A Registry Study of 240 Patients with X-Linked Agammaglobulinemia Living in the USA.

PURPOSE: To understand the natural history and clinical outcomes for patients with X-linked agammaglobulinemia (XLA) in the United States utilizing the United States Immunodeficiency Network (USIDNET) patient registry. METHODS: The USIDNET registry was queried for data from XLA patients collected from 1981 to 2019. Data fields included demographics, clinical features before and after diagnosis of XLA, family history, genetic mutation in Bruton's tyrosine kinase (BTK), laboratory findings, treatment modalities, and mortality. RESULTS: Data compiled through the USIDNET registry on 240 patients were analyzed. Patient year of birth ranged from 1945 to 2017. Living status was available for 178 patients; 158/178 (88.8%) were alive. Race was reported for 204 patients as follows: White, 148 (72.5%); Black/African American, 23 (11.2%); Hispanic, 20 (9.8%); Asian or Pacific Islander, 6 (2.9%), and other or more than one race, 7 (3.4%). The median age at last entry, age at disease onset, age at diagnosis, and length of time with XLA diagnosis was 15 [range (r) = 1-52 years], 0.8 [r = birth-22.3 years], 2 [r = birth-29 years], and 10 [r = 1-56 years] years respectively. One hundred and forty-one patients (58.7%) were < 18 years of age. Two hundred and twenty-one (92%) patients were receiving IgG replacement (IgGR), 58 (24%) were on prophylactic antibiotics, and 19 (7.9%) were on immunomodulatory drugs. Eighty-six (35.9%) patients had undergone surgical procedures, two had undergone hematopoietic cell transplantation, and two required liver transplantation. The respiratory tract was the most affected organ system (51.2% of patients) followed by gastrointestinal (40%), neurological (35.4%), and musculoskeletal (28.3%). Infections were common both before and after diagnosis, despite IgGR therapy. Bacteremia/sepsis and meningitis were reported more frequently before XLA diagnosis while encephalitis was more commonly reported after diagnosis. Twenty patients had died (11.2%). The median age of death was 21 years (range = 3-56.7 years). Neurologic condition was the most common underlying co-morbidity for those XLA patients who died. CONCLUSIONS: Current therapies for XLA patients reduce early mortality, but patients continue to experience complications that impact organ function. With improved life expectancy, more efforts will be required to improve post-diagnosis organ dysfunction and quality of life. Neurologic manifestations are an important co-morbidity associated with mortality and not yet clearly fully understood.

Health-Related Quality of Life in 91 Patients with X-Linked Agammaglobulinemia.

PURPOSE: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency (PID) caused by a defect in the gene encoding for Bruton tyrosine kinase (BTK). In the absence of a functional BTK, patients have low or absent circulating B cells and low or absent serum immunoglobulin. Despite gammaglobulin replacement and prompt use of antimicrobial agents, patients with XLA continue to experience infectious and non-infectious complications throughout their lifetime. The purpose of this study was to understand self-perceived health status of US-based patients with XLA, and examine the associations amongst clinical characteristics, treatment experience, and quality of life (QoL). METHODS: A 46 and 68 question survey, developed by the Immune Deficiency Foundation (IDF) and a Short Form-12item v2® (SF-12v2®) for adults and SF-10™ for children to assess QoL, were mailed by IDF to patients in 2017 and 2018. Those that self-identified as having XLA or males with agammaglobulinemia were selected for analysis. Mean physical and mental composite scores (PCS and MCS) from SF-12v2® and mean physical health component (PHS) and psychological health summary (PSS) from SF-10™ scores were compared to the US normative data. RESULTS: Ninety-one patients completed the surveys: 58 (63.7%) adults and 33 (36.3%) children. For the combined surveys, the overall median age at time of the survey was 28.5 years (yrs); Inter-Quartile-Range (IQR) 13-49.5 yrs; the median age at diagnosis was 2 yrs (IQR = 0-4 yrs) and the median number of years with XLA diagnosis was 23 (IQR 10.75-40yrs). Amongst adult patients, physical scores were noted to be below the general adult population but did not reach statistical significance. In contrast, 2 or more chronic conditions impacted both physical and mental QoL (p < .001) and hospitalization was associated with significantly decreased physical health QoL (p < .001); three or more infections in the past 12 months exhibited impact on physical health although was not found to be statistically significant. Adult patients with public insurance fared worse in mental health domains compared to those with combined public and private or those with private alone (p = 0.001). Employment status did not impact QoL. None of these variables met statistical significance nor demonstrated impact within the pediatric population in either physical or mental domains of health. CONCLUSION: Our study provides further insight into what factors impact both physical and mental domains of health amongst patients with XLA. Early detection to prevent the development of associated morbidity, as well as vigilant care to prevent hospitalizations and infections, can limit the impact this disease may have on the overall well-being of XLA patients.

