A single-center experience of COVID-19 infection in patients with primary immunodeficiency.

Background: Reported outcomes in patients with primary immunodeficiency (PID) infected by coronavirus disease 2019 (COVID-19) have been variable owing to a combination of viral strain heterogeneity, differences in patient populations and health systems, and local availability of vaccination and specific COVID-19 therapies. There are few reports on the experience of Australian patients with PID during the pandemic. Objectives: In this retrospective study, we describe the baseline characteristics and short-term outcomes of patients with PID who were infected by COVID-19 and known to the Royal Melbourne Hospital, a major tertiary center in Victoria, Australia. Methods: Between April 2021 and April 2022, a total of 31 of 138 patients with PID were affected by COVID-19. More than half of them had 3 vaccine doses at the time of infection (which at the time was considered being fully vaccinated) and received COVID-19-targeted treatment. Results: All of the infected patients had ambulatory disease, with no cases of morbidity or mortality. In line with the current literature, the PID subtypes described did not appear to independently predict worse outcomes. Conclusions: Some protective factors include this cohort's relatively younger average age and its high uptake of vaccination and COVID-19 therapies.

Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

A Review of the Role of Pollen in COVID-19 Infection.

There is current interest in the role of ambient pollen in the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 or COVID-19) infection risk. The aim of this review is to summarise studies published up until January 2023 investigating the relationship between airborne pollen and the risk of COVID-19 infection. We found conflicting evidence, with some studies showing that pollen may increase the risk of COVID-19 infection by acting as a carrier, while others showed that pollen may reduce the risk by acting as an inhibiting factor. A few studies reported no evidence of an association between pollen and the risk of infection. A major limiting factor of this research is not being able to determine whether pollen contributed to the susceptibility to infection or just the expression of symptoms. Hence, more research is needed to better understand this highly complex relationship. Future investigations should consider individual and sociodemographic factors as potential effect modifiers when investigating these associations. This knowledge will help to identify targeted interventions.

Omalizumab in Allergic Bronchopulmonary Aspergillosis: A Systematic Review and Meta-Analysis.

BACKGROUND: An unmet clinical need exists in the management of treatment-refractory allergic bronchopulmonary aspergillosis (ABPA). Omalizumab has shown promising effects in case series and cohort studies; however, evidence to support its routine clinical use is lacking. OBJECTIVE: The aim of this systematic review and meta-analysis was to evaluate the clinical effectiveness and safety of omalizumab in patients with ABPA. METHODS: We conducted a systematic search across standard databases using specific key words until May 13, 2021. We performed a meta-analysis to compare the effectiveness (exacerbations, oral corticosteroid [OCS] use, lung function, and patient-reported asthma control) and safety of pre- and post-omalizumab treatment. Subgroup analyses were performed for treatment duration and underlying disease. RESULTS: In total, 49 studies (n = 267) were included in the qualitative synthesis and 14 case series (n = 186) in the quantitative meta-analysis. Omalizumab treatment significantly reduced the annualized exacerbation rate compared with pretreatment (mean difference, -2.09 [95% CI, -3.07 to -1.11]; P < .01). There was a reduction in OCS use (risk difference, 0.65 [95% CI, 0.46-0.84]; P < .01), an increase in termination of OCS use (risk difference, 0.53 [95% CI, 0.24-0.82]; P < .01), and a reduction in OCS dose (milligrams per day) (mean difference, -14.62 [95% CI, -19.86 to -9.39]; P < .01) in ABPA patients receiving omalizumab. Omalizumab improved FEV1 % predicted by 11.9% (95% CI, 8.2-15.6; P < .01) and asthma control, and was well-tolerated. CONCLUSIONS: Omalizumab treatment reduced exacerbations and OCS use, improved lung function and asthma control in patients with ABPA, and was well-tolerated. The results highlight the potential role of omalizumab in the treatment of ABPA.

The role of short-term grass pollen exposure in food skin-prick test reactivity, food allergy, and eczema flares in children.

