Multiple Childhood Respiratory Viral Infections Are Associated with Allergy in Young Adults

Abstract

Introduction

Early-life viral infections have been linked to both increased and decreased risk for allergic disease later in life. Causative relationships have been difficult to prove and most likely both timing and type of infection(s) are of importance. The aim was to study the association between early-life viral infections and allergy at 20 years of age. In addition, the study aimed to examine how early viral infections are associated with other known risk factors for allergy.

Methods

A cohort of 281 individuals recruited before birth and categorized into three hereditary groups based on parental allergy status, defined by IgE-sensitized and allergic symptoms, was followed until age 20. Of these, 142 individuals completed both web-based questionnaires and clinical investigations. Infections were documented both as parent-reported between 0 and 2 years and seropositivity against 13 viruses at 2 years of age. Analyses included logistic regression and classification tree modeling.

Results

Individuals who experienced many respiratory viral infections (11–20) during their first 2 years of life had a higher prevalence of allergies compared to their peers with fewer than 10 respiratory viral infections (58% vs. 34%, p = 0.005). Cytomegalovirus (CMV) seropositivity at 2 years of age was associated with allergy at age 20 (p = 0.026). As expected, parental allergy was also linked to the development of allergy.

Conclusion

Individuals who experienced frequent respiratory viral infections during early childhood, were seropositive for CMV by age two, and had two allergic parents consistently developed allergic disease by age 20. Preventive strategies targeting early viral respiratory infections may help reduce future allergy.

Introduction

The underlying causes for the development of allergy have been extensively studied for decades. Both genetic factors such as allergic parents [1], and environmental factors [2–4] have significance. Early-life infections have been linked to both protection [5–7] and increased risk of allergic disease later in life [8, 9]. However, there are questions about the timing of infections, how many, what kind of infections, and the combination of infections contributing to the development of allergic diseases [10]. Viral infections are the most extensively studied type in relation to allergies [11]. Respiratory viral infections such as rhinoviruses [12, 13] and respiratory syncytial virus (RSV) [9, 14], as well as latent herpesviruses including cytomegalovirus (CMV) and Epstein-Barr virus (EBV) [15], have been investigated for their potential roles in the development of allergic diseases. Children uninfected with RSV in early life showed reduced asthma risk by age 5 [16], whereas high RSV-specific antibody levels at the age of 1 year correlated with increased atopy up to age 10 years [17]. In our cohort, EBV seropositivity at 2 years was associated with lower prevalence of IgE sensitization, further strengthened by CMV coinfection. This protective effect of early EBV acquisition persisted through ages 5 and 10 years [6].

Despite existing insights, key knowledge gaps remain regarding how early-life viral exposures influence allergic disease in young adulthood. Comprehensive longitudinal data on the cumulative impact of multiple infections are limited. While environmental factors interact with genetics, the extent to which genetic predisposition determines whether early viral infections pose a risk or offer protection remains largely unknown. Our research includes extensive follow-up of allergy status in relation to viral infections and parental allergy. Here, the aim was to study the association between early-life viral infections and allergy at the age of 20 years, in terms of number and type. In addition, how early viral infections are associated with other known risk factors for allergy.

Methods

The Cohort and Study Population

In Stockholm, between 1997 and 2000, parents were recruited at maternity care centers during pregnancy. Parental allergic disease was characterized by medical history confirmed with skin prick test (SPT) and specific IgE antibodies (sIgE ab). The children born into the study (n = 281) were divided into three groups depending on their parents’ allergic status: no parent with allergy, “No heredity” (NH, n = 77); allergic mother but nonallergic father, “single heredity” (SH, n = 84); and two allergic parents, “double heredity” (DH, n = 120). Several follow-ups have been performed, and the cohort has been described in detail elsewhere [1, 5, 6, 18] (shown in online suppl. eFig. 1; for all online suppl. material, see https://doi.org/10.1159/000551575). All individuals from the original cohort were invited for the 20-year follow-up, and 142 participants answered a web-based questionnaire [19] and participated in a clinical examination including height, weight, and blood samples (online suppl. eTable 1). The distribution between the heredity groups was comparable between the study population and the original cohort. Background characteristics, such as breastfeeding, furred pets, siblings, daycare, sex, and parental smoking, regarding the study population did not differ from the original study population and are described elsewhere [1].

