Wolf's Isotopic Response after Herpes Zoster Infection: A Study of 24 New Cases and Literature Review.

Wolf's isotopic response refers to the occurrence of a new skin disease at the exact site of an unrelated skin disease that had previously healed. Various cutaneous lesions have been described after herpes zoster. This study included 24 patients with Wolf's isotopic response after herpes zoster infection, which presented as manifestations ranging from inflammatory disease to carcinoma. Histopathological examinations in 12 patients and immunohistochemical analyses in 10 patients allowed exploration of secondary microscopic changes in the lesions. CD4+/CD8+ T-cell ratios were normal and infiltrating cells included mast cells, eosinophils, and tumour cells. Our study has described additional patients with confirmed Wolf's isotopic response following herpes zoster infection; moreover, it has extended the spectrum of Wolf's isotopic response to include impetigo. We suggest Wolf's isotopic response classification categories for herpes zoster-associated Wolf's isotopic response. Additionally, clinicians should consider the possibilities of different diseases in Wolf's isotopic response, especially malignancies.

Incremental Contributions of FbaA and Other Impetigo-Associated Surface Proteins to Fitness and Virulence of a Classical Group A Streptococcal Skin Strain.

Group A streptococci (GAS) are highly prevalent human pathogens whose primary ecological niche is the superficial epithelial layers of the throat and/or skin. Many GAS strains with a strong tendency to cause pharyngitis are distinct from strains that tend to cause impetigo; thus, genetic differences between them may confer host tissue-specific virulence. In this study, the FbaA surface protein gene was found to be present in most skin specialist strains but largely absent from a genetically related subset of pharyngitis isolates. In an ΔfbaA mutant constructed in the impetigo strain Alab49, loss of FbaA resulted in a slight but significant decrease in GAS fitness in a humanized mouse model of impetigo; the ΔfbaA mutant also exhibited decreased survival in whole human blood due to phagocytosis. In assays with highly sensitive outcome measures, Alab49ΔfbaA was compared to other isogenic mutants lacking virulence genes known to be disproportionately associated with classical skin strains. FbaA and PAM (i.e., the M53 protein) had additive effects in promoting GAS survival in whole blood. The pilus adhesin tip protein Cpa promoted Alab49 survival in whole blood and appears to fully account for the antiphagocytic effect attributable to pili. The finding that numerous skin strain-associated virulence factors make slight but significant contributions to virulence underscores the incremental contributions to fitness of individual surface protein genes and the multifactorial nature of GAS-host interactions.

Staphylococcus aureus penetrate the interkeratinocyte spaces created by skin-infiltrating neutrophils in a mouse model of impetigo.

BACKGROUND: Impetigo is a bacterial skin disease characterized by intraepidermal neutrophilic pustules. Previous studies have demonstrated that exfoliative toxin producing staphylococci are isolated in the cutaneous lesions of human and canine impetigo. However, the mechanisms of intraepidermal splitting in impetigo remain poorly understood. OBJECTIVE: To determine how staphylococci penetrate the living epidermis and create intraepidermal pustules in vivo using a mouse model of impetigo. METHODS: Three Staphylococcus aureus strains harbouring the etb gene and three et gene negative strains were epicutaneously inoculated onto tape-stripped mouse skin. The skin samples were subjected to time course histopathological and immunofluorescence analyses to detect intraepidermal neutrophils and infiltrating staphylococci. To determine the role of neutrophils on intraepidermal bacterial invasion, cyclophosphamide (CPA) was injected intraperitoneally into the mice to cause leucopenia before the inoculation of etb gene positive strains. RESULTS: In mice inoculated with etb gene positive S. aureus, intraepidermal pustules resembling impetigo were detected as early as 4 h post-inoculation (hpi). Neutrophils in the epidermis were detected from 4 hpi, whereas intraepidermal staphylococci was detected from 6 hpi. The dimensions of the intraepidermal clefts created in mice inoculated with etb gene positive strains at 6 hpi were significantly larger than those in mice inoculated with et gene negative strains. In CPA treated mice, staphylococci or neutrophils were not detected in the deep epidermis until 6 hpi. CONCLUSION: Our findings indicate that intraepidermal neutrophils play an important role in S. aureus invasion into the living epidermis in a mouse model of impetigo.

Selective immunoglobulin M deficiency presenting with recurrent impetigo: a case report and review of the literature.

