INTRODUCTION

Peeling hands and soles are frequently reported by scuba divers. This condition can be attributed to various factors including allergic or irritant contact dermatitis, infections, sunburn, or exacerbation of pre-existing skin conditions such as atopic dermatitis [1]. Additionally, medications may trigger unforeseen reactions, such as pseudoephedrine-induced nonpigmented bullous fixed drug eruption (NBFDE). This report describes a highly unusual case of NBFDE presenting as peeling palms and soles in a scuba diver.

Fixed drug eruption (FDE) is a medication allergy characterized by well-defined, typically pigmented lesions that recur at the same sites on the skin or mucous membranes upon re-exposure to the offending drug. NBFDE is a rarer variant of FDE, presenting without post-inflammatory hyperpigmentation. Scuba diving exposes individuals to various environmental factors that can trigger skin conditions. Although allergic reactions to diving equipment or marine life are well-documented, medications used to manage ear problems during dives can also provoke unexpected cutaneous reactions in divers.

CASE REPORT

A 38-year-old woman presented at our allergy clinic with recurrent peeling of the palms and soles. Five years earlier, during a scuba diving trip, she developed itchy, well-defined red rashes on her body after 3 days of diving. She also experienced mild flu-like symptoms, including malaise and a prodrome indicative of an impending fever, although she never developed a fever. Shortly thereafter, her hands and feet became itchy, burned, and slightly swollen. The body rashes resolved on their own, but both her palms and soles developed blisters, which were followed by significant peeling (Figure 1A and B). She experienced similar symptoms on 2 subsequent diving trips, yet the cause remained undiagnosed. Although she suspected the symptoms were related to diving, she had not previously sought medical attention.

A recent visit to an otolaryngologist for sinusitis resulted in the prescription of intranasal corticosteroids and oral pseudoephedrine. The following day, the patient developed similar skin lesions, prompting her to seek evaluation at our allergy clinic. Her medical history was notable only for rhinosinusitis and a remote hysterectomy due to uterine myoma. She denied any history of hand dermatitis, eczema, or skin peeling triggered by sun exposure, water contact, chemicals, or cosmetics.

The patient reported that she was not taking any regular medications at present. However, she occasionally used pseudoephedrine to prevent ear pain while scuba diving. Notably, she remembered developing rashes on her body, upper thighs, and inner arms, as well as experiencing swelling and peeling of her fingers after using a traditional Japanese cold medicine that contained dl-methylephedrine hydrochloride, a nasal decongestant [2,3].

As both methylephedrine and pseudoephedrine are sympathomimetic drugs with potential for cross-reactive hypersensitivity, pseudoephedrine emerged as a possible cause of the patient’s peeling palms and soles during scuba diving. To assess the drug-specific immune response, we conducted a drug patch test and an enzyme-linked immunospot (ELISpot) assay to measure interferon-gamma (IFN-γ) release from pseudoephedrine-stimulated peripheral blood mononuclear cells (PBMCs). While the patch test was negative, the ELISpot assay showed a strong positive response. Incubation with 60 ng/mL and 300 ng/mL of pseudoephedrine resulted in a significant increase in IFN-γ–releasing cells (244 and 432 cells/106 PBMCs, respectively), compared to the negative control, as shown in Figure 2. This positive in vitro test, combined with the clinical history, confirmed pseudoephedrine as the responsible drug [4].

Given her history of rhinosinusitis and the need for occasional decongestants to equalize ear pressure during scuba diving, the patient, an avid diver, volunteered for a graded challenge with pseudoephedrine. Eight hours after ingesting a quarter of a 60-mg pseudoephedrine tablet, she developed flu-like symptoms and pruritic, erythematous eruptions on her hands that extended to her elbows, as well as on her feet. Both her palms and soles became itchy and swollen. Consequently, the challenge was discontinued, and she was prescribed desoximetasone cream (0.25%), to be applied twice daily. Although she continued to experience blistering and peeling of the fingers, the reaction was less severe than in previous episodes (Figure 1C). The repeated episodes of cutaneous reactions following a single 15-mg dose of pseudoephedrine, along with positive in vitro testing, confirmed pseudoephedrine as the underlying cause in this case.

