Multidisciplinary atopic dermatitis program: A novel approach to managing difficult-to-control atopic dermatitis patients.

BACKGROUND/OBJECTIVES: Disease improvement for difficult-to-control pediatric atopic dermatitis may be more challenging to achieve when directed by single specialties due to disjointed and conflicting dialogue with patients. METHODS: The Multidisciplinary Atopic Dermatitis Program (MADP) was developed through collaborations with the Rady Children's Hospital and UC San Diego Health Divisions of Dermatology, Allergy & Immunology and Clinical Pharmacy, to create team-based evaluation and management of children and adolescents with atopic dermatitis (AD). The MADP allows concurrent, comprehensive evaluations by multiple specialists to develop treatment plans. The program includes extensive patient education to support shared decision making, incorporating patient and family's perspectives along with those of clinical experts into their care. Objective severity measures and patient reported outcome data were collected, along with assessment of patient and family satisfaction with the MADP. RESULTS: Data showed significant improvement in AD severity as assessed by providers, patients and families by the first follow-up visit. BSA mean percentage decreased by up to 56% by the 7th visit, and pruritus (NRS), CLDQI and POEM mean scores decreased by more than 4 points, 12 points, and over 11 points, respectively. After management was initiated in the MADP, 72.73% of patients achieved an EASI 50 and 47.73% achieved an EASI 75 from a baseline mean of 21.7. Patients who continued in clinic beyond the second visit showed further clinically significant decreases in disease measures. CONCLUSIONS: The multidisciplinary approach shows success in the treatment of difficult-to-control AD patients with improvements in clinician and patient reported outcome measures.

Balancing B cell responses to the allograft: implications for vaccination.

Balancing enough immunosuppression to prevent allograft rejection and yet maintaining an intact immune system to respond to vaccinations, eliminate invading pathogens or cancer cells is an ongoing challenge to transplant physicians. Antibody mediated allograft rejection remains problematic in kidney transplantation and is the most common cause of graft loss despite current immunosuppressive therapies. The goal of immunosuppressive therapies is to prevent graft rejection; however, they prevent optimal vaccine responses as well. At the center of acute and chronic antibody mediated rejection and vaccine responses is the B lymphocyte. This review will highlight the role of B cells in alloimmune responses including the dependency on T cells for antibody production. We will discuss the need to improve vaccination rates in transplant recipients and present data on B cell populations and SARS-CoV-2 vaccine response rates in pediatric kidney transplant recipients.

A CD4+ TNF+ monofunctional memory T-cell response to BCG vaccination is associated with Mycobacterium tuberculosis infection in infants exposed to HIV.

BACKGROUND: The immunologic correlates of risk of Mycobacterium tuberculosis (Mtb) infection after BCG vaccination are unknown. The mechanism by which BCG influences the tuberculin skin test (TST) remains poorly understood. We evaluated CD4+ T-cell responses in infants exposed to HIV and uninfected (HEU) who received BCG at birth and examined their role in susceptibility to Mtb infection and influence on TST induration. METHODS: HEU infants were enrolled in a randomised clinical trial of isoniazid (INH) to prevent Mtb infection in Kenya. We measured mycobacterial antigen-specific Th1 and Th17 cytokine responses at 6-10 weeks of age prior to INH randomisation and compared responses between Mtb infected and uninfected infants. Outcomes at 14 months of age included TST, QuantiFERON-Plus (QFT-Plus), and ESAT-6/CFP-10-specific non-IFN-γ cytokines measured in QFT-Plus supernatants. FINDINGS: A monofunctional mycobacterial antigen-specific TNF+ CD4+ effector memory (CCR7-CD45RA-) T-cell response at 6-10 weeks of age was associated with Mtb infection at 14 months of age as measured by ESAT-6/CFP-10-specific IFN-γ and non-IFN-γ responses (Odds Ratio 2.26; Confidence Interval 1.27-4.15; P = 0.006). Mycobacterial antigen-specific polyfunctional effector memory Th1 responses at 6-10 weeks positively correlated with TST induration in infants without evidence of Mtb infection at 14 months, an association which was diminished by INH therapy. INTERPRETATION: Induction of monofunctional TNF+ CD4+ effector memory T-cell responses may be detrimental in TB vaccine development. This study also provides mechanistic insight into the association of BCG-induced immune responses with TST induration and further evidence that TST-based diagnoses of Mtb infection in infants are imprecise. FUNDING: Thrasher Research Fund.

