Atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) are grouped under the term “atopic diseases” (1). These diseases have a common immunological mechanism based on T helper 2 (Th2) cells and therefore also termed “Type 2 inflammation diseases” (2). Usually, the first atopic disease that develops in young infants is AD, during the first months of life (1). Later, FA and asthma [termed airway hyperresponsiveness (AHR) develop in infants and toddlers]. Finally, allergic rhinitis usually develops at the end of the first or the beginning of the second decade of life (3). However, other studies suggest several patterns of timing (4).

Since the 1960s, the prevalence of all atopic diseases has steadily increased (5). According to the Israeli Ministry of Health, 25%–40% of the Israel population has at least one atopic disease (6). The National Survey of Children's Health reported that the prevalence of children with at least one atopic disease in the United States is 35.1% (7). The main explanation for this surge is partially based on the “Hygiene Hypothesis” and it is new version, the “Old Friends” Hypothesis (8–10). Those theories suggest that early exposure to allergens, foreign substances, and pathogens has a protective effect against the development of allergic diseases, as it preserves the balance between T helper 1 (Th1) and Th2 cells (5). Children in the Western world are exposed less to pathogens and more exposed to antibiotics, both of which are suggested as a cause for the increased prevalence of atopic diseases and impaired balance between Th1 and Th2 (11). This theory is supported by data showing that children who were exposed at a young age to other children, such as siblings or in day-care, were less likely to develop atopic diseases later in life (12, 13). Other immune cells are involved in the development of type 2 inflammation or its suppression including T regulatory and T helper 17 cells (14). Although many observational studies have provided evidence that support the “Hygiene hypothesis”, this hypothesis has not been examined prospectively (8, 12, 13).

On March 11, 2020, the World Health Organization announced the Coronavirus disease 2019 (COVID-19) as a world pandemic (15). The COVID-19 pandemic increased environmental hygiene, due to lockdowns, mask use, and social distancing. From March 2020–May 2021, Israel had three lockdowns, the population was required to wear masks, and kindergartens were closed for a total of more than 100 days (16). During this period, the prevalence of common infectious diseases, such as influenza and other non-COVID infections decreased significantly (17, 18).

Based on the hygiene and old friend hypotheses together with these changes in daily practices, it is reasonable to postulate that in the years to come, the prevalence of atopic diseases among children who were born during the COVID-19 pandemic will be higher compared to those who were born before it.

The study hypothesis is that atopic comorbidities will be more frequent in infants who were born during the COVID-19 pandemic.

This observational prospective longitudinal study is based on 2,252 infants recruited to the Cows' Milk Early Exposure Trial (COMEET) from April 2018 until May 2021 at a single center in Israel (19). Briefly, infants were recruited shortly before labor and evaluated monthly by phone or e-mail survey until 12 months of age. Addition details were published previously (19). The infants continue to be followed annually until the age of ten years (ongoing study). As this study started two years before the pandemic manifested in Israel and continued to recruit infants during the COVID-19 pandemic, it offers an exceptional opportunity to compare the prevalence of atopic diseases in the first year of life between infants born before, during, and after the pandemic. The current study focused only on the first 12 months of life.

The COVID-19 outbreak in Israel was first noticed on March 11, 2020, and social distancing was recommended (20). On March 19, 2020 the government announced the first lockdown (21). Overall, Israel had three lockdowns (March–May 2020, September–October 2020, and December 2020–February 2021).

The study cohort was divided into two groups, each with 2 subgroups: -

Group A: Pre-pandemic group (included all infants born from April 2018–March 10_, 2020). ○

Sub-group A1: Not affected by the pandemic during the first 12 months of life (infants older than 12 months on March 10, 2020).

