Review
Respiration 2007;74:228–236
DOI: 10.1159/000097676
A Systematic Review of the Psychological
Risk Factors Associated with Near Fatal
Asthma or Fatal Asthma
G.G. Alvarez a J.M. FitzGerald b
a
Ottawa Health Research Institute of the University of Ottawa, and Respirology Division, Ottawa Hospital, Ottawa,
and b Center for Clinical Epidemiology and Evaluation of the University of British Columbia, and Respirology Division,
Vancouver General Hospital, Vancouver, Canada
Key Words
Systematic review
Near fatal asthma
Fatal asthma

Risk factors
Abstract
Psychological factors such as anxiety, depressive disorders
and/or personality disorders may predispose patients with
asthma to near fatal asthma (NFA) or fatal asthma (FA). NFA
is defined by an asthma exacerbation resulting in respiratory
arrest requiring mechanical ventilation or a pCO2 645 mm
Hg. Most studies have used the case-control study design.
Several studies analyzing the effects of psychological factors
on the risk of NFA or FA have shown conflicting results. We
reviewed all of the literature found by the systematic search
done of psychological factors on the risk NFA or FA. A MED-
LINE search identified 423 articles between 1960 and March
2006. Seven case-controlled studies were identified follow-
ing strict applications of the inclusion and exclusion criteria.
Due to the significant heterogeneity in the measurement of
the psychological factors, a summary statistic was not calcu-
lated. The trial characteristics were tabulated and qualitative
trends were observed to explain the heterogeneity in the
results of the studies. Recommendations on future studies in
the field are outlined in detail. Following a systematic assess-
ment of all published studies, we cannot conclude that psy-
chological factors increase the risk of NFA and FA.
Copyright © 2006 S. Karger AG, Basel
© 2006 S. Karger AG, Basel
0025–7931/07/0742–0228$23.50/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
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Received: June 28, 2006
Accepted after revision: September 28, 2006
Published online: November 30, 2006
Background
Approximately 300 million people suffer from asthma
in the world [1]. It is estimated that asthma accounts for
1 in every 250 deaths worldwide [1]. There are more than
5,000 deaths reported annually in the USA and 100,000
deaths estimated yearly throughout the world [1, 2].
Psychological factors such as anxiety disorders, de-
pressive disorders, coping mechanisms and abnormal
family dynamics of asthmatics may be associated with a
higher risk of near fatal asthma (NFA) or fatal asthma
(FA). Several hypotheses may explain the link between
psychological factors and NFA or FA.
Psychological factors may predispose patients directly
to an episode of NFA or FA. Emotional factors can be re-
sponsible for aggravating or maintaining asthma [3]. Emo-
tionally induced wheezing has been reported in several
studies [4]. Psychological factors may also be confused
with worsening asthma resulting in a vicious circle. For
example, worsening of anxiety may be confused with
worsening asthma and high levels of
-agonist may be in-
haled which then results in further worsening of the anxi-
ety [5]. Breathlessness is a common somatic accompani-
ment of anxiety [6]. Furthermore, the converse may be
true, asthma may increase the risk of developing an anxi-
ety disorder [7]. Psychological risk factors may predispose
asthmatics to improper asthma management which re-
sults in poor asthma control predisposing them to NFA or
Dr. Gonzalo G. Alvarez
Ottawa Health Research Institute of the University of Ottawa, and
Respirology Division, Ottawa Hospital, General Campus
501 Smyth Rd, Box 211, Rm 1835B, K1H 8L6 Ottawa (Canada)
Tel. +1 613 737 8899/ext. 78198, Fax +1 613 739 6266, E-Mail galvarez@ohri.ca

