A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome.

ABSTRACT: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/µL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/µL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.

Outcomes of intravenous immunoglobulin treatment of immunocompromised patients with viral respiratory infections.

BACKGROUND: Limited guidelines exist for treating immunocompromised patients hospitalized for acute viral respiratory infection. Little is known about clinical and economic benefits of intravenous immunoglobulin (IVIG) administration in patients with acute viral respiratory infections. OBJECTIVE: To compare clinical and economic outcomes among immunocompromised patients hospitalized with viral respiratory infections who received IVIG with those who did not. METHODS: We performed a retrospective cohort study on all patients hospitalized for a respiratory viral infection between 2011 and 2016 at 2 large academic centers including data on age, sex, virus species, immunosuppression type, and receipt of IVIG. Outcomes included death, hospital readmission, length of stay (LOS) in the hospital, and LOS in the intensive care unit (ICU). RESULTS: A total of 270 patient admissions were reviewed, and 35.6% received IVIG. The average age was 40.6 years, 50% were female, and 74% were transplant patients. The most common virus was rhinovirus (50.7%). Use of IVIG was significantly associated with a shorter ICU LOS (ß = -0.534, P = .012) and a longer hospital LOS (ß = 0.887, P < .01). IVIG administered within 48 hours of hospitalization (n = 229) was associated with a shorter ICU LOS (ß = -2.08, P = .001) and a shorter hospital LOS for patients hospitalized at least 2 days (ß = -0.461, P = .007). There were no significant differences in readmission rates or death. CONCLUSION: This double-center, retrospective cohort analysis is one of the first studies to evaluate the effect of IVIG on immunocompromised patients hospitalized with respiratory viral infections. IVIG was associated with a shorter hospital and ICU LOS, especially when administered within 48 hours of admission.

Reduced quantity and function of pneumococcal antibodies are associated with exacerbations of COPD in SPIROMICS.

While hypogammaglobulinemia is associated with COPD exacerbations, it is unknown whether frequent exacerbators have specific defects in antibody production/function. We hypothesized that reduced quantity/function of serum pneumococcal antibodies correlate with exacerbation risk in the SPIROMICS cohort. We measured total pneumococcal IgG in n = 764 previously vaccinated participants with COPD. In a propensity-matched subset of n = 200 with vaccination within five years (n = 50 without exacerbations in the previous year; n = 75 with one, n = 75 with ≥2), we measured pneumococcal IgG for 23 individual serotypes, and pneumococcal antibody function for 4 serotypes. Higher total pneumococcal IgG, serotype-specific IgG (17/23 serotypes), and antibody function (3/4 serotypes) were independently associated with fewer prior exacerbations. Higher pneumococcal IgG (5/23 serotypes) predicted lower exacerbation risk in the following year. Pneumococcal antibodies are inversely associated with exacerbations, supporting the presence of immune defects in frequent exacerbators. With further study, pneumococcal antibodies may be useful biomarkers for immune dysfunction in COPD.

Randomized double-blind pilot study of universal, species abundant, multiallergen subcutaneous immunotherapy for moderate-severe allergic rhinitis.

BACKGROUND: Allergic rhinitis affects approximately 10% to 20% of people living in industrialized nations leading to significant morbidity and large health care expenditures. Individualized high-dose, single-species allergen immunotherapy has been found to be effective in treating allergic rhinitis but can be associated with significant risks including anaphylaxis. Few studies have evaluated the safety and efficacy of universal low-dose multiallergen immunotherapy (MAIT). OBJECTIVE: To determine the efficacy and safety of a universal MAIT formula for the treatment of allergic rhinitis. METHODS: Patients with moderate-severe perennial and seasonal allergic rhinitis were randomized in a double-blind, placebo-controlled fashion to receive a novel, subcutaneous MAIT regimen containing a unique mixture of more than 150 aeroallergens, including several cross-reactive species. All patients received the exact same universal immunotherapy formula regardless of which specific skin tests were positive. Primary outcome measures at 8 and 12 weeks of therapy included validated clinical assessments, total nasal sinus score and mini-rhinoconjunctivitis quality of life questionnaire, and the use of rescue medications. RESULTS: A total of 31 patients (n = 31) were randomized to receive MAIT vs placebo. By week 12, MAIT resulted in a -4.6 (-58%) decrease in the combined total nasal sinus score and rescue medication score (daily combined score) compared with -1.5 (-20%) for placebo (P = .04). Likewise, MAIT resulted in a decrease in the mini-rhinoconjunctivitis quality of life questionnaire score of -34.9 (-68%) compared with -17 (-42%) for the placebo (P = .04). Mild adverse events were uncommon and with similar frequency among the groups. CONCLUSION: A novel, universal, and high-species abundant MAIT formula was well tolerated and resulted in significant improvement in symptoms of moderate-severe allergic rhinitis. The results of this pilot study should be considered preliminary, pending further randomized clinical trials.

Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.

Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody loss. Clarification regarding whether the hypogammaglobulinemia is secondary or primary is important because this has implications for evaluation and management. Prior receipt of immunosuppressive medications and/or presence of conditions associated with SHG development, including protein loss syndromes, are histories that raise suspicion for SHG. In patients with these histories, a thorough investigation of potential etiologies of SHG reviewed in this report is needed to devise an effective treatment plan focused on removal of iatrogenic causes (eg, discontinuation of an offending drug) or treatment of the underlying condition (eg, management of nephrotic syndrome). When iatrogenic causes cannot be removed or underlying conditions cannot be reversed, therapeutic options are not clearly delineated but include heightened monitoring for clinical infections, supportive antimicrobials, and in some cases, immunoglobulin replacement therapy. This report serves to summarize the existing literature regarding immunosuppressive medications and populations (autoimmune, neurologic, hematologic/oncologic, pulmonary, posttransplant, protein-losing) associated with SHG and highlights key areas for future investigation.

Systemic Lupus Erythematosus and Common Variable Immunodeficiency.

ABSTRACT: Systemic lupus erythematosus (SLE) and common variable immunodeficiency (CVID) are both conditions defined by immune system dysfunction: one hyperactive, the other hypoactive. Although uncommon, these diseases can coexist in the same individual. This review aims to assess the state of the literature on the relationship between SLE and CVID, particularly when workup for CVID should be considered in individuals with SLE and how CVID in individuals with SLE should be treated.

The Cancer Risk Profile of Systemic Lupus Erythematosus Patients.

ABSTRACT: Systemic lupus erythematosus (SLE) patients have a well-established increased risk for cancer. Research from the past 2 decades has identified the specific malignancies that afflict SLE patients at disproportionate rates. Systemic lupus erythematosus patients are at heightened risk for several hematologic malignancies as well as for certain solid tumors, including lung, thyroid, and hepatobiliary cancers. They are at decreased risk for several cancers as well, including prostate and melanoma. Improved understanding of the unique cancer risk profile of SLE patients has led some professional societies to recommend specialized cancer screening and prevention measures for these patients and has enabled clinicians to better serve the SLE patient population.

Benralizumab effect on severe chronic rhinosinusitis with nasal polyps (CRSwNP): A randomized double-blind placebo-controlled trial.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) can be a severe and debilitating disease associated with significant morbidity, loss of smell, sinus pressure and asthma exacerbations. Eosinophils play a role in the majority (85%) of patients. Benralizumab, an afucosylated monoclonal antibody directed against the IL-5 receptor, has powerful apoptotic effects on eosinophils. OBJECTIVE: We sought to investigate the therapeutic benefit of inhibiting the IL-5 receptor using benralizumab to treat severe rhinosinusitis with nasal polyps. METHODS: Patients with severe NP (defined by endoscopic grade 5 or more out of 8) with elevated eosinophils and a history of previous surgical or endoscopic polypectomy met entry criteria and were randomized in a double-blind fashion to receive 30 mg benralizumab SC or placebo. Endoscopic NP score was assessed at baseline and at treatment week 20. CT scan, SNOT-22 survey and UPSIT smell test score changes were also evaluated. RESULTS: Thirty-three patients were screened, and twenty-four (n = 24) were enrolled in the study. Compared with baseline, benralizumab significantly improved NP score (-0.9 ± 0.2, P = 0.004) whereas placebo did not (-0.3 ± 0.3, P = 0.166). Benralizumab induced polyp size reduction compared with placebo did not reach statistical significance (P = 0.103). Five of 12 benralizumab-treated patients (42%) had improvements in all major outcomes (polyp score, CT, SNOT-22 and smell test) versus 2 out of 12 placebo (17%). The ratio of blood eosinophil count to allergen skin test positivity correlated with polyp reduction. CONCLUSION: Benralizumab was well-tolerated and compared with baseline achieved a statistically significant reduction in nasal polyp size, sinus occupancy, symptoms and improved sensation of smell for most patients (83%).

CT Attenuation Values Do Not Reliably Distinguish Benign Sclerotic Lesions From Osteoblastic Metastases in Patients Undergoing Bone Biopsy.

