DISCUSSION
The aim of this study was to evaluate the impact of HVS on the asthma
symptoms and lung function of asthmatic children and assess the
diagnostic value of the Nijmegen score compared to the HVT for the
diagnosis of HVS in this study population. Our results indicate that
when HVS is defined by a positive HVT, the presence of HVS in children
with severe asthma has no impact on asthma symptoms or lung function.
The diagnostic value of the Nijmegen score compared to a positive HVT
was low in this population.
Our results show that HVS predominates in adolescents, in particular
when there are allergic comorbidities. This study confirms the female
predominance described for HVS 9,12,26–28 and
underscores the potential psychological impact of the association of
several allergic diseases on HVS. Several studies have shown that
patients with food allergies, perennial allergic rhinitis, or asthma
show more anxiety or have higher depression scores29,30. Our results suggest that HVS may be related to
the higher prevalence of anxiety disorders observed in the female
population 31,32. The presence of other allergic
diseases, particularly among asthmatic teenagers, should therefore
prompt the search for HVS.
In our study, asthmatic children with HVS confirmed by a HVT did not
have more exacerbations or severe exacerbations than those without HVS,
nor did they consume more oral corticosteroids. These results appear to
contradict those of other studies 10,33. Several
factors may explain these differences. First, HVS in these studies was
most often diagnosed from the Nijmegen score, whereas we diagnosed it
based on the positivity of a HVT. Our results suggest that the
specificity of the Nijmegen score is lower than that of the HVT. The
risk of false positives is therefore possibly higher with the use of the
Nijmegen score than the HVT. The use of the Nijmegen questionnaire with
a threshold of 23 could therefore lead to an overestimation of the
number of cases of HVS and bias analyses relating to the impact of HVS
on asthma. In addition, most of the studies were carried out on adults,
and excluded patients with severe asthma, whereas our population was
essentially made up of adolescents with severe asthma. In our study, the
high amount of missing data concerning ACT scores may have biased the
analyses of asthma control. Although several studies have shown that the
presence of HVS in asthmatic patients is associated with a decrease in
the global ACT score, they did not find any impact on the various
components of asthma control taken independently, in agreement with our
results 8,13,34. Our results also indicate that the
presence of HVS diagnosed by the positivity of a HVT had no influence on
lung function, and confirms the results reported in the literature5,7,8. This result was expected because HVS is not
generally associated with the determinants of lung function, such as
bronchial inflammation, bronchoconstriction, or remodeling.
The Nijmegen questionnaire is the most frequently used tool in HVS
screening. Its main limitations are the absence of a gold standard test
to assess its validity, the lack of data on its validity for asthmatic
patients, and difficulties in understanding certain items, especially
for younger children 26. Certain items may be confused
with symptoms related to asthma control (inability to breathe deeply,
rapid breathing, shortness of breath), which could lead to an
overestimation and the over-diagnosis of HVS 8,9. The
sensitivity and specificity of the Nijmegen questionnaire with a
threshold of 23 were low in our study, making this score relatively
noninformative for the identification of HVS, with a significant risk of
false-positive children. Few studies have analyzed the value of this
score in asthmatics. The sensitivity of the Nijmegen questionnaire with
a threshold ≥ 25 was estimated to be 71.7%, and the specificity 76.4%
for 152 adults with severe asthma 6. The performance
of the questionnaire was compared to the presence of hypocapnia
< 30 mmHg with a pH > 7.45 on arterial blood
gases associated with the presence of HVS symptoms at rest or a positive
HVT. This population was exclusively made up of adults and it is
possible that the symptoms of HVS are better identified in this
population than in children or adolescents. Two tests were used, one
identifying patients with HVS symptoms at rest and the other patients
with HVS symptoms during a hyperventilation phase. In another study of
162 asthmatic patients over the age of 17, the sensitivity of the
Nijmegen Questionnaire with a threshold ≥ 23 was 23.6% and the
specificity 98.1%. A threshold of 17 showed better performance, with a
sensitivity of 92.7% and specificity of 91.6% 26. In
our study, the lower we made the threshold, the more the sensitivity
increased, to the detriment of specificity. Using a lower threshold
therefore appeared to be less useful for the diagnosis of HVS. The
difference in the sensitivity and specificity of the aforementioned
study compared to those of our study can be explained by the fact that
the gold standard was based on the identification of symptoms of
hyperventilation by the patient from a list, associated with predominant
thoracic breathing. These symptoms were similar to those of the Nijmegen
score, reducing the risk of patients being falsely identified as having
HVS or being free of disease. Furthermore, the study did not include
patients with severe asthma. No study has yet evaluated the performance
of the Nijmegen score in children with asthma, in particular those with
severe cases.