Psychological risk factors
Poor asthma control
NFA or FA
Fig. 1. Hypothetical links between psycho-
logical factors and NFA or FA.
FA. Ability to comply with asthma medications is influ-
enced by the psychological interaction between asthmatic
children and their families [8]. Many studies done in asth-
matic children have identified family dynamics as an im-
portant risk factor for poor asthma control. Disturbed
family cohesion had a negative correlation with peak expi-
ratory flow rates or hyperresponsiveness in asthmatic chil-
dren [9]. Family interaction in families of asthmatic chil-
dren may tend to be rigid, overprotecting and may avoid
conflict [9]. Family dynamics are sometimes altered nega-
tively following an NFA episode [5]. Some of the psycho-
logical defenses or coping styles used by asthmatics include
a ‘hopeless dependency’ on physicians and hospital servic-
es or they may have inappropriate excessive independence
where they are in denial of their illness [10]. Increasing de-
nial is an adaptive mechanism to cope with chronic ill-
nesses yet retain a normal social agenda [5]. Denial of asth-
ma severity could certainly result in patients not following
appropriate action plans or a delay in seeking medical at-
tention which could result in a NFA/FA episode (fig. 1).
Identification of high-risk patients according to their
specific psychological profile could allow healthcare
teams to intervene earlier and prevent NFA or FA from
occurring. Severe asthmatics could get a psychological
assessment to determine if any pathology exists. Psychi-
atric therapy and treatment could become part of the in-
tervention strategy.
We present a systematic review of all the available lit-
erature on the subject with consideration of possible
sources of heterogeneity between studies and conclude by
a series of recommendations regarding future studies. We
qualitatively reviewed the existing studies noting meth-
odological shortcomings in hopes that such a critique
may inform further research studies.
Systematic Review of Psychological Risk
Factors Associated with NFA or FA
Methods
Exposure, Outcome and Population Definitions
The exposure is defined as a psychological abnormality. The
outcome is NFA defined as an asthma exacerbation resulting in
respiratory arrest requiring mechanical ventilation or a pCO2
1 45 mm Hg [11, 12]. NFA and subjects who had FA were presumed
to be part of the same pathophysiological spectrum [13, 14]. NFA
is considered by many to be a good surrogate marker of FA [11,
15–19]. This is true because if patients with NFA did not receive
medical attention they would inevitably become a fatal case of asth-
ma [14]. Furthermore, these two groups share many characteristics
thus allowing NFA episodes to be a proxy measure for FA [19]. The
population is defined as persons diagnosed with asthma as defined
by the ATS (American Thoracic Society) standards [20].
Literature Search
A literature search in MEDLINE (1960–March 2006 inclusive)
was conducted by one of the investigators (G.G.A.). The following
search strategy was used in PubMed: (‘psychology’ [Subheading]
OR ‘Mood Disorders’ [MeSH] OR (‘Dependency (Psychology)’
[MeSH] OR ‘Codependency (Psychology)’ [MeSH])) AND (‘Fatal
Outcome’ [MeSH] AND ‘Death’ [MeSH] OR ‘fatal outcome’ [All
Fields] OR ‘life threatening’ [Text Word] OR ‘near fatal’ [All
Fields]) AND (‘asthma’ [MeSH Terms] OR asthma [Text Word]).
We also searched citations from published reviews, the original
articles, expert opinion and our own extensive bibliography. The
literature search was cross-checked by a university librarian at
The Harvard School of Public Health to ensure reproducibility
and that no other new citations were identified.
Inclusion and Exclusion Criteria
The inclusion criteria included: (1) NFA defined as an asthma
exacerbation resulting in respiratory arrest requiring mechanical
ventilation or a pCO2 645 mm Hg or asthma resulting in death
(FA); (2) the number of cases (NFA and/or FA) and controls re-
ported; (3) explicit reporting of risk factors; (4) adult and pediat-
ric cases, and (5) all study types. The exclusion criteria included:
(1) case series since they do not contain controls; (2) studies that
included COPD patients; (3) studies that contained only patients
over the age of 65 years were excluded to minimize COPD overlap,
and (4) studies in a language other than English. One of us
(G.G.A.) identified all potentially relevant articles from the ab-
stracts yielded via the comprehensive search strategy. Any study
that used human subjects that included the terms NFA or FA or
SLTA (severe life-threatening asthma) or asthma and the word
death in the abstract was examined in detail. Using a standard-
ized data extraction sheet that was developed for the purpose of
the study, each of the identified potentially relevant articles had
the data abstracted by two observers independently (G.G.A.,
J.M.F.). Data extraction sheets were filled out for each article and
then entered into an Excel spreadsheet. Differences were resolved
by consensus. Appendix 1 lists the reasons for exclusion.
Quantitative Summary Appropriateness
The data in this systematic review were not summarized in a
quantitative manner due to the following three reasons: (1) Sig-
nificant heterogeneity was detected in the measurement of the
exposure. Three different categories were identified: (a) psychiat-
ric illness assessed by reviewing medical records; (b) psychomet-
Respiration 2007;74:228–236 229
Table 1. Summary of case-control studies of psychological factors associated with NFA/FA

Group Sample size Disorder studied Data acquisition Measure Assoc.1

(first author) case/control

Yellowlees [22] 13/36 Panic, phobia, depressive, Interview with patient DSM-III No
PTSD
Barboni [23] 17/17 Personality, depression, Interview with patient DSM-IV, Zung, No
anxiety (>2 weeks after NFA) Hamilton, MMPI
Kolbe [14] 77/239 Social support, life event, Interview with patient (24–72 h HAD scale Yes2
attitudes and belief scales after admission to general ward
from ICU
Boulet [24] 19/19 Personality Interview with patient MMPI scale Yes
Strunk [25] 108/108 A battery of psychological Medical records Interviews with psychiatric No
variables staff, obtained from chart
Rea [26] 21/21 Personality, depression, Quest given to proxy, relative Info from medical Yes
alcoholic, unemployed, or friend, 6–8 weeks after FA records
bereaved
Ernst [16] 44/39 Conflict, depression Medical records or phys. quest. Info from medical records No
1
Types of scales used: DSM = clinical criteria applied by a clini- Significant association between psychological disorder as
cian; MMPI = Minnesota Multiphasic Personality Inventory, per- measured by the scale and odds ratio for NFA or FA: Yes = psy-
sonality psychometric assessment about 655 questions; HAD = chological risk factors are associated with NFA or FA; No = psy-
Hospital Anxiety and Depression scale measures the level of anx- chological risk factors are associated with NFA or FA.
iety and depression, specific for the distress in physically ill sub- 2 ‘Adverse psychological factors were more common in those

jects, and state and anxiety assessed on visual analogue scale.
Caseness for anxiety and/or depression was defined as a HAD
score >11; Zung score = (A) anxiety score and (D) depression
score; Hamilton Score = (A) anxiety score and (D) depression
score.
admitted (NFA and hospital controls) than in the community-
based control group, that is, adverse psychological factors are a
risk factor for admission for acute severe asthma.’

