A unified metric of human immune health.

Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine.

Characterization of the antispike IgG immune response to COVID-19 vaccines in people with a wide variety of immunodeficiencies.

Research on coronavirus disease 2019 vaccination in immune-deficient/disordered people (IDP) has focused on cancer and organ transplantation populations. In a prospective cohort of 195 IDP and 35 healthy volunteers (HV), antispike immunoglobulin G (IgG) was detected in 88% of IDP after dose 2, increasing to 93% by 6 months after dose 3. Despite high seroconversion, median IgG levels for IDP never surpassed one-third that of HV. IgG binding to Omicron BA.1 was lowest among variants. Angiotensin-converting enzyme 2 pseudo-neutralization only modestly correlated with antispike IgG concentration. IgG levels were not significantly altered by receipt of different messenger RNA-based vaccines, immunomodulating treatments, and prior severe acute respiratory syndrome coronavirus 2 infections. While our data show that three doses of coronavirus disease 2019 vaccinations induce antispike IgG in most IDP, additional doses are needed to increase protection. Because of the notably reduced IgG response to Omicron BA.1, the efficacy of additional vaccinations, including bivalent vaccines, should be studied in this population.

Multiomics integration of 22 immune-mediated monogenic diseases reveals an emergent axis of human immune health.

Monogenic diseases are often studied in isolation due to their rarity. Here we utilize multiomics to assess 22 monogenic immune-mediated conditions with age- and sex-matched healthy controls. Despite clearly detectable disease-specific and "pan-disease" signatures, individuals possess stable personal immune states over time. Temporally stable differences among subjects tend to dominate over differences attributable to disease conditions or medication use. Unsupervised principal variation analysis of personal immune states and machine learning classification distinguishing between healthy controls and patients converge to a metric of immune health (IHM). The IHM discriminates healthy from multiple polygenic autoimmune and inflammatory disease states in independent cohorts, marks healthy aging, and is a pre-vaccination predictor of antibody responses to influenza vaccination in the elderly. We identified easy-to-measure circulating protein biomarker surrogates of the IHM that capture immune health variations beyond age. Our work provides a conceptual framework and biomarkers for defining and measuring human immune health.

Disseminated Mycoplasma Orale Infection in Patients With Phosphoinositide-3-Kinase Regulatory Subunit 1 Mutations.

Mycoplasma orale is a rare cause of invasive infection in immunodeficient hosts. Phosphatidylinositol 3-kinase, regulatory subunit 1 (PI3KR1) mutations predispose patients to sinopulmonary infections, alongside bronchiectasis autoimmunity and lymphoproliferation. We report 2 cases of PI3KR1 deficiency with invasive M orale and effective treatment options.

Bortezomib treatment for refractory nontuberculous mycobacterial infection in the setting of interferon gamma autoantibodies.

Interferon-γ autoantibodies increase the risk of disseminated nontuberculous mycobacterial infections. Addition of rituximab to antibiotics accelerates and improves outcomes, but refractory infections can occur due to persistent production of autoantibodies. We combined bortezomib with rituximab to reduce autoantibodies leading to clinical and radiographic improvement in infection.

Daratumumab (Anti-CD38) for Treatment of Disseminated Nontuberculous Mycobacteria in a Patient With Anti-Interferon-γ Autoantibodies.

Patients with autoantibodies to interferon-γ (IFN-γ) may develop severe nontuberculous mycobacterial infections. We describe the novel use of daratumumab in a patient with autoantibodies to IFN-γ who had progressive infection, resulting in clinical and radiographic improvement.

A long-term follow-up of a single rural surgeon's experience with laparoscopic inguinal hernia repair.

INTRODUCTION: Inguinal hernia repair is one of the most common surgical procedures performed in the United States, with an estimated 700,000 or more completed annually. OBJECTIVE: This study looks at 7 years of laparoscopic totally extra-peritoneal (TEP) inguinal hernia repair at a rural Wisconsin medical center. The goal is to accurately measure recurrence rates and mechanisms of recurrences within a single professional's practice using a follow-up of no less than 2 years. A secondary goal was to record the percentage of patients with short-term and long-term complications. METHOD: Patients with laparoscopic TEP inguinal hernia repairs from 1997 through 2004 were seen in follow-up visits > or =2 years after their initial repair. Of a possible 165 patients, 100 (61%) participated, returning for a total of 141 (64%) follow-up exams. Follow-up range was 2-7 years, with a mean of 3.7 years. All repairs were completed using a single technique (TEP) by a single surgeon. Repair variables included mesh thickness, style of mesh to cord accommodation, and fixation technique. Study participants ranged from 16 to 88 years, with an average age of 65.9 years. A wide range of socioeconomic indicators were represented, including education, occupation, and household income. Five participants were female and 95 were male. MAIN OUTCOME MEASURE: The primary study outcome was the identification of an accurate recurrence rate along with the mechanism of hernia recurrence. Patients with long-term groin pain (dysesthesia) and identification of short-term complications were also noted. RESULTS: Between 2004 and 2007, 100 patients were seen for follow-up. None had symptomatic hernia recurrences. One recurrence was found at exam and confirmed with a herniogram and laparoscopic surgical exploration. Two additional patients, identified by exam and herniograms as having suspected recurrences, are awaiting surgical exploration. In the case of 1 recurrence, the mechanism appears to be partial migration of mesh from the placement area. Long-term groin dysesthesias (moderate or occasional) occurred in 2 patients or 1.4% of repairs. Spermatic cord hematoma (18% of repairs) was the most common short-term complication. CONCLUSIONS: Laparoscopic TEP inguinal hernia repairs are effective and durable in a rural setting. An acceptable recurrence rate (0.7%-2.1%) may be related to mesh placement, completeness of dissection, and the small but real risk of mesh migration or displacement prior to healing fixation. Long-term pain complications are reasonably low.