Ventilating my thoughts on severe asthma exacerbations

Editorial

In this issue of AJTCCM, Manyeruke et al. ^[1] provide a retrospective review of 110 acute asthma exacerbations requiring mechanical ventilation (103 patients) in the respiratory intensive care unit (ICU) at Groote Schuur Hospital, Cape Town, South Africa (SA), over a 6-year period (2014 - 2019). Theoretically, all hospital admissions for asthma represent failure of one or more aspects of management of this common chronic disease – timely and correct diagnosis, avoidance of precipitating factors, smoking cessation, appropriate drug therapy, proper inhaler use technique, adherence to therapy, patient education, and regular review.

The striking findings were: (i) only 60.0% of the patients were using inhaled corticosteroids (ICSs), although 91.8% were using short-acting beta-agonists (SABAs); (ii) the median partial pressure of carbon dioxide (PaCO₂ ) on admission to the ICU was 9.09 kPa (68.2 mmHg); (iii) the median pH was 7.22; (iv) 7 patients (6.4%) had had a previous ICU admission; (v) 10.9% were using long-term oral corticosteroids (OCSs); (vi) 36.4% were current smokers; and (vii) 14.5% admitted to illicit drug abuse.

Current practice mandates ICSs as the mainstay of asthma drug therapy, since these drugs address the underlying pathogenesis of airway inflammation. ICS use in asthma has been shown to control symptoms, decrease exacerbations and hospitalisations, and even reduce mortality.^[2] In 2019, the Global Initiative for Asthma (GINA) instituted a paradigm change by advocating that SABA monotherapy should never be prescribed in the treatment of asthma, even in mild disease, as this was associated with an increased risk of exacerbations and asthma-related mortality.^[3]

While there is incontrovertible evidence for the value of ICSs, these drugs demonstrate flat dose-response curves for their beneficial clinical effects, with 80 - 90% of the maximum benefit obtained with ‘low-dose’ ICSs (fluticasone propionate 100 - 250 μg daily or equivalent).^[4] In contrast, the higher the dose of ICSs, the greater are the systemic side-effects, a phenomenon that does not plateau. Notably, a large real-world study employing two electronic UK medical record databases showed that increasing the dose of ICSs in poorly controlled asthmatics to dosages considered ‘high dose’ was associated with a higher risk of exacerbations and a reduced time to first exacerbation.^[5] We also now recognise that the magnitude of response to corticosteroids varies between different asthma phenotypes and endotypes.^[6]

Even in patients co-prescribed an ICS, SABA overuse (>2 standard canisters per year) is coupled with increased asthma exacerbations and poorer asthma control. A positive relationship between the number of SABA canisters prescribed per patient per year and these unfavourable outcomes was evident in the SABINA studies.^[7,8] It is sobering to note that of 24 countries across four continents surveyed in the SABINA III study, SA fared worst, with 74.9% of mild or moderate-to-severe asthmatics prescribed ≥3 SABA canisters per year and 56.5% prescribed ≥10 canisters per year.^[7]

How do the features and outcomes of this SA study compare with the developed world? A large study of patients with asthma admitted to ICUs from 2014 - 2015 that compared Australian and New Zealand (ANZ) patients with those in the USA was reported by Abdelkarim et al. ^[9] Seven hundred and thirty patients were intubated (ANZ n=544, USA n=186). Comparing the intubated patients in the ANZ cohort with those in the US cohort, the median age was 45 and 41 years, respectively, most were female (62.3% and 64.0%), the median PaCO₂ was 54 and 46 mmHg, the median pH was identical (7.35), ICU length of stay (LoS) was 3.1 and 2.5 days, and ICU mortality was 2.0% and 5.4%. Manyeruke et al.’s patients were much younger (median age 33.5 years) and had more severe hypercapnia and acidosis. Despite the more severely deranged blood gas parameters, suggesting delayed presentation and/or greater severity of exacerbations, the ICU LoS was similar (median 3 days) and the ICU mortality comparable (4.5%). There was also a female predominance (53.6%).