ric tests measuring personality, anxiety and depression, and
(c) family members were interviewed by proxy for those patients
that endured FA. (2) Significant heterogeneity was detected in the
measurement of outcome as a result of different definitions for
NFA. (3) Lastly, several studies did not provide enough data to
calculate weighted mean differences since only p values were pro-
vided. We present a systematic review that will qualitatively focus
on key components of design and differences found rather than
quantitative aggregate scores. A formal meta-analysis was not
done since summation of individual trials would likely have re-
sulted in misleading conclusions. We followed the MOOSE Group
proposal for reporting observational studies in this systematic re-
view [21].
Results
We identified 423 potentially relevant articles from
several comprehensive searches. Review of the abstracts
of these articles yielded 47 potentially relevant articles
that met the study inclusion criteria. Of these, we exclud-
ed 40 articles (Appendix 1); 18 were excluded because
they studied risk factors for NFA and FA other than psy-
chological factors; 6 articles were case series and did not
contain controls; 3 compared NFA to FA; 3 studied severe
asthmatics but not NFA or FA; 1 included COPD patients;
1 published the same results twice; 8 did not meet the
NFA definition in the inclusion criteria, and 1 was an
editorial. Seven case-controlled studies met the inclusion
and exclusion criteria. No other observational type stud-
ies were discovered (table 1).
Exposure Assessment
Some studies assessed psychological factors (the expo-
sure) by examining the medical records [25–27]. The lim-
itation in this method is that patient’s medical records
reflect their medical encounters that may or may not have
been associated with their psychological profile. Further-
more, even if the psychological profile was assessed, if the
healthcare team did not write it in the chart the exposure

230 Respiration 2007;74:228–236 Alvarez /FitzGerald

 Table 2. NFA and FA outcome definitions
Group Assoc. ICU
(first author) adm.
Yellowlees [22] No
Barboni [23] No
Kolbe [14] Yes 冪 冪
Boulet [24] Yes 冪 冪
Ernst [16] No
Strunk [25] Yes F A
Rea [26] Yes
MV = Mechanical ventilation.
* Used pCO2 >45 mm Hg.
could not be detected. An interview with the patient is a
more precise manner in obtaining the data. Some studies
interviewed patients but only asked them yes or no ques-
tions about anxiety or depression or personality disor-
ders. The limitation in this method is its tendency to re-
sult in bias. Patients tend to interpret conditions such as
anxiety differently and their assessment of themselves
may not be accurate. A more robust manner to assess a
patient’s psychological profile is to actually measure it
with standardized psychometric questionnaires. Several
of the studies used such scales or scoring methods de-
pending on the psychological factor of interest. The
MMPI score is a personality inventory. The HAD score
measures the level of anxiety and depression, specific for
the distress in physically ill subjects, and state and anxi-
ety assessed on visual analogue scale. The Zung and
Hamilton scores measure anxiety and depression. Future
studies should delineate clearly what psychological pa-
rameters will be studied and use validated scores such as
these to obtain more objective and reproducible measures
of psychological problems. Studies using a standardized
psychometric measurement will produce more reproduc-
ible, comparable and accurate reflection of psychopathol-
ogy. Although we did not develop a quality score because
they may lack validity [28], studies that used standard-
ized scales were considered to be of higher quality. An-
other important point brought out by the studies is the
timing of the interview. The timing of the interview
should ideally occur prior to the discharge of the patient
following the NFA episode. Some studies collected data
many months after the episode had occurred which could
introduce recall bias or the patient’s psychological factor
may have improved since the event.
Systematic Review of Psychological Risk
Factors Associated with NFA or FA
Cardio- MV pH <7.2 PCO2 Alteration
pulm. >50 mm Hg or loss of
arrest consciousness
冪 冪
冪 冪 冪 冪
冪 冪 冪 冪
冪 冪*
冪 冪*
T A L
冪 冪
Outcomes Assessment
Different studies used various definitions for NFA.
Several studies recommend the definition of intubation
resulting in mechanical ventilation or a pCO2 1 45 mm
Hg during a hospitalization for asthma. Some studies
used pCO2 150 mm Hg which would have missed asth-
matics that were between 45 and 49 mm Hg. Several stud-
ies included a pH of 17.2 that would imply an elevated
pCO2. Other studies included the term alteration or loss
of consciousness [14, 22, 23, 26]. Using this term (e.g., re-
spiratory failure OR alteration or loss of consciousness)
introduces a problem since patients may have been in-
cluded for alteration or loss of consciousness alone and
not for NFA specifically [23]. One study [25] used FA as
the outcome, however the ability of the investigators to
adequately extract information on the patients’ psycho-
logical profiles was limited. The investigators had to ask
family members to answer questions by proxy. This prac-
tice is not ideal since it introduces observer bias since
family members may or may not be aware of the psycho-
logical problems faced by the patient. Instead we propose
using NFA as a surrogate or proxy for FA as interviews
with patients with NFA can capture the psychological ab-
normalities experienced by the patients with more preci-
sion. Furthermore, NFA is known to be a good proxy for
FA [11, 15–19]. Amongst studies that used a standard
scale to measure psychological profiles [14, 22–24] and
showed an association between psychological factors and
NFA or FA, a more precise definition of NFA was used.
Amongst studies that used a standard scale and did not
find an association between the outcome and exposure,
a less precise definition of NFA was used [22, 23]. The
studies that did not use a precise definition may have di-
Respiration 2007;74:228–236 231
 Table 3. Details of controls in each study