During April 2018 and May 2021, 2,252 infants were recruited to the COMEET study. Among them, 1,989 (88.3%) infants completed 12 months of follow-up. Data analyzed in the current study included 1,078 (54.2%) infants born before the pandemic (pre-pandemic—Group A), and 911 (45.8%) born during the pandemic (pandemic—Group B). Within group A, 237 infants (22%) were older than 12 months at the beginning of the pandemic (Sub-group A1), and 841 (78%) were 0–12 months old (Sub-group A2). Within group B, 676 (74.2%) were born during lockdowns (lockdowns sub-group—Sub-group B1), and 235 (25.8%) were born after the lockdowns (post-lockdowns sub-group—Sub-group B2). Figure 1 presents the distribution of the study groups. The demographic characteristics of the groups are detailed in Table 1. The number of infants born each month is presented in Supplementary Figure 1.

In infants born during the pandemic period (Group B), vaginal delivery was much more common than caesarean section (C/S) compared to the pre-pandemic group (A) (842/911 92.4% vs. 956/1,078 88.6%, p = 0.004). They also had more siblings than the pre-pandemic group did (640/911 70.3% vs. 699/1078 64.8%, p = 0.013).

Infants in sub-group A1 were at daycare more than infants in sub-groups A2 and B1 who stayed at home with a parent (71.7% vs. 58.2% vs. 62.7%, respectively, p < 0.05), and did not exhibit significant differences compared to infants in sub-group B2 (post-lockdowns) (71.7% vs. 67.7% respectively, p = 0.368). Infants in sub-group A2, pre-pandemic, affected by lockdowns, had significantly fewer routine vaccines than infants in sub-groups B1 and B2 (93.2% vs. 97% and 98.3%, respectively, p < 0.001; Table 1).

The “hygiene hypothesis” and its new version, the “Old Friend” hypothesis are currently the leading theories used to explain the constant increase in the prevalence of atopic comorbidities. The COVID-19 pandemic gave the medical world a unique opportunity to examine those hypotheses prospectively and objectively. The current study prospectively followed newborns from the first day of life until the age of 12 months. There was no significant difference in the development of AD and FA between infants born before and during the pandemic. Infants that were born after the pandemic restrictions were eased (from February 2021), were diagnosed significantly more with AHR. Although AHR is not strictly a type 2 inflammation disease, it is well established that infants suffer from AHR as infants and toddlers are more prone to develop asthma as school-age children (22, 23).

The COMEET study (19) served as an ideal platform for prospective evaluation of those hypotheses, as about half of the participants were enrolled before the COVID-19 pandemic (before March 2020), others during its eruption and associated restrictions, and a group born after most restrictions were removed. As far as we know, this is the largest prospective cohort that examines the influence of the COVID-19 pandemic on the development of atopic comorbidities. Other studies included fewer than 600 infants (24, 25).

The current study did not find that an “over-hygienic” environment caused an increase in the prevalence of allergic comorbidities during the first year of life. On the contrary, we found that infants born in the “post-lockdowns” period (sub-group B2) even though they did not receive more courses of antibiotics, they required significantly more β-agonist inhalations and ICS than the study groups born before or during the pandemic restrictions. There could be several reasons for this observation. Infants in sub-group B2 tend to visit daycare facilities more frequently than those born just before and during the pandemic-related restrictions (sub-groups A2 and B1). However, this alone does not explain why they experience a higher incidence of AHR compared to infants in sub-group A1, who were not directly influenced by the pandemic and had a similar daycare attendance pattern to sub-group B2. This discrepancy may be attributed to the increased prevalence of respiratory infections observed after the easing of restrictions (26). In contrast to the Israeli Center of Disease Control annual report (27) and a large study from China (28), Amar et al. found that Israeli children ages 0–3 years experienced an unexpected increase in the incidence of non-COVID-19 respiratory infections in the months after the restrictions were eased, beginning in April 2021 (26). Furthermore, Dagan et al. have documented a surge in the incidence of RSV, Adenovirus, and human metapneumovirus beginning in April 2021 (29). Those observations support our findings, and the high rate of AHR in sub-group B2. Another explanation for the increase in inhalation use in the post-lockdowns sub-group could be an increase in the severity of respiratory syncytial virus (RSV) infections that were observed after COVID-19 restrictions were eased (30). One speculation for the heightened severity observed could be attributed to the fact that the mothers were likely not exposed to RSV during pregnancy, possibly due to its absence from circulation and the COVID-19 restrictions. Consequently, the transfer of RSV antibodies to their fetus, which typically occurs, might not happened (31–33). The relationship between RSV bronchiolitis and recurrent wheeze is known and can explain the incidence of inhalations use in sub-group B2 (infants born at the post-lockdowns period). However, it is not known what is the cause and what is the result—does infants who are prone to recurrent wheeze develop more severe RSV bronchiolitis or infants who have severe RSV bronchiolitis are more prone to develop recurrent wheeze (34).

