Asthma Control during COVID-19 Lockdown in Patients with Severe Asthma under Biological Drug Treatment

Abstract

Introduction: Coronavirus disease 2019 (COVID-19) has deeply affected the management of patients with severe asthma, treated with add-on biological therapies. Objective: In this study, severe asthmatic patients on treatment with one of three different biologics (omalizumab, mepolizumab, benralizumab) underwent a survey to evaluate the effects of COVID-19 on the management of their clinical condition, with regard to the changes caused by the limited access to health facilities during the pandemic period. Methods: In this prospective observational study, 28 severe asthmatic outpatients referring to the Respiratory Unit of Magna Graecia University Hospital, Catanzaro (Italy), were asked to answer a telephone survey from May to July 2021. This survey included the evaluation of demographic and clinical data, as well as the number of lung function tests performed, exacerbations, biologic doses administered at hospital, or at general practitioner office, or through self-administration. Adherence to biological therapies before and during the pandemic period was also assessed. Moreover, the most recent asthma control test (ACT) score and the last forced expiratory volume in the first second (FEV₁) measurement, recorded during the pandemic phase, were compared to the pre-pandemic (baseline) period. Results: When comparing the pre-pandemic data with the pandemic observations, the mean ACT score and the exacerbation rate did not significantly change [ACT, 21.5 ± 2.8 to 23.0 ± 3.9 (p = 0.1); exacerbation rate, 0.3 ± 0.6 and 0.5 ± 1.5 (p = 0.3)]. When considering some variables related to disease management in the same periods, a statistically significant difference was detected with regard to the mean number of outpatient visits (5.2 ± 3.8 vs. 0.9 ± 2.5, p < 0.0001), as well as to the mean number of accesses to health facilities for the administration of biological drugs (from 7.0 ± 3.4 to 2.5 ± 3.9, p < 0.0001). None of the patients reported to have been infected with the SARS-CoV-2 virus and no adverse drug reactions (ADR) occurred during the study. Conclusions: The above results suggest that COVID-19 pandemic did not induce any significant change related to severe asthma control. Indeed, add-on treatment with biological drugs was regularly continued, despite the obvious limited access to health facilities.

1. Introduction

Asthma affects more than 300 million patients worldwide, and about 5–10% of these subjects complain of poorly controlled disease [1]. Severe asthma has been defined by an international consensus, jointly stated by the European Respiratory Society (ERS) and the American Thoracic Society (ATS), as a respiratory disorder that requires high dosages of inhaled corticosteroids (ICS), associated with long-acting beta₂-adrenergic agonists (LABA) for its control [2]. Moreover, long-acting muscarinic antagonists (LAMA), leukotriene modifiers, oral corticosteroids (OCS), and biologics might be also used as additional therapies for some patients [3,4]. Several biologics are currently available in Italy as add-on therapies for severe asthma, including monoclonal antibodies targeting IgE (omalizumab), interleukin (IL)-5 (mepolizumab), IL-5 receptor (benralizumab), and IL-4/13 receptors (dupilumab) [5]. Patients treated with biologics for severe asthma often require periodic access to health facilities to receive drug administration, as well as clinical and functional monitoring, occurring in a specialized professional setting.

The routes of administration of anti-asthma drugs are crucial to maintain and improve adherence to the treatment of asthmatic patients [6,7]. In this regard, providing drug formulations that are suitable for self-administration may improve adherence to therapy [8]. The above-mentioned monoclonal antibodies can be self-administered through appropriate devices, including auto-injectable pens and prefilled syringes [9]. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), rapidly escalated to a pandemic, thus representing a dramatic public health emergency worldwide [10,11]. SARS-CoV-2 is an extremely contagious virus, and social distancing plays a key role in reducing the chances of viral transmission [10]. Consequently, the health system required quick adjustments, including strict limitation of hospital access to critical cases only, as well as the implementation of remote services and telemedicine [12]. Based on a relevant update of international guidelines for asthma management, the COVID-19 pandemic has induced several changes in allergy and immunology care modalities, with the aim of delaying elective procedures, reducing nebulizers and spirometry, and maintaining adherence to prescribed therapies [4]. Therefore, the practice of self-administration of biologics has been recently favored by the lockdown imposed by the Italian government, which noticeably restricted patient contact with doctors and nurses [13].