Web-Based Mindfulness-Based Interventions for Well-being: Randomized Comparative Effectiveness Trial.

BACKGROUND: Mindfulness can improve overall well-being by training individuals to focus on the present moment without judging their thoughts. However, it is unknown how much mindfulness practice and training are necessary to improve well-being. OBJECTIVE: The primary aim of this study was to determine whether a standard 8-session web-based mindfulness-based cognitive therapy (MBCT) program, compared with a brief 3-session mindfulness intervention, improved overall participant well-being. In addition, we sought to explore whether the treatment effects differed based on the baseline characteristics of the participants (ie, moderators). METHODS: Participants were recruited from 17 patient-powered research networks, web-based communities of stakeholders interested in a common research area. Participants were randomized to either a standard 8-session MBCT or a brief 3-session mindfulness training intervention accessed on the web. The participants were followed for 12 weeks. The primary outcome of the study was well-being, as measured by the World Health Organization-Five Well-Being Index. We hypothesized that MBCT would be superior to a brief mindfulness training. RESULTS: We randomized 4411 participants, 3873 (87.80%) of whom were White and 3547 (80.41%) of female sex assigned at birth. The mean baseline World Health Organization-Five Well-Being Index score was 50.3 (SD 20.7). The average self-reported well-being in each group increased over the intervention period (baseline to 8 weeks; model-based slope for the MBCT group: 0.78, 95% CI 0.63-0.93, and brief mindfulness group: 0.76, 95% CI 0.60-0.91) as well as the full study period (ie, intervention plus follow-up; baseline to 20 weeks; model-based slope for MBCT group: 0.41, 95% CI 0.34-0.48; and brief mindfulness group: 0.33, 95% CI 0.26-0.40). Changes in self-reported well-being were not significantly different between MBCT and brief mindfulness during the intervention period (model-based difference in slopes: -0.02, 95% CI -0.24 to 0.19; P=.80) or during the intervention period plus 12-week follow-up (-0.08, 95% CI -0.18 to 0.02; P=.10). During the intervention period, younger participants (P=.05) and participants who completed a higher percentage of intervention sessions (P=.005) experienced greater improvements in well-being across both interventions, with effects that were stronger for participants in the MBCT condition. Attrition was high (ie, 2142/4411, 48.56%), which is an important limitation of this study. CONCLUSIONS: Standard MBCT improved well-being but was not superior to a brief mindfulness intervention. This finding suggests that shorter mindfulness programs could yield important benefits across the general population of individuals with various medical conditions. Younger people and participants who completed more intervention sessions reported greater improvements in well-being, an effect that was more pronounced for participants in the MBCT condition. This finding suggests that standard MBCT may be a better choice for younger people as well as treatment-adherent individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT03844321; https://clinicaltrials.gov/ct2/show/NCT03844321.

Expectations and experience: Parent and patient perspectives regarding treatment for Severe Combined Immunodeficiency (SCID).

INTRODUCTION: Infants with SCID are treated with hematopoietic cell transplantation (HCT) or gene therapy (GT). Caregiver perceptions of pre-treatment counseling and understanding of durability of HCT/GT are poorly understood. METHODS: A survey was designed and distributed to families of patients with SCID. Topics in the questionnaire included SCID genotype and treatment, family recollections of pre-treatment counseling and present clinical status. RESULTS: 151 surveys were analyzed. 132 were treated with HCT, 19 with GT. From counseling received, 37% expected HCT/GT would lead to "cure"; 43% expected HCT/GT would last a lifetime. Of 136 living patients, 59% reported overall good health but 65% reported some persistent health challenges. CONCLUSIONS: For some, interpretation of the word "cure" varied, leading to misunderstanding regarding need for continued medical evaluations and additional therapies. Clear communication regarding the importance of lifelong follow-up, no matter the treatment outcome, will help to optimize good health and quality of life.

Supporting caregivers during hematopoietic cell transplantation for children with primary immunodeficiency disorders.