Group Assoc. Sampling Matching factor Control type

(first author) of controls

Yellowlees [22] No Matched Age and gender Community

Barboni [23] No Random None Community
Kolbe [14] Yes Matched Date of event Com. & Hosp.1
Boulet [24] Yes Matched Age, sex, atopy, med. and baseline FEV1 Do not report
Ernst [16] No Matched Matched sets Community
Strunk [25] Yes Matched Gender, age, race and severity of illness Community
Rea [26] Yes Matched Age, gender, race and date of event Hospital
1
‘Adverse psychological factors were more common in those admitted (NFA and hospital controls) than in
the community-based control group, that is, adverse psychological factors are a risk factor for admission for
acute severe asthma.’

luted the effect of the exposure amongst individuals that
may not have had NFA (table 2).
Controls were fairly heterogeneous between studies.
Most matched on age, gender and date of event, but many
matched on different variables including race, severity,
baseline FEV1. Most of the studies compared cases to
community controls, one of them [14] compared cases to
hospital and community controls separately and another
[26] compared cases to only hospital controls.
The evidence for psychological risk factors associated
with NFA/FA is equivocal. Three studies by Yellowlees
et al. [22], Barboni et al. [23] and Ernst et al. [27] were
positive and three by Boulet et al. [24], Strunk et al. [25]
and Rea et al. [26] were negative. The seventh paper by
Kolbe et al. [14] found that psychopathology existed
more frequently amongst all admitted patients includ-
ing those with NFA when compared to community con-
trols, however they did not find a difference between
NFA/FA and admitted patients with acute asthma with
no NFA.
Discussion
A systematic review of all published studies was not
able to conclude that psychological factors increase the
risk of NFA and FA. Due to the significant heterogeneity
in the measurement of the psychological factors, a sum-
mary statistic was not calculated. Instead, the trial char-
acteristics were tabulated and qualitative trends were ob-
served to explain the heterogeneity in the results of the
studies.
Quality, Validity and Bias in the Identified Studies
Two major factors that can significantly affect the
quality, validity and bias of case-control studies are selec-
tion of the control group and exposure status [29]. We
identified the manner in which each control group was
chosen, the matching factor and the control type (com-
munity vs. hospital) in each study (table 3) in order to
compare them. Choice of controls is paramount in these
studies since different results were obtained when differ-
ent controls were used. For instance, Kolbe et al. [14]
showed that psychological factors played an important
role in the risk of being admitted with asthma but did not
show a difference between those that were admitted to
hospital and those that had NFA or FA. The conclusion
of this study was that psychological factors increased the
risk of admission but did not necessarily increase the risk
of a NFA or FA episode. Controls should be matched for
index date, age, gender and explicitly categorized as a
community or hospital control. It may be more instruc-
tive to use community controls to better illustrate the ef-
fect of psychological risk factors on asthmatics.
The exposure to psychological risk factors needs to be
measured with an objective validated psychometric test.
Although validated psychometric tests exist, not all stud-
ies used the same tests. Studies using such tests were gen-
erally of higher quality than those that did not. The test-
ing or questionnaire must be given in a reasonable period
of time preferably within close proximity to the NFA
event to minimize bias. A review of the medical records
is not ideal since it is fraught with recall bias as well as
recording bias. Cases need a consistent definition of
NFA which should include: (1) mechanical ventilation;
(2) pCO2 1 45 mm Hg, and (3) cardiopulmonary arrest

