Congenital ichthyosis is associated with cutaneous infections in a case–control study of 2260 patients

Teaser text

Evidence of congenital ichthyosis association with cutaneous infections is limited to case reports. We conducted a nested case–control study assessing congenital ichthyosis associations with cutaneous infections using a large national database. Compared with controls, patients with congenital ichthyosis had higher odds of onychomycosis, tinea corporis, verruca vulgaris, and tinea pedis.

Dear Editor, Congenital ichthyoses (CI) are a group of inherited keratinization disorders characterized by generalized scaling. Evidence of CI association with cutaneous infections is limited to case reports,¹ and therefore we aimed to evaluate these associations using a national database.

A nested case–control study using the National Institutes of Health All of Us database was conducted analysing people aged ≥ 18 years with CI and controls matched 1 : 9 by age, sex and self-reported race. Multivariate logistic regression assessed odds ratios (ORs) for CI and comorbidities.

In total, 226 participants with CI and 2034 controls were included in the final analysis. The mean age of participants with CI was 65.7 years, with 55.3% female and 64.6% White, similar to controls (P = 0.99, P = 1, P = 0.99, respectively) (Table 1). CI was associated with onychomycosis (OR 4.93, 95% confidence interval 1.59–14.47; P = 0.004), tinea corporis (OR 3.57, 1.77–6.88; P < 0.001), verruca vulgaris (OR 3.25, 2.14–4.85; P < 0.001) and tinea pedis (OR 2.63, 1.58–4.24; P < 0.001) (Table 2).

Table 1.

Demographic characteristics of congenital ichthyosis and control patients matched by age and self-reported race/ethnicity in the All of Us database

Characteristics	Controls (n = 2034)	Congenital ichthyosis (n = 226)	P-value
Age, mean (SD)	65.7 (15.5)	65.7 (15.5)	0.99
Sex at birth, n (%)
Men	909 (44.7)	101 (44.7)	1
Women	1125 (55.3)	125 (55.3)
Self-reported race count, n (%)
White	1314 (64.6)	146 (64.6)	0.99
Black or African American, n (%)	585 (28.8)	65 (28.8)
Asian	74 (3.6)	≤ 20a
Other	61 (3.0)	≤ 20a

^aPrevalence values are concealed in order to comply with the All of Us database policy prohibiting display of any participant count of 1–20.

Table 2.

Cutaneous infectious associations with congenital ichthyosis in the All of Us database

Associations, n (%)	Controls (n = 2034)	Congenital ichthyosis (n = 226)	OR (95% confidence interval)	P value
Onychomycosis	≤ 20a	≤ 20a	4.93 (1.59–14.47)	0.004
Tinea corporis	32 (1.6)	≤ 20a	3.57 (1.77–6.88)	< 0.001
Verruca vulgaris	114 (5.6)	43 (19.0)	3.25 (2.14–4.85)	< 0.001
Tinea pedis	82 (4.0)	33 (14.6)	2.63 (1.58–4.24)	< 0.001
Tinea manuum	≤ 20a	≤ 20a	4.78 (0.85–27.9)	0.06
Molluscum contagiosum	≤ 20a	≤ 20a	3.11 (0.39–20.12)	0.23
Tinea versicolor	≤ 20a	≤ 20a	1.55 (0.48–4.12)	0.41
Tinea cruris	≤ 20a	≤ 20a	0.62 (0.12–2.22)	0.51

Boldface indicates significance (P < 0.05). There were insufficient numbers to assess for tinea capitis, staphylococcal cutaneous infection and herpes simplex virus cutaneous infection. OR, odds ratio. ^aPrevalence values are concealed in order to comply with the All of Us database policy prohibiting display of any participant count of 1–20.

To our knowledge, this is the first case–control study assessing the risk of cutaneous infection in patients with CI. Participants with CI had almost five-fold and two-fold risk of onychomycosis and tinea pedis, respectively. Similarly, in a prospective study of 25 autosomal recessive patients with CI, mycologically confirmed onychomycosis was reported in 24% of patients, with all toenail cases due to Trichophyton rubrum,² which is the most common causative organism in the general population. Onychomycosis is associated with venous insufficiency,³ which may occur in patients with CI with impaired mobility. It may be difficult to discern CI-associated onychodystrophy from onychomycosis, both of which may share common features (e.g. xanthonychia, nail thickening, onycholysis and subungual hyperkeratosis). CI-related onychodystrophy is typically symmetrical and involves most nails, whereas onychomycosis is frequently asymmetrical and involves one or a few nails.¹ Mycological sampling may be used to rule in/out onychomycosis in patients with CI.

Participants with CI have a three-fold risk of tinea corporis. In a review of 89 publications on fungal infections in patients with CI, the most frequent causative pathogen of superficial dermatophytosis was T. rubrum, followed by Trichophyton mentagrophytes and Epidermophyton floccosum, similar to pathogens reported in the general population.¹ Most reported cases had generalized infections and up to 20% had recurrent infections.¹

Cutaneous infections may be difficult to discern in patients with CI because scaling, palmoplantar keratosis and erythema are common to clinical presentations for both dermatophyte infections and ichthyosis. Scaling and pruritus may also be attributed to atopic dermatitis (AD), which is a common CI comorbidity. Based on our study, we recommend that patients with CI who do not respond to ichthyosis treatment, with persistence of scaling, pruritus or erythroderma, be tested for concomitant fungal infection.¹ Treatment may be challenging due to poor antifungal penetration in the setting of acanthotic stratum corneum and occluded sweat ducts.¹

Participants with CI had a three-fold risk of verruca vulgaris, which has not been previously reported. AD, which is a potential risk factor for verrucae thought to be due to impaired immune response,⁴ is a common CI comorbidity. One case report demonstrated resolution of widespread verrucae following AD treatment.⁵ Treatment of underlying CI and AD may reduce cutaneous infection risk.

Increased susceptibility of patients with CI to cutaneous infections is probably multifactorial, due to defective skin barrier, keratin overproduction, which may promote pathogen colonization and complex immunological dysfunction (e.g. atopy and abnormal innate and cell-mediated immunity).¹

Limitations include small sample size, inability to stratify by ichthyosis type, lack of mycologic and pathogen confirmation, and database exclusion of paediatric participants. Strengths include case–control design and cohort diversity.

In conclusion, we demonstrate CI associations with cutaneous viral and fungal infections. Larger studies stratified by CI type are needed. We recommend mycological sampling in patients with CI unresponsive to CI treatments to rule out fungal infections.

Funding sources

The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; and 1 OT2 OD026555. IAA no.: AOD 16037. Federally Qualified Health Centers: HHSN 263201600085 U. Data and Research Center: 5 U2C OD023196. Biobank: 1 U24 OD023121. The Participant Center: U24 OD023176. Participant Technology Systems Center: 1 U24 OD023163. Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206, and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; and 1 OT2 OD025276.

Data availability

The data underlying this article is available in the article.

Ethics statement

This study was approved by the Institutional Review Board of Weill Cornell Medicine (record no. 19-11021049).

Patient consent

Written patient consent for publication was obtained.