Andrew Gillman

Asthma in the elderly

As the population increases in age, the diseases of older age will have increasing prevalence and place a greater burden on the health system. Despite asthma being usually considered a disease of younger people, asthma mortality is currently greatest in the over 55 age-group. Symptoms and emergency presentations for health care due to asthma place a great burden on the quality of life of those over age 55 with asthma. Asthma in older people is under-diagnosed due to patient and physiological factors. Medication strategies for asthma have been dominantly derived from younger cohorts so that effective medication strategies have usually not been explored in older people. Older people with asthma are very concerned regarding side effects of medication so that adherence to therapeutic regimes is often poor. In addition physical disability can lead to difficulty in accessing treatment and using inhaler devices. Practical strategies to improve asthma outcomes in older people have been studied infrequently and the goals of self-management suitable for younger age-groups may not be applicable in this group. Consequently, asthma in older people is deserving of further attention both to basic mechanisms of disease, precision in diagnosis and effective therapeutic strategies, including those that involve self-management and device use.

Effectiveness and response predictors of omalizumab in a severe allergic asthma population with a high prevalence of comorbidities: the Australian Xolair Registry

Severe asthma is a high impact disease. Omalizumab targets the allergic inflammatory pathway; however, effectiveness data in a population with significant comorbidities are limited.

What do asthmatics have to fear from food and additive allergy

International studies report marked increases in the prevalence of food allergy, along with increases in hospital admissions and emergency presentations for severe allergic reactions due to foods. The prevalence of self‐reported food allergy is common, but generally exceeds that which can be verified from challenge studies, although nut allergies appear to be an important exception to this rule. Studies examining food allergy deaths suggest that those who die of food allergy usually have co‐existent asthma. Adolescents and young adults are at most risk, and adrenaline auto‐injectors are sub‐optimally used. Food chemical sensitivity is very commonly reported but not usually verified by challenge testing. However, the exception to this is sulphite sensitivity, which can elicit reproducible reactions in some. The increasing prevalence of severe food allergies and awareness of its risk in those with asthma demands an especially rigorous approach to the diagnosis and management of co‐existent food allergy and asthma, especially in young people who appear to be at most risk from death from severe food allergy.

Galectin-10, a Potential Biomarker of Eosinophilic Airway Inflammation

Measurement of eosinophilic airway inflammation can assist in the diagnosis of allergic asthma and in the management of exacerbations, however its clinical implementation remains difficult. Galectin-10 has been associated with eosinophilic inflammation and has the potential to be used as a surrogate biomarker. This study aimed to assess the relationship between galectin-10 in sputum with sputum eosinophil counts, the current gold standard of eosinophil inflammation in the lung. Thirty-eight sputum samples were processed for both eosinophil counts by cytospins and semi-quantitative measurements of galectin-10 by western blots. A strong association was observed between galectin-10 levels in sputum and sputum eosinophil measurements, and they accurately determined sputum eosinophilia. The results support the potential for galectin-10 to be used as a surrogate biomarker of eosinophilic airway inflammation.

Real‐life effectiveness of omalizumab in severe allergic asthma above the recommended dosing range criteria

Omalizumab (Xolair) dosing in severe allergic asthma is based on serum IgE and bodyweight. In Australia, patients eligible for omalizumab but exceeding recommended ranges for IgE (30–1500 IU/mL) and bodyweight (30–150 kg) may still receive a ceiling dose of 750 mg/4 weeks. About 62% of patients receiving government‐subsidized omalizumab are enrolled in the Australian Xolair Registry (AXR).

