Leukotriene receptor antagonists as add-on therapy to antihistamines for urticaria: a systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: The benefits and harms of adding antileukotrienes to H1-antihistamines for the management of urticaria (hives, itch, and/or angioedema) remain unclear. OBJECTIVE: We sought to systematically synthesize the treatment outcomes of antileukotrienes in combination with H1-antihistamines versus H1-antihistamines alone for acute and chronic urticaria. METHODS: As part of updating American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters urticaria guidelines, we searched MEDLINE, Embase, CENTRAL, LILACS, WPRIM, IBECS, ICTRP, CBM, CNKI, VIP, Wanfang, FDA, and EMA databases from inception to December 18th, 2023 for randomized controlled trials (RCTs) evaluating antileukotrienes and H1-antihistamines versus H1-antihistamines alone in patients with urticaria. Paired reviewers independently screened citations, extracted data, and assessed risk of bias. Random effects models pooled effect estimates for urticaria activity, itch, wheal, sleep, quality of life, and harms. The GRADE approach informed certainty of evidence ratings. Open Science Framework registration: https://osf.io/h2bfx/. RESULTS: Thirty-four RCTs enrolled 3,324 children and adults. Compared to H1-antihistamines alone, the combination of a leukotriene receptor antagonist (LTRA) with H1-antihistamines probably modestly reduces urticaria activity (mean difference: -5.04, 95%CI -6.36 to -3.71; 7-day Urticaria Activity Score) with moderate certainty. We made similar findings for itch and wheal severity, and quality of life. Adverse events were probably not different between groups (moderate certainty), however, no RCT reported on neuropsychiatric adverse events. CONCLUSION: Among patients with urticaria, adding LTRAs to H1-antihistamines probably modestly improves urticaria activity with little to no increase in overall adverse events. The added risk of neuropsychiatric adverse events in this population with LTRAs is small and uncertain.

Efficacy and Safety of Systemic Corticosteroids for Urticaria: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Short courses of adjunctive systemic corticosteroids are commonly used to treat acute urticaria and chronic urticaria flares (both with and without mast cell-mediated angioedema), but their benefits and harms are unclear. OBJECTIVE: To evaluate the efficacy and safety of treating acute urticaria or chronic urticaria flares with versus without systemic corticosteroids. METHODS: We searched the MEDLINE, EMBASE, CENTRAL, CNKI, VIP, Wanfang, and CBM databases from inception to July 8, 2023, for randomized controlled trials of treating urticaria with versus without systemic corticosteroids. Paired reviewers independently screened records, extracted data, and appraised risk of bias with the Cochrane 2.0 tool. We performed random-effects meta-analyses of urticaria activity, itch severity, and adverse events. We assessed certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluations (GRADE) approach. RESULTS: We identified 12 randomized trials enrolling 944 patients. For patients with low or moderate probability (17.5%-64%) to improve with antihistamines alone, add-on systemic corticosteroids likely improve urticaria activity by a 14% to 15% absolute difference (odds ratio [OR], 2.17, 95% confidence interval [CI]: 1.43-3.31; number needed to treat [NNT], 7; moderate certainty). Among patients with a high chance (95.8%) for urticaria to improve with antihistamines alone, add-on systemic corticosteroids likely improved urticaria activity by a 2.2% absolute difference (NNT, 45; moderate certainty). Corticosteroids may improve itch severity (OR, 2.44; 95% CI: 0.87-6.83; risk difference, 9%; NNT, 11; low certainty). Systemic corticosteroids also likely increase adverse events (OR, 2.76; 95% CI: 1.00-7.62; risk difference, 15%; number needed to harm, 9; moderate certainty). CONCLUSIONS: Systemic corticosteroids for acute urticaria or chronic urticaria exacerbations likely improve urticaria, depending on antihistamine responsiveness, but also likely increase adverse effects in approximately 15% more.

Atopic dermatitis (eczema) guidelines: 2023 American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters GRADE- and Institute of Medicine-based recommendations.

