Infection contributes to considerable morbidity and mortality in patients treated for autoimmune bullous disorders because of the impaired cutaneous barrier, alteration of the protective normal flora, and host immunosuppression (inherent and iatrogenic). Prevention of cutaneous impetiginization and infection starts with excellent wound care. In patients to be started on immunosuppressive medications, consideration should be given to vaccination status and possible need for pneumocystis pneumonia prevention. Patients should be educated on the signs and symptoms of early infection and the need to seek early medical intervention as needed.
Infection contributes to considerable morbidity and mortality in patients treated for autoimmune bullous disorders. Infection in this population may occur via 3 primary mechanisms. First, when immune-mediated vesicles and bullae rupture, erosions and ulcerations result. Disturbance of the physical, chemical, and biologic barrier provided by the skin (including the keratinocytes with their intercellular scaffolding, acidic lipid secretions of sebaceous glands, antimicrobial peptides, and normal flora) renders hosts increasingly vulnerable to infection. Exudate at eroded cutaneous surfaces nourishes colonizing organisms and potential pathogens. Certain colonizing organisms are capable of forming biofilms, which may contribute to bacterial resistance to topical and systemic antibiotics. Second, most topical or systemic treatments for autoimmune blistering conditions downregulate the immune system, thereby simultaneously compromising the host’s ability to fight infection. Third, the very immune dysregulation associated with autoimmunity may increase susceptibility to infection in some patients. For example, complement deficiency associated with systemic lupus erythematosus predisposes patients to infection with encapsulated organisms (eg, Neisseria meningiditis , Streptococcus pneumoniae ).
For optimal treatment and prevention of morbidity, it is critical to recognize the increased risk for cutaneous and systemic infection among patients treated for immunobullous disease and to take measures to prevent it. This article reviews localized and systemic bacterial, fungal, viral, and mycobacterial infections associated with immunobullous disease and its treatments. Methods to prevent skin colonization and localized and systemic infection in these patients are also discussed.
Infections
Bacterial
Localized
Cutaneous fragility and resultant compromise of the skin barrier associated with autoimmune bullous dermatoses facilitates colonization of the skin (impetiginization) by bacterial organisms, such as Staphylococcus aureus and Staphylococcus epidermidis . Once bacteria counts achieve a critical level (which, for most species, is 10 5 organisms/gram of tissue ), infection and its associated signs (increased localized erythema, tenderness, drainage, edema, and temperature) ensue. Bacterial skin colonization and infection may render the underlying immunobullous disease refractory to treatment by preventing or delaying wound healing ( Figs. 1 and 2 ). A study of 30 patients with bullous pemphigoid and cutaneous infection found that 3 had impetiginization and 2 developed erysipelas. Cutaneous infection is significantly associated with increased risk of death in patients with pemphigus.
Distant or systemic
Skin colonization and infection with bacterial organisms can lead to more serious infection of the underlying bone and soft tissue. Once organisms permeate into the vasculature, life-threatening sepsis may ensue. In patients with pemphigus, sepsis is the most common cause of death, with S aureus being the most frequently implicated organism. In a study of 30 patients with bullous pemphigoid and cutaneous infection, 3 developed necrotizing fasciitis and 1 developed sepsis following lymphangiitis. Previously documented rare systemic bacterial infections in patients treated for immunobullous disease include cutaneous and disseminated nocardiosis ( Fig. 3 ), Listeria meningitis, enterococcal bacteremia, and Chryseobacterium meningosepticum cellulitis and sepsis.
Viral
Localized
Viral colonization and infection may complicate immunobullous disease. Some investigators have presented circumstantial evidence that implies a causal association between herpes simplex virus infections and the development of pemphigus. Although herpes simplex virus superinfection is best described in atopic dermatitis (ie, eczema herpeticum), it also occurs in autoimmune bullous conditions ( Fig. 4 ). In some cases, the presence of herpes simplex virus may be clinically occult. Therefore, practitioners must have a high index of suspicion to evaluate for herpes simplex in patients whose immunobullous disease fails to respond to, or worsen on, systemic immunosuppressive medications. Localized Kaposi sarcoma, a low-grade malignant vascular neoplasm caused by human herpesvirus 8 (HHV-8), has been reported in a patient with pemphigus vulgaris. The area of involvement with KS corresponded exactly to the area treated with intralesional corticosteroids. Although HHV-8 has been detected in the skin biopsy specimens of patients with pemphigus vulgaris and pemphigus foliaceus without clinical evidence of Kaposi sarcoma, the clinical and pathogenetic significance of this finding is uncertain.
Distant or systemic
Herpes zoster (HZ; shingles), caused by reactivation of Varicella zoster virus in a dermatomal distribution, usually occurs in the setting of immunosuppression. The risk for HZ in patients treated with systemic immunosuppressive agents for dermatologic conditions is greater than twice that of age-matched control patients (Lehman and Kalaaji, unpublished data, 2010). Specific risk factors for HZ in this population include: advanced age, female sex, underlying solid organ or hematologic malignancy, prednisone use in doses greater than 15 mg per day, lupus, and dermatomyositis (particularly when associated with underlying malignancy). Multifocal Kaposi sarcoma (HHV-8) has occurred in patients treated for bullous pemphigoid. Patients taking systemic immunosuppressive medications are also at increased risk for reactivation of hepatitis B virus, which may lead to irreversible liver damage.
Fungal
Localized
Superficial cutaneous fungal infections, such as dermatophytosis and candidiasis, may also complicate the course of patients being treated for autoimmune bullous dermatoses ( Fig. 5 ). The concomitant use of topical corticosteroids could render fungal colonization clinically occult, as with tinea incognito. Therefore, clinicians should adopt an increased index of suspicion for this complicating factor. Whether patients with immunobullous disease have higher rates of onychomycosis is unclear.
