The existence of systematized nickel contact dermatitis (SCD) in patients with atopic dermatitis (AD) and the association with sustained nickel exposures continues to be controversial in the literature, due to both a paucity of controlled trials and conflictual information.1

There are several factors impacting nickel sensitization in atopic eczema, which involve both the environment and genetics.2 An aspect of the environmental component concerns formation of a biofilm by Staphylococcus aureus, leading to sweat duct plugging and potentiation of inflammation and pruritus in AD affected skin.2

Staphylococcus biofilm and interaction with metals

Biofilms are a bacterial-based community enclosed by an extracellular matrix that promotes bacterial growth and alters defensive host mechanisms.3 The bacteria found within these biofilms tend to be more resistant to antibiotics and host defenses, as leukocytes and antibiotics have greater difficulty penetrating and impacting the bacteria (Staphylococcus), thus allowing supercolonization.4 It is known from research in chronic wound care that biofilms augment the inflammatory response,5 and indeed is also the case in AD.

The relationship between Staphylococcus aureus AD and nickel allergy is further complicated because nickel and other metals have an effect on the phagocytic activity of bacteria.6 One of the roles of human polymorphonuclear leucocytes (PMN) is phagocytosis of bacteria. One study exposed various metals to these PMNs in vitro, including cobalt, nickel, and chromium.6 Nickel was found to decrease the number of bacteria phagocytosed, therefore leading to a persistence of S. aureus on the skin, forming biofilms, and thus further aggravating the atopic dermatitis condition.6

A study done by Gonzalez and Jensen7 revealed that S. aureus has a role of incorporation of metals and placing them into its cellular compartments. They highlighted that polyphosphate bodies are responsible for binding to and sequestering large amounts of nickel during S. aureus infection.7 Furthermore, recent studies indicate that Staphylococcus aureus caries a trace metal transporter, the Opp1 ABC transporter.8 This unique nickel transporter has a significant role in the persistence of S. aureus infection in AD patients.8

Filaggrin and Nickel and Staphylococcus

Evidence suggests that the genetic component in a subset of AD centers on a mutation in the filaggrin (FLG) gene.2 The link between nickel allergy and AD might be explained by the shared association with loss-of-function mutation in the filaggrin gene. The compromised chelating functions of AD and the decreased acidification that are associated with filaggrin deficiency lead to enhanced penetration of nickel ions through a histidine depleted stratum corneum.9 Furthermore, it is known that filaggrin degradation products inhibit Staphylococcus growth, and therefore in this subset of AD which is associated with filaggrin deficiency there may be both a tendency to promote nickel allergy and Staphylococcus growth.9

Of interest, FLG mutation carriers reported ACD to nickel at a significantly younger age than controls with normal filaggrin, and had stronger patch test reactivity.9 This positive association between FLG mutations and contact sensitivity (CS) to nickel has been reported in German adults and confirmed in Danish adults without ear piercings.10 The sources for the majority of the nickel sensitized (non-pierced) adult patients remains to elucidated.

That said, a number of studies have looked at sources associated with generalized dermatitis (SCD) in AD children. In one study, nickel release was evaluated from 212 children’s toys, which showed 34.4 percent of the toys released sufficient nickel to lead to sensitization or reactivation in a sensitized person.11 The majority of toys were gender neutral, however, a larger proportion of the gender-intended toys were directed at females.11 In a recent study by Goldenberg et al., 67 percent of the subjects demonstrated generalized dermatitis in association with a belt buckle, notably 75 percent had concurrent AD.12 It is important to note that nickel release from objects may be below the detectable level of the Dimethylglyoxime (DMG) test, as it is only 59.3 percent sensitive, which could lead to a false sense of reassurance.13 Furthermore, it stands to reason that the release of nickel onto a normal barrier versus one with filaggrin defects would confer a relative “greater dose” due to an increased absorption into the defective skin barrier.

Immune response to nickel in Staphylococcus infected AD patients:

There are increasing reports of generalized dermatitis associated with nickel in AD children from a number of sources, including the aforementioned belt buckles and toys.11The immunology of these interactions is actually quite complex. In a recent study by Akan et al, utilizing the SCORAD (scoring atopic dermatitis) score, the extent of eczema (including trunk involvement), the score of sleep loss, and the pruritus level demonstrated a significant association with nickel sulfate (NS) sensitization than those without any reaction (P = 0.002, P = 0.001, P = 0.002, respectively).14 This has led to several authors recommending evaluation for NS sensitization for children with severe AD or larger extent of eczema.

Significant immunological alterations have been reported, in which there is a decrease in TH1 and TH2 subset genes with nickel associated AD responses, including increased TH17/IL-23, inconsistent upregulation in the levels of TH2 products and abnormal negative regulator levels compared with those seen in non-AD skin, occurring simultaneously.15 These baseline abnormalities impact allergic immune reactions through global attenuation and differential polarization in patients with AD. This skewing and subsequent hyporesponsiveness in skin from patients with a history of AD could explain the inconsistencies in the literature regarding rates of sensitization in AD versus non-AD patients.

