Atopic dermatitis (AD) is a chronic and intermittent skin inflammation associated with allergic reaction and often accompanied by elevated total serum IgE levels. Patients have a low threshold for pruritis and develop characteristic skin changes of eczema in response to rubbing or scratching. Both genetic background and environmental factors influence the incidence of this disorder. Recently, the number of affected patients has been increasing, especially in Japan.
AD is associated with a number of ocular complications. Atopic keratoconjunctivitis is one of the most common sequelae, and diffuse edema and papillary reaction of the upper and lower palpebral conjunctivae are observed in patients complaining of typical symptoms of itching and tearing. In severe cases, shield ulcer and epithelial plaque will occur as corneal complications, resulting in corneal scarring with permanent visual impairment.
Atopic cataracts are also a well-known complication of AD, usually involving the anterior subcapsular area. Hence, patients complain of photophobia and visual disturbance, especially in the daytime. Surgical treatment is necessary in some advanced cases.
Keratoconus has a higher incidence in persons with atopic disease. A defect in collagen synthesis may be important in the development of keratoconus, but eye rubbing in persons with atopy may also contribute to this condition. The relationship of eye rubbing to cataract has also been debated.
Rhegmatogenous retinal detachment is one of the most severe complications of AD. Characteristically, retinal breaks around the ora serrata are the cause of retinal detachment, and surgical intervention is mandatory.
Aside from these well-known complications, AD is closely related to the influence of microorganisms. The representative microorganisms are Staphylococcus aureus and herpes simplex virus (HSV). The microorganisms cause various ocular complications and require ophthalmologists to manage and treat AD patients on the basis of a knowledge of these relations. For instance, surgical therapy for cataract or retinal detachment in atopic patients must be carefully undertaken, given the higher risk of ocular infections.
In this chapter, the relation between AD and representative microorganisms, the characteristics of ocular infections in atopic patients, and the management and treatment of these complications are reviewed.
Our experience with serious ocular infection in an atopic patient is presented here as a representative case. A 17-year-old man with active AD suffered from cataract as well as retinal detachment in his right eye. He had already undergone cataract extraction in his left eye.
On December 12, 1996, both cataract and buckling surgeries were performed, with no intraoperative complications. On the next day, intravenous cefmenoxime and ofloxacin were administered as a matter of routine. Anterior chamber inflammation was mild, intraocular lens position was good, and the retina was attached. However, on the second postoperative day, the patient complained of eye pain and decreased vision, and slit-lamp examination disclosed severe anterior chamber inflammation with fibrin and hypopyon. This condition was diagnosed as typical postoperative endophthalmitis. We switched the patient's antibiotic to imipenem and obtained samples from the aqueous humor, eyelid skin, and eye discharge for bacterial culture. Because hypopyon increased during that evening (Fig 1A), amikacin and vancomycin were intravitreally injected.
This intervention worked well in this case and, gradually, anterior chamber inflammation ceased. From collected samples, methicillin resistant S. aureus (MRSA) was isolated, although MRSA could not be detected in the aqueous humor. Nonetheless, the overall findings indicated a diagnosis of MRSA endophthalmitis.
Twenty-five days postoperatively, increased anterior chamber cells, vitreous opacity, and eye discharge were noted. We suspected buckle infection and removed the scleral buckle the next day. Pus was detected around the buckle, where gram-positive cocci were found. After the removal of the buckle and subconjunctival injection of amikacin and vancomycin, the patient's clinical course was satisfactory, and ultimately he achieved 20/20 vision. This case is considered a rare combination of buckle infection and endophthalmitis.
MRSA Infections and AD
Because we had observed occasional cases of buckle infection we retrospectively investigated the rate of buckle infections after scleral buckling procedures for retinal detachment. In 287 operations conducted over 2 years, 32 patients suffered from AD, and buckle infection occurred in 7 patients. Amazingly, all 7 cases were caused by MRSA and, more astoundingly, 6 of these 7 cases involved patients with AD. 1
We have also observed scattered cases of MRSA keratitis in keratoconus patients with AD (see Fig 1B). Moreover, a case of unusual bilateral MRSA blepharoconjunctivitis with severe erosion of eyelid skin was seen (see Fig 1C). This blepharoconjunctivitis was unresponsive to cephems, fluoroquinolones, and aminoglycosides, and finally responded to sulfamethoxazole-trimethoprim.
These cases were presumed to be related to the affinity between S. aureus and AD (later discussed in detail), and the use of antibiotics including cephems killed methicillin sensitive S. aureus but induced MRSA, which caused refractory ocular infections.