IgE Sensitization and Allergy Definition

Skin prick test (SPT) was performed at 2 years of age and included food (egg white, cod, cow’s milk, peanut, and soybean) and inhalant allergens (cat, dog, birch, timothy, and Dermatophagoides farinae). The test was performed according to the manufacturer’s instructions (ALK, Copenhagen, Denmark). At 2 years of age, IgE antibodies (sIgE ab) sensitization was used as the outcome measure, as no food challenge tests were performed. Serological analysis of specific IgE ab was conducted at 2 and 20 years using the ImmunoCAP System (Thermo Fisher Scientific, Uppsala, Sweden). The analyses included foods (egg white, milk, fish, shrimp, peanut, hazelnut, walnut, pecan, cashew, pistachio, and sesame) and airborne allergens (birch, timothy, horse, dog, and cat).

Participants at 20 years of age were classified as allergic if their sIgE ab levels were ≥0.35 kUA/L for at least one allergen and they reported one or more allergic symptoms, including asthma, atopic dermatitis, food allergy, or rhinitis, as defined in online supplementary eTable 2 in the eSupplementary Material.

Parents´ Report of Viral Infections

From birth until age 2 years, the parents documented all their child’s infections in a structured diary, including frequency and symptoms. The recorded events were then discussed and verified by the same doctor during visits to the clinic at 6, 12, 18, and 24 months of age [5]. At start, we compiled all infections reported during the first 2 years of life. This included symptoms like runny nose, cough, vomiting, diarrhea, fever, and doctors’ diagnosis when relevant. We then divided the total number of infections into two groups: few (3–10 infections) and many (11–23 infections), based on previous reports from Finland where data indicate that infants typically experience 6–8 infections annually [20]. Next, we classified the infections into two categories: “respiratory infections” (runny nose, cough, and otitis) and “other infections” (vomiting, diarrhea, fever). Finally, respiratory infections were further categorized into clinically relevant groups: few (2–10 episodes) and many (11–20 episodes).

Serological Methods

At 2 years of age, serostatus was assessed for 13 viruses: adenovirus, influenza A/H1, A/H3, B, parainfluenza types 1–3, RSV, and herpesviruses including CMV, EBV, HSV, HHV6, and VZV. Details of the serological analysis are provided in online supplementary eTable 3.

Statistical Analysis

To compare individuals with few versus many infections, as well as seropositivity for 13 viral infections, in relation to allergy, we used the chi-square test. p values <0.05 were considered statistically significant. Logistic regression was used to examine associations between the outcome variable allergic disease (yes/no), infections, and several other clinically relevant risk factors identified from the literature [21]: respiratory infections from diary (2–10/11–20), CMV at 2 years of age (yes/no), allergic heredity (NH, SH, DH), sex (female/male), exclusive breastfeeding (≥3 months/<3 months), siblings at birth (1 or more/0), pets at birth (no/yes), age of starting daycare (12–18 months old/19–20 months old). We used two models in the analysis. First, we used a crude model to study the unadjusted association with each risk factor and allergic disease. Second, all factors were included in an adjusted model to adjust for potential confounding and to identify independent factors associated with the outcome. We present associations as odds ratios (OR) and corresponding 95% confidence intervals.

As a complement to the logistic regression, we used a classification tree analysis to stratify individuals according to the risk of being allergic at 20 years of age. We used the same variables as in the logistic regression. The groups represent individuals who are similar within the nodes and different between the nodes. The classification trees were constructed using the Chi-Square Automatic Interaction Detection (CHAID) algorithm [22], which evaluates cross-tabulations between each risk factor and the outcome using chi-square tests for significance. The criteria for building the tree were set to: a minimum of 20 individuals for parent nodes, a minimum of 10 individuals for child nodes, and the growth of the tree was stopped when the p value for splits was greater than 0.05. We present two tree models: one with Bonferroni adjustment and one without. The data were analyzed using IBM SPSS Statistics (version 28) Predictive Analytics software.

Results

Allergy at 20 Years of Age

In total, 142 young adults, 51 women, and 49 men participated in the clinical investigation at the 20-year follow-up, including blood samples and demographic data (online suppl. eTable 4). Sixty-four participants were considered allergic at 20 years (at least one reported allergic symptom and IgE antibodies (sIgE ab) >0.35 kU/L to at least one tested allergen) [1]. Among the 64 allergic participants, 44% had developed sIgE ab by the age of two (data not shown).

