A hierarchical cluster analysis of the psycological impact of the COVID-19 pandemic on Italian severe asthma patients

Abstract Introduction In the context of COVID-19 pandemic, a consistent medical concern raised among severe asthma patients, though the studies excluded an increased risk of severe disease as well as an increased susceptibility. The aim of the study was to apply the Psychological General Well-Being Index (PGWBI) questionnaire to severe asthmatics during the COVID-19 pandemic and to evaluate the data with a hierarchical cluster analysis. Methods 114 severe asthmatics were asked to respond anonymously to the PGWBI questionnaire. The patients underwent a lung functional test, fractional exhaled nitric oxide (FeNO) measurement, Asthma Control Test (ACT), and Asthma Control Questionnaire (ACQ6). A hierarchical cluster analysis was performed using an agglomerative approach and complete linkage to evaluate the results. Results The study population predominantly included female (60%), middle-aged patients, with normal lung function parameters, mild signs of airway, and satisfactory asthma control. The PGWBI score (82.46 ± 16.53) of the study population showed a good state of psychological well-being and was similar to that of a representative sample of healthy adult Italian subjects. Thus, Hierarchical cluster analysis identified 3 groups of patients: Cluster 1 (32%), Cluster 2 (64%), and Cluster 3 (4%). Whilst the Cluster 2 patients’ PGWBI score fell within the normal range, the Cluster 1 patients had a significantly lower total score (68.57 ± 7.2; p < 0.05), suggesting moderate distress. The Cluster 3 patients presented a total score markedly low. Conclusion Although the majority of the severe asthma patients studied demonstrated good mental well-being during the COVID-19 pandemic, some did indeed show moderate to severe psychological distress.


Introduction
During the Covid-19 pandemic, most of the world's population was subjected to social distancing rules and partial or complete lockdowns for as long as 3 to 4 months. For the most part, only those individuals considered "essential workers" were allowed to travel to their workplaces. Undoubtedly, the lockdowns have had a strong impact on the emotional state and lifestyle of many, dramatically reducing their social interactions as well as their physical activity levels which, in turn, negatively affected their mental health (1). Although the restrictive measures adopted by governments have been effective in controlling the spread of the virus, they have nonetheless contributed to emotional and psychological disorders. No less importantly, the COVID-19 pandemic itself has been linked to acute panic attacks, anxiety, obsessive behaviors, depression, insomnia, and/or poor sleep quality (2). Within this frame of reference, many patients suffering from severe chronic respiratory diseases have become increasingly apprehensive, and some specialists have speculated that those affected by asthma and allergic diseases might be at greater risk of COVID-19 infection.
More than two years after the beginning of the Covid-19 pandemic, recent scientific studies have shown, instead, that asthmatic patients are at lower risk of infection and severe symptoms of COVID-19 (3). Furthermore, hospitalized asthma subjects have not been found to be at increased risk of respiratory failure or mortality with respect to non-asthmatic COVID-19 patients (4). Furthermore, and unexpectedly, the researchers of many countries have reported a reduction in asthma exacerbations, hospitalizations, and diagnoses, an outcome that has been ascribed to better hand hygiene practices, the use of facial masks, physical distancing and to an overall reduced spread of influenza and other viral respiratory infections, which are known to trigger asthma attacks (5). Despite these reassuring scientific findings, asthma patients have shown higher rates of worsening mental health, perceived risk and fear of COVID-19, and longer self-isolation periods. Likewise, asthma patients seem to be more likely to skip or put off medical appointments with respect to individuals suffering from other chronic conditions because of the fear of contracting COVID-19 in a medical setting (6).
Asthma has long been associated with symptoms of mood and anxiety disorders (7). In fact, the prevalence of anxiety and depressive disorders is higher among asthma patients and in particular in severely affected patients with respect to the general population (8). On the other hand, clinical data have shown that the presence of psychiatric and psychological symptoms is associated with more severe forms of asthma, functional impairment, worse asthma control, and higher social costs. Available evidence suggests that asthma could precede and predispose the onset of anxiety and mood disorders; conversely, the presence of psychological and behavioral problems could favor the development of asthma (7,9). From a neurobiological perspective, it has been speculated that a systemic inflammation may link these conditions, as cytokines regulate a variety of processes in the central nervous system (CNS), including neurotransmission (10).
In view of the fact that emotional and psychological factors as well as life stressors can impact the severity of asthma and the efficacy of therapy, it seemed important to assess these features at this time using standardized tools during routine asthma control checkups. The current study set out to evaluate the perception of general psychological well-being in a large group of patients with severe asthma during the COVID-19 pandemic using the Psychological General Well-Being Index (PGWBI), a standardized questionnaire widely used for other chronic diseases/conditions (11,12).

