Risk of atopic dermatitis and the atopic march paradigm in children of mothers with atopic illnesses: A birth cohort study from the United Kingdom.

BACKGROUND: Atopic dermatitis (AD) is thought to precede the onset of other allergic illness (OAI) in a temporal progression (ie, atopic march), yet the timing and progression has been questioned. It is also unclear how parental allergic illness impacts the development of these illnesses in offspring. OBJECTIVE: (1) Explore risk of incident AD and (2) timing of allergic disease onset in children of mothers with AD compared with mothers without AD from the United Kingdom. METHODS: We created a birth cohort of mother-child pairs using IQVIA Medical Research Data database and developed Cox proportional models to examine the above associations (hazard ratio, HR [95% confidence interval, CI]). RESULTS: Among 1,224,243 child-mother pairs, mean child (standard deviation) follow-up time was 10.8 (8.3) years and 50.1% were males (N = 600,905). Children were 59% (HR = 1.59 [1.57, 1.60]) more likely to have AD if their mothers had AD compared with no AD with mean age of first AD diagnosis at 3.3 (4.8) years. Most children with any diagnosis of AD present with AD first (91.0%); however, in those with asthma, only 67.8% developed AD first. CONCLUSION: Children born to mothers with AD are more prone to develop AD and some develop OAI first, suggesting that not all follow the same sequential pathway.

In utero or early in life exposure to antibiotics and the risk of childhood atopic dermatitis, a population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory disease of the skin that begins early in life and can be lifelong. The purpose of our study was to evaluate whether fetal exposure and/or early life exposure of a child to antibiotics increases the risk of early onset AD. OBJECTIVE: We hypothesize that antibiotic exposure in utero or early in life (e.g., first 90 days) increases the likelihood that children develop AD. METHODS: Utilizing a large prospectively collected electronic medical records database, we studied the association of antibiotic exposure received in utero or very early in life and the relative risk of onset of AD in a population-based cohort study. Associations were estimated using proportional hazards models as hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: The risk of AD in childhood was increased after in utero or early life antibiotic exposure. For any in utero AB exposure the HR was 1.38 (1.36,1.39). However, penicillin demonstrated the strongest association with AD for both in utero exposure, 1.43 (1.41,1.44), and for childhood exposure, 1.81(1.79,1.82). HRs were higher in children born to mothers without AD than those with AD pointing to effect modification by maternal AD status. CONCLUSION: Children born to mothers exposed to antibiotics while in utero had, depending on the mother's history of AD, approximately a 20 to 40% increased risk of developing AD. Depending on the antibiotic, children who received antibiotics early-in-life had a 40 to 80% increased risk of developing AD. Our study, supports and refines the association between incident AD and antibiotic administration. It also adds population-based support to therapeutic attempts to treat AD by modifying skin microbiome.

Circulating endothelial precursor cells are associated with a healed diabetic foot ulcer evaluated in a prospective cohort study.

The goal of this multicentre study was to evaluate whether circulating endothelial precursor cells and microparticles can predict diabetic foot ulcer healing by the 16th week of care. We enrolled 207 subjects, and 40.0% (28.4, 41.5) healed by the 16th week of care. Using flow cytometry analysis, several circulating endothelial precursor cells measured at the first week of care were associated with healing after adjustment for wound area and wound duration. For example, CD34+ CD45dim , the univariate odds ratio was 1.19 (95% confidence interval: 0.88, 1.61) and after adjustment for wound area and wound duration, the odds ratio was (1.67 (1.16, 2.42) p = 0.006). A prognostic model using CD34+ CD45dim , wound area, and wound duration had an area under the curve of 0.75 (0.67, 0.82) and CD34+ CD45dim per initial wound area, an area under the curve of 0.72 (0.64, 0.79). Microparticles were not associated with a healed wound. Previous studies have indicated that circulating endothelial precursor cells measured at the first office visit are associated with a healed diabetic foot ulcer. In this multicentred prospective study, we confirm this finding, show the importance of adjusting circulating endothelial precursor cells measurements by wound area, and show circulating endothelial precursor cells per wound area is highly predictive of a healed diabetic foot ulcer by 16th week of care.