According to current evidence, both asthma and allergic diseases are not usually associated with the most severe expressions of SARS-CoV-2 infection [14,15,16]. However, careful attention should be paid to reduce the risk of potential infectious contacts in patients with severe asthma. Therefore, concomitantly with the outbreak of the COVID-19 pandemic, we encouraged the treatment shift of many severe asthmatic subjects from hospital-based management to home-care settings. Within this context, the recent changes in the management of severe asthma led to significant decreases in the numbers of medical visits, functional and hematological tests [13].

In the present study, carried out in a group of severe asthmatic patients treated with biologics, we evaluated the different attitudes induced by the COVID-19 pandemic and the related lockdown, with respect to asthma exacerbations, symptom control, and adherence to therapy. In particular, the main aim of this study was to assess the impact of the COVID-19 lockdown policy on patient access to health facilities, asthma control, and safety of biological therapies.

2. Materials and Methods

In this prospective observational study carried out at the Respiratory Unit of Magna Graecia University Hospital in Catanzaro (Italy), severe asthmatics outpatients aged at least 18 years, treated with either omalizumab, mepolizumab, or benralizumab were contacted by phone in order to evaluate both clinical efficacy and drug safety of biological therapies. The institutional ethics committee of the Central Area of Calabria Region approved the study protocol, registered with the number 156 (22 April 2021). Written informed consent was obtained from all patients for their participation.

2.1. Experimental Protocol

The telephonic survey (Supplementary Materials) focused on the assessment, performed before and during the pandemic, of the numbers of several items including lung function tests, asthma exacerbations, and doses of biological drugs administered at either hospital, general practitioner office or home. Adherence to therapy was also investigated. Moreover, the most recent asthma control test (ACT) score and the last forced expiratory volume in the first second (FEV₁) measurement, recorded during the pandemic period, were compared to pre-pandemic (baseline) evaluation. Baseline data and FEV₁ values were retrieved from available medical records of our clinical unit, whereas ACT was administered by telephone, thus referring to the last 4 weeks of the pandemic period. With the aim of carefully evaluating the influence of pandemic and lockdown policies on adherence to biologic therapies, we considered as “pre-pandemic” the period referring to the 6 months preceding 9 March 2020, and as “pandemic” the period including the subsequent 6 months. In this regard, it is important to point out that on 9 March 2020 a strict lockdown policy was applied to the entire Italian country. Finally, in agreement with our previous studies [17], the Naranjo score was used in patients that developed an adverse drug reaction (ADR), in order to evaluate its eventual correlation with the drug.

2.2. Statistical Analysis

All data are expressed as mean ± standard deviation (SD) if normally distributed, and as median with interquartile ranges (IQR) otherwise. The normality of data distribution was assessed using Anderson–Darling and Kolmogorov–Smirnov tests. Student’s t test and Mann–Whitney U test were performed to compare variables when appropriate. Statistical significance was set at a threshold of p-value < 0.05. Statistical analysis was performed with Prism 9.1.2 (GraphPad Software, San Diego, CA, USA).