Bacterial Flora of the Conjunctiva and Eyelids in Atopic Patients
These experiences with MRSA cases prompted us to investigate bacterial flora of the eyelids and conjunctiva in atopic patients. 2 We swabbed the conjunctival sacs and eyelid margins of 36 AD patients to culture aerobic and anaerobic bacteria. Then we compared the results with those in an age matched control group.
As shown in the table, many kinds of gram positive cocci were detected, S. aureus being found most frequently. Although we were anxious about the detection of MRSA, most isolates were methicillin-sensitive. Only one patient harbored MRSA in both the conjunctival sac and eyelid margin, and one more patient had MRSA in the eyelid margin. A few anaerobic bacteria also were found. In control subjects, few bacteria were isolated. Overall, significantly higher detection rates of bacteria, especially S. aureus, were noted in the AD patient group.
We also studied the relation between the bacterial detection rate and the grade of atopy or ocular complications. As indices of atopy, the grade of conjunctival papillae, conjunctival follicles, dermatitis in the facial area, and serum IgE level were evaluated. Also ocular complications of cataract, retinal detachment, and keratoconus were considered. Neither indices of atopy nor ocular complications were significantly linked to bacterial detection rates.
Owing to the high rate of bacterial colonization, especially with S. aureus, in the conjunctivae and eyelid margins, practitioners must be alert to possible postoperative endophthalmitis and buckle infection in AD patients. Preoperative isolation of bacteria from the conjunctival sac and eyelid margin, antimicrobial sensitivity testing, and prophylactic use of antibiotics are important. Also, to circumvent intraoperative contamination, the creases of surrounding skin must be thoroughly disinfected with povidone-iodine, 1.25% povidone-iodine eye drops must be instilled, and the operative field must be carefully draped in these patients.
We now use a povidone-iodine drape in cases of AD. Such a drape helps to eradicate bacteria. In addition, the prominent stickiness of this drape can prevent its detachment from irregular atopic skin intraoperatively.
Relation of S. aureus and Atopic Skin
In the field of dermatology, it is reported that S. epidermidis is detected with a high frequency from the skin of healthy persons and that S. aureus is detected very frequently from the skin of AD patients. This difference is believed to be due in part to bacterial interference between S. epidermidis and S. aureus. S. aureus is harbored on the skin of only 5% to 10% of healthy persons, and its localization is confined mainly to the vestibulum nasi, axilla, perineum, and interdigital spaces of the feet. However, this organism colonizes in 40% to 90% of AD patients, and it is found even on normal-appearing skin. 3–6 The organism is believed to be transformed from the fingernails, because AD patients usually complain of severe itching and more than 90% of the phagotypes of S. aureus derived from the skin are identical to those from the fingernails. The high rate colonization of S. aureus in atopic skin is believed to be attributable to a shortage of free fatty acids on the skin surface; easy adherence of S. aureus to corneocytes 7; ubiquitous scars by scratching and exudation; and disturbance in the function of the immune system, especially the imbalance of cytokine production from T cells, with enhanced interleukin-4 (IL-4) and diminished interferon-γ (IFN-γ). 8,9
Actually, S. aureus promotes a vicious cycle, including injury of the fragile, dry skin, colonization of bacteria, itching, scratching, infection, and more extensive destruction of the skin barrier. Toxins and proteases produced by S. aureus and the direct invasion of leukocytes to the skin further promote skin damage. The exacerbation of AD is induced when the density of S. aureus is greater than 10 6 /cm 2 at which point antibacterial therapy is indicated. 10
Many researchers have investigated the influence of S. aureus on skin condition in AD. The superantigens produced by S. aureus, such as staphylococcal enterotoxins A (SEA), B (SEB), C (SEC), and D (SED) and toxic shock syndrome toxin 1, are thought to play significant roles. Lin and colleagues 11 demonstrated that the presence of IgE antibodies to SEA and SEB is correlated with the severity of skin lesions in children with AD. Also, in adult patients with AD, skin condition was significantly worse in the patients sensitized to SEB than in unsensitized patients. Serum eosinophil cationic protein and urine eosinophil protein X levels were found to be significantly higher in SEB-sensitized patients, confirming the higher degree of cutaneous inflammation. 12 Zollner and coworkers 13 reported that superantigen production by S. aureus was positively correlated with T-cell activation (as measured by HLA-DR and CD69 expression) and expression of the T-cell skin homing phenotype, cutaneous lymphocyte-associated antigen. Bunikowski and associates 14 showed that the patients colonized with superantigen-producing S. aureus exhibited shifts in the intradermal T-cell receptor Vβ repertoire (Vβ12 and Vβ17) that correspond to the respective superantigen-responsive T-cell subsets.