Seropositivity to CMV at 2 Years of Age and Allergy at 20 Years of Age

Seropositivity to the 13 examined viruses was, on average, five viruses per participant (range: 0–9) at age 2 years, with no significant difference for being allergic or not at 20 years of age (shown in online suppl. eFig. 2). The most frequently detected infection at age 2 was HHV6 (85%), followed by adenovirus (78%). We examined the relation between seropositivity to individual viruses and allergy and found an association between CMV and allergy at 20 years of age. Specifically, CMV acquired before the age of two was significantly associated with an increased likelihood of being allergic at 20 years (p = 0.026) (Table 1, shown in eFig. 3). However, individuals who were initially seronegative for CMV and later tested positive at ages 5 or 10 years showed no significant association with allergy status at 20 years (online suppl. eTable 5). There were no other statistically significant associations between the remaining viruses and allergy at 20 years of age.

Table 1.

Seropositivity to viruses at 2 years of age and allergy at 20 years of age

​	Seropositive	N	Allergica	p value*
			% (n/tot)
Herpes virus
EBV	Yes	23	48 (11/23)	0.824
	No	106	45 (48/106)	​
CMV	Yes	55	56 (31/55)	0.026
	No	81	37 (30/80)	​
HSV	Yes	12	50 (6/12)	0.698
	No	120	44 (53/120)	​
VZV	Yes	23	52 (12/23)	0.427
	No	109	43 (47/109)	​
HHV6	Yes	112	42 (47/112)	0.135
	No	20	60 (12/20)	​
Respiratory virus
P1	Yes	40	48 (19/40)	0.669
	No	92	44 (40/92)	​
P2	Yes	10	60 (6/10)	0.311
	No	122	43 (53/122)	​
P3	Yes	83	47 (39/83)	0.491
	No	49	41 (20/49)	​
Adeno	Yes	103	42 (43/103)	0.199
	No	29	55 (16/29)	​
RSV	Yes	82	48 (39/82)	0.397
	No	50	40 (20/50	​
Beijing	Yes	55	49 (27/55)	0.391
	No	77	42 (32/77)	​
Panama	Yes	27	37 (10/27)	0.369
	No	105	47 (49/105)	​
Texas	Yes	15	47 (7/15)	0.871
	No	117	44 (52/117)	​

^asIgE ab ≥0.35 kUA/L to at least one allergen and at least one allergic symptom.

*Pearson chi-square, significant p value <0.05.

Frequent Childhood Respiratory Viral Infections Are Associated with Allergy at 20 Years of Age

Among the 142 study participants, the mean number of parent-reported infections was 13 (range: 3–23) during the first 2 years of life. The number of infections between birth and 2 years among allergic and nonallergic individuals at 20 years of age is shown in Figure 1. We divided the participants into two groups with few (3–10) or many (11–23) infections. However, we saw no association between having few or many parent-reported infections and allergy at age 20 (shown in Fig. 2, online suppl. eTable 6).

Fig. 1.

Percentage of individuals classified as allergic or nonallergic at age 20 years according to the number of all parental-reported infections in early childhood (0–2 years).

Fig. 2.

Number of all parental-reported infections from diaries, from 0 to 2 years of age, divided into having had 3–10 or 11–23 infections, and the proportion of being nonallergic or allergic at age 20 years.

Next, parent-reported infections were categorized into “respiratory infections” and “other infections”. The mean number of respiratory infections reported during the first 2 years of life was 10 (range: 2–20). The percentage of respiratory infections and allergic or nonallergic participants is shown in Figure 3. When categorized into groups with few (2–10) and many (11–20) respiratory infections, participants who experienced many infections during their first 2 years of life were significantly more likely to be allergic at age 20 compared to those with fewer infections (p = 0.005; Table 2, shown in Fig. 4). As parental allergy status was known, we further subdivided the participants into the three heredity groups: NH, SH, and DH. Among individuals in the DH group who experienced many respiratory viral infections in early life, 81% were allergic at age 20 (p = 0.009; Table 2). Additionally, in the SH group, defined by an allergic mother and a nonallergic father, participants with many respiratory viral infections were more likely to be allergic than those with fewer infections (p = 0.037). Having other infections, e.g., gastroenteritis, showed no difference between allergic or nonallergic individuals at 20 years of age (shown in online suppl. eFig. 4).

Fig. 3.

Distribution of allergic and nonallergic individuals at age 20 years according to the number of parental-reported respiratory infections during infancy.

Table 2.

