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.
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