In the situation of a significant flare of generalized dermatitis reaction during patch testing that corresponds to a negative patch test read, a low-nickel diet trial may be warranted. Improvement through implementation for a low nickel diet has been noted in some moderate-severe AD children with negative or equivocal nickel patch tests. These same patients have been seen to later demonstrate nickel reactivity once their generalized dermatitis abates (and they become a mild-moderate atopic responding to emollients and topical medicaments), despite the earlier patch test being negative (personal observation, SEJ).

This supports the hypothesis by Correa de Rosa that the significant decreases in levels of TH1 products, some increases in levels of TH17 products, and inconsistent upregulation in levels of TH2 products and negative regulators could explain the overall hyporesponsiveness in skin from patients with background AD compared with those seen in non-AD skin states.15

Of interest, Admani et al,16 noted that pre-emptive Staphylococcus skin colonization reduction measures, such as utilizing anti-Staphylococcus antibiotic treatments,17 and aseptic soak protocol18 three weeks before patch testing can result in more effective patch test readings (reduced flares and background dermatitis) in AD patients known to have a history of supercolonization.16 Furthermore, it has been shown that alkaline soaps may induce lesions of susceptible persons with atopic dermatitis and thus utilizing acid maintaining cleansers and skin acidification is paramount.20 (See Tables 1 and 2)

Of interest, a randomized control trial suggested that bleach baths showed drastic progression towards improvement for AD patients, compared to oral antibotics, topical steroids, and antibiotic ointments.21 This demonstrates the importance of counteracting the bacterial colonization, as bleach baths have an overall beneficial effect, even though they increase the pH (alkalinize) of the skin. Thus, pairing bleach baths with acidification, restoring the pH to be more acidic, rather than alkaline (pH of atopic 6.1 versus 5.24 in normal controls), enhances the skin’s antimicrobial properties, disrupts biofilm formation and restores the integrity of the normal biome and epidermal function.22 Futhermore, Staphylococcus and other pathogenic bacteria that favor growth in neutral pH are further inhibited in an acidic milieu.22

Lastly, researchers have shown elevated secretion of IL-2 under nickel sulfate stimulation in vitro, specifically in AD patients with nickel allergy infected by S. aureus.23 The enhancement of IL-2 by Staphylococcus may promote activation of the lymphocytes, as autocrine feedback action leads to cell proliferation. This process, known as clonal expansion, is critical in the afferent phase of contact sensitization, and suggests a supportive role between the expression of nickel contact allergy and S. aureus infection in AD patients.23

The environmental impact of the Staphylococcus biofilm formation and interaction with metals, the genetic component of filaggrin and nickel, and the complex immune response to nickel in mild, moderate, and severe Staphylococcus infected AD patients remains to be fully elucidated. Acidification of the skin is is necessary for antibacterial activity and barrier function.20 Therapeutic options specifically addressing pH aberrancy, in the era of antibiotic resistance, could potentially not only improve AD by inhibition of Staphylococcus and pathogenic microbes, but may also impact sensitization rates to nickel. Clinicians should be encouraged to evaluate patterns of NS sensitization in children with atopic dermatitis and consider the impact of Staphylococcus colonization. n

Sharon E. Jacob, MD is Professor of Dermatology and Director of Contact Dermatitis Clinic, Department of Dermatology, Loma Linda University.

Nikoleta Brankov, MD is a preliminary medicine resident physician at Loma Linda University.

1. Pizzutelli S. Systemic nickel hypersensitivity and diet: myth or reality? Eur Ann Allergy Clin Immunol. 2011;43(1):5-18.

2. Allen HB, Vaze ND, Choi C, Hailu T, Tulbert BH, Cusack CA, Joshi SG. The presence and impact of biofilm-producing staphylococci in atopic dermatitis. JAMA Dermatol. 2014;150(3):260-265.

3. Rippke F, Schreiner V, Doering T, Maibach HI. Stratum corneum pH in atopic dermatitis: impact on skin barrier function and colonization with Staphylococcus Aureus. Am J Clin Dermatol. 2004;5(4):217-223.

4. Vlassova N, Han A, Zenilman JM, James G, Lazarus GS. New horizons for cutaneous microbiology: the role of biofilms in dermatological disease. Br J Dermatol. 2011;165(4):751-759.

5. Zhao G, Usui ML, Lippman SI, James GA, Stewart PS, Fleckman P, Olerud JE. Biofilms and Inflammation in Chronic Wounds. Adv Wound Care (New Rochelle). 2013;2(7):389-399.