232 Respiration 2007;74:228–236 Alvarez /FitzGerald

should not on its own include altered level of conscious-
ness as it may introduce bias in the definition since pa-
tients with level of consciousness alone may in fact not
have NFA. The American and Canadian Thoracic Societ-
ies should come up with a standardized definition of
NFA.
Asthma severity is an issue in many of the studies in
our systematic review in that the cases may have had
more severe disease than the controls. Most patients were
matched for age and gender but few were matched for
asthma severity. Only Strunk et al. [25] attempted to con-
trol for severity, however it is not clear what method was
used. Ernst et al. [27] attempted to further adjust for asth-
ma severity in a study of the association of inhaled
-
agonist use and NFA [30]. They showed that after at-
tempting to adjust for confounding by severity, the over-
all effect of the use of a
-agonist and the risk of NFA was
unchanged, suggesting that confounding by severity was
less of a problem when studying NFA. Furthermore, NFA
or FA may occur to asthmatic patients belonging to the
whole spectrum of disease, from mild to severe asthma
[31] providing further evidence that asthma severity may
not be an important confounder in these studies. It is not
only confined to patients with severe disease but can af-
fect patients with mild disease as well [31]. It is very dif-
ficult to categorize patients with asthma in a manner
which is reproducible. In the 2005 Global Initiative on
Asthma (GINA), asthma severity is categorized into four
groups using an evidenced-based approach: intermittent,
mild persistent, moderate persistent, and severe. Unfor-
tunately, this has not translated into a clean tool to be
used by epidemiologists around the world because it still
remains a challenge to categorize the severity of asthma
in a way that will be easily reproduced given the dynam-
ic and complex nature of the disease. The document states
that any patients at any level of severity – even intermit-
tent asthma – can have severe attacks.
Quality and Bias in the Systematic Review
The quality of the systematic review was enhanced by
independent assessment of trials using a standardized
data extraction sheet that was used independently by two
investigators. An independent librarian (A.G.) tested the
reproducibility of the literature search. Bias may have
been introduced since the non-published data and non-
English papers were not included in the systematic re-
view. Publication bias was not assessed given that meth-
odological differences and heterogeneity were found in
the analysis of the trials.
Systematic Review of Psychological Risk
Factors Associated with NFA or FA
Study Design
A randomized controlled study would be impossible
to carry out to answer the clinical question being posed
since patients cannot be given psychological abnormali-
ties. Furthermore, a prospective cohort study, although
not impossible, would be challenging and costly since
NFA or FA is a rare event and many person-years of pa-
tient follow-up would have to be accrued to discern the
issue. A well-designed large case-controlled study could
further research in this field. Another design that has not
been used to study psychological risk factors in NFA is
the case cross-over design [32]. The case cross-over de-
sign is used to identify transient risks that are associated
with intermittent exposures. In order to find out if indi-
viduals were experiencing a psychological event or life
stressor prior to the NFA episode, this design would be
useful and cost-efficient. In this type of design the com-
parison is between different exposure periods (hazard
period and non-hazard period) within individuals in-
stead of between individuals. Incident cases of NFA could
be identified by a national or provincial registry. Cases
could be identified by intensive care unit medical admis-
sion records identifying anyone who was mechanically
ventilated or had a pCO2 1 45 mm Hg as a result of an
asthma attack. The cases would then be interviewed a
week after the episode to ensure accurate recall of the
events preceding the NFA episode. The week before the
NFA episode can be used as the hazard period for the
matched analysis. Exposure to a psychological risk factor
or stressor like a life event could be measured using a
validated scale proposed by Tennant and Andrews [33]
which allows the significance of life events to be scaled.
Possible problems with this design include the fact many
patients decompensate psychologically following a NFA
episode [5] and it may be difficult to ascertain how the
patient was feeling prior to the event, however if the scale
is applied promptly after the event this effect may be min-
imized.
Key Recommendations for Future Studies
Recommendations include: (1) Use of standardized
psychometric tests to assess exposure. (2) Interviews
should be done within a close time frame from the NFA
event. (3) Use of a standardized definition of NFA.
(4) Studies should not include COPD patients as this is a
different pathophysiological process. Excluding patients
older than age 35 would essentially eliminate the risk of
disease misclassification and allow for a firm diagnosis
of obstructive lung disease due to asthma [1]. (5) Con-
sider using the case cross-over study design.
Respiration 2007;74:228–236 233
 In summary: The systematic review presented is in- Acknowledgements
tended to generate discussion using the current literature
The author would like to thank Anna Getselman, Assistant
and explain some of the heterogeneity observed amongst Director for Reference and Education Services at the Countway
the current case-control studies. A formal meta-analysis Library of Medicine, for cross-checking our search findings and
was not done therefore a summary static was not calcu- to Emily Levitan, PhD, candidate and Teaching Assistant at Har-
lated since it would have been misleading given the het- vard University for her advice on the project.
erogeneity of the studies. There remains much to be stud-
ied in this field, however at this time we cannot defini-
tively conclude that psychological disorders increase the
risk of NFA and FA.