BACKGROUND. CT attenuation thresholds that accurately distinguish enostoses from untreated osteoblastic metastases have been published. In the Mayo Clinic practices, these thresholds have been applied more broadly to distinguish benign sclerotic bone lesions other than enostoses from osteoblastic metastases. OBJECTIVE. The purpose of this article is to determine if CT attenuation thresholds allow the distinguishing of benign sclerotic bone lesions from osteoblastic metastases in patients undergoing bone biopsy. METHODS. A retrospective search was conducted to identify sclerotic lesions described on CT between October 7, 1998, and July 15, 2018, that underwent subsequent biopsy. Two musculoskeletal radiologists recorded lesions' maximum and mean attenuation. Using previously published attenuation thresholds, sensitivity and specificity for differentiating benign sclerotic lesions from osteoblastic metastases were calculated. ROC curve analysis was performed to determine if more appropriate attenuation thresholds exist. Intraclass correlation coefficients (ICCs) were computed. RESULTS. A total of 280 patients met inclusion criteria. Of those, 162 had malignant biopsy results and 118 had benign biopsy results. Of the 162 malignant lesions, 81 had received prior treatment. Maximum and mean attenuation were not significantly different between benign and malignant lesions for either reader (all p > .05). For reader 1, to distinguish benign from malignant lesions, a maximum attenuation threshold of more than 1060 HU resulted in sensitivity of 23.7%, specificity of 87.0%, and accuracy of 60.6%. A mean attenuation threshold of greater than 885 HU resulted in sensitivity of 19.5%, specificity of 90.7%, and accuracy 60.7%. ROC curve analysis showed AUCs for mean and maximum attenuation thresholds of 51.8% and 54.6%, respectively. Subgroup analyses of benign versus malignant and treated versus untreated lesions had similar results. Similar findings were obtained for reader 2. The two readers' ICC was 0.946 for maximum attenuation and 0.918 for mean attenuation. CONCLUSION. Published attenuation thresholds for distinguishing enostoses from osteoblastic metastases had slightly decreased specificity and markedly decreased sensitivity when applied to the differentiation of benign sclerotic lesions from osteoblastic metastases in our sample of biopsy-proven lesions. ROC analysis showed no high-performing attenuation threshold alternative. CLINICAL IMPACT. Published CT attenuation thresholds intended for distinguishing enostoses from osteoblastic metastases should not be used more broadly. More accurate alternative thresholds could not be derived.

Fractured aluminum nasopharyngeal swab during drive-through testing for COVID-19: radiographic detection of a retained foreign body.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has increased the need for safe and efficient testing as a key containment strategy. Drive-through testing with nasopharyngeal swab has been implemented in many places in the USA as it allows for expeditious testing of large numbers of patients, limits healthcare workers' risk of exposure, and minimizes the use of personal protective equipment. We present a case where the aluminum shaft of the nasopharyngeal swab fractured during specimen collection at a drive-through testing facility and was suspected to have remained in the asymptomatic patient. Initial evaluation with a series of radiographs covering the skull base, neck, chest, and abdomen did not reveal the swab. On further clinical evaluation, the swab was found endoscopically, lodged between the left inferior turbinate and nasal floor, and was removed by an otorhinolaryngologist. Using a phantom model, we aimed to delineate an imaging technique to better visualize the aluminum shaft of the nasopharyngeal swab on radiographs to help in identification. A technique using lower tube voltage (kVp) with tight collimation centered at the nasal bones area produced the best visualization of the aluminum shaft of the swab. Recognition that aluminum foreign bodies may be difficult to visualize radiographically and  optimization of radiograph acquisition technique may help guide clinical management in unusual cases. Further evaluation with computed tomography or endoscopy should be considered in suspected cases where radiographs are negative.

Screening for Beta-Lactam Allergy in Joint Arthroplasty Patients to Improve Surgical Prophylaxis Practice.

BACKGROUND: The reliability of patient-reported penicillin allergies has been disputed. A Drug Allergy Clinic (DAC) was established at our institution in combination with an electronic best practice alert (BPA) in the Orthopedic Clinic. Joint arthroplasty patients with a reported history of beta-lactam allergy (HOBA) were preoperatively referred via the BPA to the DAC. The purpose of this study was to determine the effectiveness of beta-lactam allergy screening in enabling the surgical team to optimize antimicrobial prophylaxis. METHODS: Between February 2013 and May 2015, 161 patients with a HOBA were referred to the DAC where they underwent penicillin skin testing (PST), a drug challenge to a beta-lactam antibiotic, and/or had no intervention depending on the history obtained. RESULTS: PST was performed on 140 of 161 (87%) patients. A negative PST was noted in 139 (99%) patients, indicating no penicillin allergy. Cefazolin was safe to use in 145 (90%) patients evaluated. Significantly more patients evaluated in the DAC vs those not seen got cefazolin in any surgical prophylaxis regimen (90% vs 77%) without any adverse perioperative reactions. Concurrently, the use of non-beta-lactam antibiotics was significantly less in the patients evaluated vs not evaluated (16% vs 27%). The overall use of cefazolin in orthopedic surgeries in patients with HOBA was >84% over the course of the study period. CONCLUSION: Beta-lactam allergy screening using a BPA and a DAC promotes the use of standard surgical prophylaxis with cefazolin. Joint arthroplasty surgeons should consider implementing allergy screening programs to promote antimicrobial stewardship.