BACKGROUND: Guidance addressing atopic dermatitis (AD) management, last issued in 2012 by the American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force, requires updating as a result of new treatments and improved guideline and evidence synthesis methodology. OBJECTIVE: To produce evidence-based guidelines that support patients, clinicians, and other decision-makers in the optimal treatment of AD. METHODS: A multidisciplinary guideline panel consisting of patients and caregivers, AD experts (dermatology and allergy/immunology), primary care practitioners (family medicine, pediatrics, internal medicine), and allied health professionals (psychology, pharmacy, nursing) convened, prioritized equity, diversity, and inclusiveness, and implemented management strategies to minimize influence of conflicts of interest. The Evidence in Allergy Group supported guideline development by performing systematic evidence reviews, facilitating guideline processes, and holding focus groups with patient and family partners. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed rating the certainty of evidence and strength of recommendations. Evidence-to-decision frameworks, subjected to public comment, translated evidence to recommendations using trustworthy guideline principles. RESULTS: The panel agreed on 25 recommendations to gain and maintain control of AD for patients with mild, moderate, and severe AD. The eAppendix provides practical information and implementation considerations in 1-2 page patient-friendly handouts. CONCLUSION: These evidence-based recommendations address optimal use of (1) topical treatments (barrier moisturization devices, corticosteroids, calcineurin inhibitors, PDE4 inhibitors [crisaborole], topical JAK inhibitors, occlusive [wet wrap] therapy, adjunctive antimicrobials, application frequency, maintenance therapy), (2) dilute bleach baths, (3) dietary avoidance/elimination, (4) allergen immunotherapy, and (5) systemic treatments (biologics/monoclonal antibodies, small molecule immunosuppressants [cyclosporine, methotrexate, azathioprine, mycophenolate, JAK inhibitors], and systemic corticosteroids) and UV phototherapy (light therapy).

Systemic treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD systemic treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna). RESULTS: The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain. CONCLUSIONS: Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.

The Joint Task Force on Practice Parameters GRADE guidelines for the medical management of chronic rhinosinusitis with nasal polyposis.

These evidence-based guidelines support patients, clinicians, and other stakeholders in decisions about the use of intranasal corticosteroids (INCS), biologics, and aspirin therapy after desensitization (ATAD) for the management of chronic rhinosinusitis with nasal polyposis (CRSwNP). It is important to note that the current evidence on surgery for CRSwNP was not assessed for this guideline nor were management options other than INCS, biologics, and ATAD. The Allergy-Immunology Joint Task Force on Practice Parameters formed a multidisciplinary guideline panel balanced to include the views of multiple stakeholders and to minimize potential biases. Systematic reviews for each management option informed the guideline. The guideline panel used the Grading of Recommendations Assessment, Development and Evaluation approach to inform and develop recommendations. The guideline panel reached consensus on the following statements: (1) In people with CRSwNP, the guideline panel suggests INCS rather than no INCS (conditional recommendation, low certainty of evidence). (2) In people with CRSwNP, the guideline panel suggests biologics rather than no biologics (conditional recommendation, moderate certainty of evidence). (3) In people with aspirin (nonsteroidal anti-inflammatory drug)-exacerbated respiratory disease, the guideline panel suggests ATAD rather than no ATAD (conditional recommendation, moderate certainty of evidence). The conditions for each recommendation are discussed in the guideline.

Allergen immunotherapy for atopic dermatitis: Systematic review and meta-analysis of benefits and harms.

BACKGROUND: Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and microbes. The role of environmental allergens (aeroallergens) in triggering AD remains unclear. OBJECTIVE: We systematically synthesized evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD. METHODS: As part of the 2022 American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters AD Guideline update, we searched the MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, Global Resource for Eczema Trials, and Web of Science databases from inception to December 2021 for randomized controlled trials comparing subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and/or no AIT (placebo or standard care) for guideline panel-defined patient-important outcomes: AD severity, itch, AD-related quality of life (QoL), flares, and adverse events. Raters independently screened, extracted data, and assessed risk of bias in duplicate. We synthesized intervention effects using frequentist and Bayesian random-effects models. The GRADE approach determined the quality of evidence. RESULTS: Twenty-three randomized controlled trials including 1957 adult and pediatric patients sensitized primarily to house dust mite showed that add-on SCIT and SLIT have similar relative and absolute effects and likely result in important improvements in AD severity, defined as a 50% reduction in SCORing Atopic Dermatitis (risk ratio [95% confidence interval] 1.53 [1.31-1.78]; 26% vs 40%, absolute difference 14%) and QoL, defined as an improvement in Dermatology Life Quality Index by 4 points or more (risk ratio [95% confidence interval] 1.44 [1.03-2.01]; 39% vs 56%, absolute difference 17%; both outcomes moderate certainty). Both routes of AIT increased adverse events (risk ratio [95% confidence interval] 1.61 [1.44-1.79]; 66% with SCIT vs 41% with placebo; 13% with SLIT vs 8% with placebo; high certainty). AIT's effect on sleep disturbance and eczema flares was very uncertain. Subgroup and sensitivity analyses were consistent with the main findings. CONCLUSIONS: SCIT and SLIT to aeroallergens, particularly house dust mite, can similarly and importantly improve AD severity and QoL. SCIT increases adverse effects more than SLIT. These findings support a multidisciplinary and shared decision-making approach to optimally managing AD.