Selective immunoglobulin M (IgM) deficiency is a rare disorder defined by a decreased serum level of IgM and normal levels of other immunoglobulin classes. The disease has not been well described and the cause remains unknown. Patients with IgM deficiency may present with a wide spectrum of clinical manifestations, from asymptomatic to life-threatening infections, including recurrent respiratory and gastrointestinal infections, allergy and autoimmunity. Here, we report a 6.5-year-old otherwise healthy boy with selective IgM deficiency who presented with multiple recurrent impetigo. We reviewed the published data regarding selective deficiency of IgM.

Human Keratinocytes Use Sphingosine 1-Phosphate and its Receptors to Communicate Staphylococcus aureus Invasion and Activate Host Defense.

Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator generated when a cell membrane or its components are damaged by various factors. S1P regulates diverse cell activities via S1P receptors (S1PRs). Keratinocytes express S1PR1-5. Although it is known that S1PRs control keratinocyte differentiation, apoptosis, and wound healing, S1PR functions in keratinocyte infections have not been fully elucidated. We propose that the S1P-S1PR axis in keratinocytes works as a biosensor for bacterial invasion. Indeed, in human impetigo infection, we found high epidermal expression of S1PR1 and S1PR2 in the skin. Furthermore, in normal human epidermal keratinocytes in vitro, treatment with Staphylococcus aureus bacterial supernatant not only induced S1P production but also increased the transcription of S1PR2, confirming our in vivo observation, as well as increased the levels of TNFA, IL36G, IL6, and IL8 mRNAs. However, direct treatment of normal human epidermal keratinocytes with S1P increased the expressions of IL36G, TNFA, and IL8, but not IL6. In both S1P- and S. aureus bacterial supernatant-treated normal human epidermal keratinocytes, S1PR1 knockdown reduced IL36G, TNFA, and IL8 transcription, and the S1PR2 antagonist JTE013 blocked the secretion of these cytokines. Overall, we have proven that during infections, keratinocytes communicate damage by using S1P release and tight control of S1PR1 and 2.

Anaphylaxis to polyvinylpyrrolidone in povidone-iodine for impetigo contagiosum in a boy with atopic dermatitis.

BACKGROUND: Povidone-iodine (PVP-I) is widely used in antiseptic agents. Immediate allergic reaction to PVP-I preparations is very rare and often overlooked, as it is difficult to diagnose. Polyvinylpyrrolidone (PVP) is thought to play a role in the underlying mechanism. We examined the usefulness of the histamine release test (HRT) for definite diagnosis of PVP allergy. METHOD: A 9-year-old boy with eosinophilia (1,500/microl) and elevated total IgE (1,376 IU/ml) was suspected clinically of having a PVP allergy, as he had anaphylaxis twice when he was administered a PVP-I solution for impetigo contagiosum. Skin prick tests (SPTs) were performed with a PVP-I solution, PVP (K30), gentamicin sulfate and 2 other medicines containing PVP. HRT was assessed using peripheral blood basophils. RESULTS: SPTs to PVP-I solution, PVP-K30 and other medicines were all negative. Histamine release was observed on stimulation by PVP in the presence of autologous serum, although it was not observed in the absence of autologous serum. CONCLUSIONS: This observation was in line with the clinical findings that anaphylaxis had not developed despite the long use of PVP-I solution, but developed only when he received PVP-I solution treatment where basophils could contact PVP-I in the presence of serum, which was probably due to a broken skin and vessel condition. Furthermore, our results suggest the usefulness of HRT in the diagnosis of PVP allergy, and the possibility that negative SPT does not entirely rule out PVP allergy.

Complement in overt and asymptomatic nephritis after skin infection.

In an ongoing study of streptococcal skin infection and acute glomerulonephritis (AGN) begun in 1964, C'3 determinations were done in 784 patients. There were 126 patients with acute poststreptococcal nephritis, 172 of their siblings, and 486 patients with uncomplicated impetigo from families without an index case of nephritis.90% of the patients with nephritis were infected with one of the four prevalent streptococcal serotypes associated with nephritis in this population; only 12% of patients with uncomplicated impetigo were infected with similar serotypes.93% of the patients with overt nephritis had diminished complement levels. Low complement was more often observed (8%) in AGN siblings than was transient hypertension and/or hematuria (5%). Considering the relationship of low C'3 alone and low C'3 preceded hematuria in four others. Two (0.4%) of the patients with uncomplicated impetigo had low complement values, both of whom were infected with nephritogenic strains. Transient hematuria and/or hypertension was less frequently observed (2.7%) among patients with uncomplicated impetigo. Serial determinations in patients with low complement revealed a return to normal in a linear fashion within 2-12 wk. The validity of the hypothesis that the asymptomatic patients with low complement levels, with or without hematuria, likely had subclinical nephritis is strengthened by the accompanying epidemiologic data. The finding of low complement before the onset of, or in the absence of, hematuria or other evidence of nephritis supports the concept that an immunologic mechanism may precipitate the renal injury of acute streptococcal nephritis.

