Desensitization reduces some COVID-19-associated symptoms in minors with allergic rhinitis

doi:10.21203/rs.3.rs-4910056/v1

Objective

The aim of this study was to observe the symptoms after infection with coronavirus disease 19 (COVID-19) in minor and adult allergic rhinitis (AR) patients receiving different treatment therapies [Sublingual immunotherapy (SLIT) and conventional therapy].

Methods

We recruited a total of 398 patients diagnosed with AR from the clinical system and divided them into AR-S, with AR-S1 representing individuals aged < 18 years of age, and AR-S2 those ≥ 18 years of age, and AR-C groups based on their treatment modalities. Between December 2022 and February 2023, we documented the respiratory symptoms and common manifestations of AR patients infected with the novel coronavirus.

Results

The AR-S1 group may be associated with a reduced risk of symptoms after infection including dry and itchy (OR = 0.373, 95%Cl:0.184–0.755), headache (OR = 0.385, 95%Cl:0.196–0.758), fatigue (OR = 0.376, 95%Cl:0.188–0.751), chest tightness (OR = 0.160, 95%Cl:0.049–0.522), and some symptoms after improvement of infection (cough, fatigue).

Conclusion

Minor AR patients with SLIT can reduce some of the symptoms in COVID-19-infected patients.

Level of Evidence: 3

COVID-19

Allergic rhinitis

Sublingual immunotherapy

Minors

Odds ratio

House dust mite (HDM) allergy exposure is a major cause of allergic rhinitis (AR) and HDMs are common allergens in southern China [1, 2]. The self-reported prevalence of AR in China has increased significantly from 11.1–17.6% over 6 years [3, 4]. Although such patients are treated by reducing exposure to HDM allergen and using symptomatic medications such as oral or topical antihistamines, nasal corticosteroids (NCS), and inhaled corticosteroids (ICS), results are often unsatisfactory [5, 6].

Allergen immunotherapy (AIT) is a "gentle" form of immune training that can not only cure AR, but also promote the remodelling of innate and acquired immunity[7, 8]. Interestingly, recent studies have shown some benefit from AIT in COVID-19. In a double-blind, randomized study on the antiviral and inflammatory responses of sublingual immunotherapy (SLIT) to allergic asthma, HDM-SLIT improved the antiviral toxicity of bronchial epithelium against viral infection [9]. Many previous studies have suggested that SLIT for AR is a safe option without increasing the infection risks or worsening the severity of symptoms after infection[10, 11]. In additional, some studies [12–14] have demonstrated that AIT treatment may mitigate the risk of specific symptoms following COVID-19 infection and reduce the likelihood of severe illness. It remains uncertain whether minors treated with SLIT will experience similar beneficial effects following COVID-19 infection.

As is widely recognized, minors make up a large proportion of individuals undergoing AIT. During the viral epidemic, children with AR were more worried about serious viral infection[15, 16]. Several studies have reported that children allergic to house dust mites have significantly more severe nasal symptoms and an increased need for medications compared to the same period before the pandemic[17]. Stopping AIT during a pandemic seems unwise. In this study, we demonstrated the potential protective effect of SLIT treatment in minor patients over adult patients during an epidemic by comparing the risk of symptoms following COVID-19 infection in both minors and adults treated with SLIT.

Study design

This cross-sectional study recruited subjects from the Hospital of the University of Chengdu Traditional Chinese Medicine and compared the symptoms of COVID-19 infection in AR patients (with and without SLIT). We used an electronic questionnaire designed by Questionnaire Star (https://www.wjx.cn/, Tencent, Shenzhen, China) for online survey and data collection.

Participants collection

Basic information was acquired from patients who had sought previous treatment at the Ear, Nose, and Throat Department of Chengdu University of Traditional Chinese Medicine using the clinical case system. Participants meeting the diagnostic criteria for AR were selected and categorized into two groups, AR-S and AR-C, according to their historical treatment modalities. Subsequently, group AR-S was further divided into subgroups AR-S1 and AR-S2 according to the participants' age.

Data collection

A self-administered questionnaire, formulated based on a literature review and specialists’ clinical expertise in managing AR patients during the COVID-19 epidemic, encompassed four sections: patients’ demographic information, current AR treatment, symptoms post-COVID-19 infection, and residual symptoms following the initial infection. For added clarity, Attachment 1. Due to the pandemic and to minimize unnecessary contact, participants were informed about the survey's basic details and primary objectives through text messages. Upon obtaining informed consent, participants completed the questionnaire via a provided link. The survey was conducted from January 20 to February 20, 2023, aligning with the reported first wave of COVID-19 infections in late January 2023 for a significant portion of the Chinese population.