Comparison of supine-only and REM-only obstructive sleep apnoea

OBJECTIVES The effect of body position and sleep state on sleep apnoea have major clinical implications in the management of patients, yet are infrequently reported in the scientific literature. The aim of this study was to compare and contrast the prevalence and severity of supine-only and rapid eye movement (REM)-only obstructive sleep apnoea (OSA) in a population. METHODS Prospective cohort analysis of the influence of supine body position and REM sleep on the severity of apnoea in 100 consecutive patients with OSA (apnoea-hypopnoea index [AHI]>5) using attended polysomnography with continuous digital monitoring in an accredited sleep laboratory. Supine-only OSA was defined as a supine:non-supine AHI ratio of >2:1 and non-supine AHI <5 events/h. REM-only OSA was defined as an REM:non-REM ratio of >2:1 and non-REM AHI <5events/h. RESULTS Supine sleep time represented a greater proportion of total sleep time than REM sleep time (40% vs 13%). The prevalence of supine-only OSA was more than twofold greater than that of REM-only OSA (23% and 10%, respectively). The supine-only group had greater overall AHI (mean 12.6±6.1 vs 7.2±2.2 events/h; P<0.01) than the REM-only group. No significant differences in gender, age, or sleepiness were found between the two groups. CONCLUSIONS Supine-only OSA is more common and is associated with a greater AHI than REM-only OSA.

The Melbourne epidemic thunderstorm asthma event 2016: an investigation of environmental triggers, effect on health services, and patient risk factors

BACKGROUND A multidisciplinary collaboration investigated the worlds largest, most catastrophic epidemic thunderstorm asthma event that took place in Melbourne, Australia, on Nov 21, 2016, to inform mechanisms and preventive strategies. METHODS Meteorological and airborne pollen data, satellite-derived vegetation index, ambulance callouts, emergency department presentations, and data on hospital admissions for Nov 21, 2016, as well as leading up to and following the event were collected between Nov 21, 2016, and March 31, 2017, and analysed. We contacted patients who presented during the epidemic thunderstorm asthma event at eight metropolitan health services (each including up to three hospitals) via telephone questionnaire to determine patient characteristics, and investigated outcomes of intensive care unit (ICU) admissions. FINDINGS Grass pollen concentrations on Nov 21, 2016, were extremely high (>100 grains/m3). At 1800 AEDT, a gust front crossed Melbourne, plunging temperatures 10°C, raising humidity above 70%, and concentrating particulate matter. Within 30 h, there were 3365 (672%) excess respiratory-related presentations to emergency departments, and 476 (992%) excess asthma-related admissions to hospital, especially individuals of Indian or Sri Lankan birth (10% vs 1%, p<0·0001) and south-east Asian birth (8% vs 1%, p<0·0001) compared with previous 3 years. Questionnaire data from 1435 (64%) of 2248 emergency department presentations showed a mean age of 32·0 years (SD 18·6), 56% of whom were male. Only 28% had current doctor-diagnosed asthma. 39% of the presentations were of Asian or Indian ethnicity (25% of the Melbourne population were of this ethnicity according to the 2016 census, relative risk [RR] 1·93, 95% CI 1·74-2·15, p <0·0001). Of ten individuals who died, six were Asian or Indian (RR 4·54, 95% CI 1·28-16·09; p=0·01). 35 individuals were admitted to an intensive care unit, all had asthma, 12 took inhaled preventers, and five died. INTERPRETATION Convergent environmental factors triggered a thunderstorm asthma epidemic of unprecedented magnitude, tempo, and geographical range and severity on Nov 21, 2016, creating a new benchmark for emergency and health service escalation. Asian or Indian ethnicity and current doctor-diagnosed asthma portended life-threatening exacerbations such as those requiring admission to an ICU. Overall, the findings provide important public health lessons applicable to future event forecasting, health care response coordination, protection of at-risk populations, and medical management of epidemic thunderstorm asthma. FUNDING None.

