Immune reconstitution is the trigger of herpes zoster with lymphopenia and high neutrophil-to-lymphocyte ratio (NLR) in a retrospective cohort study.

BACKGROUND: Herpes zoster (HZ) rarely results in later death, but predictive biomarkers for mortality necessitates further elucidation. OBJECTIVE: To investigate immune dynamics prior to HZ event, risk factors for HZ onset, and immune status at initial HZ. METHODS: This retrospective study extracted the absolute neutrophil and lymphocyte counts (ANC and ALC, respectively) at the initial HZ date and up to 30 days before HZ. A follow-up survey was completed within 180 days of the onset of illness. RESULTS: Patients with HZ showed higher neutrophil-to-lymphocyte ratio (NLR) and lower ALC than the control at the initial date and had poorer prognosis. In the pre-onset examination, the maximum and minimum ALC values were significantly lower in patients with HZ than in the control, and the maximum ALC value in patients with HZ was lower than the minimum value in the control. The lowest ALC value was observed 7 days before the onset of HZ. An NLR value of 4.53 or more and ALC value of 0.64 × 109 cells/L or less were predictive markers of HZ development within 30 days. Patients who died after HZ had lower minimum ALC than those who survived longer. LIMITATIONS: The study had small population size, varying age distribution, and retrospective nature. The pre-onset data might have been exaggerated. CONCLUSION: HZ develops in a state of immune reconstitution with immunocompromised conditions, as part of the unmasking immune reconstitution inflammatory syndrome (IRIS). Lymphopenia prior to HZ onset is one of the most crucial factors in its pathogenesis and vital prognosis.

Sweat Protects against Contact Hypersensitivity: Transient Sweat Suppression Compromises Skin Barrier Function in Mice.

Although subtle barrier defects may facilitate allergen penetration, thereby enabling allergic sensitization, the relationship between sweating disturbance and skin barrier function is unknown. However, many studies on contact hypersensitivity in mice examined ear skin, which does not sweat, instead of the footpad, where sweating is uniquely present. In this study, we assessed whether sweat suppression in the footpad before hapten application provoked a skin barrier abnormality and reduced inflammatory thresholds to topical haptens. Mice without any genetic skin barrier dysfunction displayed markedly reduced inflammatory thresholds to haptens under transient sweat suppression before hapten application. Epicutaneously applied haptens penetrated the skin more robustly in the presence of sweat suppression compared with that in its absence, although this increase was abolished by exposure to high-humidity conditions. These mice displayed a subtle atopic dermatitis-like inflammation mediated by type 2 response-dominant inflammation and increased IgE responses, mimicking some events occurring in nonlesional atopic dermatitis skin in humans and in murine models. These lesions were dramatically attenuated by exposure to high-humidity conditions. In our model, hapten sensitization does not require mechanical injury, explaining why sensitization occurs through nonlesional atopic dermatitis skin. Awareness of the importance of preserving sweating responses is essential to prevent occupational contact dermatitis and atopic dermatitis.

Efficacy and safety of intravenous fosphenytoin for patients with acute herpes zoster-associated pain: A placebo-controlled randomized trial.

Acute zoster-associated pain develops in most patients with herpes zoster. Nonopioid analgesics are usually used to treat acute zoster-associated pain but are frequently ineffective. We administered intravenous fosphenytoin, the prodrug of phenytoin, to patients with acute zoster-associated pain to examine its analgesic efficacy and safety. At 13 medical institutions in Japan, we conducted a phase II, double-blind, placebo-controlled, randomized trial of intravenous fosphenytoin in Japanese inpatients with acute zoster-associated pain for whom nonopioid analgesics had shown an insufficient analgesic effect. The patients were randomly assigned (1:1:1) to receive a single intravenous dose of fosphenytoin at 18 mg/kg (high dose), a single intravenous dose of fosphenytoin at 12 mg/kg (low dose), or placebo. The primary endpoint was the mean change per hour (slope) in the numerical rating scale score from the baseline score until 120 min after dosing. Seventeen patients were randomly assigned to the low-dose fosphenytoin group (n = 6, median age 62.5 years, range 39-75 years), high-dose fosphenytoin group (n = 5, median age 69.0 years, range 22-75 years), and placebo group (n = 5, median age 52.0 years, range 38-72 years). One patient was excluded because of investigational drug dilution failure. This study was discontinued because of the influences of coronavirus disease 2019. The slope was significantly lower in the high- and low-dose fosphenytoin groups than in the placebo group (P < 0.001 and P = 0.016, respectively). Responsiveness to intravenous fosphenytoin (≥2-point reduction in the numerical rating scale score from baseline to 120 min after dosing) was inferred at plasma total phenytoin concentrations of 10-15 µg/mL. Treatment-emergent adverse events caused no safety concerns in the clinical setting and intravenous fosphenytoin was well tolerated. Intravenous fosphenytoin appears to be an effective and promising alternative treatment for acute zoster-associated pain. Trial Registration: ClinicalTrials.gov NCT04139330.

A Case of Mucopolysaccharidosis II Caused by a Novel Variant with Skin Linear Hyperpigmented Streaks along Blaschko's Lines.