It has been reported that other factors, especially cell wall components of S. aureus, are related to the condition of atopic skin. For instance, lipoteichoic acid and peptidoglycan induce IL-5 production in human peripheral blood mononuclear cells from patients with AD. 15 Lipoteichoic acid also can release histamine in vitro from basophils of AD patients due to an IgE-dependent mechanism. 16
The role of S. aureus colonization of the eyelid margins in allergic conjunctivitis in atopic patients has also been studied. However, neither the pattern of toxin production nor humoral or cell-mediated immunity to S. aureus were shown to play a role in the expression of chronic allergic conjunctivitis. 17
Herpes Simplex Virus
We first present, as a characteristic case, this report of serious bilateral herpetic keratitis in an atopic patients. A 37-year-old man had suffered from AD for 15 years. However, for the last 2 years his skin condition had been relatively fine and required no treatment. Then, on January 21, 1999, painful eruptions developed on his right palm. By January 25, the eruptions had spread to his entire body. A vesicular pustular rash with erosions and crusted lesions was distributed over the face (Fig 2A). Dermatological professionals diagnosed Kaposi's varicelliform eruption (KVE) and referred the patient to the author's practice. Slit-lamp examination revealed pustles and erosions on both eyelids, bilateral conjunctival hyperemia, and multiple dendritic forms of corneal epithelial edema (see Fig 2B). Despite a minimal epithelial defect and fluorescein staining, we made a diagnosis of herpetic epithelial keratitis on the basis of the form of the lesions and the dermatological diagnosis. We assumed these lesions to be an early stage of dendritic keratitis. To confirm this assumption, bilateral corneal epithelial scrapings were obtained for viral culture. Later, isolated pathogens were identified as HSV type 1. Systemic acyclovir (ACV) and ACV ointment were prescribed and, 7 days later, both KVE and bilateral herpetic keratitis had subsided.
Kaposi's Varicelliform Eruption
Eczema herpeticum, or KVE, is a generalized vesicular eruption first described in 1887 by Kaposi. KVE occurs due to superinfection of eczematous skin with HSV. It is an uncommon disseminated HSV infection and a potentially serious and life-threatening complication, especially in children, usually occurring in individuals with AD or other conditions that disrupt the epidermal barrier. There is general agreement that patients with AD are more susceptible to cutaneous viral infection than is the general population. KVE is usually caused by primary or recurrent HSV type 1 infection, although HSV type 2 may also be a causative agent. Sometimes the disease is combined with fever, malaise, and regional lymphadenopathy. In contrast to S. aureus HSV does not colonize the skin of atopic patients but, when present, is always related to infection.
There is no satisfactory explanation for the association between AD and severe HSV infections. However defects in cell-mediated immunity have been suspected, which are discussed in detail later in this chapter. Recently, tacrolimus—a macrolide immunosuppressive agent that modulates helper T-cell responses by the phosphatase calcineurin, resulting in decreased transcription of several cytokine genes implicated in cell-mediated immunity—has drawn many dermatologists' attention as a highly effective drug for AD. However, the occurrence of KVE has also been reported during treatment with tacrolimus ointment. 18
Factors other than immunity have been addressed as the cause of HSV spread in atopic skin. Amatsu and Yoshida 19 have reported the detection of HSV DNA on both hands and cutaneous surfaces clinically free of eczema herpeticum in KVE patients and suggested that HSV may be spread indirectly via manual scratching of herpetic lesions or via a contaminated bath towel or item of underwear. In addition, Goodyear and colleagues 20 demonstrated that HSV replicates more easily on explanted eczematous skin than on normal skin in vitro.
Herpetic keratitis is also seen in combination with KVE, as shown in the case cited earlier. Although ocular exposure to HSV may commonly occur in KVE, it has been reported that the occurrence of herpetic keratitis is not very common. 21 For instance, Bork and Bräuninger 22 reported only 5 cases of herpetic keratitis among 63 patients with 75 episodes of KVE, despite of 100% facial involvement. Margolis and Ostler 23 recommend the combined use of systemic ACV and topical trifluridine once herpetic keratitis occurs with KVE.