The study protocol was approved by the Ethics Committee of the Hospital of Chengdu University of Traditional Chinese Medicine (2021KL-015), and completed registration on the ClinicalTrials.gov public website (NCT05753241). Additionally, the questionnaires of pediatric participants were filled out by their parents according to their specific conditions.

Participants and diagnosis

All the study diagnoses met the international diagnostic standards for AR [18, 19]. The participants displayed obvious clinical symptoms and their allergen skin prick tests were positive. The diagnosis of COVID-19 infection was confirmed according to the international evidence-based standards; all participants completed at least one antigen or nucleic acid test and their results were positive. The information of AR population diagnosed with dust mite allergy was extracted according to the hospital diagnosis and treatment system (J30, J30.101, J30.300).

Main outcome

We compared whether there were differences in respiratory symptoms between two groups of individuals with AR when co-infected with the virus. The odds ratio of post-infection symptoms was calculated using logistic regression.

Data analysis

Clinical data were processed using SPSS V.26 software (IBM Corp, Armonk, NY, USA). The qualitative data were expressed in percentages and frequencies, whereas the quantitative data were expressed as median (interquartile range) for non-normally distributed data. The 2-sided t-test was performed for group comparisons, whereas a χ² test was used to compare categorical variables. A regression model was constructed to adjust the impact of mixed variables on the results based on the parameters of participants’ age, gender, disease status, BMI, COVID-19 vaccinations, time from the last vaccination, smoking, and drinking habits. The statistical significance was set at a p-value of < 0.05.

A total of 398 participants (227 females and 171 males) were included in this survey and were categorized into AR-S = 205 and AR-C = 193 groups. There were significant differences between the two groups’ distribution of subjects in sex, chronic diseases, vaccination history, BMI, degree of symptoms compared to influenza, the first symptom after infection (p<0.05), as seen in Table 1.

According to the distribution characteristics of AR-S population, we divided it into AR-S1 (age < 18) and AR-S2 (age > = 18) groups. In Table 2, a χ² test compared with influenza symptoms in the three study groups. AR-S1 expressed the lowest severity compare with AR-S2 and AR-C. (Total number of people in serious and very serious group, p < 0.05).

We tallied the primary symptoms post-infection in the three groups (see Table 3) and compared differences among them using the Chi-square test and ANOVA test. The results revealed statistical variances in symptoms, including dry and itchy sensations, sore throat, cough, headache, fatigue, diarrhea, chest tightness, and recovery symptoms (cough and fatigue). Notably, the AR-S1 group exhibited the lowest throat Visual Analog Scale (VAS) score.

Correlation analysis was used to explore the correlation between desensitization time and symptoms. In Table 4, the results show that there is basically no correlation between desensitization time and post-infection symptoms.

We constructed a regression model to analyze the symptom odds ratio (OR) of the three study groups after COVID-19 infection and explore the impact of SLIT on mild infection. After adjusting for the impact of confounding factors on the results, we found that AR patients who did not receive SLIT treatment, displayed a higher risk of symptoms after infection, including dry and itchy throat (OR = 2.983, 95%Cl: 1.775–5.014), sore throat (OR = 2.830, 95%Cl:1.734–4.621), fatigue (OR = 2.329, 95%Cl:1.396–3.884), diarrhea (OR = 1.814, 95%Cl:1.102–2.984), as seen in Table 5. Additionally, the AR-S1 group may be associated with a reduced risk of symptoms after infection including dry and itchy (OR = 0.373, 95%Cl:0.184–0.755), headache (OR = 0.385, 95%Cl:0.196–0.758), fatigue (OR = 0.376, 95%Cl:0.188–0.751), chest tightness (OR = 0.160, 95%Cl:0.049–0.522), and some symptoms after improvement of infection (cough, fatigue).

As shown in Fig. 1, AR-S1 had a lower risk of developing dry and itchy, head and body pain, fatigue, diarrhea, chest tightness after infection, and the AR-C group had a higher risk of throat sore and dry and itchy (use AR-S2 as a reference).

The COVID-19 pandemic outbreak spread to different parts of China in a very short period from December 2022 to January 2023 [20–22], infecting higher population densities in China [23]. A previous study reported that AR may reduce susceptibility to COVID-19 [24], but in this epidemic, almost everyone experienced an attack of infection; therefore, this theory may not be universally applicable. Interestingly, during the follow-up of outpatient AR patients, we found that AR patients who had previously received different treatments showed significant differences in the severity of the symptoms during COVID-19 infection.