The first case of methemoglobinemia associated with omalizumab

Omalizumab is a recombinant, humanized mAb that targets IgE, reducing its binding capacity to mast cells and basophils. It is a management option for chronic spontaneous urticaria. Methemoglobinemia is an uncommon but potentially fatal condition. We describe the first reported case of omalizumabassociated methemoglobinemia. A 50-year-old woman with treatment-refractory chronic spontaneous urticaria presented for an omalizumab graded challenge. Our patient had suffered from symptomatic urticaria for 3 years despite daily cetirizine 40 mg, ranitidine 300 mg, montelukast 10 mg, dapsone 50 mg, and systemic steroid bursts. She was otherwise healthy and taking no other medications, with no significant family history. Glucose-6-phosphate dehydrogenase levels were normal before starting dapsone. She had previously received omalizumab 150 mg monthly for 9 months, while on the aforementioned medications, with an excellent response. However, omalizumab was discontinued once light-headedness developed after 2 consecutive doses. This occurred 8 hours after each dose and had resolved before she sought medical review (12 hours duration). Consequently, the omalizumab was discontinued. Her urticaria eventually recurred and a poor quality of life prompted an omalizumab graded challenge, scheduled over 3 days (day 1, 50 mg; day 2, 100 mg; day 3, 150 mg). The initial dose was well tolerated with no adverse effects. Approximately 8 hours following the second dose our patient developed light-headedness and an associated headache. Upon presentation for dose 3 (never administered) she had peripheral and central cyanosis in association with tachycardia (heart rate, 130 beats/min). Hypoxia (SpO2 85%-89% on fractional inspired oxygen [FiO2] 21%) failed to correct with supplemental oxygen (FiO2 60%). Methemoglobinemia was confirmed on arterial blood gas, with a normal pH (7.41), sufficient oxygenation (204 mm Hg) and critically elevated methemoglobin of 27% (normal, 0%-2%). Methylene blue was administered intravenously as an antidote. A clinical and biochemical recovery was observed (methemoglobin dropped to 3%). Dapsone was deemed the culprit in view of its well-documented association, and an absence of other known causative agents, and discontinued. Over the following 3 months, without treatment with dapsone or omalizumab our patient remained well and methaemoglobin levels normal. Her urticaria returned, necessitating systemic corticosteroids. She was reluctant to trial treatment with alternative immunosuppressive agents; instead, she requested a rechallenge with omalizumab given its previous efficacy. In the absence of dapsone, 150 mg omalizumab was administered. Our patient developed a headache and palpitations within hours. Examination identified cyanosis, tachycardia, and hypoxia (SpO2 85%) despite supplemental oxygen. Six hours after omalizumab, her methemoglobulin level was 38%. Methylene blue provided a rapid symptomatic improvement correlating with a reduction in levels (16%). Seven hours later, worsening hypoxia accompanied a rebound elevation of methemoglobin (25%). Repeat methemoglobin saw a further increment to 28%. Methylene blue was readministered, this time with symptomatic and biochemical improvement (5%). However, her tachycardia and hypoxia did not resolve. Recurrence of headache, dizziness, and dyspnea prompted recognition of another rebound in levels (18%) and these remained elevated (15%18%). By day 3, the patient’s symptoms and hypoxia worsened (SpO2 83%) correlating with levels of 19%. A third dose of methylene blue precipitated a conclusive fall to 5%, without evidence of hemolysis. Clinical stability and well-being was determined by day 6. Evaluation 2 days postdischarge found our patient asymptomatic with normalized methemoglobin levels (1%). The patient has remained well with normal methemoglobin levels 9 months later. Following the 2017 EAACI/GA2LEN/EDF/WAO chronic urticaria guidelines, omalizumab is recommended as add on therapy. Relatively safe, the most common side effects are headaches and injection-site reactions. Anaphylaxis is the most common serious adverse reaction. Methemoglobinemia characterized by functional anemia and tissue hypoxia can be toxic, with proportional symptomatology. It develops when ferric ions in hemoglobin are irreversibly oxidized into the ferrous state, thereby decreasing the oxygencarrying capacity of hemoglobin. Healthy individuals develop a small amount of methemoglobin but equilibrium is maintained by reducing enzymes, including cytochrome B5 reductase. The presumed mechanism of medication-induced acquired methemoglobinemia relates to significant oxidative stress. Heterozygous cytochrome B5 reductase deficiency is a known predisposing risk for some cases of methemoglobinemia. Our patient elected not to undergo this testing. Patients suffering methemoglobinemia will typically have pulse oximetry values that do not correct with increased FiO2. 7 Levels above 15% to 30% may cause fatigue, headache, dyspnea, and tachycardia, whereas death may occur above 70%. This case provides strong temporal evidence that omalizumab may cause acquired methemoglobinemia. Although the initial episode of methemoglobinemia was attributed to dapsone, it could not be implicated with the second.

The 2016 Melbourne thunderstorm asthma epidemic: risk factors for severe attacks requiring hospital admission

The worlds most catastrophic and deadly thunderstorm asthma epidemic struck Melbourne, Australia, on November 21, 2016.