FATAL ASTHMA: A French multicenter study with comments about recent advance on risk factor identification


Laurent Vivès - Department of Medicine - Saint-Gaudens Hospital - France

Alain Didier - Respiratory and Allergic diseases department - Rangueil University Hospital - Toulouse - France




Acknowledgments: We wish to thank these chest physicians belonging to the Collège de Pneumologie du Sud Ouest (Southwestern France College of Pneumology) who have observed cases, filled out forms and participated in various coordination meetings: Pierre Biel, Josianne Cabréra, Alain Didier, Maurice Duffour, Maurice Durand, Michel Farny, Serge Fayas, Marie Annick Fischer, Elisabeth Goyeau, Yves Stambach, Jacques Vanche and Laurent Vivès.


§: This study has been awarded a grant by the French National Institute of Medical & Scientific Research


Death from asthma may occur by sudden fatal attack, long-lasting severe exacerbation or, in the long run, by progressive respiratory failure. Even if this events remain rare, fortunately (1-6), physicians should be able to identify high-risk patients in order to implement a preventive approach. Several studies (7-17), based on observation of fatal and/or near fatal asthma, often compared with control groups, have already released interesting results. Some of them have also included a follow-up period (18-20).  However, no prospective clinical study has thus far examined a sufficient number of deaths to permit comparison of risk factors with a group of survivors previously observed in similar conditions.  In 1995 the Collège de Pneumologie du Sud Ouest in France has conducted such a study, which up to now remains unique (21 - §).  After a brief presentation of this study and its main results, we will comment recent data entered in the literature on fatal asthma, trying to highlight the key points that might be useful for clinicians treating asthma patients to identify those with high-risk of asthma death in the short run.



From February 1989 to May 1995, a cooperative group of lung physicians has performed a prospective clinical study to observe a large number of asthmatic patients. Asthma was defined according to the 1987 A.T.S.  proposals (22). A large cohort of patients was constituted and followed. Several deaths by asthma occurred during the follow-up period, allowing identification of risk factors in comparison with patients who survived.


Methods: inclusions (T0) were done between 1989 and 1993. Each physician filled out an observation chart concerning each asthmatic patient. Patients were examined as outpatients or inpatients. Heavy smokers, COPD and patients more than 79 years old were excluded. Data collection included: occupation, living conditions, psycho-social status, antecedents, asthma history, evolution during the preceding year, asthma stability, current clinical status and therapies, spirometry, chest and sinus X-rays, pneumallergen skin tests, total and specific IgE measurement, new treatments prescribed, modality of medical follow-up, assessment of diseases severity according to the 1995 global initiative for asthma recommendations (23).  The second consultation (Tx) took place between 1993 and 1995 and was performed by the same physicians. The minimum length of observation was six months for severe asthma and one year for others (average 37,4 month +- 15,4).  In the eventuality of a patient's death, date, place and circumstances of the event were carefully established by questioning patient's relatives, general practitioner or any medical staff present at the time. Statistical analysis of factors of survival has been made with multivariate Cox proportional hazards regression . 



1/ Patients: three hundred and twelve asthmatics have met inclusion and follow-up criteria.  At T0, average age was 39.4 years +- 21.8 (<15: 16% - <35: 45.5% - 35 to 70: 46.4% - > 70: 6.5%); sex-ratio was 0.89; two-thirds of patients lived in rural area; 44% had no professional activity.  Seventy-two per cent had a good psychological status and 82% good conditions of life. Antecedents for allergy, rhinitis, nasal polyps, ASA intolerance and significant comorbidity were 77%, 56%, 14%, 8.7%, and 9.7% respectively. Age of beginning of asthma was 22 years +-19, and mean duration of the disease was 14.7 years.  Forty three per cent of patients had already been hospitalized for asthma.  Fifteen per cent had previously transited through an ICU and 12% had experienced a sudden and serious asthma attack. During the last year of the asthma evolution, 14% had permanent breathlessness, 44% signaled more than one crisis per week, 40% had a diminution of their quality of life because of asthma and 24% admitted poor medical observance. Mean FEV1 (298 measurements) was 72% predicted value, and mean post-beta-2-agonist bronchial obstruction reversibility (234 measurements) was 12.9%.  Fifty per cent of subjects presented dyspnoea and/or wheezing and 21% were hospitalized the day of the inclusion.  Asthma severity was determined for 7.4% as mild intermittent, 18.3% mild persistent, 32.4% moderated persistent and 38.1% severe persistent; 2.2% remaining unclassifiable. At the end of inclusion, 55% had received a prescription of continuous inhaled beta-2-agonist, 52.5% inhaled corticosteroïds and 24% received instructions for self-management with peakflow measurement.


