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CASE HISTORY:
male first seen at 6 months of age:PHYSICAL EXAMINATION: The eczema was generalized especially in the creases and much of the skin seemed infected. Lymph nodes were enlarged in the neck, axilla and groin.
LABORATORY: Skin testing yielded a strong positive to egg white, moderate positive to peanut but negative to milk solution and several aeroallergens including cat, dog, mites. Blood work was done to assess the immune system. Serum IgE was very high at 9364 mcg/l (normal 0-432). Total peripheral eosinophils were very high at 3.5 x 109/l (n 0.05 -0.7). There was also a lymphocytosis and monocytosis. Neutrophils were normal. Serum IgG was on the low side at 3.28. The Immunology Division at the Hospital for Sick Children was asked to see the patient because of the low IgG and extensive skin infection. Their work-up was essentially normal with a borderline low IgG but normal antibody production.
OUTCOME: As can be seen from the photographs, he improved significantly and parents attributed that to restricting milk and placing him on Alimentum hydrolysed formula. They severely restricted his diet and his environment. At 27 months of age his only areas of skin involvement were hands and feet. His diet consisted primarily of rice, chicken and 2% cow milk and he tolerated egg noodles. He avoided peanut, nuts, seafood, egg and citrus. His eczema flared after he he was given soy milk but he tolerated soy bean curd soup. His only episodes of asthma occurred when he had contact with cats and dogs. He was treated with topical tacrolimus and topical betamethasone ointment and hydrocortisone ointment. He had asthma symptoms only when he had colds. Skin tests were repeated at 32 months of age and he was positive quite strongly to milk and egg with moderate positive to peanut and small positive to soy. He was not tested to nuts. He was now positive to aeroallergens including: mites, cat, tree, ragweed, alternaria and aspergillus.
COMMENTS: This young fellow's atopic dermatitis has clearly improved and it is hard to say what the most important factor was. His skin was markedly infected, probably with staphylococcus. At 32 months of age, when he tolerated 2% cow milk, he had a very large positive skin test to milk (30 x 15mm). His parents feel that his improvement started when cow milk was removed from his diet. It seems likely that allergic reactions to milk would have created itching and scratching despite the absence of hives. In fact at 6 months of age, we did not detect IgE antibody to milk solution by skin testing but he was not skin tested to whole milk itself. Repeat testing at 32 months demonstrated a very large positive. The allergic inflammation in his skin with the resulting scratching would have led to overgrowth of staphylococcus with the staphylococcal enterotoxins acting as superantigens leading to the very high total IgE and very elevated peripheral eosinophil count seen at his first visit. The elimination of milk protein could have reduced the allergic inflammation and then the topical anti-inflammatory agents plus antibiotics might have finally reduced the skin inflammation leading to elimination of the staphylococcus and the improvement. We did not repeat the blood tests but in my experience when the skin improves, the total IgE and the peripheral eosinophil count decrease sharply. Fortunately in the majority of children the natural course of eczema is to improve spontaneously. His outcome should give hope that most children with atopic dermatitis can improve.
INTRODUCTION
Definition: Atopic dermatitis is a highly pruritic chronic inflammatory skin disease that
commonly presents during early infancy and childhood but can persist or start in
adulthood.
Alternative Definition: Atopic dermatitis (AD) is a chronically relapsing
inflammatory skin disease. It is characterized by episodes
of intense pruritus and multiple lesions with erythema,
excoriations, erosions accompanied by a serous exudate,
lichenification, papules, dry skin, and a susceptibility to
cutaneous infections. AD tends to run in families and
often coexists with other atopic diseases, such as rhinitis,
asthma, and allergic conjunctivitis. The immune pathology
of AD is not precisely understood. Skin lesions have
infiltrates of basophils, eosinophils, and cells of the
mononuclear phagocyte lineage and T cells. Elevated IgE
is found in 60% to 80% of patients with AD. Patients also
usually have elevated eosinophil counts. Leung 2000
T lymphocytes which have been characterized metaphorically as "the conductor of the inflammatory orchestra" are a characteristic component of the skin in atopic dermatitis. There is an extensive literature on the T lymphocytes infiltrating the skin in atopic dermatitis. These cells have been cloned and cultured from atopic dermatitis skin biopsies. It seems that the T lymphocytes are a different subset when recovered from acutely inflamed lesions compared to those recovered from chronic lesions.
Prevalence: Atopic dermatitis is a major public-health problem worldwide with a lifetime prevalence in children of 10–20%, and a prevalence of 1–3% in adults. At least two types of atopic dermatitis have been identified: an extrinsic type associated with IgE-mediated sensitization, which affects 70–80% of patients; and an intrinsic type without IgE-mediated sensitisation, which affects 20–30% of patients.