In some AD patients, KVE in the facial area resembles herpes zoster ophthalmicus and is called zosteriform simplex. In these cases, the detection of viral DNA by polymerase chain reaction from tear samples is useful for the differential diagnosis of herpes zoster and herpes simplex. Clinically, facial eruptions with no neuralgia are suspicious for HSV rather than herpes zoster. However the definitive diagnosis will be obtained from the polymerase chain reaction results. 24
Herpetic Keratitis in AD Patients
Individuals with atopic diseases are particularly susceptible to ocular herpetic diseases, irrespective of the presence of KVE. In this section, the characteristics of herpetic keratitis in AD patients are reviewed as they differ in several respects from the features of herpetic keratitis in the general population.
Several reports have mentioned that herpetic keratitis in patients with AD is commonly bilateral and mainly epithelial and that frequent recurrences and slow epithelial healing despite antiviral therapy lead, finally, to stromal scarring. 25,26 Conversely it has been reported that 40% of bilateral cases of herpetic keratitis also involved AD. 27 The possibility of secondary microbial keratitis must be considered in herpetic keratitis in atopic patients, because of the colonization of bacteria in atopic skin.
In some AD patients, the occurrence of atopic keratoconjunctivitis and herpetic keratitis are noted alternately or simultaneously. For instance, in the case depicted in Figure 3, prominent edema and scarring of the upper palpebral conjunctiva are observed and, occasionally, recurrent ulcers occurred on both eyes. Geographical keratitis (see Fig 3A) in his right eye responded well to ACV treatment. Shield ulcer (see Fig 3B) in his left eye was cured with steroid eye drops. However, diagnosing this ulcer in his right eye, observed on another occasion (see Fig 3C), was very difficult: Whether this is a viral ulcer or an allergy-related one was uncertain. HSV was not detected in this condition, and 1 week of ACV treatment had worsened the ulcer. Therefore, betamethasone eye drops and soft contact lens wear were used as a new regimen. The epithelial defect had healed gradually and finally subsided, with some scarring. In this patient, the conditions must be diagnosed differentially, and antiviral drugs must be used to address the viral keratitis while steroid and a soft contact lens are used to shield ulcer associated atopic keratoconjunctivitis.
There has been a report of ACV-resistant herpetic keratitis in an AD patient. 28 An ACV-resistant strain was isolated from ACV-unresponsive herpetic keratitis in a patient with long-standing AD. This strain has a mutation on the adenosine triphosphatase–binding site of thymidine kinase (TK), a critical binding site of purine and pyrimidine analogs to this enzyme and so the determinant of ACV resistance.
These TK-aberrant, ACV resistant strains are easily produced in vitro. However, clinically these TK-aberrant strains grow poorly and usually are eradicated by normal immune responses against HSV. In immunocompromised hosts, such as patients with the acquired immunodeficiency syndrome, these weak viruses can grow easily. Actually ACV-resistant HSV strains have been most frequently isolated from patients with this syndrome. It is highly possible that the HSV-susceptible nature of AD provides the background of establishing TK-aberrant, ACV-resistant strains, which usually replicate poorly in the general population. Therefore, the emergence of ACV-resistant HSV strains must be sought in AD patients.
Immunological Abnormality and Growth of Microorganisms in AD
Overall Immunological Impairment in AD Patients
It is known that AD is associated with a number of functional abnormalities of the immune system, 29 including subnormal T-cell numbers, imbalance of T-cell subpopulations, poor response to certain T-cell mitogens, cutaneous anergy and decreased susceptibility to contact sensitization, decreased monocyte and granulocyte chemotaxis, and impaired antibody-dependent cellular cytotoxicity. In infantile atopy, a transient deficiency of IgA on the surface of the skin has been reported. 30 Secretory IgA is the main protective mechanism responsible for mucous membranes, and its deficiency in infancy is believed to be associated with the uninhibited entry of allergens and consequent overstimulation of a normally responsive IgE system, which leads also to impaired immunity to microorganisms. Likewise, it has been reported that secretory IgA secretion in the tears of AD patients was significantly lower than that in normal subjects. 31
Such other factors as impaired IL-1 production, reduced number of natural killer cells, and reduced γ δT cells have been reported in association with AD. Epidermal cells and monocytes of AD patients produce significantly less IL-1 than do similar cells of healthy controls. 32 In vitro lymphoproliferation in response to stimulation with concanavalin A is significantly decreased and natural killer cells (CD16 + 56) are reduced as compared with nonatopic control subjects. 33 In addition, AD patients yield a significantly lower proportion of T-cell receptor–γ δ+ cells as compared with normal controls. 34
Abnormal Immunological Responses Against Certain Pathogens in AD Patients
The colonization of S. aureus in atopic skin is a well-known fact. However, the studies demonstrating impaired immunity to bacteria in AD patients are not as many. Jahreis and coworkers 35 demonstrated that a subgroup of patients with AD, synthesizing low levels of IFN-γ after stimulation with staphylococcal antigens, may have impaired abilities to clear S. aureus colonization. The imbalance of cytokine production from T cells, with enhanced IL-4 and diminished IFN-γ production, is presumed to enhance the growth of S. aureus.8,9
Vestey and associates 36 have reported absent cell-mediated immunity to HSV in peripheral blood mononuclear cells of 3 patients with severe AD. However, a positive cell-mediated immune response was produced by in vitro removal of CD8+ T lymphocytes from peripheral blood mononuclear cells. The dominance of Th2 cells as compared with Th1 cells also likely contributes to AD patients' susceptibility to HSV. However, there is no general agreement on this matter. Because investigations in human subjects are limited, the animal model is desirable for understanding the mechanism of HSV infection in AD patients.
