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.

 

A - THE MULTICENTER CLINICAL STUDY IN SOUTHERN FRANCE

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 . 

 

Results:

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)

Factors

Deceased (N = 16)

Alive at Tx

(N=291)

p value

Age

55,5 years

38,5 years

0,001

Absence of allergy antecedents

56,3%

21,3%

0,001

Absence of rhinitis antecedents

82,5%

41,5%

0,001

Poor psycho-affective status

41,6%

27,6%

0,05

Weak social or family status

41,6%

17,3%

0,05

Anterior stay in resuscitation

56,6%

13,2%

0,001

Permanent breathlessness

56,6%

11,5%

0,001

Decrease of life quality due to the asthma

75%

36,8%

0,001

Mean FEV1% predicted value

53,6

73,1

0,001

Asthma exacerbation at T0

87,5%

46,6%

0,01

Daily use inhaled béta2-agonist

93,7%

52,7%

0,001

Sevère asthma

75%

33,8%

0,001

 

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

Severity at T0

N.

Average age

Mean

FEV1%

Tx-T0

(in month)

N. asthma death

Annual mortality

by asthma

Mild Intermittent

23

19,51

97,09

40,94

0

0%

Mild Persistent

57

23,76

91,35

40,18

0

0%

Moderate Persistent

101

37,92

76,36

39,89

4

1,19%

Severe Persistent

119

50,76

54,41

33,99

12

3,56%

Non specified

7

43,57

87,33

26,39

 

0

0%

* 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

N

Death

Mean age

Month  follow-up

% Death

/ year

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

+ Absence of rhinitis + Asthma exacerbation at T0

3

3

48,6

26,7

44,9%

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

+ Asthma exacerbation at T0

5

3

40,2

36,4

19,7%

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

18

4

40,9

40,4

8,1%

Absence of rhinitis + Asthma exacerbation at T0

46

6

33,9

36,6

4,3%

Presence of rhinitis + Stable asthma at T0

82

0

27,7

41,3

0%

 

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.

 

 

B - RISK 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.

 

 

TO CONCLUDE:

 

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

 

---

 

 

 

 

 

 

 

 

 

 

 

 

---

 Bibliograpy

1 - Sly RM. Changing asthma mortality. Ann Allergy 1994; 73:259-268

 

2 - Markowe HJL, Bulpitt CJ, Shipley MJ, Rose G, Crombie DL, Fleming DM. Prognosis in adult asthma: a national study. BMJ 1987; 295: 949-52

 

3 - Cooreman J., Ségala C., Neukirch F.         Trends in asthma-induced mortality in France from 1970-90. Tubercle and Lung Disease 1994; 75:182-7

 

4 - Zar HJ, Stickells D, Toerien A, Wilson D, Klein M, Bateman ED. Changes in fatal and near-fatal asthma in an urban area of South Africa from 1980-1997. Eur Respir J  200; 18(1):33-7

 

5 - Romano F, Recchia G, Staniscia T, Bonitatibus A, Villa M, Nicolosi A, De Carli G, Mannino S. Rise and fall of asthma-related mortality in Italy and sales of beta2-agonists, 1980-1994.        Eur Epidemiol  2000; 16(9):783-7

 

6 - Neffen H, Baena-Cagnani CE, Malka S, Sole D, Sepulveda R, Caraballo L, Caravajal. Asthma mortality in Latin America. J Investig Allergol Clin Immunol  1997; 7(4):249-53

 

7 - Nakazawa T, Kawakami Y, Sudo M, Kobayashi S, Suetsugu S, Nakajima S, Yamakido M, Nagano H. Asthma death among adults in Japan 1995-1997. Analysis of 295 cases reported questionnaires sent to hospitals with more than 100 beds. Asthma Death Investigation Committee. Arerugi 2000; 49(6):505-11

 