Association of KIR Genes and MHC Class I Ligands with Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic illness that is associated with immune dysregulation. NK cell function has previously been associated with AD. NK cells directly interact with polymorphic HLA class I ligand variants using killer cell Ig-like receptors (KIRs). The purpose of this study was to identify potential associations between NK cell function and AD by evaluating variation in the presence of KIR genes as well as KIR gene interactions with the appropriate HLA class I KIR-specific ligands. Human DNA from the genetics of AD case-control study was used to genotype HLA class I KIR-specific ligands and the presence of KIR genes. In the full cohort, an increased risk of AD was noted for KIR2DL5 (1.51 [1.13, 2.01]), KIR2DS5 (1.72 [1.26, 2.34]), and KIR2DS1 (1.41 [1.04, 1.91]). Individuals with KIR2DS5 or KIR2DS1 and the HLA-C*C2 epitope were at an increased risk of AD (1.74 [1.21, 2.51] and 1.48 [1.04, 2.12], respectively). The HLA-B*-21T (TT) leader sequence increased the risk of AD across ethnicity. African Americans with KIR2DL2, KIR2DS1, KIR2DL5, and KIR2DS5 are more likely to have AD, and the risk increased for KIR2DS1 and KIR2DS5 in the presence of appropriate HLA-C C2 epitope. The risk of AD also increased for individuals with the HLA-B*-21T leader sequence. Future studies should focus on KIR gene allelic variation as well as consider cell-based measurements of KIR and the associated HLA class I epitopes.

HLA Class I Polymorphisms Influencing Both Peptide Binding and KIR Interactions Are Associated with Remission among Children with Atopic Dermatitis: A Longitudinal Study.

Atopic dermatitis (AD) is a disease of immune dysregulation and skin barrier dysfunction with a relapsing, remitting course and has been associated with several different genetic risk variants. HLA represent a highly variable set of genes that code for cell surface protein molecules involved in the Ag-specific immune response, including the regulation or functioning of T cells, NK cells, and APCs. The purpose of this study was to evaluate associations between HLA class I polymorphisms and the progression of AD over time. We evaluated the associations of AD symptoms and HLA class I polymorphisms based on high-resolution two-field typing in a longitudinal cohort of children with AD (up to 10 y of follow-up). Seven hundred and ninety-two children were evaluated every 6 mo, resulting in 12,752 AD evaluations. Using generalized estimating equations and corrected p values, B*44:02 was found to be associated with AD remission (1.83 [1.35, 2.47]; p = 0.0015). The HLA-B residues at position 116 (d-aspartate) and 80 (T-threonine) were associated with remission (1.42 [1.13, 1.76], p = 0.003; corrected p = 0.028) and (1.45 [1.17, 1.80], p = 0.0008; corrected p = 0.0024), respectively. B80T is a killer-cell Ig-like receptor (KIR) site. Our findings reveal that two axes of immune response (T cell and NK cell) may influence disease progression. Identifying binding pocket changes in addition to other factors (e.g., allergens) that increase the risk or severity of AD can improve our understanding of the immunologic mechanisms associated with AD and may lead to personalized therapies for improving patient care.

Association between fine mapping thymic stromal lymphopoietin and atopic dermatitis onset and persistence.

BACKGROUND: Atopic dermatitis (AD) is a common chronic relapsing skin disease. Genetic variants have been associated with skin barrier function and immune regulation. Thymic stromal lymphopoietin (TSLP), an immune regulator, has been previously associated with AD. OBJECTIVE: To fine map TSLP and evaluate associations with the onset and persistence of AD. METHODS: TSLP variation was determined using targeted massively parallel sequencing in a longitudinal cohort of children with AD. Evaluations included linkage disequilibrium and the persistence of AD for as many as 10 years of follow-up. The association between the presence of AD and rs1898671 variation was evaluated in a second independent cohort. RESULTS: The minor variant frequency for rs1898671 was 23.5% (95% CI, 21.4%-25.8%). This variant was not in linkage disequilibrium with other TSLP variants in the longitudinal cohort (n = 741). White children with AD were less likely to have rs1898671 variant (odds ratio [OR], 1.41; 95% CI, 1.20-1.66) than Genome Aggregation Database controls. Children with AD and the rs1898671 variant during follow-up were more likely to have remission than children who were wild type for rs1898671 (OR, 1.56; 95% CI, 1.26-1.91). In the second cohort (n = 585), the rs1898671 variant was less prevalent in those with AD than those without. The protective effect was greater in rs1898671 heterozygotes (OR, 1.91; 95% CI, 1.34-2.75) than homozygotes (OR, 1.28; 95% CI, 0.61-2.70). CONCLUSION: TSLP and specifically rs1898671 are important in the pathogenesis of AD and could represent a potential clinical target for the development of therapies to treat individuals with AD.