Dietary Elimination for the Treatment of Atopic Dermatitis: A Systematic Review and Meta-Analysis.

BACKGROUND: The influence of diet on atopic dermatitis (AD) is complex, and the use of dietary elimination as a treatment has conflicting views. OBJECTIVE: To systematically review the benefits and harms of dietary elimination for the treatment of AD. METHODS: We searched MEDLINE, Embase, AMED, PsycINFO, and the Cochrane Central Register of Controlled Trials from inception to January 18, 2022, without language restrictions, for randomized controlled trials (RCTs) and observational studies comparing dietary elimination and no dietary elimination for the treatment of AD. We conducted random-effects meta-analyses of eczema outcomes. We used the grading of recommendations, assessment, development, and evaluation approach to assess certainty of evidence (CRD42021237953). RESULTS: Ten RCT (n = 599; baseline median of study mean age, 1.5 years; median of study mean SCOring Atopic Dermatitis index, 20.7, range, 3.5-37.6) were included in the meta-analysis. Compared with no dietary elimination, low-certainty evidence showed that dietary elimination may slightly improve eczema severity (50% with vs 41% without dietary elimination improved the SCOring Atopic Dermatitis index by a minimally important difference of 8.7 points, risk difference of 9% [95% CI, 0-17]), pruritus (daytime itch score [range, 0-3] mean difference, -0.21 [95% CI, -0.57 to 0.15]), and sleeplessness (sleeplessness score [range, 0-3] mean difference, -0.47 [95% CI, -0.80 to -0.13]). There were no credible subgroup differences based on elimination strategy (empiric vs guided by testing) or food-specific sensitization. Insufficient data addressed harms of elimination diets among included RCTs, although indirect evidence suggests that elimination diets may increase the risk for developing IgE-mediated food allergy. CONCLUSIONS: Dietary elimination may lead to a slight, potentially unimportant improvement in eczema severity, pruritus, and sleeplessness in patients with mild to moderate AD. This must be balanced against potential risks for indiscriminate elimination diets including developing IgE-mediated food allergy and withholding more effective treatment options for AD.

Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis: A systematic review and network meta-analysis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory condition of the upper airways. Optimal management is unclear. OBJECTIVE: We compared the effects of mAbs and aspirin desensitization (ASA-D) for treatment of CRSwNP. METHODS: We searched the Medline, Embase, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform, US Food and Drug Administration, and the European Medicines Agency databases from inception to August 4, 2021, for randomized controlled trials comparing the effects of mAbs and ASA-D for CRSwNP. We conducted network meta-analysis of sinusitis symptoms, heath-related quality of life, rescue oral corticosteroids and surgery, endoscopic and radiologic scores, and adverse events. We used the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach to assess certainty of evidence. PROSPERO CRD42020177334. RESULTS: Twenty-nine randomized controlled trials evaluating 8 treatments (n = 3461) were included in the network meta-analysis. Compared to placebo, moderate to high certainty evidence showed that health-related quality of life (SNOT-22) improved with dupilumab (mean difference [MD] -19.91 [95% confidence interval (CI) -22.50, -17.32]), omalizumab (MD -16.09 [95% CI -19.88, -12.30]), mepolizumab (MD -12.89 [95% CI -16.58, -9.19], ASA-D (MD -10.61 [95% CI -14.51, -6.71]), and benralizumab (MD -7.68 [95% CI -12.09, -3.27]). The risk of rescue nasal polyp surgery likely decreased with dupilumab (risk difference [RD] -16.35% [95% CI -18.13, -13.48]), omalizumab (RD -7.40% [95% CI -11.04, -2.43]), mepolizumab (RD -12.33% [95% CI -15.56, -7.22]), and ASA-D (RD -16.00% [95% CI -19.79, 0.21]; all moderate certainty). Comparisons among agents show with moderate to high certainty that dupilumab ranks among the most beneficial for 7 of 7 outcomes, omalizumab for 2 of 7, mepolizumab for 1 of 7, and ASA-D for 1 of 7. CONCLUSIONS: Multiple biologics and ASA-D credibly improve patient-important outcomes, with clinically important differences in effects among agents; dupilumab uniquely ranks among the most beneficial for all outcomes studied.