Animal Model of AD
Recently, one promoting mouse model for human AD was discovered by Matsuda and colleagues. 39 This model is an inbred strain, NC/Nga, originally established by Kondo in Nagoya University in 1957. NC/Nga mice spontaneously suffer severe dermatitis in the presence of nonspecified allergens in conventional environment, whereas skin lesions are not expressed when the mice are kept isolated from specific pathogens. NC/Nga mice in a conventional environment show symptoms such as itching, erythema, hemorrhage, edema, crusting, drying, excoriation, erosion, and hyperplasia in the face, neck, and back. Moreover, NC/Nga mice display some characteristic features diagnosed by histopathological examination, such as macrophage and eosinophil invasion in the dermis and increased and activated mast cells and lymphocytes. In these mice, overproduction of IgE and Th2-specific chemokines (thymus-and activation-regulated chemokine; macrophage-derived chemokine) is remarkable. 38 These features suggest that this strain of mouse is a good candidate model for human AD from the clinical, pathological, and immunological points of view. Recently, a major locus responsible for AD-like skin lesions in NC/Nga mice was located on chromosome 9. 39
As a preliminary study, we infected these mice with HSV via the cornea on specific pathogen free (SPF) condition and under conventional nonsterile conditions. In mice infected under conventional conditions, the HSV titer was 1 or 2 logs higher in eyelids and eyes in the early phase of infection as compared to the titer in mice under SPF condition.
Other Microorganisms and AD
Viral warts and molluscum contagiosum are common in AD patients. A case of epibulbar conjunctival nodules from molluscum contagiosum in a patient with AD has been reported. 40
Pityrosporum orbiculare (Malassezia furfur) is a spherical lipophilic yeast that is usually among the normal cutaneous microflora. This saprophyte also becomes the cause of pityriasis versicolor in certain situations, such as the application of fatty lotions, the increase of temperature or humidity, and impaired cell-mediated immunity. In AD patients, frequent use of emollients and immunological imbalance facilitate the growth of Pityrosporum, which is abundant on the face, neck, and chest region. 10 Once sensitization occurs, it leads to flare-up of the eczema as an erythematous scaling with itching. The relation between P. orbiculare and ocular complications in AD patients is not known.
In summary, the susceptibility of AD patients to infection, especially with S. aureus and HSV, causes many problems in the diagnosis and treatment of ocular complications associated with AD. Because of colonization of S. aureus in the skin, eyelid margins, and conjunctivae, practitioners must be aware of possible postoperative endophthalmitis and buckle infections in AD patients. Preoperative bacterial isolation from conjunctival sacs and eyelid margins and circumvention of intraoperative contamination by various means, including careful draping, are imperative in these patients.
Several features distinguish herpetic keratitis in atopic patients. First, bilateral epithelial keratitis is more common in these people than in the general population. Second, herpetic keratitis with KVE and zosteriform simplex occasionally occur. Third, differential diagnosis of viral ulcer and atopic keratoconjunctivitis–related shield ulcer is important but sometimes difficult. Finally, the possible emergence of an ACV resistant strain must suspected and sought. A better understanding of the characteristics of infectious agents (e.g., drug resistance) and the nature of immune mechanisms of atopic patients will help us to control avoidable complications in AD patients and understand the basis of ocular infections.
This work was supported in part by a grant-in-aid for scientific research by the Ministry of Education, Science and Culture, Japan, No. 12470365, and a grant from Osaka Eye Bank, Osaka, Japan.
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