Background: Selective IgM deficiency (sIgMD), classified under primary immunodeficiencies, is characterized by low serum IgM(<2SD for age), normal IgG and IgA levels. The aim of this study was to define immunologic and clinical features of sIgMD. Method: We assessed a retrospective medical record of patients who fullfilled the criteria for sIgMD in a Pediatric Immunology department. Results: There were 55 patients with sIgMD. Out of 55 patients, thirteen(23.6%) diagnosed with a well-defined primary immunodeficiency (PID) during the follow-up.The ratio of the sIgMD was %0.12 in the out-patient clinic of pediatric immunology. Out of 33 patients, 8(23.5%) were asymtomatic during the follow-up period. Fifteen(45.4%) patients presented with several type of infections). Six patients (18%) had chromosomal anomaly, or syndrome (trisomy 21, 22q11.2 deletion 1p deletion, CHARGE syndrome, and Cohen Syndrome). Six (18%) had autoimmune/inflammatory diseases, such as Behcet’s disease, immune thrombocytopenic purpura, Crohn disease, Guillain Barre syndrome, and diabetes mellitus. Five(15%) had allergic disorders. Three(9%) have developed malignancy. The diagnoses of thirteen PID patients were combined immunodeficiency, common variable immunodeficiency, autoimmune lymphoproliferative syndrome, chronic granulomatous disease, adenosine deaminase deficiency, and congenital neutropenia. Genetic disorders, autoimmune/inflammatory and allergic diseases may accompany sIgMD. Approximately one third of the patients were asymptomatic in our series. Malignancy risk is relatively increased. We observed that an important ratio of patients with low IgM (23.6%) got sooner the diagnosis of a specific PID in the follow-up period. Conclusion: Thus, patients with sIgMD should be followed regularly in immunology clinics.