Our study included a total of 398 participants, 171 males and 227 females, were included. The participants were mainly young people. A total of 57 people had chronic basic diseases, 10 people smoked, 6 people often drank alcohol, and 386 people completed the vaccination of COVID-19 vaccine. Compared with common virus cold, most people (263) feel more uncomfortable after COVID-19 infection. Most people judged that they might be infected with COVID-19 by fever. Our data indicated that SLIT may be associated with a reduced risk of post-infection symptoms. In adults, SLIT demonstrated a decreased risk of sore throat, dryness, and itchiness in those undergoing AR treatment. Patients with mild viral infections may exhibit symptoms similar to AR, suggesting that AR-specific immunotherapy (AR-AIT) may similarly alleviate clinical symptoms in these individuals[25]. In our current study, no correlation was found between desensitization time and post-infection symptoms, which may be related to the small number of people at each desensitization time node. Almost all participants completed their vaccination, to some extent excluding the effect of differences in vaccination on the results.

Chronic inflammation of the airways (nasal cavity, pharynx) induced by allergens may contribute to the localized accumulation of inflammatory factors, potentially exacerbating pharyngeal symptoms[7]. Adequate control of allergic inflammation in patients with AR is essential to relieve upper respiratory symptoms and prevent recurrence of infection. Immunotherapy is thought to alter the Th1/Th2 balance, reducing the Th2 levels and indirectly alleviating the infection’s course. In a recent study on AIT and COVID-19 infection [26], the author described the associations between AIT and COVID-19 via type I/III IFNs in the airways of asthmatic patients. These findings explained that AIT might not only prevent asthma exacerbations but can also potentially reduce COVID-19 severity. From the mechanistic point of view, AIT and COVID-19 immune responses are not inversely correlated. Thus, AIT patients might be benefitted by rebalancing the innate immune system and favoring protective immune responses [27]. Itching of the eyes, nose, and throat is a major symptom of an allergic reaction[28], and the significant improvement of itchy throat symptoms may be related to the effective inhibition of allergic reaction by AIT.

An intriguing finding was that the majority of participants in all three groups perceived the infection's symptoms as more severe than those of a common cold. Fortunately, only a small number of participants reported experiencing chest tightness and comatose states during the infection. However, the easing of defense policies does not signify the end of the epidemic. It is imperative to persistently monitor the health of the AR population to prevent the occurrence of severe diseases resulting from the combination of airway inflammation and infection.

Since 89 minors and 116 adults were included in the AR-S group in this survey, we further analyzed the immunotherapy population by age and compared the differences in post-infection symptoms between minors and adults with AIT. Studies have shown that minors have a lower risk of some symptoms than adults, and can reduce the risk of persistent coughing and fatigue when they get better as seen in Table 3. The symptoms of AR begin in childhood or adolescence, and often have a negative impact on the quality of life of affected children and their families[29]. Children's immune systems are not fully developed and the effect of immunotherapy on children's AR is more profound[7]. Children's Total Nasal Symptom Score (TNSS) and Total Medication Score (TMS) increased significantly (p < 0.05) during the COVID-19 epidemic compared to the same period last year, although they remained significantly lower than baseline levels (p < 0.05)[10]. Standardized AIT treatment is essential for controlling childhood allergies. However, fear of viral infection and other factors in the pediatric population during the COVID-19 pandemic resulted in nearly one-third of children being discharged from AIT therapy[17, 30]. AIT can provide a prominent benefit on AR symptoms, and carries a protective effect against the risk of viral infection. Therefore, we suggest that it will be necessary in the future to implement healthcare measures to improve adherence to AIT treatment in minor patients during viral epidemics.

Advantages and disadvantages of this study

This study is the first to investigate the symptoms of COVID-19 infection in children undergoing immunotherapy. To mitigate result bias arising from questionnaire responses, we employed the simplest and most comprehensible symptom descriptions for this survey. Simultaneously, we conducted the investigation immediately after infection to minimize recall bias. Owing to the current medical resource shortage in China, most participants could not undergo chest CT scans; however, the surveyed participants were not hospitalized, allowing for an accurate reflection of the general conditions of mildly infected individuals. Given the participants' relatively young age, the results solely indicate trends within a specific age subset. This study exclusively focused on comparing House Dust Mite Allergic Rhinitis (HDM-AR), and additional research is warranted in the future to ascertain whether pollen AR exhibits similar phenomena.

AIT is the main treatment option for allergic diseases with evidence of a disease-modifying effect and thus, can be a potential agent for sustained benefits when therapy is terminated [31]. In this study, we found that HDM-AIT exhibited potential protective effects on minor AR patients infected with COVID-19.

Author Declaration

The author has no direct conflict of interest.