HVT is little used in practice, probably, at least in part, because it
is not standardized or validated. Thus, the voluntary hyperventilation
carried out during the test has a variable duration of 1 to 5 min,
depending on the authors 6,16,22. There are few
studies describing the results of measurements taken during an HVT. In
our study, there was a difference in the initial PETCO2between children with positive and negative HVT, but the median value of
the initial PETCO2 was not < 35 mmHg. This is
why certain authors consider that the measurement of baseline
PETCO2 in isolation is not a good diagnostic criterion
for HVS because many patients with HVS do not show chronic hypocapnia17,18,21,35. One study evaluated the sensitivity and
specificity of measuring baseline arterial capnia < 30 mmHg
associated with a pH > 7.4. The sensitivity was 24.4% and
the specificity 88.5% with respect to the HVT, suggesting that capnia
measurement is not a good diagnostic test 6. In our
study, the value of the low PETCO2 after the
hyperventilation phase was lower in the positive HVT group, as in other
studies 17,20,21. The return time from the low
PETCO2 to the initial PETCO2, which was
longer for the HVT-positive group, was 5 min. The reported threshold
value varies from 3 to 5 min, depending on the study16–18,36–38. All agree that the absence of a return
to the initial PETCO2 after a recovery phase of 3 to 5
min is an additional argument to confirm the positivity of the HVT. By
combining PETCO2 measurements with reproduced symptoms,
the HVT makes it possible to objectively establish the diagnosis of HVS.
Our results indicate that the most frequently reproduced symptoms during
the HVT are extra-respiratory symptoms: headache, dizziness, tingling
sensations or paresthesia, and palpitations, in agreement with certain
studies 11,14,39. However, the symptoms reproduced
vary according to the study. Several studies on adults found a
predominance of respiratory symptoms (tachypnea, feeling of shallow
breathing, feeling of chest tightness) 14,39. We could
not analyze the concordance between the symptoms described before the
HVT and those that were reproduced. The concordance of the symptoms
reproduced during the HVT and those of the Nijmegen score appear to be
between 74 and 86%, depending on the study 14,17.
This means that the symptoms reproduced during the HVT are very close to
those of HVS experienced by patients on a daily basis, reinforcing the
interest of the HVT in the diagnosis of HVS.
In our study, the search for HVS was motivated by the presence of
suggestive symptoms in 47% of cases; 54% of children with a positive
HVT had suggestive symptoms versus 29% in the negative group. In the
group with a negative HVT, we found a higher proportion of children who
had had systematic screening for HVS as part of their severe asthma
assessment. Our results therefore suggest that the HVT should be offered
to adolescents with severe asthma when suggestive clinical signs are
present, rather than routinely.
Our study had several limitations. Its unicentric and retrospective
nature certainly induced a patient selection bias, and data were often
missing. However, the analyzed population was well phenotyped and HVS
was diagnosed based on the positivity of a HVT performed by a single
operator. We had an over-representation of patients with severe asthma
corresponding to GINA step 4 and 5. Our results cannot therefore be
generalized to patients with non-severe asthma. In addition, there was a
selection bias for patients presenting with uncontrolled asthma or
symptoms suggestive of HVS on questioning, which may have led to an
overestimation of the frequency of HVS. The ACT score had not been
evaluated for many patients. However, it did not show any impact of HVS
on the control of asthma. Some authors showed that respiratory
rehabilitation of HVS can allow an improvement in the quality of life of
patients as well as a reduction in anxiety
scores40,41. The present study did not assess the
impact of HVS rehabilitation and psychological care on asthma control.
Despite its limitations, our study is one of the rare studies to focus
on HVS in a pediatric population of asthmatics and to analyze the
interest of the Nijmegen screening score and HVT in the diagnosis of HVS
in children. Indeed, we had a large number of patients evaluated by the
HVT and few studies have yet investigated its parameters.
In summary, HVS does not appear to have an impact on asthma symptoms or
respiratory function for children with severe asthma. The Nijmegen
questionnaire appears to show low sensitivity in this population. HVS is
likely more common in asthmatic adolescents, children with allergic
comorbidity, and, in particular, those with perennial allergic rhinitis.