Asthma patients are not immune to tobacco addiction. In a nationally representative telephonic survey of 12 339 asthmatics in the USA (21.8% of whom were current smokers) who had visited the emergency department (ED) over the past year,^[10] the odds of current smokers having visited the ED was 1.82 compared with never smokers. In another study, 35% of 1 847 patients who presented to the ED with acute asthma were current smokers (median 10 pack-years).^[11] Interestingly, only 4% of these subjects considered this acute episode to be related to their smoking habit, although 50% acknowledged that cigarette smoke was a triggering factor for their asthma.

Asthmatics who are also cannabis users are known to have poorer asthma control and more frequent exacerbations. This association is complex, as many are also tobacco users, have poor socioeconomic circumstances and are poorly adherent to treatment. In a case-control observational study, 44% of asthmatics who presented to the ED with an acute exacerbation either admitted to use of illicit drugs or had a positive urine test for illicit drugs.^[12] Smoked cannabis has been shown to cause bronchodilation lasting ~60 minutes,^[13] probably mediated via CB1 receptor stimulation in airway parasympathetic nerves that leads to inhibition of acetylcholine release. Despite isolated reports of cannabis improving asthma control,^[14] a Norwegian study based on asthma prescriptions suggests that current cannabis smoking may be a risk factor for asthma.^[15] A laboratory-based study suggests that smoking cannabis decreases the conversion of beclomethasone dipropionate (BDP) to its active metabolite, beclomethasone-17- monopropionate.^[16] The clinical significance of possible interactions between inhaled cannabis and BDP or other ICSs has not been studied. Cannabis has been reported to cause allergic manifestations,^[17,18] including asthma, allergic rhinitis, eczema and even anaphylaxis. Sensitivity may be related to exposure to pollen or seeds of the Cannabis sativa plant, recreational use or occupational exposure.

In Manyeruke et al.’s study, 10.9% of the patients were using chronic OCSs. The mean daily dose was not stated. Low-dose systemic steroids (prednisone ≤7.5 mg/d) is an option in step 5 of the GINA guideline, but only ‘as a last resort’.^[19] In a systematic review of the use of systemic corticosteroids prescribed for asthma,^[20] long-term corticosteroid use ranged from 1.2% to 30.9% in patients with any degree of asthma severity. Long-term OCS use was associated with a 3.6-fold increase in steroid-related side-effects compared with no use. The risks of adverse effects are related to the cumulative dose, so even patients prescribed frequent courses of short-term OCSs are predisposed to these unintended consequences.

Of concern is that only 61.5% of survivors in Manyeruke et al.’s study returned for a follow-up visit to the respiratory clinic at Groote Schuur Hospital. A history of substance abuse was a significant risk factor for defaulting.

The World Asthma Day 2023 theme for 2 May was ‘Asthma care for all’. SA remains far from addressing asthma, one of the most common chronic respiratory diseases, in an adequate manner. Despite having world experts in asthma and comprehensive national asthma guidelines in our country, translation at grassroots level remains woefully poor. Cape Town is a thriving metropolis with arguably the best primary healthcare infrastructure in the country, yet the statistics for severe asthma exacerbations do not reflect this. Like most chronic diseases, diagnosis and management of asthma extend beyond scientifically based guidelines. Important aspects beyond our control include political commitment and support, improved access to healthcare and emergency services, availability and cost of drugs, transport, socioeconomic deprivation, pollution control, and tobacco and illicit drug use.

Things we can do to improve the situation are education (of the lay public, patients with asthma, medical students, primary healthcare providers, general practitioners, specialists), ensuring that all asthmatics are prescribed an ICS, advocacy for drugs and newer formulations to be available and at lower cost (including biological agents), checking inhaler technique at every visit, promotion of smoking cessation, regular follow-up, and earlier interventions in acute exacerbations. We have a lot of work to do.