Non-IFNγ Whole Blood Cytokine Responses to Mycobacterium tuberculosis Antigens in HIV-exposed Infants.

BACKGROUND: HIV-exposed uninfected (HEU) infants have increased risk of tuberculosis (TB). Testing for Mycobacterium tuberculosis (Mtb) infection is limited by reduced Quantiferon (QFT) sensitivity in infants and tuberculin skin test (TST) cross-reactivity with Bacillus Calmette-Guérin vaccine. Our objective is to assess if non-IFNγ cytokine responses to Mtb-specific antigens have improved sensitivity in detecting Mtb infection in HEU infants compared with QFT. METHODS: HEU infants were enrolled in a randomized clinical trial of isoniazid preventive therapy (IPT) to prevent Mtb infection in Kenya (N = 300) and assessed at 12 months postrandomization (14 months of age) by TST and QFT-Plus. Non-IFNγ cytokine secretion (IL2, TNF, IP10, N = 229) in QFT-Plus supernatants was measured using Luminex assay. Logistic regression was used to assess the effect of IPT on Mtb infection outcomes in HEU infants. RESULTS: Three of 251 (1.2%) infants were QFT-Plus positive. Non-IFNγ Mtb antigen-specific responses were detected in 12 additional infants (12/229, 5.2%), all TST negative. IPT was not associated with Mtb infection defined as any Mtb antigen-specific cytokine response (odds ratio = 0.7, P = 0.54). Mtb antigen-specific IL2/IP10 responses had fair correlation (τ = 0.25). Otherwise, non-IFNγ cytokine responses had minimal correlation with QFT-Plus and no correlation with TST size. CONCLUSIONS: We detected non-IFNg Mtb antigen-specific T-cell responses in 14-month HEU infants. Non-IFNg cytokines may be more sensitive than IFNg in detecting infant Mtb infection. IPT during the first year of life was not associated with Mtb infection measured by IFNg, IL2, IP10 and TNF Mtb-specific responses.

Biologic Therapies for Allergic Rhinitis and Nasal Polyposis.

PURPOSE OF REVIEW: There is an emerging body of research on targeted biologic therapies for the treatment of severe inflammatory nasal disorders, especially chronic rhinosinusitis with nasal polyposis (CRSwNP). This paper will evaluate the efficacy of biologic therapies for severe nasal inflammation by summarizing key preclinical trials of biologics for animal models of allergic rhinitis and the recent phase 2 and 3 clinical trials of biologic therapies for CRSwNP. RECENT FINDINGS: Biologics that target the IL-4 receptor (dupilumab), IgE (omalizumab), and IL-5 (mepolizumab, reslizumab, and benralizumab) in patients with CRSwNP have shown improvement of various metrics including Sino-Nasal Outcome Test (SNOT-22) scores, Nasal Polyp Scores (NPS), Nasal Congestion Scores (NCS), and Lund-Mackay sinus opacification scores. The efficacy demonstrated through the dupilumab phase 3 trials (LIBERTY NP SINUS-24 and SINUS-52) led to approval of the first biologic for the treatment of CRSwNP. Phase 3 trials for omalizumab (POLYP 1 and 2) and mepolizumab (SYNAPSE study) and post hoc analyses of phase 3 asthma studies for reslizumab and benralizumab have also demonstrated positive results for the use of biologics for patients with CRSwNP. Future efficacy studies and risk/benefit and cost analyses of these biologics and other cytokine targets for allergic rhinitis with and without nasal polyposis need to be performed.

Quality of Life Differences for Primary Immunodeficiency Patients on Home SCIG versus IVIG.