Methods
The current investigation is an observational study that was carried out in a real-life setting at the Referral Centre for Severe Asthma of the University Hospital of Padua in Northeastern Italy. The study was performed in accordance with the principles of the Helsinki Declaration (1996), and was approved by the Hospital's Local Ethical Committee (Prot 2559P). Informed consent was obtained from each subject before any study-related procedures were initiated. The inclusion criteria were: being affected by severe asthma according to the ERS/ATS 2014 recommendations (13), having regular checkups at the Referral Center, voluntarily attending the vaccination campaign, having a reasonably long time (at least 120 days) since a previous Covid-19 infection or a previous vaccine booster. The exclusion criteria were: experiencing ongoing acute asthma exacerbation, ongoing COVID-19 infection, refusal to vaccination.
The patients were requested to anonymously fill out the PGWBI questionnaire at the time they received their third dose of mRNA SARS-CoV-2/COVID-19 (Pfizer) vaccine at the hospital.

Population
All patients with severe asthma were evaluated in the same day. Forced Expiratory Volume in the 1 st second (FEV 1 ) and fractional exhaled nitric oxide (FeNO) values recorded during pulmonary function testing performed within approximately 30 days of recruitment were recorded.

Intervention
The PGWBI consists of 22 self-administered items, rated on a 6-point scale, assessing the psychological and general well-being of respondents in six HRQoL domains: anxiety (5 items), depressed mood (3 items), positive well-being (4 items), vitality (4 items), general health (3 items), and self-control (3 items) (Appendix 1) (11). The scores of each domain are added to attain a total score, which can range from zero to a maximum of 110 points. According to the criteria of H. Dupuy, who developed the index, a global score between 73 and 110 reflects individuals' perception of positive mental health, a score of 61-72 reflects moderate distress, and values between 0 and 60 could indicate severe distress (14).
The MAPI Research Institute coordinated the efforts to adapt and validate the questionnaire for several languages and cultures. Different language versions of the PGWBI are presently available for use on the MAPI website (15).
The patients surveyed were also administered the Asthma Control Test (ACT) and the Asthma Control Questionnaire (ACQ6) at the same time and place.

Statistical analysis
A hierarchical cluster analysis (Härdle W.K., Simar L. (2019). Applied Multivariate Statistical Analysis, Springer) was performed using an agglomerative approach and complete linkage (16). The Calinski-Harabasz pseudo-F statistic was used to choose the number of clusters (16). A dendogram was used to visualize the clustering results.
To obtain a simple characterization of the clusters, the principal components of the responses were considered, and the groups were projected onto the first two components. The parametric t-test was used to compare groups with regard to the subjects' "positive well-being" items. Normality was checked by the Shapiro-Wilk test. All other domains have been compared using Wilcoxon's non-parametric test.
P values were obtained for all the tests, and 5% was considered the critical level of significance. The R: a language and environment for statistical computing (17), was used for all of the analyses. The data are expressed as mean ± standard error or median with the first and third quartiles.

Results
Out of the 142 patients who were originally contacted, 24 were excluded: 6 (4.2%) because they declined receiving the vaccination; 5 (3.5%) because they reported experiencing ongoing acute asthma exacerbation, and 13 (9.2%) because they reported having a paucisymptomatic COVID-19 infection. As a result, 116 patients with severe asthma were administered the PGWBI questionnaire at the time they received their third dose of the COVID-19 vaccine. Two of the questionnaires were excluded because there were too many missing answers. Table 1 summarizes the patients' features. The majority of the patients were middle-aged females with rhinitis, who showed clinically stable conditions, normal lung function, and low levels of eosinophilic inflammation.
The hierarchical cluster analysis identified 3 groups of patients: 37 subjects (32%, Cluster 1), 73 subjects (64%, Cluster 2), and 4 subjects (4%, Cluster 3) (Figure 1). The two-dimensional representation of the three clusters showed a clear distinction between the groups, in particular between the first and the other two clusters (Figure 2). The Cluster 2 patients showed a normal mental condition, with elevated positivity  Figure 3). Notably, the study participants were characterized by low anxiety and high vitality levels. Additionally, the Cluster 1 patients had significantly lower scores with respect to their Cluster 2 counterparts on all 6 domains (p < 0.05). Finally, the Cluster 3 subjects had significantly lower scores on all 6 domains with respect to the subjects in the other two clusters (p < 0.01).