BACKGROUND: Caregivers of children with primary immunodeficiency disorders (PIDs) experience significant psychological distress during their child's hematopoietic cell transplantation (HCT) process. OBJECTIVES: This study aims to understand caregiver challenges and identify areas for health care system-level improvements to enhance caregiver well-being. METHODS: In this mixed-methods study caregivers of children with PIDs were contacted in August to November 2017 through online and electronic mailing lists of rare disease consortiums and foundations. Caregivers were invited to participate in an online survey assessing sociodemographic variables, the child's medical characteristics, psychosocial support use, and the World Health Organization-5 Well-Being Index. Open-ended questions about health care system improvements were included. Descriptive statistics and linear multivariate regression analyses were conducted. A modified content analysis method was used to code responses and identify emergent themes. RESULTS: Among the 80 caregiver respondents, caregivers had a median age of 34 years (range, 23-62 years) and were predominantly female, white, and married with male children given a diagnosis of severe combined immune deficiency. In the adjusted regression model lower caregiver well-being was significantly associated with lower household income and medical complications. Challenges during HCT include maintaining relationships with partners and the child's healthy sibling or siblings, managing self-care, and coping with feelings of uncertainty. Caregivers suggested several organizational-level solutions to enhance psychosocial support, including respite services, online connections to other PID caregivers, and bedside mental health services. CONCLUSIONS: Certain high-risk subpopulations of caregivers might need more targeted psychosocial support to reduce the long-term effect of the HCT experience on their well-being. Caregivers suggested several organizational-level solutions for provision of this support.

Psychosocial services for primary immunodeficiency disorder families during hematopoietic cell transplantation: A descriptive study.

OBJECTIVE: Caregivers for patients undergoing hematopoietic cell transplantation (HCT) are susceptible to significant psychosocial distress. This cross-sectional study aimed to describe psychosocial support services offered and used by caregivers of pediatric primary immune deficiency (PID) during HCT at 35 hospitals across North America. METHOD: Caregivers of pediatric patients with PID were recruited by e-mail to participate in an anonymous 140-question survey instrument between April and May 2016 (N = 171). RESULT: Of those meeting inclusion criteria (53%), family counseling services were only offered to fewer than half of caregivers (42%). Of the survey participants not offered counseling services, the majority desired family counseling (70%) and sibling counseling (73%). That said, when offered counseling, utilization rates were low, with 22% of caregivers using family counseling and none using sibling counseling. SIGNIFICANCE OF RESULTS: These results indicate the need to offer and tailor counseling services for families throughout the HCT process. Further research should focus on reducing barriers to utilization of counseling services such as offering bedside counseling services, online modalities, and/or financial assistance.

Pulmonologist perspectives regarding diagnosis and management of primary immunodeficiency diseases.

BACKGROUND: The time from symptom onset to diagnosis for patients with primary immunodeficiency diseases (PIDD) is an average of 12 years, but prompt diagnosis and treatment can promote best outcomes. OBJECTIVE: Because the manifestations of PIDD are often sinopulmonary in nature, patients with undiagnosed PIDD are frequently referred to pulmonologists. This study sought to identify opportunities among these specialists to improve diagnosis and clinical management of patients with PIDD. METHODS: A survey was sent to American Medical Association and American Osteopathic Association members whose specialty was pulmonology. Responses were compared with those from a historical survey of 71 subspecialist immunologists (American Academy of Allergy, Asthma Immunology members who devoted 10% of their practice to patients with PIDD). RESULTS: The surveys were returned by 485 pulmonologists, 49% of whom had diagnosed at least one patient with PIDD. In comparison with subspecialist immunologists, fewer pulmonologists were aware of the professional PIDD diagnosis and management guidelines and fewer followed up patients with various PIDDs. Pulmonologists and subspecialist immunologists also differed in the practice of prescribing prophylactic antibiotics and immunoglobulin replacement and in avoiding live viral vaccines. CONCLUSION: Differences in the diagnosis and treatment of patients with PIDD between these two groups of specialists revealed areas in which PIDD-focused educational initiatives may be helpful for pulmonologists.

Fertility, pregnancies and outcomes reported by females with common variable immune deficiency and hypogammaglobulinemia: results from an internet-based survey.