Cryptococcus gattii Capsule Blocks Surface Recognition Required for Dendritic Cell Maturation Independent of Internalization and Antigen Processing.

Cryptococcus gattii is an emerging fungal pathogen on the west coast of Canada and the United States that causes a potentially fatal infection in otherwise healthy individuals. In previous investigations of the mechanisms by which C. gattii might subvert cell-mediated immunity, we found that C. gattii failed to induce dendritic cell (DC) maturation, leading to defective T cell responses. However, the virulence factor and the mechanisms of evasion of DC maturation remain unknown. The cryptococcal polysaccharide capsule is a leading candidate because of its antiphagocytic properties. Consequently, we asked if the capsule of C. gattii was involved in evasion of DC maturation. We constructed an acapsular strain of C. gattii through CAP59 gene deletion by homologous integration. Encapsulated C. gattii failed to induce human monocyte-derived DC maturation and T cell proliferation, whereas the acapsular mutant induced both processes. Surprisingly, encapsulation impaired DC maturation independent of its effect on phagocytosis. Indeed, DC maturation required extracellular receptor signaling that was dependent on TNF-α and p38 MAPK, but not ERK activation, and the cryptococcal capsule blocked this extracellular recognition. Although the capsule impaired phagocytosis that led to pH-dependent serine-, threonine-, and cysteine-sensitive protease-dependent Ag processing, it was insufficient to impair T cell responses. In summary, C. gattii affects two independent processes, leading to DC maturation and Ag processing. The polysaccharide capsule masked extracellular detection and reduced phagocytosis that was required for DC maturation and Ag processing, respectively. However, the T cell response was fully restored by inducing DC maturation.

Allergen immunotherapy in pregnancy.

BACKGROUND: Allergic diseases such as asthma and allergic rhinitis constitute a significant burden of disease among women of childbearing age and those who are pregnant. Adequately managing these conditions is paramount in reducing negative fetal outcomes as well as maternal complications during pregnancy. However, the potential for harm to both the mother and fetus demands carefully balancing efficacy and safety of treatment. Allergen immunotherapy (AIT) has emerged as a relatively safe and efficacious mode of therapy in both children and adults. AIT has also been considered for use during pregnancy. METHODS: A review of the literature was conducted for data regarding the safety of initiation and continuation of AIT during pregnancy as well as the effect of AIT on the development of atopy in offspring. MEDLINE and the Cochrane Library were searched for clinical trials, randomized control trials, observational studies and journal articles in English using the terms "Pregnancy" and "Immunotherapy" from 1900 to present. This yielded 4 studies (totaling 422 pregnancies receiving AIT) investigating the continuation of AIT in pregnancy, 2 (totaling 31 pregnancies receiving AIT) evaluating AIT initiation during pregnancy and 5 observing the effect of AIT on atopy in offspring. RESULTS: No significant difference was found in the incidence of prematurity, hypertension (HTN)/proteinuria, congenital malformations or perinatal deaths between the women continued on AIT (both subcutaneous (SC) IT and sublingual (SL) IT to inhalant allergens as well as venom IT) during pregnancy and controls. Similarly, there was no significant difference in maternal or fetal complications between pregnant women initiated on AIT and controls. Among the few pregnant women (10/453 pregnancies) who experienced generalized reactions while receiving AIT, none were found to have fetal complications. Neither SCIT nor SLIT during pregnancy altered the risk of developing atopic disease in offspring. CONCLUSIONS: Based on these data, the continuation of AIT during pregnancy appears safe. Furthermore, the few data available suggest that the initiation of AIT during pregnancy might also be safe, however, more data is required for a definitive conclusion. Lastly, available studies do not show a convincing reduction in the development of atopy in offspring from the administration of AIT during pregnancy.

The NK receptor NKp30 mediates direct fungal recognition and killing and is diminished in NK cells from HIV-infected patients.