3. Results

3.1. Patients

In the present study, we enrolled 28 patients (20 females and 8 males) with a mean age of 58 ± 10.1 years. The mean body mass index (BMI) was 26.7 ± 4.7 kg/m²; 14 patients were normal weight (50%), and the other 14 were overweight or obese (50%). However, despite such a relevant number of overweight/obese subjects enrolled in this study, BMI does not appear to have exerted any impact on overall results. All patients underwent a skin prick test to investigate the allergic status. Among them, 25 were positive to at least one antigen (89.3%), and only 3 patients (10.7%) were non-allergic. In particular, 17 (60.7%) patients were taking omalizumab as add-on biological therapy, 4 (14.3%) mepolizumab, and 7 (25.0%) benralizumab (Table 1). In regard to comorbidities, 11 patients (39.3%) had nasal polyposis, and 19 (67.9%) complained of gastroesophageal reflux disease (GERD). When considering the previous or current smoking habit, 19 patients (67.9%) were never smokers, 3 (10.7%) were former smokers, and 6 (21.4%) were current smokers, characterized by an exposure ranging between 10 and 20 packs/year. Asthma was diagnosed at the mean age of 38 ± 13.7 years.

3.2. Clinical and Functional Results

Between the pre-pandemic and the pandemic period, the mean ACT score insignificantly increased from 21.5 ± 2.8 to 23.0 ± 3.9 (p = 0.1) (Table 2). Due to lockdown limitations, FEV₁ was recorded before and during the pandemic only in seven patients, resulting in mean values of 1.9 ± 0.6 L and 1.9 ± 0.5 L detected before and during the pandemic, respectively (p = 0.9). The exacerbation rate was very low, with mean values of 0.3 ± 0.6 and 0.5 ± 1.5 recorded before and during the pandemic, respectively (p = 0.3) (Table 2). Therefore, enrolled patients did not require therapeutic changes. When considering some variables related to disease management during pre-pandemic and pandemic periods, statistically significant differences were found in the median number of lung function tests, 1.0 (0.0–1.0) vs. 0.0 (0.0–0.75), respectively (p < 0.01). A significant difference was also detected with regard to the mean number of outpatient visits (5.2 ± 3.8 vs. 0.9 ± 2.5, respectively) (p < 0.0001). On the contrary, the median number of routine blood tests did not show any significant variation between the two periods, 0.0 (0.0–1.0) vs. 0.0 (0.0–1.0), respectively (p = 0.8).

3.3. Biological Drug Administration

The mean number of biologic drug administrations at hospital decreased from 7.0 ± 3.4 to 2.5 ± 3.9 (p < 0.0001), while the mean number of administrations at general practitioner office increased from 0.1 ± 0.6 to 2.7 ± 3.5 (p = 0.0006), and the mean number of self-administrations increased from 0.04 ± 0.2 to 1.9 ± 3.3 (p = 0.006). All the above-mentioned values are referred to the pre-pandemic and pandemic periods, respectively.

3.4. Adherence and Side Effects

All patients experienced 100% adherence to asthma therapy, before and during the course of the pandemic, regardless of the place where they received drug administration. No patient reported to be infected by the SARS-CoV-2 virus, and no ADR occurred during the study observation.

4. Discussion

In the present study, we evaluated the treatment with biological drugs in patients with severe asthma during the COVID-19 lockdown. In particular, when comparing the results referring to pre-pandemic and pandemic periods, we found non-significant differences with regard to mean values of ACT score, FEV₁, and exacerbation rate. Such observations are consistent with other studies conducted during the pandemic outbreak [13,18,19,20,21], which failed to report in patients with severe asthma relevant increases in exacerbation number or SARS-CoV-2 infections. Therefore, the lockdown policy did not affect the overall asthma control. As anecdotal evidence supporting our data, two case studies referring to severe asthmatics patients treated with biologics reported no changes in asthma control, even during SARS-CoV-2 infection [22,23]. Furthermore, it is noteworthy that the mean frequency of hospital accesses finalized to receive biologic therapies decreased, whilst the numbers of biologic drug administrations performed as either self-injections or treatments at general practitioner’s office increased. According to other studies [13,24], self-administration could thus be a useful tool to maintain adherence to biological therapies. Consistently with recent reports [15,25], our survey does not support the hypothesis that severe asthmatic patients could be more susceptible to COVID-19. However, awareness of the possible risk of exacerbations due to viral infections might prompt a self-containment behavior, respectful of the kindly recommended social distancing policy. On the other hand, several studies suggest that asthmatic patients, particularly those under biologic treatment, can be more susceptible to SARS-CoV-2 infection when compared to the general population [26,27]. Nevertheless, the severity of COVID-19 was similar between these two groups [26,27]. Anyway, it is still hard to predict whether asthma patients are more likely to be infected by SARS-CoV-2 [28].