Longitudinal atopic dermatitis control and persistence vary with timing of disease onset in children: A cohort study.

BACKGROUND: Wide variation exists in the timing of atopic dermatitis (AD) disease onset among children. Distinct trajectories of early-onset, mid-onset, and late-onset AD have been previously described. OBJECTIVE: To evaluate longitudinal disease control and persistence with respect to age at onset of AD. METHODS: A cohort study was performed using the Pediatric Eczema Elective Registry, a prospective observational cohort of subjects with childhood-onset AD. AD control and persistence were assessed biannually for up to 10 years. RESULTS: A total of 8015 subjects with 41,934 person-years of follow-up were included. In longitudinal analyses using generalized linear latent and mixed modeling, older age at onset of AD was associated with better disease control and less-persistent AD. For each additional year of age at onset of AD, the adjusted odds ratios for poorer AD control and for persistent AD were 0.93 (95% confidence interval, 0.91-0.94) and 0.84 (95% confidence interval, 0.80-0.88), respectively. Differences in AD control and persistence among subjects with early-, mid-, and late-onset AD were most pronounced from early adolescence onward. LIMITATIONS: Misclassification bias may arise from using self-reported data on age at onset. Attrition and missing data in longitudinal studies may introduce bias. CONCLUSION: Early-, mid-, and late-onset pediatric AD appear to be clinically distinct subtypes of the disease.

Lack of association of biologic therapy for psoriasis with psychiatric illness: An electronic medical records cohort study.

BACKGROUND: Psoriasis and biologic therapies have been associated with psychiatric illnesses. OBJECTIVE: To determine if persons with psoriasis or those exposed to biologics are more likely to develop a psychiatric illness. METHODS: Retrospective electronic medical records cohort study. RESULTS: Individuals with psoriasis were significantly more likely to have a history of several medical (eg, cardiovascular illnesses) and psychiatric (eg, depression, suicide) illnesses than those without psoriasis. Those with psoriasis who were prescribed a biologic therapy were significantly less likely than those with psoriasis not prescribed a biologic agent to receive a psychiatric illness diagnosis (hazard ratio for any psychiatric illness 0.52, 95% confidence interval 0.51-0.53, P < .0001). With respect to any psychiatric illness, this finding was confirmed when comparing biologic therapy versus methotrexate treatment (0.80, 95% confidence interval 0.76-0.84, P < .0001). LIMITATIONS: These findings were likely attributable to treatment selection bias. CONCLUSION: Individuals with psoriasis have an increased risk of several medical and psychiatric illnesses. Individuals with psoriasis prescribed biologic agents are less likely than those not prescribed biologic agents to develop psychiatric illnesses. Most likely because of treatment selection, individuals with psoriasis prescribed biologic therapy are not currently at increased risk of a psychiatric outcome.

NOS1AP genetic variation is associated with impaired healing of diabetic foot ulcers and diminished response to healing of circulating stem/progenitor cells.

It is unclear why many with diabetes develop foot ulcers (DFU) and why some do not heal. It could be associated with genetic variation. We have previously shown that NOS1AP variation is associated with lower extremity amputation in those with diabetes and that circulating stem progenitor cell concentration (SPC) is associated with impaired foot ulcer healing in those with diabetes. The goal of this study was to determine if NOS1AP variation is associated with impaired wound healing and with SPC mobilization in those with DFU. In longitudinal cohort study we demonstrate that NOS1AP variants rs16849113 and rs19649113 are associated with impaired wound healing and with SPC mobilization in those with DFU. We believe that further study of NOS1AP is merited and that it NOS1AP might be associated with a functional impairment.