8 - Nakazawsa T, Kawakami Y, Sudo M, Kobayashi S, Suetsugu S, Nakajima S, Yamakido M, Nagano H. Trends of asthma death among adults in Japan 1992-1994. Analysis of 313 cases

reported questionnaires sent to hospitals with more than 100 beds. Arerugi 1998;47(1):41-7

 

9 - Campbell DA., McLennan G., Coates JR., Frith PA., Gluyas PA., Latimer KM., Luke CG., Martin AJ., Roder DM., Ruffin RE., Yellowlees PM. A comparison of asthma deaths and near-fatal asthma attacks in South Australia. Eur Respir J 1994; 7:490-497

 

10 - Matsuse H, Shimoda T, Kohno S, Fujiwara C, Sakai H, Takao A, Asai S, Hara K. A clinical study of mortality due to asthma. Ann Allergy Asthma Immunol 1995; 75(3):267-72.

 

11 - Tan WC, Lim KP, Ng TP, Chao TC, Ong YY, Chee YC. Long-term outcome and disease control in near-fatal asthma. Ann Acad Med Singapore  1999; 28(3):384-8

 

12 - Jalaludin BB, Smith MA, Chey T, Orr NJ, Smith WT, Leeder SR. Risk factors for asthma deaths: a population-based, case-control study. Aust N Z J Public Health  1999; 23(6):595-600

 

13 - Hessel PA, Mitchell I, Tough S, Green FH, Cockcroft D, Kepron W, Butt JC. Risk factors for death from asthma. Prairie Provinces Asthma Study Group. Ann Allergy Asthma Immunol  1999; 83(5):362-8

 

14 - Turner MO, Noertjojo K, Vedal S, Bai T, Crump S, Fitzgerald JM. Risk factors for near-fatal asthma. A case-control study in hospitalized patients with asthma. Am J Respir Crit Care Med. 1998; 157(6 Pt 1):1804-9.

 

15 - Strunk RC, Nicklas RA, Milgrom H, Ikle D. Fatal and near-fatal asthma questionnaire: prelude to a national registry. J Allergy Clin Immunol  1999; 104(4 Pt 1):763-8

 

16 - Kolbe J, Fergusson W, Vamos M, Garrett J. Case-control study of severe life threatening asthma (SLTA) in adults: demographics, health care, and management of the acute attack. Thorax  2000; 55(12):1007-15

 

17 - Hannaway PJ. Demographic characteristics of patients experiencing near-fatal and fatal asthma: results of a regional survey of 400 asthma specialists. Ann Allergy Asthma Immunol. 2000; 84(6):587-93.

 

18 - Moore BB, Wagner R, Weiss KB. A community-based study of near-fatal asthma. Ann Allergy Asthma Immunol. 2001; 86(2):190-5.

 

19 - Rufin RE., Latimer KM., Schembri DA. Longitudinal study of near fatal asthma. Chest. 1991; 99(1): 77-863

 

20 - Molfino NA., Nannini LJ., Rebuck AS., Slutsky AS. The fatality-prone asthmatic patient. Follow-up and study after near-fatal asthma. Chest 1992; 101: 621-23

 

21 - Vivès L., Fayas S., Fischer M.A., Vanche J., Cabréra J., Goyeau E., Biel P., Stambach Y., Farny M., Duffour M., Durand M., Didier A., Duchange M., Neukirch F., Charlet .P. Fatal asthma. Description and study of risk factors, in the heart of an asthmatic population followed by the College of Pneumonology of the Southwest. Rev Mal Resp 1997; 14:473-80

 

22 - American Thoracic Society   Standards for the diagnosis and care of patients with chronic obstrucitve pulmonary disease (C.O.P.D.) and asthma. Am Rev Resp Dis 1987; 136: 225-44

 

23 - Global initiative for asthma-global strategy for asthma management and prevention (NHLBI/WHO workshop report). National Institute of Health. Medical Communication Resources, Inc. Publication Number 95-3659; ppl-24, 69-117, 1995