Number of parental-reported respiratory infections from 0 to 2 years of age, in relation to allergy status (allergic vs. nonallergic) at 20 years of age, presented for all participants (n = 142) and stratified by allergic heredity

​	Number of respiratory infections		p value*
	2–10	11–20
	allergic, % (n/tot)a	allergic, % (n/tot)
All	34 (26/76)	58 (38/66)	0.005
Heredityb
NH (n = 43)	15 (3/20)	30 (7/23)	0.203
SH (n = 34)	24 (4/17)	59 (10/17)	0.040
DH (n = 65)	49 (19/39)	81 (21/26)	0.009

^aAllergic – sIgE ab ≥0.35 kUA/L to at least one allergen and at least one allergic symptom.

^bNo heredity (NH); single heredity (SH) = mother allergic; double heredity (DH) = both parents allergic.

*Pearson chi-square, significant p value <0.05.

Fig. 4.

Number of parental-reported respiratory virus infections from 0 to 2 years of age, categorized as 2–10 and 11–20 respiratory infections, and the proportion of individuals classified as nonallergic or allergic at 20 years of age.

Association between Allergy, Viral Infections, and Other Risk Factors for Allergy

Allergic disease compared to having no allergic disease at the age of 20 years was associated with an increased OR for the following clinically relevant factors (online suppl. eTable 7): having many parent-reported respiratory infections (11–20) from birth to 2 years of age, both in crude and adjusted ORs, 2.6 (1.3–5.1) and 4.2 (1.6–11.2), respectively, CMV seropositivity at 2 years, crude OR 2.1 (1.0–4.4), and adjusted OR 2.9 (1.1–7.4), and having two allergic parents (DH) 5.3 (2.2–12.6) and adjusted OR of 9.8 (2.8–33.3). Adjustment included respiratory infections from diary (2–10/11–20), CMV at 2 years of age (yes/no), allergic heredity (NH, SH, DH), sex (female/male), exclusive breastfeeding (≥3 months/<3 months), siblings at birth (1 or more/0), pets at birth (no/yes), age of starting daycare (12–18 months or 19–20 months old). No other variables showed any significant association to allergy at age 20 years (online suppl. eTable 7).

Viral Infections in a Classification Tree Calculating the Risk of Being Allergic at 20 Years of Age

The classification tree (shown in Fig. 5 and online suppl. eFig. 5) showed that the strongest factor associated with being allergic at 20 years of age was having allergic parents (p = 0.001 with Bonferroni). The other factors associated with allergy were parent-reported respiratory infections during early childhood and seropositivity for CMV at 2 years of age (shown in Fig. 5). The highest percentage of allergic 20-year-olds was found in the group (node) with participants with two allergic parents (DH), many parent-reported respiratory infections during early childhood (11–20), and acquired CMV infection before the age of 2 years. In the node combining participants with no (NH) and single heredity (SH) predisposition to allergy, the likelihood of being allergic at age 20 was also higher among those having had many respiratory infections, 43% (11–20) compared to those with few infections, 19% (2–10) (p = 0.026). Furthermore, if the participants also were seropositive to CMV, 62% were allergic compared to 29% if the participants were seronegative (p = 0.037 without Bonferroni). The primary difference between the trees was the inclusion of “CMV at 2 years of age” in the tree without Bonferroni specifically within the NH/SH group (shown in Fig. 5, online suppl. eFig. 5).

Fig. 5.

Classification tree for being allergic at 20 years of age. The highest percentage of allergy was found among young adults with two allergic parents and a high number (11–20) of parental-reported respiratory infections during the first two years of life: amomg those who additionally were seropositive for CMV at 2 years of age, all individuals (100%, 11/11) were allergic. p value <0.005 without Bonferroni. ¹Allergic – sIgE ab ≥0.35 kUA/L to at least one allergen and at least one allergic symptom. ²Heredity – no heredity (NH), single heredity, allergic mother (SH), and double heredity, both parents allergic (DH). ³Resp inf diary – parental-reported respiratory viruses 0–2 years. ⁴CMV 2 years – seropositive to CMV at 2 years.

Discussion

In this prospectively followed cohort, from birth to 20 years of age, with parents well-characterized regarding allergic status, we have investigated serostatus for 13 viral infections at 2 years of age and parent-reported infections during the first 2 years of life in relation to allergy at 20 years of age. Our key findings show three significant risk factors for allergic diseases at the age of 20: serology-verified CMV acquisition before the age of two, having had many parent-reported respiratory viral infections (11–20) in early childhood (0–2 years of age), and having allergic parents. Participants in the study having all three risk factors exhibited the highest risk of being allergic at the age of 20 years.