Variations in risk of asthma and seasonal allergies between early- and late-onset pediatric atopic dermatitis: A cohort study.

BACKGROUND: Atopic dermatitis is associated with other allergic conditions, but variations in this "atopic march" are poorly understood. OBJECTIVE: To determine the impact of the age of atopic dermatitis onset on the risk for asthma and seasonal allergies. METHODS: A cohort study was performed using the Pediatric Eczema Elective Registry, which is an observational cohort of subjects with pediatric onset atopic dermatitis. RESULTS: In total, 3966 children were included, and 73% reported atopic dermatitis onset before age 2 years. At baseline, subjects with atopic dermatitis onset at ages 3 to 7 or 8 to 17 years had significantly lower rates of seasonal allergies and asthma than those with onset before age 2. During follow-up, the adjusted relative risks for incident seasonal allergies were 0.82 (95% confidence interval, 0.72-0.91) and 0.64 (95% CI confidence interval, 0.47-0.83) in the 3- to 7- and 8- to 17-years-old at onset groups compared with the age 2 years or younger at onset group. The adjusted risk for incident asthma was not significantly different between the older onset groups and the earliest onset group. LIMITATIONS: Misclassification bias may arise from using self-reported onset age data. CONCLUSIONS: The timing of atopic dermatitis onset may explain part of the variation in the atopic march. These findings may improve future risk stratification of patients for treatment.

Duration of oral tetracycline-class antibiotic therapy and use of topical retinoids for the treatment of acne among general practitioners (GP): A retrospective cohort study.

BACKGROUND: Guidelines recommend limiting the duration of oral antibiotic therapy in acne to 3 to 6 months and prescribing concomitant topical retinoids for all patients. OBJECTIVE: We sought to evaluate the duration of therapy with oral tetracyclines and the use of topical retinoids among patients with acne treated primarily by general practitioners in the United Kingdom. METHODS: We conducted a retrospective cohort study using the Health Improvement Network database. RESULTS: The mean duration of therapy was 175.1 days. Of antibiotic courses, 62% were not associated with a topical retinoid; 29% exceeded 6 months in duration. If all regions were to achieve uses similar to the region with the shortest mean duration of therapy, approximately 3.3 million antibiotic days per year could be avoided in the United Kingdom. LIMITATIONS: The Health Improvement Network does not include information on acne severity and clinical outcomes. CONCLUSIONS: Prescribing behavior for oral antibiotics in the treatment of acne among general practitioners is not aligned with current guideline recommendations. Increasing the use of topical retinoids and considering alternative agents to oral antibiotics when appropriate represent opportunities to reduce antibiotic exposure and associated complications such as antibiotic resistance and to improve outcomes in patients treated for acne.

Health literacy and diabetic foot ulcer healing.

The adherence by patients to diabetic foot ulcer therapy is often difficult. The goal of this study was to begin to understand how a patient's health literacy affects their foot ulcer management decisions. Initially using a cross-sectional study design, we evaluated diabetics with foot ulcers within 4 weeks of being asked to participate in a longitudinal study. We assessed health literacy using measures of general health literacy, diabetes health literacy, diabetes self-efficacy, and diabetes numeracy. Individuals enrolled in the study had higher health literacy based on the Short Test of Functional Health Literacy in Adults [33.8 (SD 2.3) versus 27.3 (SD 9.6); p = 0.009] as compared to individuals who previously declined an invitation to enroll in the study. Furthermore, patients with lower Short Test of Functional Health Literacy in Adults scores had larger (p = 0.04) and older (p = 0.125) wounds (markers for poorer prognosis). Other measures of literacy showed similar results. In conclusion, those with diminished health literacy were less likely to enroll in an investigational study and had wounds that were less likely to heal.

Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects.