To the Editor:Severe asthma (SA) affects less than 5% of the pediatric asthma population but is considered to account for approximately half of total pediatric asthma healthcare costs. Allergic comorbidities, including food allergies (FA) and allergic rhinitis (AR), are frequent in children with SA (1). The presence of FA and AR increases asthma severity (1–6) and medication use (4–6). Treating AR improves asthma symptoms (3). However, the economic burden of allergy in children with SA has been poorly studied. We aimed to determine the economic contribution of allergy for the French national health insurance (NHI) for the treament of children with SA at the individual level.Children with SA, defined as those requiring step 4 or 5 of treatment of the Global Initiative for Asthma (GINA), regularly followed in the Department of Pediatric Pulmonology of Necker Hospital were included as previously described (7). The diagnosis of SA, FA, and AR were made by a physician according to guidelines (8-10). A physician-guided questionnaire was completed with parents to assess individual expenditures related to asthma and allergic comorbidities in the previous six months. Parental claims were confirmed by analysis of the medical records. The methods are detailed elsewhere (7). First, we determinated the direct, indirect, and global costs of SA over a six-month period (7) and then assessed the allergy-related costs. The costs related to allergy included anti-allergic medications (oral antihistamines, steroid nasal sprays, anti-allergic eye drops, adrenaline autoinjectors, and allergen immunotherapy), anti-IgE treatment, scheduled ambulatory or hospital outpatient visits to an allergist, pulmonologist, ophthalmologist, or dermatologist, skin tests, blood tests for allergy-specific IgE, and day care unit (DCU) admissions for oral food challenge (OFC) (7). Finally, we compared the economic burden of allergy between children with SA and those without (NSA) (7). Parents were informed and accepted to participate in the study. The local ethical committee confirmed that Institutional Review Board approval was not required.Forty-eight children with SA and 26 with NSA were included. Their general characteristics are summarized in Table 1. The individual global cost of SA was \euro3,982 (4,422) over the six-month study period (7). For children with allergic SA, the cost attributed to allergy was \euro2,803 (3,709), representing 48.1% (35.2) of the direct SA costs and 45.8% (34.9) of the global SA costs. Overall, the number of allergic comorbidities for children with SA weakly correlated with global (r = 0.33, p = 0.02) and direct SA costs (r = 0.35, p = 0.01). The global and direct costs of SA were higher for children with allergic comorbidities than for those without (\euro4,646 (4,635) vs. \euro1,107 (1,173), p = 0.02; respectively). However, these figures partially reflect the actual economic contribution of allergy in children with allergic SA. For those requiring omalizumab, the economic burden of allergy was \euro5,057 (3,809) representing 74.1% (24.4) of direct SA costs and 71.6% (24.3) of global SA costs. In this group, omalizumab was the main driver of costs, representing 73.6% of direct SA costs and 71.5% of global SA costs. For children with allergic SA not requiring omalizumab, the economic burden of allergy was \euro174.50 (289.7), representing 17.8% (16.1) of direct SA costs and 15.8% (15.9) of global SA costs. Regardless of omalizumab use, the economic burden of allergy was similar among children with allergic SA (\euro153.3 (159.4) vs \euro174.50 (289.7), p = 0.99). However, the burden of allergy expressed as a percentage of direct and global SA costs was lower for children with SA requiring omalizumab than those who did not (3% (4.2) vs. 17.8% (16.1), p < 0.01 and 2.9% (4.2) vs. 15.8% (15.9), p < 0.01, respectively).Global, direct, and indirect costs did not differ between children with NSA, with or without allergic comorbidity (Table 3). For children with allergic NSA, the cost of allergy was \euro134.40 (213.90), representing 40.8% (33.3) of the asthma direct costs and 34.7 % (32.2) of the asthma global costs. Thus, regardless of omalizumab use, the cost of allergy for children with allergic SA and that for those with allergic NSA was similar (\euro163.1 (225.9) vs . \euro134.40 (213.9) (p = 0.19). However, the economic burden of allergy was greater for children with NSA than those with SA: 40.8% vs 9.8% of direct costs and 34.7% vs. 8.9% of global costs, respectively (both p < 0.01). Finally, the economic burden of allergy was similar between children with allergic SA not requiring omalizumab and those with allergic NSA (\euro174.5 (289.7 vs. \euro134.4 (213.9), p = 0.29).This study shows that the costs attributed to allergy for children with SA are substantial and mostly driven by omalizumab, but are minor when omalizumab is not taken into account. The economic burden of allergy was similar between children with allergic SA not requiring omalizumab and those with allergic NSA, suggesting a low cost-effectiveness ratio, at least in the latter group. The global and direct costs of children with allergic SA were higher than those of children with non-allergic SA. This finding confirms that the presence of allergic comorbidities increases the costs of asthma management (11) and supports that allergy is associated with asthma severity. Our study had several limitations. Only a small number of children were included. However, we included children with well-defined doctor-confirmed SA, with and without omalizumab, reflecting the heterogenity of this population. In addition, our study was performed in a tertiary-care center. Thus the children with NSA may not be representative of community children. Our estimation was based on parental declarations, with a potential memory bias and a risk of misestimation of certain expenditures. We limited this risk by analyzing the medical records, which confirmed the parental claims. The best design would have been to obtain the data of children selected by a physician from the NHI. However, this approach is rarelly authorized in France. Moreover, the study covered a short period of time including winter and two months of spring, which may lead to underestimation of costs related to seasonal allergy treatments. In addition, the number of children under allergen immunotherapy was small (1 in the group of children with allergic SA vs. 4 children with allergic NSA (p = 0.03)).In summary, this study is the first to precisely analyse the proportion of costs attributed to allergy in pediatric SA. As expected, allergy-related costs are mainly driven by omalizumab. However, for children with allergic SA who do not require omalizumab, the economic contribution of allergy to SA costs is relatively small, suggesting a low cost-effectiveness ratio.