Finally, despite the relatively high number (14 out of 28) of overweight/obese patients enrolled in this study, obesity did not appear to have affected our results. In fact, our patients were characterized by type 2 asthma phenotype, whereas obesity is mainly associated with T2-low severe asthma [29].

Several limitations affect the reliability of our results. Due to the monocentric setting of this study, recruiting an extensive number of patients was difficult. In this regard, the small sample size prevents a certain generalization of the results. Moreover, the study design, the subjectivity bias related to ACT, and the unavoidable memory bias dependent on the effort to recall events that occurred several months earlier, represent relevant factors challenging our data. Finally, because in our study population the number of female patients was over two times higher than males, it was not possible to correctly analyze any gender-related variability.

Taken together, our findings suggest that the COVID-19 pandemic did not affect the global health status of patients with severe asthma. Indeed, the lack of any significant difference related to asthma control encourages the continuation of biological therapies, even under circumstances that limit the access to health facilities. However, more studies are needed to assess any eventual worsening of severe asthma control during lockdown periods.

Author Contributions

Conceptualization, C.P. (Corrado Pelaia) and A.C.; methodology, C.P. (Corrado Pelaia) and L.G.; software, R.C.; validation, V.R., G.M., L.M., G.P., C.P. (Caterina Palleria) and R.R.; formal analysis, C.P. (Corrado Pelaia) and R.C.; investigation, V.R., C.P. (Corrado Pelaia), G.M. and G.P.; data curation, C.P. (Caterina Palleria); writing—original draft preparation, C.P. (Corrado Pelaia) and A.C.; writing—review and editing, L.G.; supervision, G.D.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by Ethic Committee Calabria Center 156/21.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Tables

Table 1

Clinical data related to omalizumab, benralizumab, and mepolizumab administration, sorted for pre-pandemic and pandemic period.

	Pre-Pandemic(Median ± SD)	Pandemic(Median ± SD)	p-Value
Omalizumab
Spirometry	0 ± 0.5	0 ± 0.6	0.99
FEV1	1.8 ± 0.7	2 ± 0.6	0.94
ACT	21 ± 2.8	25 ±4.7	0.27
Blood tests	0 ± 0.3	0 ± 2.4	0.16
Clinical examination	6 ± 4.6	0 ± 3.1	0.006
Exacerbations	0 ± 0.7	0 ± 1.9	0.18
Biologic administration
At hospital	9 ± 2.9	1 ± 4.5	<0.0001
At medical office	0 ± 0.8	1 ± 4	0.007
At home	0 ± 0.2	0 ± 4.1	0.04
Mepolizumab
Spirometry	1 ± 0	0 ± 0.5	0.25
FEV1	1.5 ± 0	1.5 ± 0	not available
ACT	20 ± 0.5	24 ± 0.5	0.006
Blood tests	0 ± 0.5	0.5 ± 1	0.5
Clinical examination	6 ± 2.2	0 ± 0.5	0.02
Exacerbations	0.5 ± 0.6	0 ± 0	0.18
Biologic administration
At hospital	6 ± 0	2 ± 2.6	0.08
At medical office	0 ± 0	4 ± 2.6	0.08
At home	0 ± 0	0 ± 0	not available
Benralizumab
Spirometry	3 ± 1.1	0 ± 0	0.02
FEV1	not available	not available	not available
ACT	24 ± 0.5	24 ± 2.2	0.7
Blood tests	1 ± 1.4	1 ± 0.5	0.2
Clinical examination	3 ± 0.6	0 ± 0	<0.0001
Exacerbations	0 ± 0	0 ± 0	not available
Biologic administration
At hospital	3 ± 0	0 ± 0.4	<0.0001
At medical office	0 ± 0	0 ± 1.3	0.18
At home	0 ± 0	3 ± 1.5	0.008

Asthma control test (ACT), forced expiratory volume in 1 s (FEV₁).