Further studies are needed to define a gold standard diagnosis of HVS
and to measure its impact on asthma.
REFERENCES
1. Lewis RA, Howell JB. Definition of the hyperventilation syndrome.
Bull Eur Physiopathol Respir 1986;22(2):201–205.
2. Gardner WN. The pathophysiology of hyperventilation disorders. Chest
1996;109(2):516–534.
3. Sauty A, Prosper M. [The hyperventilation syndrome]. Rev Med
Suisse 2008;4(180):2500, 2502–2505.
4. Global Initiative for Asthma (GINA). Global Strategy for Asthma
Management and Prevention. 2021.
5. Osborne CA, O’Connor BJ, Lewis A, Kanabar V, Gardner WN.
Hyperventilation and asymptomatic chronic asthma. Thorax
2000;55(12):1016–1022.
6. Garcia G, Frija-Masson J, Godinas L, Piedvache C, Belguendouz A,
Plantier L, Sarni M, Rolland-Debord C, Laveneziana P, Sattler C, et al.
Performance des tests diagnostiques du syndrome d’hyperventilation dans
une population de patients asthmatiques difficiles. Revue des Maladies
Respiratoires 2019;36:A84–A85. (23e Congrès de Pneumologie de Langue
Française).
7. Tiotiu A, Ioan I, Poussel M, Schweitzer C, Kafi SA. Comparative
analysis between available challenge tests in the hyperventilation
syndrome. Respir Med 2021;179:106329.
8. Veidal S, Jeppegaard M, Sverrild A, Backer V, Porsbjerg C. The impact
of dysfunctional breathing on the assessment of asthma control. Respir
Med 2017;123:42–47.
9. D’Alba I, Carloni I, Ferrante AL, Gesuita R, Palazzi ML, de
Benedictis FM. Hyperventilation syndrome in adolescents with and without
asthma. Pediatr Pulmonol 2015;50(12):1184–1190.
10. Agache I, Ciobanu C, Paul G, Rogozea L. Dysfunctional breathing
phenotype in adults with asthma - incidence and risk factors. Clin
Transl Allergy 2012;2(1):18.
11. van Dixhoorn J, Duivenvoorden HJ. Efficacy of Nijmegen Questionnaire
in recognition of the hyperventilation syndrome. J Psychosom Res
1985;29(2):199–206.
12. Thomas M, McKinley RK, Freeman E, Foy C, Price D. The prevalence of
dysfunctional breathing in adults in the community with and without
asthma. Prim Care Respir J 2005;14(2):78–82.
13. Stanton AE, Vaughn P, Carter R, Bucknall CE. An observational
investigation of dysfunctional breathing and breathing control therapy
in a problem asthma clinic. J Asthma 2008;45(9):758–765.
14. Vansteenkiste J, Rochette F, Demedts M. Diagnostic tests of
hyperventilation syndrome. Eur Respir J 1991;4(4):393–399.
15. Robson A. Dyspnoea, hyperventilation and functional cough: a guide
to which tests help sort them out. Breathe (Sheff) 2017;13(1):45–50.
16. Vansteenkiste J, Rochette F, Demedts M. Evaluation of the clinical
usefulness of capnography curves during a hyperventilation provocation
test in the diagnosis of hyperventilation syndrome. Acta Clin Belg
1991;46(3):142–149.
17. Hornsveld HK, Garssen B, Dop MJ, van Spiegel PI, de Haes JC.
Double-blind placebo-controlled study of the hyperventilation
provocation test and the validity of the hyperventilation syndrome.
Lancet 1996;348(9021):154–158.
18. Grossman P, de Swart JC. Diagnosis of hyperventilation syndrome on
the basis of reported complaints. J Psychosom Res 1984;28(2):97–104.
19. Stoop A, de Boo T, Lemmens W, Folgering H. Hyperventilation
syndrome: measurement of objective symptoms and subjective complaints.
Respiration 1986;49(1):37–44.
20. Dubreuil C, Prosper M. Le syndrome d’hyperventilation. Réanimation
2014;(23). (Réanimation).
21. Ringsberg KC, Akerlind I. Presence of hyperventilation in patients
with asthma-like symptoms but negative asthma test responses:
provocation with voluntary hyperventilation and mental stress. J Allergy
Clin Immunol 1999;103(4):601–608.