Appendix Excluded Articles

No. Group (first author) Year Reason for exclusion

1 Campbell [11] 1994 Compared NFA to FA

2 Campbell [34] 1995 Case series, no controls
3 Godding [35] 1997 Not all NFA cases
4 Innes [36] 1998 Compared NFA to FA
5 Janson [37] 1994 Not NFA or FA
6 Martin [38] 1995 Case series, no controls
7 Miller [39] 1989 Compared NFA to FA
8 Rocco [40] 1998 Published same data from Barboni
9 Sturdy [41] 2002 Used COPD patients (40%)
10 Wjst [42] 1996 No NFA or FA but regular asthma
11 Yellowlees [5] 1989 Case series, no controls
12 Kean [43] 2006 NFA definition not met (incl. criteria)
13 Turner [44] 1998 Psychological factors not assessed
14 Davenport [45] 2001 Psychological factors not assessed
15 Kesten [46] 1995 Psychological factors not assessed
16 Suissa [47] 2000 Psychological factors not assessed
17 Suissa [48] 1994 Psychological factors not assessed
18 Spitzer [30] 1992 Psychological factors not assessed
19 Joseph [49] 1996 Psychological factors not assessed
20 O’Hollaren [50] 1991 Psychological factors not assessed
21 Lanes [51] 2002 Psychological factors not assessed
22 de Klerk [52] 2002 Psychological factors not assessed
23 Tanihara [53] 2002 Psychological factors not assessed
24 Crane [54] 1989 Psychological factors not assessed
25 Tough [55] 1998 Psychological factors not assessed
26 Corn [56] 1995 Psychological factors not assessed
27 Hessel [57] 1999 Psychological factors not assessed
28 Mitchell [58] 2002 Psychological factors not assessed
29 Dhuper [59] 2003 Psychological factors not assessed
30 Kikuchi [60] 1994 Psychological factors not assessed
31 Heaney [61] 2005 No controls
32 Garden [62] 1993 Not NFA or FA
33 Vamos [63] 1999 No controls
34 Romero-Frais [64] 2005 No controls
35 Kean [43] 2006 Not NFA or FA
36 Gillaspy [65] 2002 Not NFA or FA
37 Goodwin [66, 67] 2004 Not NFA or FA
38 Pendergraft [68] 2004 Not NFA or FA
39 Adams [69] 2004 Not NFA or FA