The inflammation in the atopic is likely to be quite different from inflammation in the non-atopic since atopy involves a specific T lymphocyte helper type that makes a certain set of cytokines that recruit eosinophils as the cytotoxic cell. In contrast the non-atopic eczema is may not involve eosinophils and presumably will involve a different set of T cell cytokines and therefore a different T lymphocyte. It has been known for a long time that the inflamed skin in atopic dermatitis is colonized by staphylococcus aureus and that some of the immune response in eczema is directed towards this bacteria. In 1993, Leung and co-workers found that a subset of patients with atopic dermatitis formed IgE antibodies to staphylococcal toxins Leung 1993 and later these toxins were shown to function as "superantigens". Thus as will be discussed further, the allergic immune response has been involved with creating inflammation by responding to "allergens" that are not the typical ones found in most other allergic diseases.
Parallels with asthma: There are epidemiologic parallels in asthma and atopic dermatitis. AD is often the first manifestation of an atopic diposition in genetically predisposed individuals which also includes asthma and allergic rhinitis. Up to 80% of children with AD will eventually develop allergic rhinitis or asthma later in childhood. This classic "atopic triad" has numerous immunologic elements in common, including cyclic nucleotide regulatory abnormalities, immune cell alterations, and inflammatory mediators and allergic triggers. Eichenfield 2003
The immune response in the skin in "atopic" dermatitis is known to be "allergic" in nature in 80% of children (extrinsic eczema) and since atopic dermatitis commonly presents in infancy when the atopic immune response is directed towards foods, initial research was directed towards proving that allergy to food was important in the development of eczema. This aspect of atopic dermatitis will not be reviewed. It is now known that atopic immune activity is also directed towards micro-organisms on the skin, particularly Staphylococcus aureus. New treatments which target the immune response in the skin have become available and the subjects of this review will specifically focus on Staphylococcus and the new treatments.
Staphylococcus aureus:
Staphylococcus aureus is found on the skin of 78-100% of children and adults with atopic dermatitis but only on the skin of 2-25% of healthy subjects. Leyden1974 Maibach 1977 Hoeger PH 1992 Morishita 1999. On the unaffected skin of infants with AD, bacterium colonization rate is significantly lower than on affected skin. Monti 1996 There is a relationship such that the worse the skin, the more colonization with S. aureus. Hauser 1985 Goodyear 1993.
Morishita et al found that more than half of the AD patients in the their study had specific IgE antibodies to enterotoxin A and/or enterotoxin B in their serum. They concluded that S. aureus and their endotoxins have important roles in the exacerbation and prolongation of atopic dermatitis.
Superantigens:
Marrack and Kappler first established that staphylococcal enterotoxins acted as "superantigens" White 1989 Kappler 1989 Choi 1989. The staphylococcal enterotoxins stimulate T lymphocytes that carry V beta sequences as part of their receptors for major histocompatibility complex protein-associated antigen regardless of the antigenic specificity of the receptor. That can stimulate many T cells and leads to a very potent T cell response. Marrak, Kappler 1990 These staphylococcal toxins cause the massive stimulation of T cells and accessory cells such as macrophages, Langerhans cells, and activated keratinocytes and that accounts for most of their pathologic effects. In 1993, Leung and co-workers found that a subset of patients with atopic dermatitis formed IgE antibodies to staphylococcal toxins Leung 1993 and later these toxins were shown to function as "superantigens". McFadden and co-workers McFadden 1993 also found that the stapylococci isolated from the skin of patients with atopic dermatitis produces exotoxins that had superantigenic properties. They suggested that these superantigens could activate T-cells and release cytokines accounting in part for the exacerbation of atopic dermatitis by staphylococcus infection. Staphylococcal enterotoxin B applied on intact normal and intact atopic skin induced dermatitis Strange 1996. Bunikowski and colleagues Bunikowski 2002 examined the severity of atopic dermatitis in relation to the presence of toxogenic strains of staphylococcus (i.e. strains producing the "superantigens") compared to patients with atopic dermatitis colonized with non-toxogenic strains of staphylococcus or not colonized with staphylococcus at all. They found that patients colonized with the superantigen positive strains of staphylococcus had greater severity of atopic dermatitis. They also found that the T lymphocytes in the skin of patients colonized by the superantigen positive strains of staphylococcus had antigen receptor types that were shifted to the type responsive to the superantigens. this suggests that the superantigen secreting staphylococcus can modulate the severity of atopic dermatitis and the type of T cell infiltrating the skin.