The timing and type of infections may be significant in allergy development. In this study, we have followed the participants from birth up to 20 years of age. At 2, 5, and 10 years, EBV, a herpes viral infection transmitted by saliva, was the viral infection associated with protection against IgE sensitization [5, 6]. At these ages, the most common allergic disease was food allergy, and since no food challenges were performed, IgE sensitization was the main outcome. However, by the age of 20 years, seropositivity to EBV was no longer associated with either an increased or a decreased risk of allergy. Another herpes virus, CMV, that enhanced EBV's negative association for IgE sensitization at age 2 years, was at 20 years of age instead associated with allergy. This may be explained by the fact that young children’s immune systems and their risk of developing allergies are more strongly influenced by family and the immediate environment, whereas the environmental exposures have changed by the age of 20. In addition, the immune system in early childhood is highly plastic, and infections may affect immune development differently depending on the timing in life. It is also well established that young children rarely develop severe illness from CMV infection, whereas infection during adolescence can lead to prolonged and severe disease. CMV is primarily transmitted through direct contact with bodily fluids, including saliva, blood, urine, semen, vaginal secretions, and breast milk. Vertical transmission can occur from mother to child during pregnancy, delivery, or lactation. Additionally, person-to-person transmission may result from close interactions such as kissing or sexual contact [23].

Other infections of interest are respiratory viral infections. RSV leading to hospitalization has for many years been linked to wheezing and asthma [16, 24] as well as IgE sensitization [25, 26]. This has traditionally been explained by RSV-induced lung damage with subsequent impairment on airway function. Recent experimental evidence provides further mechanistic insight; a neonatal murine model demonstrated that recurrent early-life RSV infection alters airway barrier function and promotes type 2 immunity [27]. An alternative explanation is that some children are predisposed to developing asthma and therefore exhibit increased sensitivity to RSV, for example, due to an atopic predisposition that has not yet manifested clinically. However, this cannot be seen in our cohort, neither for allergy nor asthma in childhood at 20 years of age. Moreover, several reports suggest that an impaired epithelial barrier, as seen in eczema in early childhood, can promote the development of IgE sensitization [28]. The discrepancy between our study and others may be explained by the fact that we, in our cohort, analyzed seropositivity to RSV without linking it to disease severity and did not investigate RSV-related hospitalizations. This needs to be considered when studying individual viruses. Other infections of interest are human rhinoviruses (HRV), which have been associated with wheezing in young children. However, in our study, we were unable to analyze seropositivity to HRV due to the lack of reliable tests in the 1990s. Interesting data from a prospective birth cohort with children at high risk for developing allergies and asthma suggest that allergic sensitization precedes HRV-associated wheezing and that allergic sensitization may lead to more severe HRV infection [12].

In our study, the mean number of parent-reported infections during the first 2 years of life was 13, which aligns with international estimates for young children [20]. When stratified by infection burden, a larger proportion of individuals with many (11–20) respiratory infections developed allergy by age 20, compared to those experiencing fewer (2–10) respiratory infections. One possible explanation is that children with frequent respiratory viral infections in the first 2 years of life may already have developed allergy by the age of two, thereby increasing their susceptibility to subsequent infections [29]. However, as 44% of allergic 20-year-olds were IgE-sensitized before the age of two, our data do not support the notion that infections precede IgE sensitization. Although HRV was not serologically confirmed, the lack of antibiotic treatment indicates that most parent-reported respiratory infections were likely viral, particularly HRV. A high frequency of these early respiratory viral infections was associated with allergic disease at 20 years of age.

Similarly, the CORAL cohort, where children born in Ireland during the COVID-19 lockdown were followed from birth to study the effects of the pandemic on allergic disease, showed lower-than-expected rates of food sensitization and allergy. One possible explanation for this trend could be changes in infection patterns [30]. The children stayed at home, and most did not interact with other children outside their family or attend daycare, which may have resulted in fewer infections. Studies on wheezing and asthma in relation to the frequency of early infections or indirectly assessed through early daycare enrollment or having many siblings are available [4, 31]. A review examining CMV prevalence in daycare settings identified a significant association between daycare attendance and increased CMV infection rates in early childhood [32]. In our study, approximately two-thirds of the children entered daycare between 12 and 18 months of age. However, there was no significant difference in the age of daycare start between the allergic and nonallergic group.