Phenylephrine, a sympathomimetic medication within the phenethylamine group, can also aid in equalizing ear pressure during diving. Due to potential cross-reactivity among various sympathomimetic drugs [5], a graded challenge using phenylephrine was conducted. Since phenylephrine as a standalone ingredient is not widely available, the challenge was carried out using a combination tablet that contained 4 mg of brompheniramine maleate and 10 mg of phenylephrine hydrochloride over a period of 5 days. Fortunately, the results of the 5-day challenge indicated that, although the medication caused some skin dryness and mild peeling, the reaction was significantly less severe than that observed with pseudoephedrine.

Ethics Statement

Written consent for publication was obtained from the patient. Institutional review board approval was not required for publication of this case report.

DISCUSSION

Palmoplantar exfoliation following scuba diving can be attributed to various factors. Additionally, adverse drug reactions such as drug-induced keratolysis exfoliativa-like syndrome, hand-foot syndrome, and NBFDE may also cause palmoplantar exfoliation [6-8]. In this case, the acute inflammatory reaction characterized by itching and burning within hours of drug rechallenge at previous lesion sites, coupled with well-defined red lesions on the body and flu-like symptoms, strongly supported the diagnosis of NBFDE caused by pseudoephedrine. Pseudoephedrine has been previously identified as a drug responsible for causing FDE and, less frequently, NBFDE [9,10]. The pathogenesis of FDE involves resident memory CD8+ T cells in the epidermis. Upon re-exposure to the drug, these cells become activated, migrate upwards, and adopt a cytotoxic phenotype, expressing granzyme B and perforin. This results in epidermal necrosis, the hallmark of FDE. Concurrently, CD4+ Foxp3+ regulatory T cells infiltrate the lesion, facilitating resolution through the release of IL-10, which explains the self-limited nature of FDEs [11].

Nevertheless, the absence of post-inflammatory hyperpigmentation in this non-pigmented subtype of FDE can lead to an overlooked diagnosis of drug allergy, especially when other differential diagnoses are more prevalent. Patch testing with the suspected drug is the recommended method to confirm an FDE diagnosis. Unfortunately, in our case, the test did not yield a positive result. Recently, however, more sensitive diagnostic tools such as sequential in situ patch testing and repeated open application testing have been introduced for FDE [12]. Although the skin test was negative, the positive IFN- γ ELISpot assay confirmed a strong T-cell-mediated hypersensitivity response in our patient.

Since a challenge with brompheniramine/phenylephrine resulted in a minimal skin reaction, phenylephrine appeared promising for preventing ear barotrauma in this case. However, the potential sedative effects of this combination decongestant pose a concern when diving. Unfortunately, phenylephrine tablets containing only 1 ingredient are not widely available, and phenylephrine has a shorter duration of action compared to pseudoephedrine, which reduces its effectiveness in preventing ear barotrauma during longer dives. Nevertheless, its rapid action could be advantageous for addressing mild congestion that occurs during a dive. Ultimately, the patient was advised to completely avoid pseudoephedrine. Alternatives such as ad hoc oral phenylephrine, if accessible, first-generation antihistamines, nasal decongestant sprays, or a short course of systemic steroids, combined with proper ear equalization techniques like the Valsalva maneuver, were suggested to prevent ear issues before scuba diving when necessary.

This case study suggests that the peeling of hands and soles observed in scuba divers may be due to an allergic reaction to drugs frequently used during diving, such as pseudoephedrine. A thorough medical history and clinical examination are essential to accurately determine the causes of diver’s dermatitis and identify the responsible drug. This case underscores the significance of including drug allergies in the differential diagnosis when assessing palmoplantar exfoliation in scuba divers.

Notes

Conflict of Interest

The authors have no conflicts of interest associated with the material presented in this paper.

Funding

None.

Author Contributions

Conceptualization: Kajornchaikul P, Klaewsongkram J. Data curation: Klaewsongkram J. Formal analysis: Klaewsongkram J. Funding acquisition: None. Methodology: Thantiworasit P. Project administration: Klaewsongkram J. Writing – original draft: Kajornchaikul P. Writing – review & editing: Thantiworasit P, Klaewsongkram J.

Acknowledgements

Figure. 1.

Erythematous rashes on the body (A), peeling palms (B), and swollen (C) observed after the patient took and was rechallenged with pseudoephedrine.