BACKGROUND: Atopic dermatitis (AD) is a common skin disease characterized by recurrent episodes of itching. Genetic variation associated with the persistence of AD has not been described for African American subjects. OBJECTIVE: We sought to evaluate genetic variation of filaggrin-2 (FLG2) in African American subjects with AD. METHODS: We evaluated a multiyear prospective cohort study of African American children with AD with respect to FLG2 variation based on whole-exome sequencing, followed by a targeted analysis. We ultimately evaluated the association of rs12568784 and rs16833974 with respect to the persistence of AD symptoms over time. RESULTS: Whole-exome analysis was conducted on 60 subjects, revealing a premature stop codon in exon 3 at S2377X (rs12568784) and X2392S (rs150529054) and a large exon 3 deletion mutation, Q2053del224. On the basis of a priori criteria, we then studied rs12568784, rs16833974 (H1249R), and Q2053del224. We noted that patients with S2377X (odds ratio [OR], 0.44; 95% CI, 0.25-0.46) and H1249R (OR, 0.23; 05% CI, 0.12-0.46) were significantly less likely to be free of symptoms of AD, and Q2053del224 (OR, 0.54; 95% CI, 0.16-1.80) trended toward this outcome. S2377X and H1249R were in high linkage disequilibrium (D' = 0.95). CONCLUSIONS: In an African American cohort with AD, FLG2 mutations were associated with more persistent AD. This is the first finding of genetic variation of a skin barrier protein in subjects of African ancestry with AD.

Diabetes, lower extremity amputation, loss of protective sensation, and neuronal nitric oxide synthase associated protein in the chronic renal insufficiency cohort study.

Lower extremity amputation (LEA) is a life-altering complication of diabetes. The goal of our study was to investigate the possibility that genetic variation in neuronal nitric oxide synthase associated protein (NOS1AP) is associated with LEA and diabetic peripheral neuropathy (DPN). Our work used data from the Chronic Renal Insufficiency Cohort (CRIC) study. CRIC is a multicenter investigation undertaken to pursue the relationship between chronic renal insufficiency and cardiovascular disease. We evaluated 3,040 CRIC study subjects; 1,490 individuals were African Americans and 1,550 were whites. LEA occurred in 162 (5.3%) subjects, 93 (6.2%) of African Americans and 69 (4.4%) of whites. In whites, NOS1AP single nucleotide polymorphism rs1963645 was most strongly associated with LEA (1.73 [1.23, 2.44]). In African Americans three NOS1AP single nucleotide polymorphisms were associated with LEA: rs6659759 (1.65 [1.21, 2.24]); rs16849113 (1.58 [1.16, 2.14]); rs880296 (1.54 [1.14, 2.10]). We tested a subset of 100 CRIC participants for DPN using Semmes-Weinstein filaments. DPN in those with diabetes was associated with rs1963645 (16.97 [2.38, 120.97]) in whites and rs16849113 and rs6659759 (3.62 [1.11, 11.83] and 3.02 [0.82, 11.12], respectively) in African Americans. In conclusion, this is one of the first studies to show that NOS1AP gene variants are associated with DPN and LEA.

Asthma and frequency of wheeze: risk factors for the persistence of atopic dermatitis in children.

BACKGROUND: Studies have examined the development of asthma in children with atopic dermatitis (AD); however, none have looked at the association of asthma or the frequency of wheeze with respect to persistence or difficulty in achieving AD clinical improvement in children. OBJECTIVE: To determine whether children with AD who have asthma and increasing frequency of wheezing have more persistent AD. METHODS: This is a cohort study using the Pediatric Eczema Elective Registry (PEER) database, which includes data obtained at enrollment and 3 years later. The AD outcome was the persistence of skin symptoms. Our covariates of interest were asthma diagnosis and wheezing symptoms, which were measured at enrollment and again at year 3 of the study. Multivariate logistic regression models assessed the magnitude of associations among AD symptoms, asthma diagnosis, and the frequency of wheeze. All models were adjusted for sex, age, and ethnicity. RESULTS: A total of 2104 children were enrolled in the PEER study and had at least 3 years of follow-up at the time of this study. At enrollment, an asthma diagnosis decreased the likelihood of being rash free in the preceding 6 months by 30% (odds ratio, 0.70; 95% confidence interval, 0.59-0.84). At year 3, having asthma decreased the likelihood by 40% (odds ratio, 0.60; 95% confidence interval, 0.49-0.72). Increasing frequency of wheezing also decreased the likelihood that a child was rash free (P < .001). CONCLUSION: For children with AD, a history of asthma and an increasing frequency of wheezing correlate strongly with more persistent AD.

The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort.