In our study, having allergic parents was an additional factor associated with allergy at 20 years of age. Previous research has established this association in younger children, and our findings confirm that it also applies to young adults. Genetic predisposition to allergy and atopic diseases is significant and involves multiple genes. A large cohort study examined the relationship between parental allergic diseases and their offspring, demonstrating that parental allergy strongly influences the child’s likelihood to develop allergy, with effects persisting into adolescence [33].

In the logistic regression model and classification tree, several clinically relevant environmental factors were included; however, none showed an association with allergy at 20 years of age. We acknowledge that performing multiple tests increases the risk of type I errors. Socioeconomic status was not included in the model but had previously shown no association with IgE sensitization at 2 years of age [5].

The small cohort size is a limitation of the study, and since this is a non-population-based cohort, the results cannot be generalized. However, the small sample size enabled more detailed data collection, which was essential to ensure that all necessary information was gathered to address the predefined research questions effectively. The cohort was not intended to represent the general population and has a higher prevalence of allergic outcomes due to a disproportionate number of allergic parents among the participants. Additionally, other studies from this cohort have conducted extensive immunological analyses, offering valuable insights into immune responses and contributing to a deeper understanding of the research objectives [34–38].

The main strengths of our study are its longitudinal cohort design and the meticulously documented data on early viral infections, including their frequency and type during the first 2 years of life. This information was obtained from unique infection diaries, recorded from birth until 2 years of age, prior to the assessment of IgE sensitization. In these diaries, parents reported all infections, which were verified by the same pediatrician every 6th month.

Additionally, seroconversion at 2 years of age was analyzed for 13 common childhood viral infections. Furthermore, parental allergy was rigorously validated prior to the child’s birth, requireing concordance between self-reported allergic symptoms, skin prick test results. and sIgE ab levels to qualify for study participation.

In summary, the classification tree analysis reveals a strong association between frequent respiratory infections in early childhood, CMV seropositivity at 2 years of age, and parental allergy, with the presence of diagnosed allergy at age 20. These findings suggest that a combination of early viral exposures and genetic predisposition may substantially increase the risk of developing allergic conditions in young adulthood.

Acknowledgments

We would like to thank all participants and staff in the study and Carina Wallén for IgE antibody analysis.

Statement of Ethics

The study was approved by the Regional Ethic Committee, in Stockholm (Dnr: 0–2 years – 75/97, 117/97, 5 years – 331/02, 10 years – 2007/858-31/2, 20 years – 2019/02034). Written and informed consent was obtained from the participants at 20 years of age, while for earlier time points, their parents provided informed verbal consent. At the time of the initiation of the study, no written documentation of participants’ approval was required, which was agreed to by the Ethics Committee.

Conflict of Interest Statement

C.N. reports grants to institution from Aimmune Therapeutics a Nestlé Company. Material for IgE analyses from Thermo Fisher was used in academic studies. Lecture fees were received from: MEDA, ALK, Thermo Fisher, and GSK. Eva Sverremark-Ekström has received honoraria for lectures and a grant for another research project from BioGaia AB. No conflicts of interest were reported by the other authors.

Funding Sources

This study was financially supported by Hesselmans Foundation, Stiftelsen Samariten, the Asthma and Allergy Association’s Research Foundation, the Golden Jubilee Memorial, Föreningen Mjölkdroppen, the Cancer and Allergy Foundation, the Swedish Research Council (2020-01839 and 2023-02616), the Swedish Heart-Lung Foundation, and the Swedish Order of Freemasons.

Author Contributions

Data collection was managed by C.N., and U.H. C.N., E.S.-E., A.N., and U.H. participated in the design of the study. Statistical analysis was conducted by U.H. with support from senior biostatistician (H.J.-P.). Analysis and drafting of the manuscript were conducted by U.H. and C.N. All authors participated in the critical revision of the manuscript and provided important input and approved the final manuscript.

Funding Statement

This study was financially supported by Hesselmans Foundation, Stiftelsen Samariten, the Asthma and Allergy Association’s Research Foundation, the Golden Jubilee Memorial, Föreningen Mjölkdroppen, the Cancer and Allergy Foundation, the Swedish Research Council (2020-01839 and 2023-02616), the Swedish Heart-Lung Foundation, and the Swedish Order of Freemasons.

Data Availability Statement

The data supporting the findings of this study are available upon request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.