IgE to S. aureus enterotoxins:
Bunikowski et at. reported that "Twenty of 58 children (34%) were sensitized to superantigens (45% to SEB, 10% to SEA, 45% to SEA and SEB). In this group, severity of atopic dermatitis and levels of specific IgE to food and air allergens were significantly higher. The degree of disease severity correlated to a greater extent with the presence of SEA/SEB-specific antibodies than with total serum IgE levels. Density of colonization with superantigen-secreting S aureus strains was higher in the superantigen IgE-positive group. Sixty-three percent of these children experienced repeated episodes of superficial S aureus skin infections." Bunikowski 1999 Nomura et al. confirmed the correlation between IgE to staph enterotoxin and severity of AD in children. Nomura 1999 Lin et al. also found that children with atopic dermatitis have higher levels of IgE antibody to staph enterotoxins than atopic children without atopic dermatitis. The antibody levels correlate with the degree of involvement of the skin. Lin YT 2001 Children with AD had significantly higher levels of serum SEB-specific immunoglobulin G (IgG; p = 0.0193), IgM (p = 0.011), and IgE (p = 0.0001) than the nonatopic children. The proportions of IgG, IgM, and IgE seropositivity in children with AD were 52.5% (21/40), 62.5% (25/40), and 67.5% (27/40), respectively. The levels of SEB-specific IgE and the severity of AD (p = 0.0004) were correlated, Sohn 2003 Breuer confirmed the relationship between sensitization to SEB but not SEA in adults. Breuer 2000
The data cited suggests that there is a relationship between the severity of atopic dermatitis and the degree of colonization of the skin with S. aureus but also between the degree of dermatitis and the IgE response to the "superantigens". This "atopic" response is likely to lead to a significant inflammatory response in the skin and increased immune activity which in turn would damage the skin.
TREATMENT
As discussed previously, most patients with atopic dermatitis show colonization of the skin with Staphylococcus and there is a correlation between the degree of colonization and the severity of the dermatitis. This understanding provides a rationale for attempting to reduce the staphylococcal skin colonization of patients with severe atopic dermatitis and correlates with the clinical observation in a number of situations of marked improvement in atopic dermatitis following antibiotic treatment. Kemp, Campbell review 1996 Treatment of the Staphylococcus is correlated with improvement in the skin. Luber 1988 Lever 1988 For severe infection, treatment with a systemic anti-staphylococcal antibiotic is required but for localized lesions, topical Fucidic acid is appropriate. Treatment of the Staphylococci is associated with improvement in the skin. Abeck review 1998 However it is not clear that the result achieved with antibiotics is long-lasting. Boguniewicz 2001 found that the level of staphylococci on the skin very quickly rebounds after the antibiotic, in this case, cefuroxime, is stopped. Moreover treatment with topical steroid alone has been found to reduce the level of Staphylococci on the skin at the same time as there is clinical improvement of the skin. Stalder 1994 There is also a report demonstrating that treating atopic dermatitis with the topical immunosupressive agent, tacrolimus, reduces staphylococcal colonization of the skin. Remitz 2001 It seems likely that simply reducing inflammation in the skin with topical steroid of tacrolimus results in reduced colonization of the skin with staphylococcus aureus and therefore decreased immune activity against the bacteria which in turn leads to further improvement.
CALCINEURIN INHIBITORS (tacrolimus and pimecrolimus)
Recently, treatment of atopic dermatitis with the calcineurin inhibitor tacrolimus, in ointment form, has been reported. The calcineurins, tacrolimus and pimecrolimus, are immunosuppressive agents and oral tacrolimus is used in renal and liver transplantation.
TACROLIMUS
Nakagawa et al 1994 reported that skin biopsy specimens from patients with atopic dermatitis taken after 3 and 7 days of treatment with topical tacrolimus showed markedly diminished T-cell and eosinophilic infiltrates. Recent studies indicate that the T-cell activation in atopic dermatitis is biphasic with activation of the TH2-like cytokines, IL-4, IL-5 and IL-13 during the acute phase of the eruption. In contrast, the chronic inflammatory atopic dermatitis skin lesion is associated with increased expression of the TH1-cytokines interferon-gamma and IL-12. Thus the capacity of tacrolimus to inhibit the activation of multiple cell types and different cytokines may account for its ability to effectively reduce skin inflammation in atopic dermatitis.