2/ Asthma death: Among the group of 312 subjects who were followed, 21 died during follow-up, 16 by asthma and 5 due to other causes (average annual mortality for asthma 1.6%). Two patients dead by asthma were less than 30 years old and 9 were more than 60 years old. Five have died at home by a sudden attack, 2 during hospital transportation and 9 within the hospital (6 in ICU). We did not notice any seasonal recrudescence and it was not always possible to precisely determine precipitating factors (3 allergen exposures, 2 respiratory infections, 2 delays in seeking care, 1 irritant exposure and 8 cases of unknown etiology). For six patients, death has occurred rapidly, either at home or during transportation.  In comparison with the 10 other patients whose death had occurred more slowly, they were younger (38.8 years versus 65.8), more often atopic (66.6% versus 30%), and they had more previous life-threatening exacerbations (66.6% versus 20%).  However asthma severity was similar in the two groups.


3/ Asthma death risk factors: Using Cox’s model regression analysis, among 75 studied variables, 38 were linked to survival to the threshold of 5%. Main variables not linked to survival were: gender, current smokers, aspirin-induce asthma, nasal polyps, comorbidities, length of asthma, previous sudden and serious crisis, more of 5 years of asthma remission, periodicity and trigger factors of crisis, radiological abnormalities (chest and sinus), beta-2-agonist reversibility of bronchial obstruction, medical observation by specialist or by general practitioner, admitted poor observance, self-management of asthma including regular utilization of the peak-flow meter.  A lot of variables were associated with bad prognosis, increase of age, previous stay in ICU, permanent breathlessness, decrease in FEV, asthma exacerbation at T0, severe asthma. Table I presents main variables that, after multivariate analysis, have shown the most significant link with the asthma death. Table II presents mortality according to severity (25% of deaths concerned non-severe asthma). We also identified variables correlated with a good prognosis: antecedents of allergy and/or rhinitis (independent of age and severity), good conditions of life and psychological status.  Table III shows that, by combining 5 of the most significant variables, one obtains annual mortality rate with figure variations sufficiently great to envisage calculation of a risk score.


Table I: Factors (observed at T0) linked to the death by asthma (Cox’s model)


Deceased (N = 16)

Alive at Tx


p value


55,5 years

38,5 years


Absence of allergy antecedents




Absence of rhinitis antecedents




Poor psycho-affective status




Weak social or family status




Anterior stay in resuscitation




Permanent breathlessness




Decrease of life quality due to the asthma




Mean FEV1% predicted value




Asthma exacerbation at T0




Daily use inhaled béta2-agonist




Sevère asthma





Table II: Mortality by asthma according to severity classification at T0 inclusion*

Severity at T0


Average age




(in month)

N. asthma death

Annual mortality

by asthma

Mild Intermittent







Mild Persistent







Moderate Persistent







Severe Persistent







Non specified








* excluded 5 death by other reason

Table III: Increase of the mortality by asthma according to a combination of variables observed to T0 among subjects of less than 60 years old

Factors combination



Mean age

Month  follow-up

% Death

/ year

Permanent dyspneae + Previous stay in ICU  + FEV1<60%

+ Absence of rhinitis + Asthma exacerbation at T0






Previous stay in ICU  + FEV1<60% + Absence of rhinitis

+ Asthma exacerbation at T0






FEV1<60% + Absence of rhinitis + Asthma exacerbation at T0






Absence of rhinitis + Asthma exacerbation at T0






Presence of rhinitis + Stable asthma at T0







To sum up: We observed an annual death rate by asthma of 1.6%, which is 42 times higher than the average rate observed in France. This permitted us to determine predisposing factors of fatal asthma in the short term, and to identify the most endangered patients: adults with severe intrinsic asthma, a durable bronchial obstruction, having previously transited in an ICU, recently worsened and having poor life conditions and an unfavorable psychological status. However this determination might be limited, because even if affected by moderate asthma and well observant, some asthmatics may experiment sudden fatal attack if exposed to precipitating factors.





Clinical studies and identification of fatal asthma risk factors.

Risk factors have already been checked out by Strunk in 1989 (24) then by Molfino (25) and Campbell (9) in 1994. More recent clinical studies (8, 11, 13-18) have used methods so different that meta-analysis is not possible; furthermore, they did not really brought out new elements. Some factors are not sufficiently proven or still under discussion: gender (12-14, 16, 21), race (16, 26), access to medical care (7, 16), sociodemographic features (12, 15, 16), psychosocial disturbances (16, 27, 28), continuous use of inhaled beta-2-agonist (5, 29, 30), aspirin (31) and NSAIDs (32) induced asthma. Low-dose inhaled corticosteroïds now appear to be able to reduce the number of hospitalizations and deaths from asthma (33, 34). Table IV summarizes main risk factors that are not anymore contested. If with the association of several of these factors, one can easily enough suspect a mortal risk, it is very important to consider that approximately 25 to 50% of patients can die unexpectedly despite having mild or moderate asthma (8, 9, 21).  Some of them were even considered as compliant (15, 17). 