The low incidence of AHR found in sub-groups A2 and B1 (infants affected by the lockdowns) is probably because of the low incidence of respiratory infections during the pandemic restrictions (18). This is in concordance to the results of a small retrospective study that compared the prevalence of respiratory morbidity during the first year of life between infants born at the beginning of the pandemic (February–March 2020) and a matched group of infants born during the same period in 2019 (24). That study reported that infants born at the beginning of the pandemic had significantly fewer respiratory comorbidities (24). The same results were shown in the CORAL birth cohort (25, 35) that compared infants born in Ireland during the first two months of the pandemic to a United Kingdom birth cohort from 2008 as a control group. The first year of life of the infants in those two studies was during the pandemic when there were fewer respiratory and influenza infections (18), similar to sub-groups A2 and B1.

In contrast to what we expected to find based on the hygiene and old friend hypotheses, we did not find an increase in the prevalence of atopic comorbidities in infants born before and during the pandemic in our study groups. Possible explanations for this observation include: A. The pandemic changed not only the hygiene level, but also other parameters including fewer Cesarean sections and more infants staying at home with their parents for the first 12 months of life. Moreover, environmental changes, including the diversity of pathogens were noted (36) and even air pollution (37) was dramatically reduced during lockdowns. Do those changes affect the trend and prevalence of atopic comorbidities? Maybe the following years and a longer follow-up period might provide this information. B. Although all four atopic comorbidities are grouped, they are different diseases with different mechanisms of acquisition. We speculate that asthma (presented until the age of 5 years as AHR) and AR are more sensitive to viral exposure and respiratory infections. A longer follow-up period is needed to find significant differences in these two diseases.

As far as our knowledge extends, this study marks the pioneering attempt to investigate the influence of the COVID-19 pandemic and its associated restrictions on the development of atopic comorbidities. While the elevated incidence of AHR may serve as an initial indicator of the pandemic's effect on the prevalence of other atopic comorbidities, it is imperative to conduct further investigations before drawing broad-reaching conclusions.

We are planning to follow the COMEET study cohort until the age of 10 years. We anticipate that longer follow-up will provide a better understanding of the influence of the COVID-19 restrictions on the development of atopic comorbidities.

This study had several limitations: First, the groups were not randomized, and several characteristics differed significantly between the groups. We stratified the groups to control these differences. Second, the COMEET study was designed for a different purpose and the questionnaires were designed accordingly. This led to some deficits in the data, including COVID-19 infections that might have influenced the results. Third, the infants in group B2 were born in a very short period and seasons (the end of winter and part of the spring), and this differs from the other groups that were born in all seasons. However, because we have a representation of all seasons we can compare the trends between the different groups. Additionally, Infants in sub-group A2 received fewer routine vaccinations without changes in the National immunization schedule. We assume this difference is technical due to lockdowns and restrictions that made it difficult to schedule visits for routine vaccines. However, this did not influence the prevalence of AHR.

This study is the largest prospective study in infants analyzing the incidence of atopic comorbidities during a real-life situation of hygiene restrictions.

Infants born at the end of the COVID-19 pandemic restrictions (after February 2020) had more AHR and received more inhalations than infants born before and during the pandemic restrictions. We did not find significant differences in the prevalence of atopic comorbidities between infants born before, during or after the pandemic lockdowns. The results of this study suggest that the hygiene hypothesis is probably only one of many factors involved in the complex pathogenesis of atopy. However, a longer follow-up might provide different results.