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE mediated food allergic disorder with a well-characterised clinical phenotype, but limited understanding of factors associated with food cross-reactivity, severity and tolerance. Methods: A retrospective cohort study spanning 20 years on children with acute FPIES from a single paediatric tertiary centre in New South Wales, Australia focusing on identifying food trigger co-associations and factors associated with reaction severity, multiple trigger FPIES and/or tolerance was performed. Results: 169 individuals with 329 recorded FPIES episodes between 1997 and 2017 were included. 49% were male. The median age at first FPIES reaction was 5 months and median age at diagnosis was 9 months. 73% experienced at least one severe FPIES reaction. Rice (45%), cow’s milk (30%), soy (13%) were the most common triggers. FPIES to rice or cow’s milk were strongly associated with increased odds of having multiple trigger FPIES. Associations between causative foods were seen with rice/oats, cow’s milk/soy, and fish/shellfish. No factors were associated with increased risk of severe reactions. Infants with rice and grains FPIES outgrew their reactions at an earlier age, compared to those with fish FPIES. Conclusions: Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE mediated food allergic disorder with a well-characterised clinical phenotype, but limited understanding of factors associated with food cross-reactivity, severity and tolerance. Methods: A retrospective cohort study spanning 20 years on children with acute FPIES from a single paediatric tertiary centre in New South Wales, Australia focusing on identifying food trigger co-associations and factors associated with reaction severity, multiple trigger FPIES and/or tolerance was performed. Results: 169 individuals with 329 recorded FPIES episodes between 1997 and 2017 were included. 49% were male. The median age at first FPIES reaction was 5 months and median age at diagnosis was 9 months. 73% experienced at least one severe FPIES reaction. Rice (45%), cow’s milk (30%), soy (13%) were the most common triggers. FPIES to rice or cow’s milk were strongly associated with increased odds of having multiple trigger FPIES. The odds of having multiple food FPIES and severe reactions were slightly decreased with vaginal delivery. No factors were associated with increased risk of severe reactions. Infants with rice and grains FPIES outgrew their reactions at an earlier age, compared to those with fish FPIES. Conclusions: Rice remains the most common trigger for FPIES in this region with co-associations between rice/oats and cow’s milk/soy observed. The co-associations among food groups suggest that taxonomically related foods share similar protein structure and trigger similar mechanisms of antigen recognition. Vaginal delivery appears to have a mild protective effect on the development of multiple FPIES and severe reactions.

Rhinitis and especially allergic rhinitis (AR) remain the most frequent hypersensitivity condition, affecting up to a quarter of the population and impacting upon the quality of life of individual patients and the health economy. Data, especially in respect to underlying pathophysiological mechanisms mainly derive from adult studies and are subsequently extrapolated in the pediatric population. Therapeutic algorithms for children with rhinitis in children are long based on the same principles as in adults. We explore and describe novel aspects of rhinitis, ranging from mechanisms to disease classification, phenotypes, diagnostic and monitoring tools, and the use of treatments, with focus on the traits of pediatric age groups.

Atopic dermatitis (AD) is a chronic remitting-relapsing inflammatory skin disorder. Due to the multifactorial pathogenesis, there are numerous therapeutic management approaches, mainly based on symptomatic treatments. In recent years Allergen Immunotherapy (AIT) has been progressively advanced as targeted disease-modifying treatment of allergic disease. The most recent guideline from the American Academy of Dermatology concludes that data available do not support its use in AD. The Joint Task Force and The European Academy of Dermatology suggest that clinicians can consider AIT treatment in selected patients characterized by aeroallergen sensitization, prevalently HDM, severe AD, clinical exacerbation after exposure to the causative allergen. Nevertheless, its role in AD is still under debate, especially in children.

Background: Anaphylaxis is increasing at pediatric age; however, its characterization is hampered by underdiagnosis and underreporting. The aim of this study was to identify the causes of anaphylaxis in children and adolescents in Portugal, thus contributing to a better knowledge of its etiology, clinical manifestations and management. Methods: During a 10-year period a nationwide notification system for anaphylaxis was implemented, with voluntary reporting by allergists. Data on 533 patients under 18 years of age with anaphylaxis were included. Results: Mean age was 8.5±4.9 years, 61% were male; 45% had asthma. Mean age at the first anaphylaxis episode was 5.3±4.7 years (ranging from 1 month to 17 years of age), 63% at preschool age. Most reactions occurred at home (57%). Food-induced anaphylaxis was the leading cause (77%). The main culprit foods were cow’s milk (32%), tree nuts (16%), shellfish (13%), egg (12%), fresh fruits (11%), fish (8%) and peanut (8%). Other causes included drugs (11%), insect-sting (5%), cold-induced anaphylaxis (4%), exercise-induced (2%), latex (1%) and idiopathic anaphylaxis (1%). Most patients (83%) were admitted to the emergency department; only 46% received adrenaline treatment. Recurrence of anaphylaxis occurred in 41% of the patients (3 or more episodes in 21%). An adrenaline autoinjector was used in 9% of the patients. Conclusions: In the Portuguese pediatric population, food is the leading cause of anaphylaxis. Undertreatment with adrenaline and high recurrence of anaphylaxis highlight the need to improve both the diagnosis and the therapeutic management of this life-threatening entity.