22. Hornsveld H, Garssen B. The low specificity of the Hyperventilation
Provocation Test. J Psychosom Res 1996;41(5):435–449.
23. de Groot EP, Duiverman EJ, Brand PLP. Dysfunctional breathing in
children with asthma: a rare but relevant comorbidity. Eur Respir J
2013;41(5):1068–1073.
24. Garcelon N, Neuraz A, Salomon R, Faour H, Benoit V, Delapalme A,
Munnich A, Burgun A, Rance B. A clinician friendly data warehouse
oriented toward narrative reports: Dr. Warehouse. J Biomed Inform
2018;80:52–63.
25. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock
IM, Bateman ED, Bel EH, Bleecker ER, et al. International ERS/ATS
guidelines on definition, evaluation and treatment of severe asthma. Eur
Respir J 2014;43(2):343–373.
26. Grammatopoulou EP, Skordilis EK, Georgoudis G, Haniotou A,
Evangelodimou A, Fildissis G, Katsoulas T, Kalagiakos P.
Hyperventilation in asthma: a validation study of the Nijmegen
Questionnaire–NQ. J Asthma 2014;51(8):839–846.
27. Martínez-Moragón E, Perpiñá M, Belloch A, de Diego A. [Prevalence
of hyperventilation syndrome in patients treated for asthma in a
pulmonology clinic]. Arch Bronconeumol 2005;41(5):267–271.
28. Thomas M, McKinley RK, Freeman E, Foy C. Prevalence of dysfunctional
breathing in patients treated for asthma in primary care: cross
sectional survey. BMJ 2001;322(7294):1098–1100.
29. Kovács M, Stauder A, Szedmák S. Severity of allergic complaints: the
importance of depressed mood. J Psychosom Res 2003;54(6):549–557.
30. Marshall PS, Colon EA. Effects of allergy season on mood and
cognitive function. Ann Allergy 1993;71(3):251–258.
31. Pigott TA. Anxiety disorders in women. Psychiatr Clin North Am
2003;26(3):621–672, vi–vii.
32. Lépine J-P, Gasquet I, Kovess V, Arbabzadeh-Bouchez S, Nègre-Pagès
L, Nachbaur G, Gaudin A-F. [Prevalence and comorbidity of psychiatric
disorders in the French general population]. Encephale
2005;31(2):182–194.
33. Denton E, Bondarenko J, Tay T, Lee J, Radhakrishna N, Hore-Lacy F,
Martin C, Hoy R, O’Hehir R, Dabscheck E, et al. Factors Associated with
Dysfunctional Breathing in Patients with Difficult to Treat Asthma. J
Allergy Clin Immunol Pract 2019;7(5):1471–1476.
34. Tay TR, Radhakrishna N, Hore-Lacy F, Smith C, Hoy R, Dabscheck E,
Hew M. Comorbidities in difficult asthma are independent risk factors
for frequent exacerbations, poor control and diminished quality of life.
Respirology 2016;21(8):1384–1390.
35. Spinhoven P, Onstein EJ, Sterk PJ, Le Haen-Versteijnen D. The
hyperventilation provocation test in panic disorder. Behav Res Ther
1992;30(5):453–461.
36. Lum LC. Hyperventilation: the tip and the iceberg. J Psychosom Res
1975;19(5–6):375–383.
37. Han JN, Stegen K, Simkens K, Cauberghs M, Schepers R, Van den Bergh
O, Clément J, Van de Woestijne KP. Unsteadiness of breathing in patients
with hyperventilation syndrome and anxiety disorders. Eur Respir J
1997;10(1):167–176.
38. Folgering H, Colla P. Some anomalies in the control of PACO2 in
patients with a hyperventilation syndrome. Bull Eur Physiopathol Respir
1978;14(5):503–512.
39. Enzer NB, Walker PA. Hyperventilation syndrome in childhood. A
review of 44 cases. J Pediatr 1967;70(4):521–532.
40. Thomas M, McKinley RK, Freeman E, Foy C, Prodger P, Price D.
Breathing retraining for dysfunctional breathing in asthma: a randomised
controlled trial. Thorax 2003;58(2):110–115.
41. Bruton A, Lee A, Yardley L, Raftery J, Arden-Close E, Kirby S, Zhu
S, Thiruvothiyur M, Webley F, Taylor L, et al. Physiotherapy breathing
retraining for asthma: a randomised controlled trial. Lancet Respir Med
2018;6(1):19–28.