BACKGROUND: While the relationship between pollen and respiratory allergies is well-documented, the role of short-term pollen exposure in food allergy and eczema flares has not previously been explored. We aimed to investigate these associations in a population-based sample of children. METHODS: We investigated 1- (n = 1108) and 6-year-old (n = 675) children in the grass pollen season from the HealthNuts cohort. Grass pollen concentrations were considered on the day of testing (lag 0), up to three days before (lag 1-lag 3) and cumulatively (lag 0-3). Associations between grass pollen and food skin-prick test reactivity (SPT ≥ 2 mm at age 1 year and ≥ 3 mm at age 6 years), eczema flares, challenge-confirmed food allergy, reaction threshold to oral food challenges (OFC), and serum food-specific IgE levels were analyzed using either logistic or quantile regression models. Atopy and family history of allergic disease were considered as potent effect modifiers. RESULTS: Grass pollen at lag 0-3 (every 20 grains/m3 increase) was associated with an up to 1.2-fold increased odds of food SPT reactivity and eczema flares in 6-year-olds. In 1-year-olds, the associations were only observed for peanut in those with a family history of food allergy. Increasing grass pollen concentrations were associated with a lower reaction threshold to OFC and higher serum IgE levels in peanut-allergic 1-year-olds only. CONCLUSION: Increasing grass pollen concentration was associated with increased risk of food SPT reactivity and eczema flares in children. The associations in peanut-allergic infants may be related to immune activation and/or peanut and grass pollen cross-reactivity leading to a lower reaction threshold.

Overview of recent advancements in asthma management.

Asthma is a common but complex heterogenous inflammatory airway disorder. Despite significant developments in our understanding of the pathophysiology and treatment of asthma, it remains a major cause of mortality and morbidity. Optimal management involves addressing modifiable risk factors, titration of inhaled pharmacotherapy in a stepwise approach and, in severe disease, consideration of biologic agents. Appreciation of the clinical characteristics of asthma and recognition of the immune pathways involved has allowed the development of phenotypic and endotypic subtypes of asthma to be better defined. This has revolutionised asthma management, allowing risk stratification of patients, targeted use of biologic agents to modify cytokine responses that drive asthma and improved patient outcomes. Patient education and engagement are critical to the management of this disease in an era of personalised medicine and a rapidly changing global environment.

Small airways dysfunction is associated with increased exacerbations in patients with asthma.

There is a poor understanding of why some patients with asthma experience recurrent exacerbations despite high levels of treatment. We compared measurements of peripheral ventilation heterogeneity and respiratory system mechanics in participants with asthma who were differentiated according to exacerbation history, to ascertain whether peripheral airway dysfunction was related to exacerbations. Three asthmatic groups: "stable" (no exacerbations for >12 mo, n = 18), "exacerbation-prone" (≥1 exacerbation requiring systemic corticosteroids within the last 12 mo, but stable for ≥1-mo, n = 9), and "treated-exacerbation" (exacerbation requiring systemic corticosteroids within the last 1 mo, n = 12) were studied. All participants were current nonsmokers with <10 pack yr smoking history. Spirometry, static lung volumes, ventilation heterogeneity from multibreath nitrogen washout (MBNW), and respiratory system mechanics from oscillometry were measured. The exacerbation-prone group compared with the stable group had slightly worse spirometry [forced expired volume in 1 s or FEV1 z-score -3.58(1.13) vs. -2.32(1.06), P = 0.03]; however, acinar ventilation heterogeneity [Sacin z-score 7.43(8.59) vs. 3.63(3.88), P = 0.006] and respiratory system reactance [Xrs cmH2O·s·L-1 -2.74(3.82) vs. -1.32(1.94), P = 0.01] were much worse in this group. The treated-exacerbation group had worse spirometry but similar small airway function, compared with the stable group. Patients with asthma who exacerbate have worse small airway function as evidenced by increases in Sacin measured by MBNW and ΔXrs from oscillometry, both markers of small airway dysfunction, compared with those that do not.NEW & NOTEWORTHY This study assessed the relationship between peripheral airway function, measured by multiple breath nitrogen washout and oscillometry impedance, and exacerbation history. We found that those with a history of exacerbation in the last year had worse peripheral airway function, whereas those recently treated for an asthma exacerbation had peripheral airway function that was comparable to the stable group. These findings implicate active peripheral airway dysfunction in the pathophysiology of an asthma exacerbation.

A Review of the Respiratory Health Burden Attributable to Short-Term Exposure to Pollen.