 

24 - Strunk RC.      Identification of the fatality-prone subject with asthma. J. Allergy Clin Immunol 1989; 83 (2 part 1):477-85

 

25 - Molfino NA., Slutsky AS. Near-fatal asthma. Eur Resp J 1997; 7:981-90

 

26 - Grant EN, Lyttle CS, Weiss KB. The relation of socioeconomic factors and racial/ethnic differences in US asthma mortality. Am J Public Health  2000; 90(12):1923-5

 

27 - Innes NJ, Reid A, Halstead J, Watkin SW, Harrison BD. Psychosocial risk factors in near-fatal asthma and in asthma deaths. J R Coll Physicians Lond  1998; 32(5):430-4

 

28 - Rocco PL, Barboni E, Balestrieri M. Psychiatric symptoms and psychological profile of patients with near fatal asthma: absence of positive findings. Psychother Psychosom  1998; 67(2):105-8

 

29 - Williams C, Crossland L, Finnerty J, Crane J, Holgate S, Pearce N, Beasley R. Case-control study of salmeterol and near-fatal attacks of asthma. Thorax  1998; 53(1):7-13

 

30 - Ernst P., Habbick B., Suisa S., Hemmelgarn B., Cockcroft D., Buist S., Horwitz R., McNutt M., Spitzer WO. Is the association between Inhaled Beta-Agonist Use and Life-threatening Astma because of Confounding by Severity? Am Rev Respir Dis 1993; 148:75-9

 

31 - Matsuse H, Shimoda T, Matsuo N, Fukushima C, Takao A, Sakai H, Asai S, Kohno S. Aspirin-induced asthma as a risk factor for asthma mortality. J Asthma 1997; 34(5):413-7.

 

32 - Asamoto H, Kawakami A, Sato S, Sasaki Y. Clinical characteristics of near-fatal asthma attack induced by NSAIDs. Arerugi  1999; 48(11):1230-7

 

33 - Suissa S, Ernst P. Inhaled corticosteroids: impact on asthma morbidity and mortality. J Allergy Clin Immunol  2001; 107(6):937-44

 

34 - Ishihara K, Hasegawa T, Nishimura T, Okazaki M, Katakami N, Umeda B.          Increased use of inhaled corticosteroids and reduced hospitalizations in adult asthmatics: 11 years' experience in a Japanese hospital. Respirology  1998; 3(3):193-7

 

35 - Tough SC, Green FH, Paul JE, Wigle DT, Butt JC.         Sudden death from asthma in 108 children and young adults. J Asthma. 1996; 33(3):179-88.

 

36 - Rodrigo GJ, Rodrigo C. Rapid-onset asthma attack: a prospective cohort study about characteristics and response to emergency department treatment. Chest  2000; 118(6):1547-52

 

37 - Tonnel AB, Gosset P, Tillie-Leblond I. Characteristics of the Inflammatory response in bronchial lavage fluids from patients with status asthmaticus. Int Arch Allergy Immunol 2001; 124 (1-3):247-71

 

38 - Bai TR, Cooper J, Koelmeyer T, Pare PD, Weir TD. The effect of age and duration of disease on airway structure in fatal asthma.  Am J Respir Crit Care Med  2000; 162(2 Pt 1):663-9

 

39 - Fahy JV, Corry DB, Boushey HA. Airway inflammation and remodeling in asthma. Curr Opin Pulm Med  2000;6(1):15-20

 

40 - Wasserfallen JB, Leuenberger P, Schaller MD, Perret C. Extreme hypercapnia is not a long-term prognostic factor after near-fatal asthma: a 12-year follow-up study. Schweiz Med Wochenschr  1998; 28 128(9):323-30

 

41 - Abramson MJ, Bailey MJ, Couper FJ, Driver JS, Drummer OH, Forbes AB, McNeil JJ, Haydn Walters E. Are asthma medications and management related to deaths from asthma? Am J Respir Crit Care Med 2001; 163(1):12-8

