked Delphi factor, did not predict healing at week 4 or 12. Expanded models found that at week 4, baseline PrU size, PrU stage IV, PrU pain, and American Spinal Injury Association grade A significantly predicted 100% healing, while at week 12, only PrU stage (IV) significantly predicted 100% healing. Significant predictors of 50% healing at week 4 included baseline PrU size, stage, ischial/perianal location body mass index >30kg/m2, foul odor, and signs of infection. At week 12, PrU duration, paraplegia predicted 50% healing. SCI center identifiers consistently showed 2- to 5-fold variation in predicting 50% PrU healing at weeks 4 and 12. CONCLUSIONS: Delphi panel-recommended factors (eg, patient compliance) did not predict PrU healing. Reducing center-level variability in wound healing by learning from best practices should be a health system goal. PrU healing in SCI is still poorly understood, and future studies should focus on as yet unidentified or underappreciated factors.

Use of Munsell color charts to measure skin tone objectively in nursing home residents at risk for pressure ulcer development.

AIMS: To assess the feasibility of classifying skin tone using Munsell color chart values and to compare Munsell-based skin tone categories to ethnicity/race to predict pressure ulcer risk. BACKGROUND: Pressure ulcer classification uses level of visible tissue damage, including skin discoloration over bony prominences. Prevention begins with early detection of damage. Skin discoloration in those with dark skin tones can be difficult to observe, hindering early detection. DESIGN: Observational cohort of 417 nursing home residents from 19 nursing homes collected between 2009-2014, with weekly skin assessments for up to 16 weeks. METHODS: Assessment included forearm and buttocks skin tone based on Munsell values (Dark, Medium, Light) at three time points, ethnicity/race medical record documentation, and weekly skin assessment on trunk and heels. RESULTS: Inter-rater reliability was high for forearm and buttock values and skin tone. Mean Munsell buttocks values differed significantly by ethnicity/race. Across ethnicity/race, Munsell value ranges overlapped, with the greatest range among African Americans. Trunk pressure ulcer incidence varied by skin tone, regardless of ethnicity/race. In multinomial regression, skin tone was more predictive of skin damage than ethnicity/race for trunk locations but ethnicity/race was more predictive for heels. CONCLUSIONS: Given the overlap of Munsell values across ethnicity/race, color charts provide more objective measurement of skin tone than demographic categories. An objective measure of skin tone can improve pressure ulcer risk assessment among patients for whom current clinical guidelines are less effective.

Data and Doing: Using Wound Size to Evaluate Wound Care in Venous Ulcers.

Measuring and monitoring wound progress by size are an important management tool. Wound progress and size can help assess effectiveness of therapy and predict healing, while preparing for application of advanced wound products and treatments. The authors outline methods of tracking wound size and predictors of healing in venous leg ulcers.

A Multisite Quality Improvement Project to Standardize the Assessment of Pressure Ulcer Healing in Veterans with Spinal Cord Injuries/Disorders.

OBJECTIVE: The objective was to implement the evidence-based Spinal Cord Impairment Pressure Ulcer Monitoring Tool (SCI-PUMT) in 23 Spinal Cord Injury/Disorders Centers (SCI/D) in the Veterans Health Administration (VHA). SETTING: A collaborative was held in Minnesota that was attended by key personnel from SCI/D Centers in the VHA. METHODS: This initiative was based on a 3-year longitudinal study that established the validity and reliability of a novel pressure ulcer monitoring tool for persons with spinal cord impairment. A multifaceted evidence-based strategy was used to implement the Institute for Healthcare Improvement's framework of Plan-Do-Study-Act. The plan was executed by clinical champions who implemented the tool in their respective SCI/D Centers following a conference that used both didactic and practicum approaches. OUTCOMES: A 15-item toolkit was developed to educate clinicians and patients regarding use of the SCI-PUMT. Toolkit elements were frequently accessed over the VA intranet (n = 3254). The 1.5-day national conference rolled out the new tool to the SCI/D Centers. Pre/post SCI-PUMT knowledge of the SCI-PUMT improved by 78% during the conference. Following the conference, periodic conference calls cemented the implementation efforts of the SCI-PUMT clinical champions and barriers were mitigated.

Comparing multicomponent interventions to improve skin care behaviors and prevent recurrence in veterans hospitalized for severe pressure ulcers.

OBJECTIVE: To compare a multicomponent motivational interviewing (MI)/self-management (SM) intervention with a multicomponent education intervention to improve skin-protective behaviors and prevent skin worsening in veterans with spinal cord injury (SCI) hospitalized for severe pressure ulcers (PrUs). DESIGN: Single-blinded, prospective, randomized controlled trial. SETTING: Six Veterans Affairs SCI centers. PARTICIPANTS: Veterans admitted for a severe (stage III/IV) PrU were followed up to 6 months postdischarge. INTERVENTION: Telephone-based individual MI counseling plus SM skills group (SM+MI; n=71) versus an active control group of telephone-based individual educational counseling plus group education (n=72). MAIN OUTCOME MEASURES: Self-reported skin-protective behaviors, objective skin worsening. RESULTS: Intention-to-treat analyses found nonsignificant increases in skin behaviors in the SM+MI versus education control intervention arms at 3 and 6 months. The difference in behaviors used between SM+MI and education control intervention participants was 4.6% (95% confidence interval [CI], -11.3 to 2.7) (0-3mo) and 3.0% (95% CI, -8.7 to 3.9) (0-6mo). High rates of skin worsening were observed (n=74, 51.7%), usually within 3 months postdischarge and most frequently within the month postdischarge. Skin worsening, skin-related visits, and readmissions did not differ by study arm. Study limitations are presented. CONCLUSIONS: For persons with chronic SCI and severe PrUs, complicated by multiple comorbidities, a primary focus on improving patient behavior is likely insufficient to address the complex problem of PrUs in SCI. More health care systems-level changes such as collaborative care may be needed to reduce PrU recurrence, especially in this era in which many people are discharged from the hospital unhealed or with little sitting tolerance.