Infection-related glomerulonephritis in a renal allograft.

Infection-related glomerulonephritis (IRGN) is an immune-mediated glomerulo-nephritis, most commonly caused by bacterial infections. Although there is an increased incidence of infectious episodes in renal transplant recipients, IRGN as a cause of de novo glomerulonephritis is rarely seen probably due to impaired immunity. We hereby report a 28-year-old male renal transplant recipient, who developed IRGN following impetigenous skin lesions after six years of transplant. He developed rapid worsening of allograft function and was started on hemodialysis. Allograft renal biopsy showed diffuse exudative endocapillary proliferation with crescents. Electron microscopy revealed large subepithelial hump-like deposits. Despite pulse steroid therapy, he became dialysis dependent. Our patient is unique in the way that poststreptococcal glomerulonephritis in an adult after renal transplantation has not been reported so far. We conclude that IRGN after renal transplant, though rare is a possible etiology for allograft dysfunction. There is no definitive treatment protocol for this de novo glomerulonephritis which has an overall poor prognosis.

Biofilm formation of Staphylococcus aureus strains isolated from impetigo and furuncle: role of fibrinogen and fibrin.

The formation of membranous structure (thickness from the plastic tissue-culture coverslip (hematoxylin-eosin) > 1 mm; periodic acid-Schiff-positive) was more prominent with Staphylococcus aureus (S. aureus) strains isolated from impetigo (coagulase types I.V origin) than with S. aureus strains isolated from furuncle (coagulase type IV origin) (P < 0.05) in the plastic tissue-culture coverslip in human plasma after 72 h. Attachment of S. aureus cells to a plastic tissue-culture coverslip was more marked in 0-3% fibrinogen/tryptic soy broth (TSB) than in plasma (P < 0.05). The formation of the membranous structure was observed on the plastic tissue-culture coverslip with 0.3% fibrinogen/human serum but not with 0.3% fibrinogen + 5% glucose/TSB. Electron microscopy revealed abundant fibrin around S. aureus cells at 4 h and Ruthenium red-positive materials increased at 24 and 72 h in plasma. Staphylococcus aureus cell attachment to the plastic tissue-culture coverslip in plasma decreased by addition of levofloxacin (LVFX) at 1/2 minimum inhibitory concentration (MIC) and clarithromycin (CAM) at 1/4 MIC. Polysaccharide production of S. aureus cells on the plastic tissue-culture coverslip in plasma decreased with the addition of CAM at 1/4 MIC. Fibrinogen is closely related to initiation of infection but biofilm formation requires the conversion of fibrinogen to fibrin. Thus, attachment of S. aureus cells to the plastic tissue-culture coverslip, conversion of fibrinogen to fibrin by coagulase-prothrombin complex, and production of abundant glycocalyx by S. aureus cells are at least required for the production of biofilm in staphylococcal skin infection.

Immunological heterogeneity among the M-associated protein antigens of group-A streptococci.

Different serotypes of group-A streptococci share common antigens that are closely associated with the type-specific determinant of M protein. By the use of selected human sera containing antibody to these M-associated antigens, we have shown that group-A streptococci can be divided into three categories. The majority of the opacity-factor-negative respiratory serotypes possess a shared M-associated antigen or antigens, to which high titres of antibody are common in patients with rheumatic fever, or patients recovering from upper respiratory infections with certain opacity-factor-negative serotypes. The antibody in these sera has a demonstrable but limited affinity for the M-associated antigens of strains belonging to a second category of M types, the majority of which are opacity-factor-positive serotypes of "throat" or "skin" origin. A third group, consisting mainly of opacity-factor-negative pyoderma serotypes, gave variable results and seemed to be intermediate between the other two categories. Complement-fixation-inhibition tests and absorption studies showed a marked degree of cross-reactivity between the M-associated antigens of the three categories.

Bullous impetigo. Occurrence of localized scalded skin syndrome in an adult.