Figure. 2.

The IFN-γ ELISpot assay showed a significant number of IFN-γ–releasing cells when the patient’s PBMCs were incubated with pseudoephedrine (A: 60 ng/mL, B: 300 ng/mL). These concentrations of pseudoephedrine did not induce a response in a control subject’s PBMCs (C: negative control, D: positive control). IFN-γ, interferon gamma; ELISpot, enzyme-linked immunospot; PBMCs, peripheral blood mononuclear cells.

REFERENCES

• 1. Thornton NJ, Garcia B, Hoyer P. Aquatic antagonists: marine rashes (seabather’s eruption and diver’s dermatitis). Cutis 2022;109(5):255-260. https://doi.org/10.12788/cutis.0522ArticlePubMed
• 2. Okamoto H, Nakajima T, Ito Y, Aketo T, Shimada K, Yamato S. Simultaneous determination of ingredients in a cold medicine by cyclodextrin-modified microemulsion electrokinetic chromatography. J Pharm Biomed Anal 2005;37(3):517-528. https://doi.org/10.1016/j.jpba.2004.11.011ArticlePubMed
• 3. Kim KH, Jun M, Lee MK. Bioavailability of the common cold medicines in jellies for oral administration. Pharmaceutics 2020;12(11):1073. https://doi.org/10.3390/pharmaceutics12111073ArticlePubMedPMC
• 4. Chongpison Y, Sriswasdi S, Buranapraditkun S, Thantiworasit P, Rerknimitr P, Mongkolpathumrat P, et al. IFN-γ ELISpot-enabled machine learning for culprit drug identification in nonimmediate drug hypersensitivity. J Allergy Clin Immunol 2024;153(1):193-202. https://doi.org/10.1016/j.jaci.2023.08.026ArticlePubMed
• 5. Barranco R, Rodríguez A, de Barrio M, Trujillo MJ, de Frutos C, Matheu V, et al. Sympathomimetic drug allergy: cross-reactivity study by patch test. Am J Clin Dermatol 2004;5(5):351-355. https://doi.org/10.2165/00128071-200405050-00008ArticlePubMed
• 6. Pierobon E, Germi L, Sechi A, Trevisan G, Pezzolo E, Feliciani C, et al. Keratolysis exfoliativa-like eruption induced by ranolazine. Dermatol Reports 2022;14(1):9264. https://doi.org/10.4081/dr.2022.9264ArticlePubMedPMC
• 7. Nikolaou V, Syrigos K, Saif MW. Incidence and implications of chemotherapy related hand-foot syndrome. Expert Opin Drug Saf 2016;15(12):1625-1633. https://doi.org/10.1080/14740338.2016.1238067ArticlePubMed
• 8. Otsuka H, Fukumoto T, Oka M, Nishigori C. Case report: severe non-pigmenting fixed drug eruption showing general symptoms caused by chondroitin sulfate sodium. Front Med (Lausanne) 2022;9: 1041492. https://doi.org/10.3389/fmed.2022.1041492ArticlePubMedPMC
• 9. Vidal C, Prieto A, Pérez-Carral C, Armisén M. Nonpigmenting fixed drug eruption due to pseudoephedrine. Ann Allergy Asthma Immunol 1998;80(4):309-310. https://doi.org/10.1016/S1081-1206(10)62974-2ArticlePubMed
• 10. Shelley WB, Shelley ED. Nonpigmenting fixed drug eruption as a distinctive reaction pattern: examples caused by sensitivity to pseudoephedrine hydrochloride and tetrahydrozoline. J Am Acad Dermatol 1987;17(3):403-407. https://doi.org/10.1016/s0190-9622(87)70220-5ArticlePubMed
• 11. Anderson HJ, Lee JB. A review of fixed drug eruption with a special focus on generalized bullous fixed drug eruption. Medicina (Kaunas) 2021;57(9):925. https://doi.org/10.3390/medicina57090925ArticlePubMedPMC
• 12. Traineau H, Milpied B, Soria A, Assier H, Tetart F, Bernier C, et al. In situ patch test and repeated open application test for fixed drug eruption: a multicenter study. J Allergy Clin Immunol Pract 2024;12(2):460-468. https://doi.org/10.1016/j.jaip.2023.10.021ArticlePubMed

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References

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