Seventeen cases of fatal asthma, all occurring in the same Italian region within the last 3 years, have been detected and analyzed. A prevalence of male gender, young age and atopic condition was observed. Several risk factors have been identified such as sensitization to Alternaria, previous near fatal asthma attacks, incorrect treatment of the disease. Weather condition or thunderstorms did not trigger the fatal exacerbation, whereas among the pollutants only ozone was detected over the accepted limits during the days when the deaths occurred.
We observed an increased asthma rate in young males, much younger then in ISTAT asthma deaths database [8], compared to young females [16]. It may be related to the prevalence of male gender among the described cases. However, the prevalence of male gender reflects what is known in the general population [8]. Most of subjects (44%) were students whereas three adult patients were unemployed. The last were all immigrants, suggesting difficult access to the health care resources as a potential risk factor for uncontrolled asthma. In fact, one patient had been admitted to the Emergency Room several hours before his death, but voluntarily he went away from the waiting room. Four hours later he was found dead in a street nearby, with the inhaler in his hand. The other two cases had the fatal attack at home, but they had not been visited by a doctor during the last years. The autopsy proved the causal role of asthma in all these fatal cases. This finding is in agreement with the higher mortality noticed in populations with lower income, such as black or Hispanic in the United States. However, differently from economical issues, racial factors at least in youngsters seemed not to affect asthma severity [17]. Of note, according to a large USA study that investigated the outcomes of patients hospitalized for asthma, race was not relevant as a risk factor for hospital deaths. Caucasian patients show an overall lower risk of death in comparison with black patients, but factors preceding hospitalization, such as lower income, do probably account for it [18].
The cluster of fatal attacks during the weekend emphasizes the potential role of smoking, drug or alcohol abuse, which are quite common during parties or other entertainment among youngsters, as negative cofactors in determining the decease. Smoking habit is still common in young people. All the studies including adolescents reported higher rates of smoking in asthmatics than in non-asthmatic peers, though this trend is less consistent in adults [19]. Moreover, an increased prevalence of asthma and COPD has been reported in patients who smoke crack or cocaine [20].
In our series, most of the fatal cases occurred in the evening and during the night. It is well known that nocturnal exacerbations occur in 2/3 of asthmatics, contributing to the morbidity and mortality of the disease [21]. Several factors might account for this finding, such as changes in respiratory function related to sleep as well as processes related to circadian regulation. Furthermore, concomitant diseases, such as gastro-esophageal reflux or sleep apnea may negatively affect the airway resistance overnight [21].
Weather conditions seemed not to be related to fatal attacks, as temperatures were in line with the average values of the season and there was no rainfall or thunderstorm in the critical days (Table 2). Only ozone was over the permitted threshold for 3 days. It has been shown that this pollutant is responsible for airway inflammation, as it increases the pro-inflammatory markers and oxidative stress in bronchial epithelial cells [22]. This finding was mainly observed in atopic individuals, in children as well as in adults [22, 23]. In our series one of the fatal events occurred in concomitance with a high level of ozone. He was atopic and a heavy smoker and it is possible that the pollution might have played a negative role by increasing airways inflammation.
Regarding the aerobiological data, the high concentration of Alternaria spores, with an overall low pollen count, also suggests a relevant role of this allergenic source [12]. The sensitization to this fungal mould was confirmed in five patients and maybe related to the fatal events. Moreover in one patient, besides the massive lymphocytic and eosinophilic inflammation in the bronchial airways, Alternaria was detected in the airways (Fig. 4). As previously described [24], the inflammatory reaction triggered by an allergen is responsible for a massive production of mucus and a decrease of the airway clearance function. Once the mucus plugging becomes extensive, even a slight bronchial muscle constriction on top of the plugs can cause the complete airway occlusion. Since 1991 Alternaria has been reported as responsible for NFA and fatal asthma [25], and epidemic asthma in the late summer and autumn was repeatedly reported with a peak of multiple hospital admissions in young asthmatics [26–28]. Several mechanisms may account for alternaria-induced exacerbations. In fact, besides the IgE mediated allergic inflammation, an Alternaria-specific serine protease activity is responsible for an immediate release of IL-33, which drives a robust Th2 inflammation and exacerbation of allergic airway disease [29]. Furthermore, the Alternaria induced IL-33 production can provoke a steroid resistance, as in children sensitized to this fungal mould a relationship between levels of IL-33 and use of oral steroids has been demonstrated [30]. In our series most of the patients were atopic, although not in all the cases the sensitization could possibly account for the death. Nevertheless, several patients of our series seemed to belong to a cluster of a recently identified NFA phenotype, whose features are the younger age, the smoking habit and the sensitization to Alternaria [14].
Respiratory infections might account for the cases of fatal asthma registered in winter [31], but this connection cannot be confirmed according to the clinical files of our cases.
In our case series, three patients were previously admitted to Emergency Rooms or Hospitals for near-fatal asthma (respiratory failure with hypercapnia). These patients, who can be classified as severe asthmatics according to the European Respiratory Society (ERS) Guidelines [32], indirectly confirm that severe asthma exacerbations remain a robust predictive risk factor for asthma mortality [33–35]. In the other patients the identification of the level of asthma severity is not easy. In fact according to the concomitant treatment reported in medical files, patients were affected by GINA level 2 or 3 [36], but detailed data about the concomitant asthma control are lacking. According to the UK National Review of Asthma Deaths [35], the largest study worldwide investigating asthma deaths, only 39% of patients were affected by severe asthma at the time of death. The other subjects suffered from mild to moderate asthma. Those findings suggest that undertreated and poorly controlled asthma rather than severe asthma is at high risk of fatal exacerbation.
Among the cases we have investigated, only one patient was regularly monitored, whereas the remaining cases were not regularly followed-up by their GPs. The lack of specialist and general practitioner supervision during the 12 months prior to death also characterizes the majority of fatal cases reported in the UK National Review of Asthma Deaths. As a probable consequence, a minority of patients was provided with a personal action plan and 45% of people seemed not to seek medical assistance before death [35].
All the described subjects shared the use of SABA as needed and only intermittent courses of ICS alone or in combination with LABA. This finding suggests that all the patients were using a rescue treatment but they did not follow a regular anti-inflammatory action plan. Moreover the underuse of ICS in comparison with SABA, confirmed by the GPs prescription in seven cases, suggests a low adherence to the anti-inflammatory treatment. Recently in patients with mild asthma the excessive use of SABA was identified as a reliable marker of poor control and increased risk of severe exacerbation [33, 34]. The over-prescription of SABA and the under-prescription of preventer medication have been described as a key finding of the UK National Review of Asthma Deaths [35]. Inappropriate prescribing of long-acting beta agonists was also highlighted: 14% of fatal asthma cases were prescribed a single-component bronchodilator, without any inhaled corticosteroid preventer treatment. However, the treatment of life-threatening asthma during the acute phase still represents a challenge. Some authors have suggested the use of epinephrine intramuscular auto-injector as an extreme emergency treatment able to save lives [37].
In our case series, for one patient the concomitant use of complementary medicine was reported. The intake of herbal or homeopathic remedies has been reported as a risk factor for uncontrolled asthma, as patients reduce or stop the pharmacological treatment in favor of the complementary treatment [38].
One major flaw of this survey is the method used for searching fatal asthma cases. The prevalence of patients below 40 years may be due to a “mediatic bias” since deaths at younger ages are more striking and more easily reported. Given this limitation, the identification of causes and risk factors can be more understandable at younger ages for the lack of relevant concomitant diseases, which are common in elderly and can be a confounding factor.