Background: Vernal keratoconjunctivitis (VKC) is a rare chronic conjunctivitis characterized by a predominantly eosinophil-mediated inflammatory disorder that could develop critical complications such as blindness. Oxidative stress plays a pivotal role in the pathogenesis of several allergic diseases. The role of oxidative stress has been hypothesized in VKC, but no study explored this issue.Furthermore, cyclosporine A (CsA) exerts an anti-inflammatory and antioxidant action on the conjunctiva. This study aims to assess oxidative stress in VKC patients and controls and to study the effect ofCsA on oxidative stress in these subjects. Methods:Thirty-six consecutive children, including 12 VKC(9 males, 75%; mean age 10,17; SD ± 2.48) patients without treatment,12 VKC treated with CsA(9 males, 75%; mean age 9,08; SD± 2.75) and 12 controls (CT) (7males,58%; mean age8,58; SD ±1,78) were recruited. A cross-sectional study was performed to compare H2O2 in the serum and the tears ofthese children. Results: Compared with CT and VKC children treated with CsA, VKCuntreated children had significantly higher values ofHydrogen peroxide (H2O2) in theserum and the tears.No significant differences were observed between CT and VKC treated with CsA. A significant correlation was found at the linear regression analysis between serum and tear H2O2 levels. Conclusion: This study provides the first report attesting that patients with VKC have high oxidative stress; furthermore, it suggests that CsA could have an anti-inflammatory and antioxidant action that could be useful to prevent the poor VKC outcome.

Atopic dermatitis (AD) is a common skin disease during infancy, which imposes a considerable burden on patients, their families, and the society, requiring effective treatment options that result in rapid and sustained symptom relief. Additionally, early treatment may prevent the development of atopic comorbidities by restoring the skin barrier. Currently, topical standard-of-care for AD in infants includes emollients and topical corticosteroids (TCS) to treat and reduce the risk of flares. However, only few have been approved for infants and long-term maintenance therapy with TCS is not indicated due to potential local and systemic side effects, including skin atrophy. Accordingly, the recently updated European guidelines for treatment of AD recommend topical calcineurin inhibitors (TCIs) for long-term use, treatment of sensitive skin areas, and for use in the pediatric population. Evidence on the use of TCIs for infants has almost been exclusively collected for pimecrolimus, with >4,000 infants evaluated in clinical trials, consistently confirming that pimecrolimus is a safe and effective treatment for infants with AD. Nevertheless, its use is still restricted in most countries to children above the age of 2 years due to initial and mostly theoretical safety concerns. Based on a careful review of the available evidence of clinical trials, post-marketing surveillance, and epidemiological studies, an Expert Panel of European dermatologists and pediatric allergologists concluded that these safety concerns are no longer valid. Therefore, pimecrolimus offers a safe and effective alternative to TCS in infants aged 3 months and above, and labeling restrictions in this age group are no longer justified.

Food allergy is a major public health issue with growing prevalence in the urbanized world and significant impact on the lives of allergic patients and their families. Research into the risk factors that have contributed to this increase and their underlying immune mechanisms could lead us to definitive ways for treatment and prevention of food allergy. For the time being, introduction of peanut and other allergenic foods in the diet at the time of weaning seems to be an effective way to prevent the development of food allergy. Improved diagnosis and appropriate management and support of food allergic patients are central to patient care with food immunotherapy and biologicals making the transition to clinical practice. With the new available treatments it is becoming increasingly important to include patient's and family preferences to provide a management plan tailored to their needs.

Background: Existing knowledge suggests that gestational diabetes mellitus was inconsistently associated with children allergic diseases. The aim of this study was to identify the association between gestational diabetes mellitus (GDM) and the risk of children allergic diseases by systematic review. Methods: We searched and retrieved three databases (PubMed, Web of Science and Cochrane Library) for articles on the association between GDM and children allergic diseases published before December 31, 2019. Stata software version 16.0 was used for statistical analysis. Results: Eight published studies were included in this meta-analysis. The pooled effect estimates showed the association between GDM and allergic outcomes, including asthma (OR:1.13,95%CI:1.01-1.27), wheezing (OR:1.12,95%CI:1.08-1.16), and atopic dermatitis (OR:1.41,95%CI:1.31-1.53). GDM was not associated with the risk of allergic sensitization, with a pooled effect estimate of 1.45 (95%CI: 0.40, 5.23). Conclusion: GDM may increase the risk of allergic diseases in children. However, this finding should be validated with future large-sample epidemiological studies covering a wider spectrum of allergic diseases.