6. Rae T. The action of cobalt, nickel and chromium on phagocytosis and bacterial killing by human polymorphonuclear leucocytes; its relevance to infection after total joint arthroplasty. Biomaterials. 1983;4(3):175-180.

7. Gonzalez H, Jensen TE. Nickel sequestering by polyphosphate bodies in Staphylococcus aureus. Microbios. 1998;93(376):179-185.

8. Remy L, Carrière M, Derré-Bobillot A, Martini C, Sanguinetti M, Borezée-Durant E. The Staphylococcus aureus Opp1 ABC transporter imports nickel and cobalt in zinc-depleted conditions and contributes to virulence. Mol Microbiol. 2013;87(4):730-743.

9. Ross-Hansen K, Ostergaard O, Tanassi JT, Thyssen JP, Johansen JD, Menne T et al. Filaggrin Is a Predominant Member of the Denaturation-Resistant Nickel-Binding Proteome of Human Epidermis. J Invest Dermatol. 2014;134(4):1164-1166.

10. Thyssen JP1, Johansen JD, Linneberg A, Menné T, Nielsen NH, Meldgaard M, Szecsi PB, Stender S, Carlsen BC. The association between null mutations in the filaggrin gene and contact sensitization to nickel and other chemicals in the general population. Br J Dermatol. 2010;162(6):1278-1285.

11. Jensen P, Hamann D, Hamann Cr, Jellesen MS, Jacob SE, Thyssen JP. Nickel and cobalt release from children’s toys purchased in Denmark and the United States. Dermatitis. 2014;25(6):356-365.

12. Goldenberg A, Admani S, Pelletier JL, Jacob SE. Belt Buckles-Increasing Awareness of Nickel Exposures in Children: A Case Report. Pediatrics. Pediatrics. 2015;136(3):e691-693.

13. Thyssen JP, Skare L, Lundgren L, Menne T, Johansen JD, Maibach HI, Liden C. Sensitivity and specificity of the nickel spot (dimethylglyoxime) test. Contact Dermatitis. 2010;62(5):279-288.

14. Akan A, Toyran M, Vezir E, Azkur D, Kaya A, Erkocoglu M, Civelek E, Misirlioglu ED, Kocabas CN. The patterns and clinical relevance of contact allergen sensitization in a pediatric population with atopic dermatitis. Turk J Med Sci. 2015;45(6):1207-1213.

15. Correa da Rosa J, Malajian D, Shemer A, Rozenblit M, Dhingra N, Czarnowicki T, Khattri S, Ungar B, Finney R, Xu H, et al. Patients with atopic dermatitis have attenuated and distinct contact hypersensitivity responses to common allergens in skin. J Allergy Clin Immunol. 2015;135(3):712-720.

16. Admani S, Matiz C, Jacob SE. Coutnering Staphylococcus Overgrowth During Patch Testing in Children with Moderate to Severe Atopic Dermatitis. Pediatr Dermatol. 2016;33(1):56-61.

17. Goh CL, Wong JS, Giam YC. Skin colonization of Staphylococcus aureus in atopic dermatitis patients seen at the National Skin Centre, Singapore. Int J Dermatol. 1997;36(9):653-657.

18. McGowan MA, Jacob SE. Bleach Baths. Journal of the Dermatology Nurses’ Association. 2016;8(3):230.

19. Weitz NA, Brody E, Lauren CT, Morel KD, Paladine H, Garzon MC, Krause MC. Management of Infectious Aspects of Atopic Dermatitis in Primary Care: A Resident Survey. Clin Pediatr (Phila). 2016. Feb 1. Pii: 0009922815627347. [Epub ahead of print].

20. Panther DJ, Jacob SE. The Importance of Acidification in Atopic Eczema: An Underexplored Avenue for Treatment. J Clin Med. 2015;4(5):970-978.

21. Shi VY, Foolad N, Ornelas JN, Hassoun L, Monico G, Takeda N, Saric S, Prakash N, Eichenfield LF, Sivamani RK. Comapring the Effect of Bleach and Water Baths on Skin Barrier Function in Atopic Dermatitis: A Split-Body Randomzied Controlled Trial. Br J Dermatol. 2016 Feb 15. doi: 10.1111/bjd.14483. [Epub ahead of print]

22. Knor T, Meholjic’-Fetahovic’ A, Mehmedagic’ A. Stratum corneum hydration and skin surface pH in patients with atopic dermatitis. Acta Dermatovenerol Croat. 2011;19(4):242-247.

23. Anna BM, Grazyna A, Wojciech D, Aleksander O, Anna B, Andrzej K, Zofia M, Krystyna O. Nickel allergy and relationship with Staphylococcus aureus in atopic dermatitis. J Trace Elem Med Biol. 2016;33:1-7.

24. An Employer’s Guide to Skin Protection. 2016; ttp://elcosh.org/document/59/d000457/an-employers-guide-to-skin-protection.html. Accessed online 7/7/2016, 2016.