Funding

This work was supported by ‘Xinlin Scholar’ Scientific Research Promotion Plan for Young Scholars of Chengdu University of TCM (No. QNXZ2019016).

Ethical Approval

The article belongs to the review category and does not require the approval of the ethics committee.

Consent for Publication

Not Applicable

Availability of data and materials

All the original data of this survey have been uploaded to the public database for storage and disclosure. (DOI: 10.6084/m9.figshare.22794470)

Competing interests

The author has no direct conflict of interest.

Acknowledgments

Thank you for the great contribution to the field included in the article.

Author Contribution

SZ, MZ, YJ conducted data collection and analysis. SZ, MZ and QL designed the test plan. QZ as the paper guide, control the quality of the paper, SZ and XW drew the chart. MZ and QZ complete the writing of the test plan.

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Table 1. Participant Demographics and COVID-19 information after infection
	Treatment Group		p value
	AR-S	AR-C
	(N=205)	(N=193)
Sex, No. (%)			0.004**
male	97(47.31)	74(38.34)
female	108(52.69)	119(61.66)
Age, mean (SD); No. (%)	21.97-12.706	27.39-8.469	0.924
＜18	89(43.41)	0(0)
＞18	116(56.59)	193(100)
Chronic diseases, No. (%)			0.002**
yes	40(19.51)	17(8.81)
no	165(80.49)	176(91.19)
Vaccination history, No. (%)			0.000***
no needles	10(4.88)	2(1.04)
1-2 needles	95(46.34)	54(27.98)
3 needles	100(48.78)	137(70.98)
Timing of vaccination, No. (%)			0.072
＜3 months	11(5.37)	7(3.63)
3-6 months	9(4.39)	13(6.73)
6-12 months	92(44.88)	77(39.90)
＞12 months	83(40.48)	94(48.70)
no injection	10(4.88)	2(1.04)
Smoking, No. (%)			0.461
yes	4(1.95)	6(3.11)
no	201(98.05)	187(96.89)
Alcohol, No. (%)			0.941
yes	3(1.46)	3(1.55)
no	202(98.54)	190(98.44)
BMI, mean (SD), No. (%)	20.186±4.041	22.186-5.565	0.000**
Median (range)	20.177(17.600,22.574)	20.812(18.896,23.581)
＜18.5 kg/m²	62(30.24)	22(11.40)
18.5-25.0 kg/m²	116(56.59)	126(65.28)
25.0~29.9 kg/m²	19(9.27)	29(15.03)
≥30 kg/m²	8(3.90)	16(8.29)
The first symptom after infection, No. (%)			0.000***
dry throat and itching	41(20.00)	60(31.09)
sore throat	23(11.22)	40(20.73)
fever	70(34.15)	38(19.69)
head and body pain	29(14.15)	22(11.40)
fatigue	21(10.24)	23(11.92)
others	21(10.24)	10(5.18)
Degree of symptoms compared to influenza, No. (%)			0.001**
very mild	6(2.93)	12(6.22)
mild	18(8.78)	6(3.11)
no difference	55(26.83)	38(19.69)
severe	103(50.24)	86(44.56)
very severe	23(11.22)	51(26.42)
Allergen immunotherapy time(month), No. (%)
<6	50(24.39)	NA
6-12	48(23.41)
13-24	55(26.83)
25-35	42(20.49)
＞36	10(4.88)

AR-S means Allergic rhinitis participants with sublingual immunotherapy

AR-C means Allergic rhinitis with conventional therapy

* means p ＜0.05

** means p ＜0.01

*** means p ＜0.001

Table 2. Compare with influenza symptoms
	AR-S1 (N=89)		AR-S2 (N=116)		AR-C (N=193)		P
	n	%	n	%	n	%	P
Compare with cold symptoms
very mild	5	5.62	1.00	0.86	12	6.22	0.001**
mild	7	7.87	11.00	9.48	6	3.11
same	34	38.20	21.00	18.10	38	19.69
serious	38	42.70	65.00	56.03	86	44.56
very serious	5	5.62	18.00	15.52	51	26.42

AR-C means AR with conventional therapy.

AR-S1 means AR (minor) with sublingual immunotherapy.

AR-S2 means AR (adult) with sublingual immunotherapy.