Interleukin (IL)-5 is a potent mediator of the inflammatory cascade in the allergic response.Its predominant role in atopic reactions makes this cytokine an ideal target for blocking the eosinophilic inflammatory hyper-responsiveness to allergens. The management of allergic diseases in childhood – such as severe asthma, atopic dermatitis, and eosinophilic esophagitis - is a challenge. In particular, there are concerns regarding the use of high-dose corticosteroids. Over the last few years, biologics targeting IL-5 or IL-5 receptor - that are mepolizumab, reslizumab, and benralizumab - represent a new, promising, and more personalized therapeutic option.

Gastrointestinal symptoms are common findings in children with SARS-CoV-2 infection.Diarrhea and vomiting have been reported in about 8-9% of cases, reaching more than 20% in some studies. Children with gastrointestinal involvement appear to be younger than those without, but the severity of the disease seems to be similar between the two groups of subjects.Fecal shedding in children has been reported in 20-30% of children and has been observed both in those with and those without overt gastrointestinal involvement. Moreover, prolonged fecal elimination, lasting several days after negativization of real-time polymerase chain reaction assay on respiratory swabs, have been reported with variable frequency in children with SARS-CoV-2 infection. These observations raise the question regarding the possibility of oral-fecal transmission and the possible role of children in spreading the infection, particularly when they appear asymptomatic or with gastrointestinal symptoms but with no respiratory involvement, as well as during their convalescent phase.

Childhood rashes or exanthemas are common and are usually relatively benign. There are many causes of rash in children, including mainly viruses, and less often bacterial toxins, drugs, allergens, and other diseases. Viral exanthema often appears while children are taking a medication in the course of a viral infection; it can mimic drug exanthema, and is perceived as a drug allergy in 10% of cases. The drugs most commonly implicated are beta-lactams (BL) and nonsteroidal anti-inflammatory drugs (NSAIDs). Viruses, commonly Epstein Barr virus (EBV), human herpesvirus 6 (HHV6) and cytomegalovirus (CMV), and the bacterium Mycoplasma pneumoniae, may cause exanthema either from the infection itself (active or latent) or because of interaction with drugs that are taken simultaneously. Determination of the exact diagnosis requires a careful clinical history and thorough physical examination. Haematological and biochemical investigations and histology are not always helpful in differentiating between the two types of exanthema. Serology or polymerase chain reaction (PCR) can be helpful, although a concomitant acute infection does not exclude drug hypersensitivity. A drug provocation test (DPT), although considered the gold standard for the diagnosis, is not preferred by the patients. Skin tests are not well tolerated, and in vitro tests, such as the basophil activation test and lymphocyte transformation, are of low sensitivity and specificity and their relevance is debatable. Based on current evidence, we propose a systematic clinical approach for timely differential diagnosis and management of rashes in children who present a cutaneous eruption while receiving a drug.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, is a new strain of coronavirus that has not been previously identified in humans. SARS-CoV-2 is recognized as a highly contagious respiratory virus with severe morbidity and mortality, especially in vulnerable populations. Being a novel disease, everyone is susceptible, there are no vaccine and no treatment. To contain the spread of the disease, health authorities throughout the world have restricted the social interactions of individuals in various degrees. Allergists like other physicians are faced with the challenge of providing care for their patients, while protecting themselves and patients from getting infected, with strategies that are in continuous evolution as States work through the different stages of social distance. Allergist provides care for patients with the most common noncommunicable disease in the world: asthma, allergic rhinitis, food allergy, venom allergy, drug allergy atopic dermatitis, and urticarial. Some of these diseases are not only considered risk factors for severe reactions but also have symptoms like cough and sneezing that are in differential diagnosis with COVID-19, and as we move forward may prevent allergy patient from working, go to school or access medical services that increasingly are allowing only asymptomatic patients. In this review, we will outline how to take care safety of different allergic patients during the pandemic.