 

42 - Josephs LK., Gregg I., Mullee MA., Holgate ST. Non-Specific Bronchial Reactivity and Its Relationship to the Clinical Expression of Asthma. A Longitudinal Study. Am Rev Respir Dis 1989; 140:350-57

 

43 - Cartier A, Malo JL. Role of non-allergenic bronchial hyperreactivity follow-up studies in the assessment of prognosis of asthma. Rev Mal Respir  1994; 11(2):209-15

 

44 - Peat JK, Toelle BG, Marks GB, Mellis CM. Continuing the debate about measuring asthma in population studies. Thorax  2001; 56(5):406-11

 

45 - Lee P, Abisheganaden J, Chee CB, Wang YT. A new asthma severity index: a predictor of near-fatal asthma? Eur Respir J 2001; 18(2):272-8

 

46 - Baker RR, Mishoe SC, Zaitoun FH, Arant CB, Lucas J, Rupp NT.      Poor perception of airway obstruction in children with asthma. J Asthma. 2000; 37(7):613-24.

 

47 - Kikuchi Y, Okabe S, Tamura G, Hida W, Homma M, Shirato K, Takishima T. Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med. 1994; 12 330(19):1329-34.

 

48 - Roisman GL, Peiffer C, Lacronique JG, Le Cae A., Dusser DJ. Perception of bronchial obstruction in asthmatic patients. J Clin Invest 1995;  (96): 12-21

 

49 - Connolly CK, Mamun M, Alcock SM, Prescott RJ. The Darlington and Northallerton Prospective Asthma Study: best function predicts mortality during the first 10 years. : Respir Med  1998;92(11):1274-80

 

50 - O'Sullivan S, Cormican L, Faul JL, Ichinohe S, Johnston SL, Burke CM, Poulter. Activated, cytotoxic CD8(+) T lymphocytes contribute to the pathology of asthma death. Am J Respir Crit Care Med  2001; 15 164(4):560-4

 

51 - Christodoulopoulos P, Leung DY, Elliott MW, Hogg JC, Muro S, Toda M, Laberge S, Hamid QA. Increased number of glucocorticoid receptor-beta-expressing cells in the airways in fatal asthma.        J Allergy Clin Immunol  2000; 106(3):479-84

 

52 - Sandford AJ, Chagani T, Zhu S, Weir TD, Bai TR, Spinelli JJ, Fitzgerald JM, Behbehani NA, Tan WC, Pare PD. Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J Allergy Clin Immunol 2000; 106(1 Pt 1):135-40

 

53 - Chagani T, Pare PD, Zhu S, Weir TD, Bai TR, Behbehani NA, Fitzgerald JM, Sandford AJ. Prevalence of tumor necrosis factor-alpha and angiotensin converting enzyme polymorphisms in mild/moderate and fatal/near-fatal asthma. Am J Respir Crit Care Med. 1999; 160(1):278-82.

 

54 - Weir TD, Mallek N, Sandford AJ, Bai TR, Awadh N, Fitzgerald JM, Cockcroft D, James A, Liggett SB, Pare PD. Beta2-Adrenergic receptor haplotypes in mild, moderate and fatal/near fatal asthma. Am J Respir Crit Care Med. 1998; 158(3):787-91.

 

55 - Hughes JM, Rimmer SJ, Salome CM, Hodge L, Liu-Brennan D, Woolcock AJ, Armour CL. Eosinophilia, interleukin-5, and tumour necrosis factor-alpha in asthmatic children. Allergy  2001; 56(5):412-8

 

56 - Hospers JJ, Schouten JP, Weiss ST, Rijcken B, Postma DS. Asthma attacks with eosinophilia predict mortality from chronic obstructive pulmonary disease in a general population sample. Am J Respir Crit Care Med  1999;160(6):1869-74

 

Retour vers le haut

*