A number of studies in adults demonstrated their efficacy and safety in the treatment of atopic dermatitis. Nakagawa 1994 Ruzicka 1997 Hanifen 2001 Soter 2001 Reitamo 2002
Similar studies have been reported in children. Boguniewicz et al reported the results of treatment of treatment of children aged 7 to 17 for 3 weeks with three concentrations of tacrolimus ointments versus vehicle as control (about 40 children per group) in a double-blind placebo controlled trial. There was significantly greater improvement in the tacrolimus treatment groups compared to placebo and no safety concerns over the three week period. Boguniewicz 1998 Reitamo et al. 2002 reported a 21 day comparison between Hydrocortisone and tacrolimus in moderate to severe eczema in children age 2 - 17. They found that the tacrolimus gave better control of the eczema than the hydrocortisone without any side effects. Paller et al. 2001 examined the safety and efficacy of 0.03% and 0.1% tacrolimus ointment for the treatment of atopic dermatitis in a 12-week, randomized, double-blind, vehicle-controlled study of 351 children 2 to 15 years of age with moderate to severe atopic dermatitis. Both tacrolimus ointment concentrations (0.03% and 0.1%) were safe and significantly more effective than vehicle for the treatment of atopic dermatitis in children. Adverse events with a statistically significantly greater incidence in the 0.03% tacrolimus ointment treatment group compared with vehicle were limited to the sensation of skin burning, pruritus, varicella, and vesiculobullous rash ("blisters").
There is a theoretical risk for an increase in skin infections with viruses after tacrolimus treatment since it is a potent immunosuppressive agent. Kang et al 2001 examined this aspect of safety. A total of 255 children, 2 to 15 years of age, with moderate to severe atopic dermatitis applied 0.1% tacrolimus ointment twice daily for up to 12 months to assess long-term safety and efficacy. Patients on average were treated with tacrolimus ointment for 279 days or 87% of study days. Substantial improvements in the signs and symptoms of atopic dermatitis, percent body surface area affected, and the patient's or parent's assessment of pruritus were observed during the first week of treatment and were maintained throughout the study. Transient skin burning and itching were the most common drug application site adverse events. Occurrence of these symptoms decreased after the first few days of treatment. There was no increased incidence of infections or other significant adverse events. Fleischer et al. 2002 reevaluated studies done with topical tacrolimus and found that in a three week treatment period there was no increase in skin infection, bacterial, viral or fungal, in tacrolimus-treated patients versus those treated with the control vehicle. Allen et al. 2001 reported significant absorption of tacrolimus in patients with Netherton's syndrome which is a rare syndrome with generalized skin redness and scaling that presumably allowed increase absorption of the tacrolimus. The three patients had elevated blood levels of the tacrolimus but none showed toxic effects. Lubbe and Saurat 2003 described two cases of eczema herpeticum in patients being treated with topical tacrolimus and suggest that because it is rare, current studies are too small to determine whether the incidence of this herpetic infection of the skin is increased in patients treated with tacrolimus. Fleischer 2003 defended the data and suggested that while "individuals may experience eczema herpeticum while undergoing treatment with topical tacrolimus, the risk does not appear higher with active treatment than with vehicle, and there is no dose-response relationship".
Allen 2002 commented on the role of tacrolimus in the management of atopic dermatitis and concluded "Short- and long-term trials have demonstrated a clear, positive risk-benefit ratio in the treatment of this chronic, relapsing disease that affects the quality of life of many families. The safety profile of tacrolimus ointment has indicated that these patients have not been exposed to any new or significant adverse effects, though as with the introduction of any other novel agent we should remain alert to the possibility that long-term use in large numbers of patients could reveal hazards not identified in the extensive trials to date. Tacrolimus ointment introduces the potential for long-term intermittent monotherapy in the treatment of moderate to severe AD, and its introduction is likely to change the approach that we use to manage the disease. "
PIMECROLIMUS
Ascomycin compounds such as pimecrolimus (Elidel) , which has the same mechanism of action as tacrolimus, have been developed in topical and oral forms. Zuberbier examined the effect of pimecrolimus on T cells, mast cells and basophils in vitro and found they inhibit production of Th1 and Th2 cytokines from T cells and inhibit mediator release from mast cells and basophils. Zuberbier 2001 This topical agent was developed specifically for treatment of inflammatory skin conditions such as atopic dermatitis. Eichenfield et al. found pimecrolimus to be safe and effective in treatment of mild to moderate atopic dermatitis of children and adolescents in a 6 week trial. Eichenfield 2002 Kapp et al. in a 1-year, double-blind controlled study of 251 infants aged 3 to 23 months with AD ( randomized 4:1 to a pimecrolimus-based regimen (n = 204) or a conventional treatment regimen (n = 47)) found the treatment to be effective and safe. Kapp 2002
CONCLUSIONS
Successful management of atopic dermatitis requires a multipronged approach involving skin care, elimination of aggravating factors (allergens and irritants), and anti-inflammatory treatment plus or minus anti-microbial agents.
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