Preventing Community-Acquired Pressure Injuries in Spinal Cord Injury: Online Healthcare Provider Curriculum.

PURPOSE: The aim of this study was to develop and pilot an educational curriculum for healthcare providers to better understand community-acquired pressure injury (CAPrI) prevention in veterans living with spinal cord injury (SCI). METHODS: The Thomas six-step process model guided curricular development and evaluation. Curriculum development followed six steps: (1) problem identification and general needs assessment from a literature review and qualitative research triangulating provider and veteran perspectives of CAPrI prevention in SCI, (2) target needs assessment using a focus group with 14 experienced practicing interprofessional SCI providers, (3) creation of module goals and objectives with content review from experts ( n = 8), (4) development of curriculum content and educational strategies, (5) implementation of a pilot ( n = 4), and (6) evaluation of satisfaction and curriculum content via survey and focus group. RESULTS: A five-module online curriculum was evaluated positively and is available publicly. Modules include (1) CAPrI Prevention Clinical Guidelines for the Provider, (2) CAPrI Prevention from the Veteran Perspective, (3) Building Collaborative Relationships, (4) Accessing Resources, and (5) Team Approach. Pilot participants stated objectives were met; they were satisfied with the module. The participants did recommend some changes. CLINICAL RELEVANCE: Understanding CAPrI prevention can inform rehabilitation nursing care. CONCLUSIONS: An asynchronous educational curriculum can support nurses in integrating preventive care in community-dwelling veterans living with SCI.

Neuroinflammation, autoinflammation, splenomegaly and anemia caused by bi-allelic mutations in IRAK4.

We describe a novel, severe autoinflammatory syndrome characterized by neuroinflammation, systemic autoinflammation, splenomegaly, and anemia (NASA) caused by bi-allelic mutations in IRAK4. IRAK-4 is a serine/threonine kinase with a pivotal role in innate immune signaling from toll-like receptors and production of pro-inflammatory cytokines. In humans, bi-allelic mutations in IRAK4 result in IRAK-4 deficiency and increased susceptibility to pyogenic bacterial infections, but autoinflammation has never been described. We describe 5 affected patients from 2 unrelated families with compound heterozygous mutations in IRAK4 (c.C877T (p.Q293*)/c.G958T (p.D320Y); and c.A86C (p.Q29P)/c.161 + 1G>A) resulting in severe systemic autoinflammation, massive splenomegaly and severe transfusion dependent anemia and, in 3/5 cases, severe neuroinflammation and seizures. IRAK-4 protein expression was reduced in peripheral blood mononuclear cells (PBMC) in affected patients. Immunological analysis demonstrated elevated serum tumor necrosis factor (TNF), interleukin (IL) 1 beta (IL-1ß), IL-6, IL-8, interferon α2a (IFN-α2a), and interferon ß (IFN-ß); and elevated cerebrospinal fluid (CSF) IL-6 without elevation of CSF IFN-α despite perturbed interferon gene signature. Mutations were located within the death domain (DD; p.Q29P and splice site mutation c.161 + 1G>A) and kinase domain (p.Q293*/p.D320Y) of IRAK-4. Structure-based modeling of the DD mutation p.Q29P showed alteration in the alignment of a loop within the DD with loss of contact distance and hydrogen bond interactions with IRAK-1/2 within the myddosome complex. The kinase domain mutation p.D320Y was predicted to stabilize interactions within the kinase active site. While precise mechanisms of autoinflammation in NASA remain uncertain, we speculate that loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production. Blockade of IL-6 resulted in immediate and complete amelioration of systemic autoinflammation and anemia in all 5 patients treated; however, neuroinflammation has, so far proven recalcitrant to IL-6 blockade and the janus kinase (JAK) inhibitor baricitinib, likely due to lack of central nervous system penetration of both drugs. We therefore highlight that bi-allelic mutation in IRAK4 may be associated with a severe and complex autoinflammatory and neuroinflammatory phenotype that we have called NASA (neuroinflammation, autoinflammation, splenomegaly and anemia), in addition to immunodeficiency in humans.

Case Report: ISG15 deficiency caused by novel variants in two families and effective treatment with Janus kinase inhibition.

ISG15 deficiency is a rare disease caused by autosomal recessive variants in the ISG15 gene, which encodes the ISG15 protein. The ISG15 protein plays a dual role in both the type I and II interferon (IFN) immune pathways. Extracellularly, the ISG15 protein is essential for IFN-γ-dependent anti-mycobacterial immunity, while intracellularly, ISG15 is necessary for USP18-mediated downregulation of IFN-α/ß signalling. Due to this dual role, ISG15 deficiency can present with various clinical phenotypes, ranging from susceptibility to mycobacterial infection to autoinflammation characterised by necrotising skin lesions, intracerebral calcification, and pulmonary involvement. In this report, we describe novel variants found in two different families that result in complete ISG15 deficiency and severe skin ulceration. Whole exome sequencing identified a heterozygous missense p.Q16X ISG15 variant and a heterozygous multigene 1p36.33 deletion in the proband from the first family. In the second family, a homozygous total ISG15 gene deletion was detected in two siblings. We also conducted further analysis, including characterisation of cytokine dysregulation, interferon-stimulated gene expression, and p-STAT1 activation in lymphocytes and lesional tissue. Finally, we demonstrate the complete and rapid resolution of clinical symptoms associated with ISG15 deficiency in one sibling from the second family following treatment with the Janus kinase (JAK) inhibitor baricitinib.