Table 2

Clinical data related to omalizumab, benralizumab, and mepolizumab administration, sorted for gender.

	Males			Females
	Pre-Pandemic (Median ± SD)	Pandemic(Median ± SD)	p-Value	Pre-Pandemic (Median ± SD)	Pandemic(Median ± SD)	p-Value
Omalizumab
Spirometry	0 ± 0.5	0 ± 0.7	0.4	0 ± 0.5	0 ± 0.6	0.6
FEV1	2.1 ± 0.7	1.8 ± 0.7	not available	2.1 ± 0.6	2 ± 0.6	not available
ACT	21 ± 2.9	25 ± 4.9	0.22	21 ± 2.8	25 ± 4.7	0.7
Blood tests	0 ± 0.3	0 ± 2.8	0.3	0 ± 0.3	0 ± 2.4	0.3
Clinical examination	6 ± 4.5	0 ± 0.9	0.003	6 ± 4.6	0 ± 3.1	0.1
Exacerbations	0 ± 0.8	0 ± 2.1	0.4	0 ± 0.7	0 ± 1.9	0.37
Biologic administration
At hospital	6 ± 2.8	1 ± 4.3	0.03	7 ± 3.1	1 ± 4.5	0.1
At medical office	0 ± 0.3	0 ± 4.4	0.2	0 ± 0.8	1 ± 4.1	0.02
At home	0 ± 0.3	0 ± 4.4	0.1	0 ± 0.2	1 ± 4.1	0.3
Mepolizumab
Spirometry	not available	not available	not available	1 ± 0	0 ± 0.5	0.06
FEV1	not available	not available	not available	1.9 ± 0.3	not available	not available
ACT	not available	not available	not available	20 ± 0.5	24 ± 0.5	0.001
Blood tests	not available	not available	not available	0 ± 0.5	0.5 ± 1	0.2
Clinical examination	not available	not available	not available	6 ± 2.2	0 ± 0.5	0.02
Exacerbations	not available	not available	not available	0.5 ± 0.6	0	0.2
Biologic administration
At hospital	not available	not available	not available	6 ± 0.5	2 ± 2.6	0.08
At medical office	not available	not available	not available	0	4 ± 2.6	0.08
At home	not available	not available	not available	0	0	0.2
Benralizumab
Spirometry	2 ± 0.8	0	0.1	3 ± 1.3	0	0.01
FEV1	2.4 ± 0.8	not available	not available	2.4 ± 0.3	not available	not available
ACT	24 ± 0.5	25 ± 0.4	not available	24 ± 0.4	25 ± 2.6	0.5
Blood tests	1 ± 1.1	1 ± 0.4	0.5	1 ± 1.3	0 ± 0.5	0.2
Clinical examination	3 ± 0.4	0	0.1	3 ± 0.7	0	<0.0001
Exacerbations	0	0 ± 0.5	not available	0	0	not available
Biologic administration
At hospital	3 ± 0.4	0 ± 0.5	0.1	4 ± 0.5	0 ± 0.4	<0.0001
At medical office	0	2 ± 1.3	not available	0	0 ± 0.9	0.4
At home	0 ± 1.1	0 ± 1.6	not available	0 ± 0.9	3 ± 1.3	0.02

Asthma control test (ACT), forced expiratory volume in 1 s (FEV₁).

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/app112412089/s1.

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