The localized form of staphylococcal scalded skin syndrome, bullous impetigo, occurs commonly in children but rarely in adults. We will describe a case of bullous impetigo in an adult which developed while the patient was receiving short-term therapy with orally administered corticosteriods. Scalded skin syndrome in this case was characterized by isolation of phage group 2 staphylococci from intact bullae and by the presence of an intraepidermal, subgranular cleavage plane in histological sections. Features that differentiate the localized form of scalded skin syndrome from generalized forms include the presence of dermal infiltrate and the absence of cutaneous erythema and tenderness. On the basis of available experimental evidence, the rarity of both localized and generalized scalded skin syndrome in adults can be attributed to immunologic competence or enhanced capacity of adults to metabolize the staphylococcal exfoliatin.

Incidence of circulating immune complexes in patients with acute poststreptococcal glomerulonephritis and in patients with streptococcal impetigo.

In an attempt to further study the possible contribution of circulating immune complexes (CIC) in the pathogenesis of acute poststreptococcal glomerulonephritis, 61 patients with APSGN were studied during the first three weeks of the disease, and 13 patients with noncomplicated streptococcal impetigo as a control group. C1q solid phase ELISA and Conglutinin (K) solid phase ELISA were used to measure the levels of immune complexes. The incidence of CIC in a single serum sample from patients with APSGN was 48%. Elevated levels of immune complexes were found in 46% of the patients with streptococcal impetigo. The absolute levels of CIC were comparable in both groups of patients. No correlation was found among the presence of CIC and the clinical, immunoserological or pathological findings of the disease. Our results do not support the hypothesis that trapping of the circulating immune complexes play an important role on the renal injury poststreptococcal infection. Instead, we suggest that CIC are an epiphenomena present in APSGN, and may represent rather a systemic inflammatory immune response in patients with group A streptococcal infection.

Incidence and studies on antigenic specificities of antineutrophil-cytoplasmic autoantibodies (ANCA) in poststreptococcal glomerulonephritis.

Sera from 210 patients with Acute Poststreptococcal Glomerulonephritis (APSGN) and 14 patients with streptococcal impetigo without glomerular disease were tested for the presence of IgG-ANCA using an indirect immunofluorescence assay (IIF) on ethanol fixed normal human neutrophils. In the group of nephritic patients, ANCA were detected by IIF in 9% (18 out of 210 cases) in an atypical diffuse cytoplasmic pattern (a-ANCA) in 14 cases and in a (p-ANCA) perinuclear staining in the remaining 4 cases. Longitudinal studies performed on six IIF positive patients, showed persistence of the phenomenon for up to six months, without relationship with activity of disease. No patient with streptococcal impetigo showed positivity on the IIF assay. Positive sera were analyzed on ELISA plates for their IgG reactivity against specific purified ANCA antigens: Proteinase-3 (PR3), Myeloperoxidase (MPO). Cathepsin-G and Bactericidal/Permeability Increasing Protein (BPI). Anti-MPO antibodies were present in 4 cases (3 a-ANCA and 1 p-ANCA). No reactivity was identified against PR-3, BPI and Catepsin-G in any of the samples. The presence of ANCA was significantly associated with a more severe glomerular disease as assessed by the serum creatinine and the crescents formation. Further studies are required to identify other antigenic specificities of these autoantibodies. Their absence in the streptococcal impetigo control group might suggest that their presence in APSGN could play some pathogenic role in kidney disease.

Role of some infectious agents in atopic dermatitis.

Certain infections such as Kaposi's herpetic eruption, impetigo, recurrent cutaneous herpes simplex and warts are more frequent in subjects with atopic dermatitis. It is likely that the continuous alterations of the skin are more important than immunological factors in increasing the frequency of some infections in subjects with atopic dermatitis. Moreover, these infections do not seem to affect significantly the clinical course of atopic dermatitis.

Staphylococcal scalded skin syndrome. II. Serum level of anti exfoliatin and anti alpha-toxin in patients with staphylococcal scalded skin syndrome or bullous impetigo.

In order to study the differences between staphylococcal scalded skin syndrome (SSSS) and bullous impetigo, the anti exfoliatin level was assessed in the sera from both groups of patients, and no significant difference in the level was found. However a significant difference was noted in the anti alpha-toxin levels in sera from both group of patients; that of SSSS patients was much lower than that of impetigo patients and of children in a control group. Five out of 6 patients with SSSS showed an unchaged level of anti alpha-toxin at the second examination, while an increased anti exfoliatin level was noted in 4 out of 6 SSSS patients.