BACKGROUND: Patients with primary immunodeficiency disease (PIDD) and antibody deficiency require lifelong immunoglobulin replacement therapy. While both subcutaneous immunoglobulin (SCIG) and intravenous immunoglobulin (IVIG) replacement therapy are effective in preventing infection, patients with PIDD still experience worse health-related quality of life (hrQOL) outcomes. OBJECTIVE: Assess differences in hrQOL for PIDD patients receiving home SCIG versus IVIG. METHODS: SF-36 surveys were administered by a specialty pharmacy to 630 PIDD patients receiving home SCIG and IVIG at baseline and then every 3 months between 2014 and 2016. Results were analyzed using two-sample t tests and linear mixed effects model. Analysis was repeated for different age categories and trended over time. RESULTS: Patients receiving SCIG reported statistically significant higher energy fatigue scores (+ 9 points, p < 0.001) but lower perceived role limitations due to physical health scores (- 14 points, p < 0.001). These differences were only observed in patients > 36 years of age. There were no differences in the composite SF-36 score for patients receiving SCIG versus IVIG (+ 1, p = 0.66). Immunoglobulin-naïve patients all improved their hrQOL, but a larger improvement was seen in those initiating SCIG versus IVIG. CONCLUSION: Patients with PIDD on home IVIG versus SCIG have similar composite hrQOL scores as measured by the SF-36. In the adult population, initiating immunoglobulin replacement with SCIG may result in more hrQOL improvement compared with IVIG, although personal preferences should also be considered. CLINICAL IMPLICATIONS: Patients with PIDD on home IVIG versus SCIG have similar composite health-related quality of life scores as measured by the SF-36. Patients with primary immune-deficiency on home IVIG versus SCIG have similar composite health-related quality of life scores as measured by the SF-36. Personal preferences are important in deciding whether to treat with IVIG or SCIG.

Penicillin skin testing in the management of penicillin allergy in an outpatient pediatric population.

BACKGROUND: Eight to ten percent of patients believe that they are allergic to penicillin, yet only 10% of those patients have evidence of an immunoglobulin E (IgE) mediated allergy upon penicillin skin testing (PST). In the adult population, a negative PST result is associated with a low risk of immediate reaction on oral challenge, but further studies are needed in the pediatric population. OBJECTIVE: To calculate the negative predictive value (NPV) of the current skin testing regimen of penicillin, benzylpenicilloyl-polylysine (the major determinant), and ampicillin in a pediatric outpatient population to assess the utility of adding the minor determinant mixture to the skin testing regimen. METHODS: A retrospective chart review was conducted of all pediatric patients seen in a single-center pediatric allergy/immunology outpatient clinic between January 1, 2010, and March 1, 2016, who underwent PST for presumed penicillin drug allergy. RESULTS: Only 38% of patients who underwent PST had a drug reaction history consistent with an IgE-mediated reaction. 28.8% of the patients had a positive PST result. The addition of ampicillin to the standard PST regimen of penicillin and benzylpenicilloyl-polylysine identified an additional 4.1% of patients. Two patients (3.2%) reacted on oral challenge with a minor rash. The NPV of the PST regimen was 98%. No significant predictive variables for a positive PST result were identified. CONCLUSION: Given the high NPV of the current PST regimen, we do not recommend additional testing with the minor determinant mixture. Despite this high NPV, the utility of PST in the low-risk, low-pretest probability outpatient pediatric population was limited, and select patients may be able to proceed directly to oral challenge.

The SLP-76 Src homology 2 domain is required for T cell development and activation.

