This nationwide population-based cohort study evaluated the comorbidity between AD and infectious disorders using SPM. Our study also investigated the onset duration to infectious disorders from AD. According to our results, there was a significantly greater risk of infectious disorders in patients with AD than in individuals without AD. Among the infectious disorders, molluscum contagiosum showed the highest increased risk in AD patients compared to that in controls. Furthermore, the time to first diagnosis duration of infectious disorders, especially molluscum contagiosum, was relatively shorter in patients with AD than in patients without AD, which was approximately 2 months after the diagnosis of AD.
In our study, the percentage of new-onset infectious disorders in patients with AD was defined as confidence. As the value of the parameter “confidence” is similar to comorbidity in epidemiology, we considered the value of confidence to serve as a value of comorbidity.(7) In addition, the parameter “onset duration” is, in other words, the time to first diagnosis.
According to previous reports, AD predisposes patients to cutaneous and extracutaneous infectious disorders. Similar to those reports, our results suggest that AD increases the risk of infectious disorders, such as molluscum contagiosum, impetigo, viral wart, EH, viral conjunctivitis and otitis media. Previous studies suggest that bacterial infection is the most common infection and that Staphylococcus aureus is by far the most common bacterial infection in AD.(9, 10) The suggested mechanism for increased bacterial infection is barrier dysfunction, immune dysregulation, low antimicrobial peptides, increased bacterial colonization and the use of immunosuppressant medications for the management of AD.(4)
According to our study, AD patients were at a 2.8-fold higher risk for impetigo than controls, which resembled the results of a previous cohort study. A previous cohort study from the USA that evaluated three million subjects under 18 years old showed that impetigo developed 55% more often in AD patients than in controls after adjusting for age and sex.(11)
A previously reported study suggested that AD in children is related to recurrent ear infections as well as other bacterial disorders.(4, 12) A USA population-based study suggested that recurrent ear infection increased 1.33-fold in patients with AD.(13) Our data show that the risk of otitis media was 1.75-fold higher in AD patients than in non-AD patients, which is consistent with prior data. According to our data, the comorbidity of otitis media was 0.84, and the onset duration was 99.17 days.
Similar to in other reports, skin viral infections, such as molluscum contagiosum, viral wart, herpes simplex infection, especially EH, chicken pox and viral conjunctivitis, increased in AD.(11, 14) The epidermal skin barrier defect, innate and adaptive immune dysfunction, decreased antimicrobial peptides, increased skin pH and Th2 cytokines are considered enhancing factors for increased risk of viral infection in AD patients.(13, 15, 16)
In our results, the highest risk among viral infections in AD patients was that for molluscum contagiosum. In a case-control study with pediatric patients that analyzed the epidemiology and predisposing factors for molluscum contagiosum, patients with AD with local cellular immune dysregulation and an impaired skin barrier had a major incidence of molluscum contagiosum.(17) In addition, other reports observed an increased prevalence of AD in children with molluscum contagiosum.(18, 19) Patients with AD are reported to not only have more molluscum contagiosum but also have more severe and widespread disease than individuals without AD.(14) In accordance with prior studies, our results showed a 5.2-fold increase in the risk of molluscum contagiosum in AD patients after adjusting for age and sex, which was the highest result in this study, and a comorbidity of 1.06%. The onset duration of molluscum contagiosum was 77.42 days, which was the earliest among the infectious disorders.
Our results showed that the risk of chicken pox was increased by 2.251-fold in patients with AD compared with that in patients without AD, and the confidence of chicken pox was 0.39%. Similar to our results, a previous study of childhood AD in the USA also reported risk of chicken pox that was 1.19 times higher in AD patients than in individuals without AD.(13) In addition, another study on adult AD in the USA showed a 1.31-fold increase in the risk of chicken pox in AD patients.(4) In the case of herpes zoster, our results indicate that AD patients have a 58% lower risk than normal controls, and the confidence was 0.213%. Few studies have confirmed a correlation between AD and herpes zoster. A previous population-based case-control study with children demonstrated that the risk of herpes zoster is increased in asthma patients, which is contrary to our data.(20)
According to our study, the risk of viral wart was 1.105 times higher in AD patients than in individuals without AD, and the confidence was 0.16%. The onset duration was approximately 5–6 months after the AD diagnosis. It is known that warts can spread more easily in the setting of AD.(21) In one study, warts and atopic dermatitis in children were accompanied by a higher number of infections and food allergies and a higher chance of hay fever and asthma than either condition alone.(13) According to this previous study, AD without other atopic diseases had slightly lower odds of warts (0.91 [95% CI, 0.90–0.92]) than controls, which was different from our study. However, AD with other atopic diseases showed an increased risk of warts (1.83 [95% CI, 1.82–1.84]).
The confidence of EH was 0.032%, which was slightly lower than that for other infectious disorders. However, the risk of EH was 1.292 times higher than that for controls. EH, which is caused by herpes simplex virus (HSV), is a potentially serious complication of AD that shows generalized vesicles with general symptoms, such as viremia, fever and lymphadenopathy. HSV exposure is common in the general population, which is present in approximately 60% of the adult population and 20% of children. However, according to other studies, only 3% of AD patients develop EH, and compared with AD patients without EH, patients with AD who have EH seem to have more severe AD, early onset of AD and increased accompanying atopic diseases.(6) Although the comorbidity of EH in AD patients is low, as the clinical manifestation of EH in AD patients tends to appear more widespread and severe, we should always keep in mind the seriousness and risk of EH in AD patients.
This study has some limitations. First, the data were collected from the NHIS claim database, and data such as smoking, physical activity, and family history were not available in our study. Second, there are some limitations in that our study was a retrospective cohort study. In addition, it is also possible to underestimate the diagnosis if the disease is mild and if the patient does not visit the medical center. Third, our study has limitations in that there is no information on each infectious species; however, one of the strengths of the study is that we analyzed all the bacterial, and viral infections.
The major strength of our study is that the data we used are maintained by the government or public agencies that provide national health information, and the data are thus standardized and stable. Additionally, we used a large sample size, the sample was representative of the entire country, and our study has the advantage of including all age groups, while most of the existing studies were conducted by surveys, interviews or with a small number of subjects. Finally, for the first time, the correlation between AD and infectious diseases was confirmed using SPM, and comorbidity, risk and onset duration were analyzed.
In conclusion, our study demonstrates that AD could increase the risk of infectious disorders, and these findings might be meaningful for early diagnosis and also for management. The early detection and treatment of infectious disorders in AD patients will prevent the aggravation of AD. In particular, care should be taken because of the high relevance of AD with impetigo, molluscum contagiosum and otitis media, and these results may help with prevention of worsening of disease and appropriate management in AD patients.