Respiratory diseases such as asthma, allergic rhinitis (AR) and chronic obstructive pulmonary disease (COPD) affect millions worldwide and pose a significant global public health burden. Over the years, changes in land use and climate have increased pollen quantity, allergenicity and duration of the pollen season, thus increasing its impact on respiratory disease. Many studies have investigated the associations between short-term ambient pollen (i.e., within days or weeks of exposure) and respiratory outcomes. Here, we reviewed the current evidence on the association between short-term outdoor pollen exposure and thunderstorm asthma (TA), asthma and COPD hospital presentations, general practice (GP) consultations, self-reported respiratory symptoms, lung function changes and their potential effect modifiers. The literature suggests strong evidence of an association between ambient pollen concentrations and almost all respiratory outcomes mentioned above, especially in people with pre-existing respiratory diseases. However, the evidence on sub-clinical lung function changes, COPD, and effect modifiers other than asthma, hay fever and pollen sensitisation are still scarce and requires further exploration. Better understanding of the implications of pollen on respiratory health can aid healthcare professionals to implement appropriate management strategies.

Children With Food Allergy Are at Risk of Lower Lung Function on High-Pollen Days.

BACKGROUND: Grass pollen exposure is a risk factor for childhood asthma hospital attendances. However, its short-term influence on lung function, especially among those with other allergic conditions, has been less well-studied. OBJECTIVE: To investigate this association in a population-based sample of children. METHODS: Within the HealthNuts cohort, 641 children performed spirometry during the grass pollen season. Grass pollen concentration was considered on the day of testing (lag 0), up to 3 days before (lag 1-lag 3), and cumulatively (lag 0-3). We used linear regression to assess the relevant associations and examined potential interactions with current asthma, hay fever or eczema, and food allergy. RESULTS: Associations were observed only in children with allergic disease (P value for interaction ≤ 0.1). In children with food allergy, grass pollen concentration was associated with a lower ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) and lower mid-forced expiratory flows (FEF25%-75%) at all lags (eg, at lag 2, FEV1/FVC z-score = -0.50 [95% CI -0.80 to -0.20] and FEF25%--75% z-score = -0.40 [-0.60 to -0.04] per 20 grains/m3 pollen increase), and increased bronchodilator responsiveness (BDR) at lag 2 and lag 3 (eg, at lag 2, BDR = (31 [95% CI -0.005 to 62] mL). In children with current asthma, increasing grass pollen concentration was associated with lower FEF25%-75% and increased BDR, whereas children with current hay fever or eczema had increased BDR only. CONCLUSIONS: A proactive approach needs to be enforced to manage susceptible children, especially those with food allergy, before high-grass pollen days.

Case Report: Cytomegalovirus Disease Is an Under-Recognized Contributor to Morbidity and Mortality in Common Variable Immunodeficiency.

BACKGROUND: Common Variable Immunodeficiency (CVID) is classified as a 'Predominantly Antibody Deficiency' (PAD), but there is emerging evidence of cellular immunodeficiency in a subset of patients. This evidence includes CVID patients diagnosed with cytomegalovirus (CMV) infection, a hallmark of 'combined immunodeficiency'. CMV infection also has the potential to drive immune dysregulation contributing to significant morbidity and mortality in CVID. We aim to determine the extent of cellular immune dysfunction in CVID patients, and whether this correlates with CMV infection status. METHODS: We conducted a single-center retrospective cohort study of individuals with CVID at the Royal Melbourne Hospital, and identified patients with and without CMV disease or viraemia. We then isolated T-cells from patient and healthy donor blood samples and examined T-cell proliferation and function. RESULTS: Six patients (7.6%, 6/79) had either CMV disease (pneumonitis or gastrointestinal disease), or symptomatic CMV viraemia. A high mortality rate in the cohort of patients with CVID and CMV disease was observed, with 4 deaths in the period of analysis (66.6%, 4/6). Individuals with CMV infection showed reduced T-cell division in response to T-cell receptor (TCR) stimulation when compared with CMV-negative patients. DISCUSSION: This study demonstrates the morbidity and mortality associated with CMV in CVID, and highlights the need for focused interventions for patients with CVID at risk of CMV disease.

A Multi­Center, Open­Label, Single­Arm Trial to Evaluate the Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency.

PURPOSE: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI). METHODS: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured. RESULTS: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate. CONCLUSIONS: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.

Thunderstorm asthma in seasonal allergic rhinitis: The TAISAR study.