Discussion
Other surveys examining COVID-19-related data have reported worsening anxiety, depression, asthma symptoms, disease control, and quality of life in asthmatic patients during the pandemic (1-6,18-21). According to one study, worse outcomes were significantly associated with the female sex, asthma severity, and history of anxiety and depression (22). Uncontrolled asthmatics (Asthma Control test, ACT < 20) were more likely to consider themselves at higher risk of COVID-19 and to be strongly psychologically distressed by the lockdown. As compared to persons with controlled asthma (ACT > 20), the uncontrolled  individuals displayed more feelings of anxiety and depression (p < 0.001) and abandonment (p < 0 0.001), and they reported more difficulties in addressing their needs (p < 0.001) (22). A study by Coelkesen et al., which was based on an online questionnaire administered to 264 participants, found that 70% of the patients had poorly controlled asthma ACT scores and 46% reported a worsening of symptoms during the lockdown due to the use of disinfectants (23). Basing their data on the Hospital Anxiety and Depression Scale (HADS), the researchers found that 35% and 30% of the study participants suffered from anxiety and depression, respectively, and that these symptoms were associated with uncontrolled asthma in 50% of the cases (23). The psychological impact that the COVID-19 pandemic had on the patients with severe asthma studied here was, according to our results, less marked with respect to that reported by other investigators (1)(2)(3)(4)(5)(6)(16)(17)(18)(19)(20)(21)(22)(23). Indeed, according to the criteria of H. Dupuy who developed the PGWB, our patients had a good level of subjective psychological well-being (14), which could at least be partially explained by their satisfactory asthma control, which in turn was linked to the inhalation therapy, biologics and anti-Sars-Cov2 vaccinations they were receiving on a routine basis. These results are consistent with our previous study (24) and with data from other investigators showing that asthmatic patients are not particularly susceptible to the Sars-Cov2 infection nor are they at increased risk of developing severe symptoms of the disease (3,4,25). Compellingly, the satisfactory control of the disease demonstrated by the lung function test, ACT and ACQ6 scores corresponded in our patients to their perception of general good health and well-being, something that has only infrequently been reported by others (26).
The mean PGWBI score for the entire study population was similar to that reported by Grossi et al. in 1129 healthy adult Italians (82.46 ± 16.53 vs 78 ± 17.89, respectively) ( Figure 3) (11). Comparable PGWBI scores have also been reported in 567 patients with gastroesophageal reflux disease six months after they initiated proton pump inhibitor therapy (84.3 ± 14.27) (12).
For the first time in our studies, the hierarchical cluster analysis approach was utilized to examine the results of the PGWBI questionnaire. It revealed that approximately 30% of our patients (Cluster 1) suffered from moderate psychological distress, in particular poor general health. Cluster 1 included subjects with severe asthma who complained about marked subjective emotional distress despite the stability of their disease state, prompting them to prefer a sedentary life, as previously reported in the literature (22,23,26).
Finally, a very small proportion of patients (Cluster 3) revealed a condition of severe distress. These patients were prone to anxiety and depression, associated with poor general health. Our results are in line with those of previous studies showing that significantly higher levels of anxiety and depression are associated with more severe asthma levels (7,8). Psychological interventions could help to control the distress experienced by this type of patient.
The fact that the PGWBI questionnaire was administered at the time our asthma patients were receiving their third dose of the anti-Sars-Cov2 vaccination could be considered one of the study's limitations in view of the fact that vaccinations may be associated to pain or fear and thus may constitute another stress factor (28). Concerns about the safety of the vaccination, in particular the fear of a severe allergic reactions has represented, moreover, an ongoing challenge for allergists/immunologists and a cause for concern for many patients following the report of two cases of anaphylactic reactions in health care workers (27)(28)(29).
The exclusion of patients with exacerbated or uncontrolled asthma could be considered another study limitation, given that concomitant unstable diseases may negatively affect PGWBI scores. Clearly, studies focusing on severe asthma patients regardless of their clinical stability are warranted. The fact that it was impossible to analyze the correlation between the PGWBI data and the patients' clinical and lung function parameters is another unavoidable weakness due to the fact that the questionnaires were anonymously compiled. Anonymity and confidentiality were preferred to protect the privacy of those who voluntarily agreed to participate in the study. The third limitation was the limited number of subjects and that the study was single-center, even if the sample is still considerable and in any case representative of the Italian scenario. Moreover, these are patients suffering from severe asthma, a disease fortunately not so widespread and which notoriously affects a very limited percentage of subjects (4-8%) (30). On the other hand, one of our study's strengths was the use of a standardized psychological questionnaire permitting researchers to compare the mental states of patients with various kinds of diseases and with various classifications of asthma, and to address not only their medical but also their psychological features.

Conclusion
The outbreak of the COVID-19 pandemic was associated with a consistent medical concern among patients suffering from severe asthma. However, the reported data showed that asthmatic patients were not at an increased risk of susceptibility or of developing a severe form of the disease. Regular inhalation therapy, biologic therapy and anti-Sars-Cov2 vaccinations have continued to prove to be effective strategies for controlling severe asthma. Higher rates of worsening mental health, anxiety and depression continue, however, to be reported in asthmatic patients. Our study has pointed out that a small proportion of even well-controlled, clinically stable severe asthmatic patients may develop moderate to severe psychological distress. The PGBWI seems to be able to provide important data to physicians caring for asthmatic patients, indicating which are more in need of psychological support and other types of interventions.