* means p ＜0.05

** means p ＜0.01

*** means p ＜0.001

Table 3. Symptom frequency statistics of three groups after COVID-19 infection
	AR-S1	AR-S2	AR-C	total p value
	(N=89)	(N=116)	(N=193)	total p value
Symptoms after COVID-19 infection
dry and itchy	26	64	151	0.000***
sore throat	33	53	134	0.000***
cough	55	88	159	0.001**
fever	63	88	152	0.167
headache	36	72	135	0.000***
fatigue	34	70	148	0.000***
diarrhea	17	67	138	0.000***
chest tightness	4	29	66	0.000***
coma	0	1	2	0.638
Symptoms after improvement of infection
cough	10	28	56	0.006**
fatigue	4	15	47	0.000***
chest tightness	4	12	19	0.203
Symptom score
throat vas score	4.36-1.851	6.02-2.382	6.07-2.351	0.001**
temperature	38.926-0.752	38.648-0.734	38.582-3.247	0.081

AR-C means AR with conventional therapy.

AR-S1 means AR (minor) with sublingual immunotherapy.

AR-S2 means AR (adult) with sublingual immunotherapy.

* means p ＜0.05

** means p ＜0.01

*** means p ＜0.001

Table 4.Correlation analysis between desensitization time and symptoms
	Allergen immunotherapy time
	Minor	Adult
Symptoms after COVID-19 infection
dry and itchy	0.095	0.143
sore throat	0.06	0.210*
cough	0.073	0.044
fever	0.022	-0.073
headache	-0.051	0.169
fatigue	0.076	-0.100
diarrhea	0.093	0.170
chest tightness	0.004	0.040
coma	0.029	NA
Symptoms after improvement of infection
cough	0	0.018
fatigue	0.063	-0.080
chest tightness	-0.126	0.122
compare with cold	0.081	-0.139

* means p ＜0.05

Table 5. Constructed logistic regression models to compare two groups differences. (AR-S2 group as reference)
	modle 1							modle 2
	OR(95%Cl)	p value	OR(95%Cl)		p value		OR(95%Cl)		p value			OR(95%Cl)	p value
Symptoms after COVID-19 infection
dry and itchy	0.335(0.187,0.602)	0.000***		2.921(1.770-4.820)	0.000***	0.373(0.184-0.755)				0.00**6	2.983(1.775-5.014)			0.000***
sore throat	0.700(0.398,1.232)	0.700		2.700(1.676,4.349)	0.000***	0.762(0.389-1.494)				0.000**	2.83(1.734-4.621)			0.000***
cough	0.515(0.282-0.951)	0.031*		1.488(0.847-2.615)	0.167	1.013(0.467-2.195)				0.975	1.599(0.879-2.908)			0.124
fever	1.592(0.836,3.030)	0.157		1.602(0.947,2.709)	0.079	1.335(0.619-2.879)				0.461	1.582(0.924-2.706)			0.094
headache	0.415(0.236-0.731)	0.002**		1.422(0.876-2.311)	0.155	0.385(0.196-0.758)				0.006**	1.358(0.825-2.233)			0.229
fatigue	0.406(0.230-0.716)	0.002**		2.161(1.311-3.562)	0.003**	0.376(0.188-0.751)				0.006**	2.329(1.396-3.884)			0.001**
diarrhea	0.173(0.091-0.329)	0.000***		1.835(1.132-2.975）	0.01*4	0.176(0.083-0.371)				0.000***	1.814(1.102-2.984)			0.019*
chest tightness	0.141（0.048-0.419）	0.000***		1.559（0.932-2.609）	0.091	0.16(0.049-0.522)				0.002**	1.622(0.947-2.776)			0.078
coma	NA			1.204（0.108-13.429）	0.880	NA					1.492(0.101-21.973)			0.770
Symptoms after improvement of infection
cough	0.398（0.182-0.871）	0.021*		1.313（0.775-2.226）	0.311	0.281(0.112-0.704)				0.007	1.256(0.730-2.159)			0.411
fatigue	0.317（0.101-0.991）	0.048*		2.213（1.173-4.174）	0.014*	0.337(0.099-1.150)				0.083	2.158(1.121-4.157)			0.021*
chest tightness	0.408(0.127-1.311)	0.132		0.963(0.449-2.065)	0.923	0.584(0.145-2.354)				0.450	0.93(0.423-2.042)			0.856

modle 1: unadjusted

modle 2: adjusted for Sex, Age, BMI, Chronic disease, Smoking, Alcohol, Vaccination history, Timing of vaccination

* means p ＜0.05

** means p ＜0.01

*** means p ＜0.001

No competing interests reported.

Desensitization reduces some COVID-19-associated symptoms in minors with allergic rhinitis

Status:

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Abstract

Objective

Methods

Results

Conclusion

Level of Evidence: 3

Figures

Introduction

Materials and methods

Study design

Participants collection

Data collection

Participants and diagnosis

Main outcome

Data analysis

Results

Discussion

Advantages and disadvantages of this study

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1