POSITIVE TEST FOR ANTITHYROGLOBULIN ANTIBODIES DUE TO ADMINISTRATION OF IMMUNOGLOBULIN REPLACEMENT THERAPY IN A PATIENT WITH THYROID CANCER.

OBJECTIVE: Thyroglobulin (Tg) is used as a tumor marker to monitor differentiated thyroid cancer progression and recurrence. However, Tg measured by standard immunoassay (IMA) is not a reliable marker in the presence of anti-Tg antibodies (TgAbs) due to interference that may result in either false-positive or false-negative results. TgAbs levels can be high due to thyroid cancer and also exogenous immunoglobulin (Ig) administration, thus making it difficult to identify differentiated thyroid cancer recurrence. METHODS: We present an example of elevated TgAbs due to subcutaneous Ig (SCIg) administration in a patient with thyroid cancer. RESULTS: A 57-year-old male was diagnosed with stage I papillary thyroid cancer (PTC). His TgAbs were negative prior to the diagnosis of thyroid cancer and became positive after thyroidectomy and radioactive iodine administration. A detailed work-up including a whole body scan did not reveal recurrent disease. He had been diagnosed with common variable immune deficiency (CVID) and dermatomyositis at the age of 50 and was started on immunoglobulin (Ig) replacement therapy shortly after diagnosis. His Tg was negative when assessed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Therefore, elevated TgAb titers were attributed to concomitant SCIg treatment. We also demonstrated that SCIg treatment had TgAb activity that was removed by protein A column treatment. Dilutions of SCIg medication also caused positive IgG serologies for cytomegalovirus and herpes simplex, measles, mumps, rubella, and varicella zoster viruses. CONCLUSION: An exogenous source of TgAbs from SCIg led to extensive imaging work-up to assess for PTC recurrence. LC-MS/MS is a conceptually attractive approach to overcome TgAb interference with Tg IMA measurement.

Case Report: Aplastic anemia related to a novel CTLA4 variant.

A 20-year-old male patient with a history of celiac disease came to medical attention after developing profound fatigue and pancytopenia. Evaluation demonstrated pan-hypogammaglobulinemia. There was no history of significant clinical infections. Bone marrow biopsy confirmed hypocellular marrow consistent with aplastic anemia. Oncologic and hematologic evaluations were unremarkable for iron deficiency, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndromes, T-cell clonality, and leukemia. A next generation genetic sequencing immunodeficiency panel revealed a heterozygous variant of uncertain significance in CTLA4 c.385T >A, p.Cys129Ser (C129S). Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor important in maintaining immunologic homeostasis. To determine the functional significance of the C129S variant, additional testing was pursued to assess for diminished protein expression, as described in other pathogenic CTLA4 variants. The results demonstrated severely impaired CTLA-4 expression and CD80 transendocytosis, consistent with other variants causing CTLA-4 haploinsufficiency. He was initially treated with IVIG and cyclosporine, and became transfusion independent for few months, but relapsed. Treatment with CTLA-4-Ig fusion protein (abatacept) was considered, however the patient opted for definitive therapy through reduced-intensity haploidentical hematopoietic stem cell transplant, which was curative.

Evaluation and treatment of rhinosinusitis with primary antibody deficiency in children: Evidence-based review with recommendations.

BACKGROUND: There is clear evidence that prevalence of primary antibody deficiency (PAD) is higher in children with chronic rhinosinusitis (CRS) than in the general population. The purpose of this multi-institutional and multidisciplinary evidence-based review with recommendations (EBRR) is to thoroughly review the literature on rhinosinusitis with PAD, summarize the existing evidence, and provide recommendations on the evaluation and management of rhinosinusitis in children with PAD. METHODS: The PubMed, Embase, and Cochrane databases were systematically reviewed from inception through December 2023. Studies on the evaluation and management of rhinosinusitis in PAD patients were included. An iterative review process was utilized in accordance with EBRR guidelines. Levels of evidence and recommendations on the evaluation and management principles for PAD were generated. RESULTS: A total of 50 studies were included in this evidence-based review. These studies were evaluated on the incidence of PAD in rhinosinusitis patients, the incidence of rhinosinusitis in PAD patients, and on the different treatment modalities used and their outcome. The aggregate quality of evidence varied across the reviewed domains. CONCLUSION: Based on the currently available evidence, the incidence of PAD in children with recalcitrant CRS can be significantly elevated. Despite the presence of multiple studies addressing rhinosinusitis and PAD, the level of evidence supporting different treatment options continues to be lacking. Optimal management requires a multidisciplinary approach through collaboration with clinical immunology. There is need for higher level studies that compare different treatments in children with PAD and rhinosinusitis.