BACKGROUND: Asthma epidemics associated with thunderstorms have had catastrophic effects on individuals and emergency services. Seasonal allergic rhinitis (SAR) is present in the vast majority of people who develop thunderstorm asthma (TA), but there is little evidence regarding risk factors for TA among the SAR population. OBJECTIVE: We sought to identify risk factors for a history of TA and hospital presentation in a cohort of individuals with SAR. METHODS: This multicenter study recruited adults from Melbourne, Australia, with a past diagnosis of TA and/or self-reported SAR. Clinical information, spirometry results, white blood cell count, ryegrass pollen-specific (RGP-sp) IgE concentration, and fractional exhaled nitric oxide were measured to identify risk factors for a history of TA in individuals with SAR. RESULTS: From a total of 228 individuals with SAR, 35% (80 of 228) reported SAR only (the I-SAR group), 37% (84 of 228) reported TA symptoms but had not attended hospital for treatment (the O-TA group), and 28% (64 of 228) had presented to the hospital for TA (the H-TA group). All patients in the H-TA group reported a previous asthma diagnosis. Logistic regression analysis of factors associated with O-TA and H-TA indicated that lower FEV1 value and an Asthma Control Questionnaire score higher than 1.5 were associated with H-TA. Higher blood RGP-sp IgE concentration, eosinophil counts, and fractional exhaled nitric oxide level were significantly associated with both O-TA and H-TA. Receiver operating curve analysis showed an RGP-sp IgE concentration higher than 10.1 kU/L and a prebronchodilator FEV1 value of 90% or lower to be biomarkers of increased H-TA risk. CONCLUSION: Clinical tests can identify risk of a history of TA in individuals with SAR and thereby inform patient-specific treatment recommendations.

Effective Management of Severe Asthma with Biologic Medications in Adult Patients: A Literature Review and International Expert Opinion.

Severe asthma often remains uncontrolled despite effective treatments and evidence-based guidelines. A group of global experts in asthma and biologic medications from 9 countries considered the most relevant clinical variables to manage severe asthma in adult patients and guide treatment choice. The resulting recommendations address the investigation of biomarker levels (blood eosinophil count along with fractional concentration of exhaled nitric oxide [FeNO]), clinical features (oral corticosteroid [OCS] dependence, specific comorbid disease entities associated with severe type 2 asthma), and safety considerations. Current evidence suggests that biomarkers, including both blood or sputum eosinophil counts as well as FeNO, add prognostic and predictive value and should be measured in all patients with severe asthma. OCS use is an important factor in biologic selection, especially given the documented ability of some biologics to reduce OCS dependence. Comorbid diseases and relevant safety considerations to each biologic should also be considered. More data are needed to determine whether biomarker profiles identify patients suited to one biologic versus another as limited data support differential predictors of response. Further prospective head-to-head trials and post hoc analyses of clinical trial data are warranted. The authors believe that these recommendations have value as they offer expert opinion to assist health care providers in making difficult decisions regarding the quality of care in severe, type 2 asthma with biologic medications. They remain conditional and are based on limited data owing to a lack of head-to-head comparisons.

Outdoor pollen-related changes in lung function and markers of airway inflammation: A systematic review and meta-analysis.

BACKGROUND: Experimental challenge studies have shown that pollen can have early and delayed effects on the lungs and airways. Here, we qualitatively and quantitatively synthesize the evidence of outdoor pollen exposure on various lung function and airway inflammation markers in community-based studies. METHODS: Four online databases were searched: Medline, Web of Science, CINAHL and Google Scholar. The search strategy included terms relating to both exposure and outcomes. Inclusion criteria were human-based studies published in English that were representative of the community. Additionally, we only considered cross-sectional or short-term longitudinal studies which investigated pollen exposure by levels or season. Study quality assessment was performed using the Newcastle-Ottawa scale. Meta-analysis was conducted using random-effects models. RESULTS: We included 27 of 6551 studies identified from the search. Qualitative synthesis indicated associations between pollen exposure and predominantly type-2 inflammation in both the upper and lower airways, but little evidence for lung function changes. People with ever asthma and/or seasonal allergic rhinitis (SAR) were at higher risk of such airway inflammation. Meta-analysis confirmed a positive relationship between pollen season, eosinophilia and eosinophil cationic protein (ECP) in people with ever SAR but the results between studies were highly variable. Heterogeneity was reduced after further subgrouping by age, and the forest plots indicated that eosinophilic airway inflammation to outdoor pollen exposure increased with age. CONCLUSION: Among people with ever asthma and ever SAR, exposure to increased ambient pollen triggers type-2 upper and lower airway inflammation rather than a non-specific or innate inflammation. These findings can lead to the formulation of specific pollen immunotherapy for susceptible individuals. Future research should be directed towards investigating lagged associations and effect modifications using larger and more generalized populations. SYSTEMATIC REVIEW REGISTRATION: CRD42020146981 (PROSPERO).