The adapter protein Src homology 2 (SH2) domain-containing leukocyte protein of 76 kDa (SLP-76) is critical for multiple aspects of T cell development and function. Through its protein-binding domains, SLP-76 serves as a platform for the assembly of multiple enzymes and adapter proteins that function together to activate second messengers required for TCR signal propagation. The N terminus of SLP-76, which contains three tyrosines that serve as docking sites for SH2 domain-containing proteins, and the central proline-rich region of SLP-76 have been well studied and are known to be important for both thymocyte selection and activation of peripheral T cells. Less is known about the function of the C-terminal SH2 domain of SLP-76. This region inducibly associates with ADAP and HPK1. Combining regulated deletion of endogenous SLP-76 with transgenic expression of a SLP-76 SH2 domain mutant, we demonstrate that the SLP-76 SH2 domain is required for peripheral T cell activation and positive selection of thymocytes, a function not previously attributed to this region. This domain is also important for T cell proliferation, IL-2 production, and phosphorylation of protein kinase D and IκB. ADAP-deficient T cells display similar, but in some cases less severe, defects despite phosphorylation of a negative regulatory site on SLP-76 by HPK1, a function that is lost in SLP-76 SH2 domain mutant T cells.

Management and outcomes of tumor recurrence after focal ablation renal therapy.

BACKGROUND AND PURPOSE: Cryoablation (CA) and radiofrequency ablation (RFA) have emerged as viable treatment options for patients with small renal masses. Although the intermediate oncologic outcomes are comparable to those of surgery, the management of a recurrence is still controversial. This review intends to provide a comprehensive overview of management options and outcomes after failed focal ablation renal therapy. In addition, it presents how patients in whom CA and RFA fail are treated at our institution. METHODS: A systematic review of the Pub-Med database was performed to identify articles on renal CA and RFA. The keywords used were "small renal mass," "enhancing renal mass," "cryoablation," "radiofrequency ablation," "tumor recurrence," "postablation," "management," "salvage nephrectomy," "partial nephrectomy," "laparoscopy," and "active surveillance." English-language articles between 1995 and 2009 were reviewed. RESULTS: A total of 30 articles were included in this review; however, only 6 original articles were found that dealt specifically with the theme of this review. In the case of tumor recurrence after failed CA or RFA, viable management options include active surveillance, repeated ablation, and salvage partial/radical nephrectomy. Active surveillance up to 1 year appears to be a safe option in patients with early enhancement after CA or RFA, because the majority of the enhancements may be from postoperative inflammation. Repeated CA and RFA remain the most commonly performed procedures after a failed ablation with excellent oncologic outcomes. When significant tumor progression is present on postoperative follow-up, however, surgery is necessary. Although a partial nephrectomy would be advisable to preserve renal function, intraoperative and postoperative complications are a concern because of scarring and fibrosis from the initial ablation. For this reason, a radical nephrectomy is most commonly preferred. This could be performed through an open or a laparoscopic approach. CONCLUSIONS: When a recurrence is suspected after CA or RFA, different options are available. This review has highlighted that active surveillance, reablation, and surgery (usually radical nephrectomy) are all viable options for the management of a failed ablative procedure.

Fuhrman grade provides higher prognostic accuracy than nucleolar grade for papillary renal cell carcinoma.

PURPOSE: Recent evidence suggests that nucleolar grade but not Fuhrman grade is applicable to papillary renal cell carcinoma. We tested this hypothesis in an independent large series from a single institution. MATERIALS AND METHODS: One dedicated uropathologist regraded 158 cases of papillary renal cell carcinoma by nucleolar and Fuhrman grades. The prognostic value and predictive accuracy of these grading systems to predict disease specific survival were analyzed by Cox proportional hazards models and the concordance index. RESULTS: There were 39 papillary renal cell carcinoma related deaths (25%) at a mean followup of 50 months. On univariate analysis nucleolar grade predicted disease specific survival with a concordance index of 67.8% but the survival difference between grades 1 and 2 did not attain statistical significance (p = 0.1441). Fuhrman grade predicted disease specific survival significantly better (concordance index 74.7%, p <0.001). Comparison of survival estimates between the grades revealed statistical significance across each grade category (each p <0.05). Fuhrman but not nucleolar grade was retained as an independent prognostic factor on multivariate analysis (p = 0.027 and 0.128, respectively). CONCLUSIONS: Each grading system performs well but the predictive accuracy of Fuhrman grade is statistically superior to that of nucleolar grade and only Fuhrman grade provides independent prognostic information on patients with papillary renal cell carcinoma. Thus, Fuhrman grade should be the standard grading system for papillary renal cell carcinoma.