234 Respiration 2007;74:228–236 Alvarez /FitzGerald

 References
1 Masoli M, Fabian D, Holt S, Beasley R: The
global burden of asthma: executive summa-
ry of the GINA Dissemination Committee
report. Allergy 2004;59:469–478.
2 National Heart LaBI: Guidelines for the Di-
agnosis and Management of Asthma, Expert
Panel Report 2, 1997, Publ No 97-4051.
3 Godfrey S, Silverman M: Demonstration by
placebo response in asthma by means of ex-
ercise testing. J Psychosom Res 1973;17:293–
297.
4 Rodenstein DO, Francis C, Stanescu DC:
Emotional laryngeal wheezing: a new syn-
drome. Am Rev Respir Dis 1983; 127: 354–
356.
5 Yellowlees PM, Ruffin RE: Psychological de-
fenses and coping styles in patients following
a life-threatening attack of asthma. Chest
1989;95:1298–1303.
6 Bass C, Gardner W: Emotional influences on
breathing and breathlessness. J Psychosom
Res 1985;29:599–609.
7 Yellowlees PM, Kalucy RS: Psychobiological
aspects of asthma and the consequent re-
search implications. Chest 1990; 97: 628–
634.
8 Weinstein AG, Faust D: Maintaining the-
ophylline compliance/adherence in severely
asthmatic children: the role of psychologic
functioning of the child and family. Ann Al-
lergy Asthma Immunol 1997;79:311–318.
9 Gustafsson PA, Kjellman NI, Ludvigsson J,
Cederblad M: Asthma and family interac-
tion. Arch Dis Child 1987;62:258–263.
10 Dirks JF, Schraa JC, Brown EL, Kinsman RA:
Psycho-maintenance in asthma: hospitaliza-
tion rates and financial impact. Br J Med Psy-
chol 1980;53:349–354.
11 Campbell DA, McLennan G, Coates JR, Frith
PA, Gluyas PA, Latimer KM, Luke CG, Mar-
tin AJ, Roder DM, Ruffin RE, et al: A com-
parison of asthma deaths and near-fatal
asthma attacks in South Australia. Eur
Respir J 1994;7:490–497.
12 Molfino NA, Nannini LJ, Rebuck AS, Slutsky
AS: The fatality-prone asthmatic patient.
Follow-up study after near-fatal attacks.
Chest 1992;101:621–623.
13 Molfino NA, Nannini LJ, Martelli AN,
Slutsky AS: Respiratory arrest in near-fatal
asthma. N Engl J Med 1991;324:285–288.
14 Kolbe J, Fergusson W, Vamos M, Garrett J:
Case-control study of severe life-threatening
asthma (SLTA) in adults: psychological fac-
tors. Thorax 2002;57:317–322.
15 Burgess C, Pearce N, Thiruchelvam R,
Wilkinson R, Linaker C, Woodman K, Crane
J, Beasley R: Prescribed drug therapy and
near-fatal asthma attacks. Eur Respir J 1994;
7:498–503.
16 Ernst P, Spitzer WO, Suissa S, Cockcroft D,
Habbick B, Horwitz RI, Boivin JF, McNutt
M, Buist AS: Risk of fatal and near-fatal asth-
ma in relation to inhaled corticosteroid use.
JAMA 1992;268:3462–3464.
Systematic Review of Psychological Risk
Factors Associated with NFA or FA
17 Garrett JE, Lanes SF, Kolbe J, Rea HH: Risk
of severe life-threatening asthma and
-ago-
nist type: an example of confounding by se-
verity. Thorax 1996;51:1093–1099.
18 Beasley R, Pearce N, Crane J: Use of near fatal
asthma for investigating asthma deaths.
Thorax 1993;48:1093–1094.
19 Richards GN, Kolbe J, Fenwick J, Rea HH:
Demographic characteristics of patients
with severe life-threatening asthma: com-
parison with asthma deaths. Thorax 1993;
48:1105–1109.
20 American Thoracic Society: Lung function
testing: selection of reference values and in-
terpretative strategies. Am Rev Respir Dis
1991;144:1202–1218.
21 Stroup DF, Berlin JA, Morton SC, Olkin I,
Williamson GD, Rennie D, Moher D, Becker
BJ, Sipe TA, Thacker SB: Meta-analysis of
observational studies in epidemiology: a pro-
posal for reporting. Meta-analysis of Obser-
vational Studies in Epidemiology (MOOSE)
group. JAMA 2000;283:2008–2012.
22 Yellowlees PM, Haynes S, Potts N, Ruffin
RE: Psychiatric morbidity in patients with
life-threatening asthma: initial report of a
controlled study. Med J Aust 1988; 149: 246–
249.
23 Barboni E, Peratoner A, Rocco PL, Sabadini
P: Near fatal asthma and psychopathological
characteristics: a group-control study. Mo-
naldi Arch Chest Dis 1997;52:339–342.
24 Boulet LP, Deschesnes F, Turcotte H, Gignac
F: Near-fatal asthma: clinical and physiolog-
ic features, perception of bronchoconstric-
tion, and psychologic profile. J Allergy Clin
Immunol 1991;88:838–846.
25 Strunk RC, Mrazek DA, Fuhrmann GS, La-
Brecque JF: Physiologic and psychological
characteristics associated with deaths due to
asthma in childhood. A case-controlled
study. JAMA 1985;254:1193–1198.
26 Rea HH, Scragg R, Jackson R, Beaglehole R,
Fenwick J, Sutherland DC: A case-control
study of deaths from asthma. Thorax 1986;
41:833–839.
27 Ernst P, Habbick B, Suissa S, Hemmelgarn B,
Cockcroft D, Buist AS, Horwitz RI, McNutt
M, Spitzer WO: Is the association between
inhaled
-agonist use and life-threatening
asthma because of confounding by severity?
Am Rev Respir Dis 1993;148:75–79.
28 Juni P, Witschi A, Bloch R, Egger M: The
hazards of scoring the quality of clinical tri-
als for meta-analysis. JAMA 1999;282:1054–
1060.
29 Schulz KF, Grimes DA: Case-control studies:
research in reverse. Lancet 2002; 359: 431–
434.
30 Spitzer WO, Suissa S, Ernst P, Horwitz RI,
Habbick B, Cockcroft D, Boivin JF, McNutt
M, Buist AS, Rebuck AS: The use of
-ago-
nists and the risk of death and near death
from asthma. N Engl J Med 1992; 326: 501–
506.
Respiration 2007;74:228–236
31 Ruffin RE, Latimer KM, Schembri DA: Lon-
gitudinal study of near fatal asthma. Chest
1991;99:77–83.
32 Mittleman MA, Maclure M, Tofler GH, Sher-
wood JB, Goldberg RJ, Muller JE: Triggering
of acute myocardial infarction by heavy
physical exertion. Protection against trigger-
ing by regular exertion. Determinants of
Myocardial Infarction Onset Study Investi-
gators. N Engl J Med 1993;329:1677–1683.
33 Tennant C, Andrews G: A scale to measure
the stress of life events. Aust NZ J Psychiatry
1976;10:27–32.
34 Campbell DA, Yellowlees PM, McLennan G,