Is short-term exposure to grass pollen adversely associated with lung function and airway inflammation in the community?

BACKGROUND: The association between grass pollen exposure and early markers of asthma exacerbations such as lung function changes and increase in airway inflammation is limited. We investigated the associations between short-term grass pollen exposure and lung function and airway inflammation in a community-based sample, and whether any such associations were modified by current asthma, current hay fever, pollen sensitization, age, and other environmental factors. METHODS: Cross-sectional and short-term analyses of data from the Melbourne Atopy Cohort Study (MACS) participants (n = 936). Lung function was assessed using spirometry. Airway inflammation was assessed by fractional exhaled nitric oxide (FeNO) and exhaled breath condensate pH and nitrogen oxides (NOx). Daily pollen counts were collected using a volumetric spore trap. The associations were examined by linear regression. RESULTS: Higher ambient levels of grass pollen 2 days before (lag 2) were associated with lower mid-forced expiratory flow (FEF25%-75% ) and FEV1 /FVC ratio (Coef. [95% CI] = -119 [-226, -11] mL/s and -1.0 [-3.0, -0.03] %, respectively) and also 3 days before (lag 3). Increased levels of grass pollen a day before (lag 1) were associated with increased FeNO (4.35 [-0.1, 8.7] ppb) and also at lag 2. Adverse associations between pollen and multiple outcomes were greater in adults with current asthma, hay fever, and pollen sensitization. CONCLUSION: Grass pollen exposure was associated with eosinophilic airway inflammation 1-2 days after exposure and airway obstruction 2-3 days after exposure. Adults and individuals with asthma, hay fever, and pollen sensitization may be at higher risk.

How can air quality affect health?

Over recent years, Australians have been subject to an unprecedented number of environmental events materially and visibly affecting air quality, including thunderstorm asthma and bushfire smoke. There is increasing evidence that poor air quality adversely affects health with consequences for mortality and morbidity with measured particulates (PM2.5) in January 2019 frequently exceeding World Health Organization standards. Biological factors can also impact air quality with thunderstorm asthma epidemics evidence of a prime example, the 2016 event being associated with severe impacts on health services. Given these events, consideration needs to be given to environmental health literacy which will support individuals with pre-existing illness to recognise and mitigate as far as possible the effects of adverse air quality. Recognising the impact of poor air quality should also urge physicians to advocate for clean air as a necessity for good health.

Thunderstorm asthma: an overview of mechanisms and management strategies.

INTRODUCTION: Epidemic thunderstorm asthma (ETSA) is due to a complex interaction of environmental and individual susceptibility factors, with outbreaks reported globally over the last four decades. Australia has been particularly susceptible with nearly half of episodes reported internationally, culminating in the catastrophic Melbourne 2016 event. AREAS COVERED: Reported ETSA episodes are reviewed for common environmental and meteorological risk factors. Allergen aerobiology interaction with thunderstorm activity and rapid weather condition changes is examined. Assessment of the clinical and immunological data highlights risk factors for ETSA presentation, hospital admission, and intensive care admission. Risk factors associated with ETSA deaths are evaluated. Public health strategies, as well as pharmacological and immunological management approaches to reduce individual susceptibility and prevent ETSA are discussed. EXPERT OPINION: Improved understanding of the specific meteorological factors predisposing to the greatest risk of ETSA to improve forecasting is required. Better monitoring of aeroallergen levels in areas of greatest geographic risk, with further research into allergen aerobiology underpinning mechanisms of allergen exposure is needed. The role of climate change in increasing the risk of ETSA outbreaks requires further research. Public awareness and education are required to reduce exposure, and to improve uptake of pharmacological and immunological risk reduction and preventive strategies.