Natural killer (NK) cells are a subset of immune effectors that directly bind and kill fungi via a perforin-dependent mechanism. The receptor mediating this activity and its potential role in disease remain unknown. Using an unbiased approach, we determined that NKp30 is responsible for recognition and killing of the fungal pathogens Cryptococcus and Candida. NKp30 was required for NK cell-fungal conjugate formation, phosphatidylinositol 3-kinase (PI3K) signaling, and perforin release. Because fungal infections are a leading cause of death in AIDS patients, we examined NKp30 expression in HIV-infected patients. NK cells from these patients had diminished NKp30 expression, defective perforin release, and blunted microbicidal activity. Surprisingly, interleukin-12 (IL-12) restored NKp30 expression and fungal killing. Thus, the NKp30 receptor plays a critical role in NK cell antifungal cytotoxicity, and diminished expression of NKp30 is responsible for defective antifungal activity of NK cells from HIV-infected patients, which can be corrected with IL-12.

Requirement and redundancy of the Src family kinases Fyn and Lyn in perforin-dependent killing of Cryptococcus neoformans by NK cells.

Natural killer (NK) cells directly recognize and kill fungi, such as the pathogenic fungus Cryptococcus neoformans, via cytolytic mechanisms. However, the precise signaling pathways governing this NK cell microbicidal activity and the implications for fungal recognition are still unknown. Previously, it was reported that NK cell anticryptococcal activity is mediated through a conserved phosphatidylinositol 3-kinase-extracellular signal-regulated kinase 1/2 (PI3K-ERK1/2) pathway. Using YT (a human NK-like cell line) and primary human NK cells, we sought to identify the upstream, receptor-proximal signaling elements that led to fungal cytolysis. We demonstrate that Src family kinases were activated in response to C. neoformans. Furthermore, pharmacologic inhibition with an Src kinase inhibitor blocked C. neoformans-induced downstream activation of PI3K and ERK1/2 and abrogated cryptococcal killing. At the same time, the inhibitor disrupted the polarization of perforin-containing granules toward the NK cell-cryptococcal synapse but had no effect on conjugate formation between the organism and the NK cell. Finally, small interfering RNA (siRNA) double (but not single) knockdown of two Src family kinases, Fyn and Lyn, blocked cryptococcal killing. Together these data demonstrate a mechanism whereby the Src family kinases, Fyn and Lyn, redundantly mediate anticryptococcal activity through the activation of PI3K and ERK1/2, which in turn facilitates killing by inducing the polarization of perforin-containing granules to the NK cell-cryptococcal synapse.

An acidic microenvironment increases NK cell killing of Cryptococcus neoformans and Cryptococcus gattii by enhancing perforin degranulation.

Cryptococcus gattii and Cryptococcus neoformans are encapsulated yeasts that can produce a solid tumor-like mass or cryptococcoma. Analogous to malignant tumors, the microenvironment deep within a cryptococcoma is acidic, which presents unique challenges to host defense. Analogous to malignant cells, NK cells kill Cryptococcus. Thus, as in tumor defense, NK cells must kill yeast cells across a gradient from physiologic pH to less than 6 in the center of the cryptococcoma. As acidic pH inhibits anti-tumor activities of NK cells, we sought to determine if there was a similar reduction in the anticryptococcal activity of NK cells. Surprisingly, we found that both primary human NK cells and the human NK cell line, YT, have preserved or even enhanced killing of Cryptococcus in acidic, compared to physiological, pH. Studies to explore the mechanism of enhanced killing revealed that acidic pH does not increase the effector to target ratio, binding of cytolytic cells to Cryptococcus, or the active perforin content in effector cells. By contrast, perforin degranulation was greater at acidic pH, and increased degranulation was preceded by enhanced ERK1/2 phosphorylation, which is essential for killing. Moreover, using a replication defective ras1 knockout strain of Cryptococcus increased degranulation occurred during more rapid replication of the organisms. Finally, NK cells were found intimately associated with C. gattii within the cryptococcoma of a fatal infection. These results suggest that NK cells have amplified signaling, degranulation, and greater killing at low pH and when the organisms are replicating quickly, which would help maintain microbicidal host defense despite an acidic microenvironment.

Direct microbicidal activity of cytotoxic T-lymphocytes.

Cytotoxic T-lymphocytes (CTL) are famous for their ability to kill tumor, allogeneic and virus-infected cells. However, an emerging literature has now demonstrated that CTL also possess the ability to directly recognize and kill bacteria, parasites, and fungi. Here, we review past and recent findings demonstrating the direct microbicidal activity of both CD4(+) and CD8(+) CTL against various microbial pathogens. Further, this review will outline what is known regarding the mechanisms of direct killing and their underlying signalling pathways.