Coates JR, Frith PA, Gluyas PA, Latimer KM,
Luke CG, Martin AJ, Ruffin RE: Psychiatric
and medical features of near fatal asthma.
Thorax 1995;50:254–259.
35 Godding V, Kruth M, Jamart J: Joint consul-
tation for high-risk asthmatic children and
their families, with pediatrician and child
psychiatrist as co-therapists: model and
evaluation. Fam Process 1997;36:265–280.
36 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;32:430–434.
37 Janson C, Bjornsson E, Hetta J, Boman G:
Anxiety and depression in relation to respi-
ratory symptoms and asthma. Am J Respir
Crit Care Med 1994;149:930–934.
38 Martin AJ, Campbell DA, Gluyas PA, Coates
JR, Ruffin RE, Roder DM, Latimer KM, Luke
CG, Frith PA, Yellowlees PM, et al: Charac-
teristics of near-fatal asthma in childhood.
Pediatr Pulmonol 1995;20:1–8.
39 Miller BD, Strunk RC: Circumstances sur-
rounding the deaths of children due to asth-
ma. A case-control study. Am J Dis Child
1989;143:1294–1299.
40 Rocco PL, Barboni E, Balestrieri M: Psychi-
atric symptoms and psychological profile of
patients with near fatal asthma: absence of
positive findings. Psychother Psychosom
1998;67:105–108.
41 Sturdy PM, Victor CR, Anderson HR, Bland
JM, Butland BK, Harrison BD, Peckitt C,
Taylor JC: Psychological, social and health
behaviour risk factors for deaths certified as
asthma: a national case-control study. Tho-
rax 2002;57:1034–1039.
42 Wjst M, Roell G, Dold S, Wulff A, Reitmeir
P, Fritzsch C, Seth V, Nicolai T, von Mutius
E, Bach H, Thiemann HH: Psychosocial
characteristics of asthma. J Clin Epidemiol
1996;49:461–466.
43 Kean EM, Kelsay K, Wamboldt F, Wamboldt
MZ: Posttraumatic stress in adolescents with
asthma and their parents. J Am Acad Child
Adolesc Psychiatry 2006; 45:78–86.
44 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;157:1804–1809.
235
45 Davenport PW, Kifle Y: Inspiratory resistive
load detection in children with life-threaten-
ing asthma. Pediatr Pulmonol 2001; 32: 44–
48.
46 Kesten S, Chew R, Hanania NA: Health-care
utilization after near-fatal asthma. Chest
1995;107:1564–1569.
47 Suissa S, Ernst P, Benayoun S, Baltzan M, Cai
B: Low-dose inhaled corticosteroids and the
prevention of death from asthma. N Engl J
Med 2000;343:332–336.
48 Suissa S, Blais L, Ernst P: Patterns of increas-
ing
-agonist use and the risk of fatal or
near-fatal asthma. Eur Respir J 1994;7:1602–
1609.
49 Joseph KS, Blais L, Ernst P, Suissa S: In-
creased morbidity and mortality related to
asthma among asthmatic patients who use
major tranquillisers. BMJ 1996;312:79–82.
50 O’Hollaren MT, Yunginger JW, Offord KP,
Somers MJ, O’Connell EJ, Ballard DJ, Sachs
MI: Exposure to an aeroallergen as a possible
precipitating factor in respiratory arrest in
young patients with asthma. N Engl J Med
1991;324:359–363.
51 Lanes SF, Garcia Rodriguez LA, Huerta C:
Respiratory medications and risk of asthma
death. Thorax 2002;57:683–686.
52 De Klerk A, van Schalkwyk E, Williams Z,
Lee W, Bardin P: Risk factors for near-fatal
asthma – a case-control study in a Western
Cape teaching hospital. S Afr Med J 2002;92:
140–144.
236 Respiration 2007;74:228–236
53 Tanihara S, Nakamura Y, Matsui T, Nishima
S: A case-control study of asthma death and
life-threatening attack: their possible rela-
tionship with prescribed drug therapy in Ja-
pan. J Epidemiol 2002;12:223–228.
54 Crane J, Pearce N, Burgess C, Beasley R: Fe-
noterol and asthma death. NZ Med J 1989;
102:356–357.
55 Tough SC, Hessel PA, Ruff M, Green FH,
Mitchell I, Butt JC: Features that distinguish
those who die from asthma from community
controls with asthma. J Asthma 1998; 35:
657–665.
56 Corn B, Hamrung G, Ellis A, Kalb T, Sperber
K: Patterns of asthma death and near-death
in an inner-city tertiary care teaching hospi-
tal. J Asthma 1995;32:405–412.
57 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;83:362–368.
58 Mitchell I, Tough SC, Semple LK, Green FH,
Hessel PA: Near-fatal asthma: a population-
based study of risk factors. Chest 2002; 121:
1407–1413.
59 Dhuper S, Maggiore D, Chung V, Shim C:
Profile of near-fatal asthma in an inner-city
hospital. Chest 2003;124:1880–1884.
60 Kikuchi Y, Okabe S, Tamura G, Hida W,
Homma M, Shirato K, Takishima T: Chemo-
sensitivity and perception of dyspnea in pa-
tients with a history of near-fatal asthma. N
Engl J Med 1994;330:1329–1334.
61 Heaney LG, Conway E, Kelly C, Gamble J:
Prevalence of psychiatric morbidity in a dif-
ficult asthma population: relationship to
asthma outcome. Respir Med 2005;99:1152–
1159.
62 Garden GM, Ayres JG: Psychiatric and social
aspects of brittle asthma. Thorax 1993; 48:
501–505.
63 Vamos M, Kolbe J: Psychological factors in
severe chronic asthma. Aust NZ J Psychiatry
1999;33:538–544.
64 Romero-Frais E, Vazquez MI, Sandez E,
Blanco-Aparicio M, Otero I, Verea H: Pre-
scription of oral corticosteroids in near-fatal
asthma patients: relationship with panic-
fear, anxiety and depression. Scand J Psychol
2005;46:459–465.
65 Gillaspy SR, Hoff AL, Mullins LL, Van Pelt
JC, Chaney JM: Psychological distress in
high-risk youth with asthma. J Pediatr Psy-
chol 2002;27:363–371.
66 Goodwin RD, Fergusson DM, Horwood LJ:
Asthma and depressive and anxiety disor-
ders among young persons in the commu-
nity. Psychol Med 2004; 34:1465–1474.
67 Goodwin RD, Marusic A: Asthma and sui-
cidal ideation among youth in the commu-
nity. Crisis 2004;25:99–102.
68 Pendergraft TB, Stanford RH, Beasley R,
Stempel DA, Roberts C, McLaughlin T: Rates
and characteristics of intensive care unit ad-
missions and intubations among asthma-re-
lated hospitalizations. Ann Allergy Asthma
Immunol 2004;93:29–35.
69 Adams RJ, Wilson D, Smith BJ, Ruffin RE:
Impact of coping and socioeconomic factors
on quality of life in adults with asthma. Res-
pirology 2004; 9:87–95.
Alvarez /FitzGerald