BACKGROUND: Issues of fertility and pregnancy place an extra burden on females with primary immunodeficiencies. Patients lack reliable information and providers lack guidelines to counsel patients on these anxiety-provoking matters. OBJECTIVE: To collate concerns and experiences related to fertility and pregnancy from females with humoral immune deficiencies. METHODS: We conducted an internet-based survey of female patients who self-identified as having a diagnosis of primary humoral immune deficiency. RESULTS: Responses from 490 women with common variable immune deficiency and 100 with hypogammaglobulinemia were evaluated. The reported fertility measure (% of women who had had a birth) was statistically significantly lower as compared to the general US population (70 % vs. 85 %, p < 0.0001) whereas the rates of spontaneous pregnancy loss were comparable. This group reported a total of 966 pregnancies; 72 % resulted in a live birth. A majority of the pregnancies progressed with no incident and with continuation of their IgG replacement therapy; 23 % reported an increase in IgG dosing during pregnancy. Only 15 % of those reporting a first pregnancy indicated that they had been diagnosed with immune deficiency prior to their first pregnancy; these women expressed concern regarding the effect of immune deficiency on their fertility, pregnancy and decision to have children. CONCLUSION: With inherent limitations of self-reported responses to surveys, females with humoral immune deficiencies reported relatively good rates of fertility and pregnancies ending in live births. Results of the survey will serve as peer support for patients and inform counseling guidelines for providers.

Perceived Health in Patients with Primary Immune Deficiency.

PURPOSE: Perceived health (PH) is a subjective measure of global health of individuals. While many studies have evaluated outcomes in patients with primary immune deficiency (PID), published literature evaluating PH among patients with PID is sparse. We evaluated the results of the largest self-reported survey of patients with PID to determine the factors that may contribute to differences in PH. METHODS: Data from a National Survey of Patients with Primary Immune Deficiency Diseases conducted by the Immune Deficiency Foundation was studied. Multivariate logistic regression was employed for data analysis. RESULTS: Thirty percent of the patients perceived their health status as excellent or very good (EVG), 31 % as good (G), and 39 % as fair, poor or very poor (P). Older patients were less likely to have EVG-PH compared to G-PH. Ones with college degrees were more likely to have P-PH compared to G-PH, and less likely to have EVG-PH. Patients who were acutely ill and hospitalized in the past 12 months, ones with limited activity, and chronic diseases, were more likely to have P-PH compared to G-PH. Patients with "on demand" access to specialty care and ones on regular IVIG had higher OR of having EVG-PH as opposed to G-PH. Patients cared for mostly by an immunologist were less likely to have P-PH compared to G-PH. CONCLUSIONS: Our results emphasize the importance of PH in clinical practice. We suggest that recognizing the factors that drive PH in patients with PID is important for the development of disease prevention and health promotion programs, and delivery of appropriate health and social services to individuals with PID.

Early vs. delayed diagnosis of severe combined immunodeficiency: a family perspective survey.

Infants affected with severe combined immunodeficiency (SCID) are susceptible to severe and recurrent infections and do not survive unless provided with immune reconstituting treatments. In the absence of population-based newborn screening, infants with SCID who do not have an affected older relative are ascertained only after they have developed infections. However, only limited data are available from the perspective of patients and families to indicate what proportion of SCID cases might benefit from earlier detection by pre-symptomatic screening, whether adequate treatment facilities are available, and how screening could improve SCID treatment outcomes. A survey of parents of children with SCID evaluated family history, pre- and post-diagnosis events, outcomes, and impact of SCID on families. Affected infants diagnosed with SCID as neonates had better survival, demonstrating the potential benefit of universal newborn screening.

Persons Living With Primary Immunodeficiency Act as Citizen Scientists and Launch Prospective Cohort Body Temperature Study.