Distant or systemic
Pneumocystis pneumonia (PCP), a frequently fatal opportunistic infection caused by the unicellular fungus Pneumocystis jiroveci , may occur in patients treated for autoimmune bullous dermatoses. In patients without human immunodeficiency virus infection, mortality from PCP can be high. PCP is known to occur in patients taking immunosuppressive medications for dermatologic conditions. Particular risk factors for PCP include immunosuppression, advanced age, hypoalbuminemia, underlying pulmonary dysfunction, treatment with prednisone in doses greater than 15 mg per day for greater than 8 weeks, or treatment with cyclophosphamide. Uncommonly reported systemic fungal infections occurring in patients with immunobullous disease include necrotizing fasciitis, cellulitis, or disseminated disease caused by Cryptococcus neoformans and pulmonary aspergillosis ( Fig. 6 ).
Mycobacterial
Localized
Immunosuppression is a known permissive factor for mycobacterial infections of the skin and soft tissues. This is shown by a case report of cutaneous infection with Mycobacterium chelonae in a patient with paraneoplastic pemphigus treated with rituximab.
Distant or systemic
Patients receiving systemic immunosuppression are at increased risk for primary infection with or reactivation of latent tuberculosis by the mycobacterium, Mycobacterium tuberculosis . Tuberculosis reactivation in patients with pemphigoid has been reported. Moreover, tuberculosis is a well-described risk in patients taking agents that inhibit tumor necrosis factor-α.
Prevention
Primary Prevention
Primary prevention of infection should be designed to reduce exposure to potentially pathogenic organisms, improve the barrier function of the damaged skin, reduce the density of colonizing organisms, and optimize factors promoting wound healing in the host.
Measures that can reduce exposure to infectious organisms include avoidance of health care settings, crowded environments, or those with recirculated air (eg, airplanes), people known to have active infections, travel to places with endemic disease, and other high-risk behaviors, such as getting tattoos. If foreign travel is necessary, it is advisable for patients to be seen by a travel medical specialist familiar with their underlying condition and immunosuppressive medication regimen. Wearing a respiratory mask in high-risk areas (eg, heavily populated areas, doctor’s waiting room, airplane) may be considered.
The barrier function of the skin is enhanced with vigilant attention to excellent wound care and the minimization of wound colonization ( Box 1 ). In patients with limited mobility or cognitive impairment, the use of a home health nurse or equivalent may be required to assist with personal hygiene regimens and labor-intensive wound dressings. In poorer countries, where infection in the community is a significant risk, patients with autoimmune bullous dermatoses are typically hospitalized for nursing care and dressings. Studies have shown that nursing assistants may also be helpful in identifying early infection in elderly patients.
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Avoid use of alkaline soap or excessive bathing
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Maintain a moist (not overly wet or dry) wound healing environment
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Optimize nutrition and blood glucose levels
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Maintain skin hydration
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Practice regular hand washing/nail cleaning
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Where possible, avoid hospital, group-home settings, or other facilities with high numbers of colonized individuals
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Be educated about early signs and symptoms of infection
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Seek medical interventions early if infection is suspected
Gentle cleansing with water and the sparing use of soaps reduces organism counts and thereby reduces the chance for infection. Alkaline soaps, which increase the cutaneous pH and emulsify cutaneous lipids, are to be avoided. The atopic dermatitis literature supports the use of dilute bleach baths in decreasing S aureus colonization. Moreover, loofah sponges and other fomites making regular contact with the skin should be avoided. When chronic granulation tissue or bacterial biofilms are present, careful manual debridement may be necessary. Wet-to-moist gauze dressings and high-pressure irrigation are reasonable methods for gentle debridement, whereas curettes or a scalpel blade may be used with caution when more extensive debridement is needed. Dressings that maintain an appropriate level of hydration and prevent excessive shearing of the skin should be selected. Silver-containing dressings are nontoxic, have a broad antimicrobial spectrum, and may minimize the development of bacterial resistance.
In patients known to be colonized with methicillin-resistant S aureus , interventions known to be safe and effective include topical mupirocin, chlorhexidine gluconate washes, oral rifampin (with careful attention to potential medication interactions), and doxycycline. Intranasal mupirocin is only marginally effective.
Optimizing other localized and systemic wound healing parameters, such as nutritional status, blood glucose control, lymphedema, and nicotine cessation, is essential. Finding an effective treatment regimen for the underlying immunobullous condition is also important in removing the stimulus for new skin wounds. Patients with autoimmune bullous dermatoses must be educated on signs of infection (eg, fever, increasing skin erythema or drainage) and to seek early medical attention if suspicion for infection exists.
Primary prophylaxis measures for specific infections should be considered in a case-by-case basis. Adult vaccinations for HZ, influenza, and pneumococcal pneumonia are effective methods of disease prevention ( www.cdc.gov ). Vaccination guidelines have been established for immunosuppressed patients ( Table 1 ) but not specifically for patients taking immunosuppressive medications for immunobullous disease. The organ transplantation literature supports delivery of inactivated vaccinations but not live attenuated vaccinations in iatrogenically immunosuppressed patients, with the recognition that immunosuppression may attenuate vaccination efficacy. However, physician lack of familiarity with vaccine protocols in immunocompromised patients can lead to missed opportunities to immunize these patients. Although recent general immunization guidelines have been published, the most up-to-date vaccination information can be found on the Centers for Disease Control Web site ( www.cdc.gov ).
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Rituximab and its Use in Autoimmune Bullous Disorders
Pemphigoid Gestationis: Current Management
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Management of Autoimmune Bullous Diseases in France: A Nationwide Network of 30 Centers
Treatment of Chronic Bullous Disease of Childhood
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