Coronavirus disease 2019 (COVID-19)diagnosis is based on molecular detection of SARS-CoV-2 in respiratory samples such as nasal swab (NS). However, the evidence that NS in patients with pneumonia were sometimes negative raise the attention to collect other clinical specimens. SARS-CoV-2 was shown in 10.3%rectal swabs (RS), 7.7% plasma,1% urine, 0% feces from 143NS positive patients. Potential infection by fluids different from respiratory secretion is possible but unlikely.

Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disease caused by Aspergillus induced hypersensitivity that occurs in immunocompetent but susceptible patients with asthma and/or cystic fibrosis (CF). In children, ABPA remains mostly undiagnosed, resulting in one of the most common causes of poorly controlled asthma and highly significant morbidity in children with CF. Currently, no specific diagnostic criteria of ABPA for children are available. Corticosteroids and itraconazole are the mainstays of therapy, althoughthere is a lack of randomized clinical trials regarding their usefulness for ABPA in children. Several monoclonal antibodies, such asomalizumab and mepolizumab, may be potential therapies for refractory ABPA in pediatric patients; however, further data are required to clarify the optimal dose and duration of therapy as a routine treatment approach.

Autoimmune neutropenia of infancy (AIN) is a relatively frequent cause of neutropenia in children. The disease is caused by antibodies recognizing membrane antigens of neutrophils, mostly located on immunoglobulin G (IgG) Fc receptor type 3b (FcγIIIb receptor). In this study, we investigated the possible association of human neutrophil antigens (HNA), human leukocyte antigen (HLA)-DR and HLA-DQ alleles with AIN and the association of these genotypes with the presence of anti-HNA-1a autoantibodies. Eighty AIN cases with a median age of 13.5 months were included in this study. Controls were healthy unrelated Danish blood donors. Anti-HNA-1a autoantibodies were detected using a flow cytometric granulocyte immunofluorescence test (Flow-GIFT). Molecular determination of HNA genotypes was determined using real-time polymerase chain reaction (q-PCR). High-resolution HLA-DR and HLA-DQB1 were determined by next-generation sequencing. Antibodies against HNA-1a were detected in 51% (n=41) of AIN patients, and anti-HNA-1b was detected in 3% (n=2) of cases. FCGR3B*01+,*02-,*03- was more common (odds ratio, 6.70; p < 0.0001), and FCGR3B*01-,*02+,*03- was less common (odds ratio, 0.30; p < 0.0001) among AIN cases. HNA-1a antibodies were significantly more frequent among AIN cases with the FCGR3B*01+,*02-,*03-genotype (odds ratio, 3.86; p < 0.007). The HLA-DR*14 and HLA-DQB1*05:03 alleles were significantly more common (odds ratio, 7.44; p < 0.0001 and odds ratio, 2.50; p < 0.0001, respectively) in AIN patients. In conclusion the HLA haplotype HLA-DR*14- DQB1*05:03 is associated with Danish AIN cases. Among Danish AIN patients, anti-HNA-1a is the most common autoantibody, and the antibody is more common in cases with the FCGR3B*01-,*02+,*03- genotype.

Background: recent epidemiological studies state that a high dose of folic acid status during pregnancy increases the risk of asthma, wheezing, and respiratory disease in childhood. As potential biological mechanism, folate acid can modify inflammation and immune susceptibility of offspring with some epigenetic differentiation, including DNA methylation. This study evaluated the association between maternal folate levels during pregnancy with childhood wheeze, and whether DNA methylation differentiation of children in genes is related to wheezing or not. Methods: the cohort comprised 6651 mother–child pairs who were evaluated for an association between maternal folate level during pregnancy and childhood wheeze at 1, 2, 4, and 7 years age, which were assessed by the International Study of Asthma and Allergies in Childhood questionnaire. Results: the median of maternal serum was 16.76 nmol/l, assayed by chemiluminescent immunoassay. We found significantly increased adjusted odds ratios of childhood wheeze at 2 years age according to maternal folate levels, compared with lowest folate quartile (odds ratio [95% confidence interval] = highest; 1.27 [1.03, 1.56], and second; 1.27 [1.05, 1.55]), however, no changes were observed at 1, 4, and 7 years age. In a case-control study of childhood wheeze due to DNA methylation at 7 years age, no association of maternal folate levels with DNA methylation was observed. Conclusion: our result proposes that the negative effect of maternal folate on an infant’s wheeze did not remain until 7 years of age and no association with maternal folate levels and DNA methylation (at the same age) was observed.