BACKGROUND: Although fever is considered a sign of infection, many individuals with primary immunodeficiency (PI) anecdotally report a lower-than-normal average body temperature on online forums sponsored by the Immune Deficiency Foundation (IDF). There is limited knowledge about the average body temperature and fever response in PI. OBJECTIVE: This study aims to compare median body temperatures between adults with and without PI diagnoses living in the same household and to engage individuals living with PI throughout the research process. METHODS: Patients with PI designed and launched a prospective cohort comparison study as citizen scientists. A multidisciplinary team designed and implemented a patient-informed study with continuous patient-driven input. Median body temperatures were compared between the 2 cohorts using the Mann-Whitney test with Bonferroni correction. The IDF conducted a post-study patient experience survey. RESULTS: Data from 254 households were analyzed (254/350, 72.6% participation rate). The PI population was predominantly female (218/254, 85.8%), White (248/254, 97.6%), and with a median age of 49 years. The non-PI population was largely male (170/254, 66.9%), White (236/254, 92.9%), and with a median age of 53 years. Common variable immunodeficiency was the most common PI diagnosis (190/254, 74.8%). Of the 254 individuals with PI, 123 (48.4%) reported a lower-than-normal nonsick body temperature, whereas 108 (42.5%) reported a normal (between 97°F and 99°F) nonsick body temperature. Among individuals with PI, when infected, 67.7% (172/254) reported the absence of fever, whereas 19.7% (50/254) reported a normal fever response. The recorded median body temperature was minimally but statistically significantly higher for patients with PI in the morning. Although 22.4% (57/254) of patients with PI self-reported illness, a fever of 100.4°F or higher was uncommon; 77.2% (196/254) had a normal temperature (between 97°F and 99°F), and 16.2% (41/254) had a lower-than-normal temperature (between 95.0°F and 96.9°F) when sick. For these sick patients with PI, the median body temperature was minimally but statistically significantly higher for patients in the morning and early evening. Overall, 90.9% (231/254) of participants would be very likely to participate in future IDF studies, although 94.1% (239/254) participants had never taken part in previous studies. CONCLUSIONS: To our knowledge, this is the first study to evaluate average body temperature in individuals with PI. Although there were small statistically significant differences in body temperatures between PI and non-PI subjects, the clinical significance is unclear and should be interpreted with caution, given the methodological issues associated with our small convenience sample and study design. As PIs are heterogeneous, more research is needed about how the fever response differs among diverse PIs compared with healthy controls. This study highlights that individuals with PI are knowledgeable about their health and can offer unique insights and direction to researchers and clinicians.

PROMIS-29 survey confirms major impact of fatigue on health-related quality of life in common variable immunodeficiency.

Health-related quality of life (HRQOL) is an emerging topic of interest in patients with immunodeficiency. Information about HRQOL in common variable immunodeficiency (CVID) is limited. The primary objective was to compare primary immunodeficiency disease (PIDD) patients with and without common variable immunodeficiency (CVID) on HRQOL domains using Patient-Reported Outcomes Measurement Information System (PROMIS-29) survey data from the United States Immunodeficiency Network (USIDNET) registry. The primary endpoint variables were scores on 7 HRQOL domains. The USIDNET registry was used to select patients with baseline PROMIS-29 data collected between 2015 and 2018. Descriptive statistics, Fisher's exact test, and Student's two-sample t test were used to compare patients with CVID versus patients with non-CVID on demographic and clinical characteristics. The single-sample t test was used to compare sample means to the normed population mean of 50. A general linear model approach to multiple regression with backward selection was used to remove factors that did not contribute significant information to the multivariable models, while controlling for multiple testing. Potential explanatory variables included group (CVID/non-CVID), sex, age, and BMI. Among 184 PIDD patients, 146 (79%) were diagnosed with CVID. Patients had a mean (SD) age of 53 (13.8), were predominantly female (83%), and were Caucasian (98%). PROMIS-29 results revealed a significant effect of group (CVID/non-CVID) on the anxiety, fatigue, and social participation domains, with fatigue being the most statistically significant. Fatigue, anxiety, and social participation may be key factors influencing HRQOL among patients with CVID. Future prospective longitudinal studies using PROMIS-29 will be needed to confirm these findings and to determine the mechanisms through which these factors develop in CVID, and how they can be improved.

Family Physician Perspectives on Primary Immunodeficiency Diseases.

Primary immunodeficiency diseases (PIDs) include over 250 diverse disorders. The current study assessed management of PID by family practice physicians. The American Academy of Allergy, Asthma, and Immunology Primary Immunodeficiency Committee and the Immune Deficiency Foundation conducted an incentivized mail survey of family practice physician members of the American Medical Association and the American Osteopathic Association in direct patient care. Responses were compared with subspecialist immunologist responses from a similar survey. Surveys were returned by 528 (of 4500 surveys mailed) family practice physicians, of whom 44% reported following ≥1 patient with PID. Selective immunoglobulin A deficiency (21%) and chronic granulomatous disease (11%) were most common and were followed by significantly more subspecialist immunologists (P < 0.05). Use of intravenously administered immunoglobulin and live viral vaccinations across PID was significantly different (P < 0.05). Few family practice physicians were aware of professional guidelines for diagnosis and management of PID (4 vs. 79% of subspecialist immunologists, P < 0.05). Family practice physicians will likely encounter patients with PID diagnoses during their career. Differences in how family practice physicians and subspecialist immunologists manage patients with PID underscore areas where improved educational and training initiatives may benefit patient care.