Table IV: Mains risk factors of fatal asthma, that are not anymore contested

Main predisposing  factors

Main precipitating factors

Previous stay in ICU (and intubation)

Delay of appropriate care and transportation

Severe and/or instable asthma

Insufficient perception of gravity of the crisis

Age increase

Recent respiratory infection

Hospital admission within the last year

Allergens and/or irritant exposure

Poor medical observance and self-management

Stress and emotionals upsets

Poor psychological and social status

Air pollution and/or bad climatic conditions


It is clear that death of asthmatics do not occur in the same manner. At least three groups can be distinguished: - 1) sudden asthma attack occurring in an unpredictable manner in younger, atopic, non-severe asthma, due to acute bronchospasm and susceptible to respond rapidly to adequate inhaled beta2-agonist (35, 36) - 2) status asthmaticus following a prolonged crisis, often facilitated by carelessness, due to important inflammation (37) and susceptible to respond more slowly to corticosteroids - 3) delayed respiratory distress, in older patients whose disease has evolved long enough to induce irreversible remodeling with narrowing of the airways (38, 39). 


Long term follow-up studies after near-fatal asthma (11, 40) have shown that around eighty per cent of patients were alive ten years later.  The main factors of surviving were trigger avoidance, satisfactory treatment and a fair understanding of medication usage (11).  Although a recent study (41) has found that written action plans were associated with a 70% reduction in the risk of death, we have found none effect of self-management on mortality in our study (21), even by taking severity into account.



Predictive value of physiological and biological markers


Prognosis value of bronchial hyperresponsiveness (B.H.R.) at baseline is not well established (42-44), even if severe B.H.R. is a characteristic finding in patients recovering from a life-threatening asthmatic attack (10, 14, 45). Up to now, there are not enough arguments to recommend non-specific-B.H.R. measures as predicting factor of the evolution, including in severe asthma. Poor perception of airway obstruction in asthmatics is well known (46), that increased in acute conditions (47), is associated with inflammation and improved with good observed inhaled corticosteroid treatment (48). The measure of the relationship between the respiratory discomfort and the FEV1% by an analogical or a Borg scale, can be recommended to individualize hypoperceivers subjects, being able to be part of a "risk group" during future exacerbation. In a long term survey (49), FVC value at baseline was a particularly powerful predictor of mortality in subjects <65 years old, but most of the excess in respiratory deaths was not due to acute severe asthma, but to the development of chronic obstructive pulmonary disease.


Recent studies have focused on biological markers: autopsies after death of asthmatics (50, 51), genotype and others determinations in different groups (52-56), bronchial lavage fluid from patients with status asthmaticus (37).  Main results of those studies have shown that: - hypereosinophilia is well correlated with asthma severity in children (55), and is a risk factor for COPD mortality in the long run in the adult asthmatic population (56) - interleukin-5 and tumor necrosis factor-alpha are not associated with an increased risk of asthma severity (55) - IL4*-589T allele could be a risk factor for life threatening asthma (49) - TNF-alpha-308 polymorphism may be a risk factor for asthma occurrence but does not increase the risk of fatal asthma in asthmatics patients (53) - the Beta-2-Adrenergic Receptor genotype is not a major determinant of fatal or near fatal asthma (54) - GRbeta expression is associated with an increase risk of fatal or near fatal asthma (51) - presence of aberrant CD8 (+) T-cell population is founded in subjects who die of acute asthma (50) - neutrophil and eosinophil influx, large quantities of chemokines are present in bronchial secretions of patients who have experimented a status asthmaticus (37).  Although these data are interesting, further studies are necessary prior to establishing a routine for the detection of some genotypic anomalies potentially linked with asthma risk. However hypereosinophilia may reflect an increased inflammatory response, resulting in a tissue injury that could be associated with an increased risk of death in asthmatics and could justify his measurement in case of doubt concerning the risk to short-run.





No study has so far been able to validate a risk score with a good predictive value. Results of our study (21) have shown that with five variables, the rate of asthma death varies from 0 to 45% per year, which, although relevant, needs confirmation by more studies before implementing a routine.

However we can recommend considering with great care patients with permanent breathlessness, who have previously transited in an ICU and whose asthma is unstable. Low FEV1, absence of rhinitis, poor perception of bronchial obstruction and hypereosinophilia should also be considered as an indication. Studying asthma death risk factors involves to consider the heterogeneity of asthma and requires multifactorial assessment (figure I). Prevention might be based on a "heavy risk" patient identification that would have to be recorded in assistance programs, on a collective approach using public information, on education of patients, on care and rescue effectiveness, and, if possible, on irritant and allergen eviction.


Figure I: Multifactorial assessment of main risk factors of asthma death

















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