BACKGROUND: Atopic dermatitis (AD) is a common skin disease that is characterized by recurrent episodes of itching. Filaggrin (FLG) loss-of-function (FLG null) mutations have been associated with an increased risk of AD. OBJECTIVE: We sought to evaluate the effect of individual FLG null mutations on the persistence of AD over time. METHODS: We evaluated a multiyear prospective cohort study of children with AD with respect to FLG null mutations (R501X, 2282del4, R2447X, and S3247X). We evaluated the association of these mutations with the persistence of AD symptoms over time with respect to reports of no symptoms of AD and whether topical medication was needed for symptom resolution. RESULTS: Eight hundred fifty-seven subjects were followed for 3684 person-years. One or more FLG null mutations were noted in 16.3% of subjects and specifically in 27.5% of white subjects and 5.8% of African American subjects. Subjects with an FLG null mutation were less likely (odds ratio [OR], 0.54; 95% CI, 0.41-0.71) to report that their skin was symptom free at any time compared with those without an FLG null mutation. The effect of these mutations was similar in white subjects (OR, 0.42; 95% CI, 0.31-0.57) and African-American subjects (OR, 0.53; 95% CI, 0.25-1.12; P = .62). Children with the R501X mutation (OR, 0.44; 95% CI, 0.22-0.88) were the least responsive to therapy. CONCLUSIONS: In a US cohort with AD, FLG null mutations were common. Children with FLG null mutations were more likely to have persistent AD. Although these mutations were more common in those of European ancestry, their effect on persistence was similar in those of African ancestry. Response to therapy was not uniform among children with FLG null mutations.

KIR Allelic Variation and the Remission of Atopic Dermatitis Over Time.

Atopic dermatitis (AD) is a common chronic skin disease. Although generally thought to be a disease of T-cell dysregulation, recent studies have suggested that immune dysregulation of NK cells is also important. Killer cell Ig-like receptors (KIRs) are involved with NK cell regulation. The Pediatric Eczema Elective Registry is a U.S. nationwide longitudinal cohort with up to 10 y of follow-up in which 655 children had DNA available for full allelic KIR sequencing. Every 6 mo, AD activity was reported by Pediatric Eczema Elective Registry children. Using generalized estimating equations, we evaluated the association of KIR allelic variation in concert with known HLA binding ligands and whether the child reported AD in "remission" (no skin lesions and not using AD medication). KIR2DS4*001:01 (odds ratio 0.53, 95% CI [0.32, 0.88]) and KIR2DL4*001:02 (0.54, [0.33, 0.89]) in the presence of C*04:01 had the largest effect on decreasing the likelihood of AD remission. The haplotype KIR 2DL4*001:02 ∼ 2DS4*001:01 ∼ 3DL2*002:01 (0.77, [0.60, 0.99]) was also associated with a decreased likelihood of AD remission. Our findings add to the general body of evidence of a growing literature on the importance of NK cells with respect to the immunopathogenesis and natural history of AD.

Association between atopic dermatitis, autoimmune illnesses, Epstein-Barr virus, and cytomegalovirus.

Atopic dermatitis (AD) is a Th2-driven inflammatory skin disease that has been associated with other autoimmune illnesses (AI) and has a well-known predisposition to infection with herpes simplex virus infection. Yet, few studies have evaluated the association between atopic dermatitis, autoimmune illness, and other human herpes virus (HHV) infections such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV). We aimed to evaluate the association between AD, specific AIs, CMV, and EBV in a random sample of the Optum Clinformatics Data Mart database, a US administrative claims database. AD was defined based on ICD diagnostic codes. Patients with AD were exact matched to those without AD on sex, age at enrollment, time observed in the dataset and census division. Our outcomes of interest were rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), CMV, and EBV infection as defined by specific ICD codes. Logistic regression models were used to examine the association between AD and our outcomes of interest [odds ratio (95% confidence intervals)]. Our full cohort included 40,141,017 patients. In total, 601,783 patients with AD were included. As expected, patients with AD had a higher prevalence of asthma and seasonal allergies versus controls. Individuals with AD have an increased risk of EBV, CMV, RA, CD, UC, and MS. While we cannot demonstrate a causal association, the observed associations between AD and AI may be in part mediated by these types of HHV (i.e., CMV and EBV), a finding that merits further study.