We report a case of an eight-year-old boy with mucopolysaccharidosis (MPS) II with atypical skin lesions of hyperpigmented streaks along Blaschko's lines. This case presented with mild symptoms of MPS such as hepatosplenomegaly, joint stiffness, and quite mild bone deformity, which was the reason for the delay in diagnosis until the age of seven years. However, he showed an intellectual disability that did not meet the diagnostic criteria for an attenuated form of MPS II. Iduronate 2-sulfatase activity was reduced. Clinical exome sequencing of DNA from peripheral blood revealed a novel pathogenic missense variant (NM_000202.8(IDS_v001):c.703C>A, p.(Pro235Thr)) in the IDS gene, which was confirmed in the mother with a heterozygous state. His brownish skin lesions differed from the Mongolian blue spots or "pebbling" of the skin that are observed in MPS II.

Herpes simplex virus-induced murine dry skin model through sweating disturbance.

BACKGROUND: Given that ocular glands become infected secondarily to herpes simplex virus 1 (HSV-1) keratitis, resulting in the loss of tear production, sweat glands may also be susceptible to HSV-1 infection, resulting in sweating disturbance, which is observed frequently in atopic dermatitis. However, due to the lack of sweat glands on the hairy skin of mice, the role of sweating in the maintenance of skin hydration has not been elucidated. OBJECTIVE: To determine the relationship between HSV-1 infection of sweat glands and sweating disturbance-induced dry skin. METHODS: By using the impression mold technique, we examined the sweating response together with the detection of HSV-1 DNA in the sweat glands of footpads, the only area with sweat glands in mice, after local cutaneous HSV-1 inoculation of immunocompetent mice. RESULTS: The sweating response and skin surface hydration were significantly decreased at 7-14 days post-infection. Sweating disturbance and dry skin was markedly enhanced when HSV-1 inoculation was followed by hyperthermic stress. Both resolved spontaneously and became resistant to a second HSV-1 inoculation, associated with increased anti-HSV-IgG antibodies. HSV-1 DNA was detected in sweat glands and dorsal root ganglia. The sweating response remained decreased after subcutaneous injection with pilocarpine, correlating histologically with marked dilatation of sweat gland lumens. These findings indicate that sweating disturbance is unlikely to be the outcome of nerve damage by HSV-1 infection. CONCLUSION: Sweating disturbance could be due to HSV-induced dysfunction of sweat glands. We developed a sweating disturbance-induced dry skin mouse model by infection with HSV-1.

Anti-Cytomegalovirus Therapy: Whether and When to Initiate, Those Are the Questions.

Cytomegalovirus (CMV) reactivation in patients with autoimmune bullous disease (AIBD) or severe drug eruption treated with immunosuppressive therapy was traditionally thought to be merely an epiphenomenon of the underlying immunosuppression. However, a detailed review of the clinical course of these patients revealed that CMV reactivation occurs upon rapid immune recovery, which is termed immune reconstitution inflammatory syndrome (IRIS), and that the timely initiation of anti-CMV therapy, when combined with maintenance doses of immunosuppressive agents, contributes to a rapid resolution of severe infectious complications thought to be refractory to conventional immunosuppressive therapies and unrelated to CMV reactivation. Thus, CMV reactivation resulting in fatal outcomes (CMV-IRIS) can be prevented by the timely detection of CMV DNA or antigens in the blood and by rapidly starting anti-CMV therapy while maintaining immunosuppressive therapy. Anti-CMV therapy is highly recommended for patients with CMV-IRIS or severe drug eruption who have risk factors for CMV reactivation resulting in fatal outcomes.

Clinical features of dipeptidyl peptidase-4 inhibitor-associated bullous pemphigoid in Japan: A nationwide retrospective observational study.

Many cases of bullous pemphigoid (BP) have been reported in patients taking dipeptidyl peptidase-4 inhibitors (DPP-4i), which are the most widely used antidiabetic drug for type 2 diabetes mellitus. However, no large-scale survey has been conducted in Japan. This retrospective study investigated the incidence, clinical presentation, and clinical course of DPP-4i-associated BP (DPP-4i-BP) using epidemiological data from a nationwide registry for BP. In 2016, 713 new BP patients at 94 dermatological institutes were registered, 243 (34.1%) with DPP-4i-BP and 461 (64.7%) with non-DPP-4i-BP. The male-to-female ratio was 1.9 and 0.84, respectively. Patients with DPP-4i-BP were predominantly male. Non-inflammatory BP was more common in DPP-4i-BP (33.3%) than in non-DPP-4i-BP (14.6%), while inflammatory BP was common in both. No specific subtype or difference in disease severity was evident in DPP-4i-BP. The most common gliptins administered to DPP-4i-BP patients were vildagliptin (37.2%) and linagliptin (23.8%). DPP-4i intake was discontinued in 79.9% of cases after diagnosis. Some DPP-4i-BP patients (17.6%) achieved spontaneous remission after discontinuing DPP-4i without requiring the use of systemic corticosteroids and/or adjuvant therapy. Mean duration to achieve disease control was 2.87 months. The odds ratio for non-inflammatory BP requiring systemic corticosteroids and/or adjuvant therapy was low (0.52), suggesting that remission was achieved easily with supportive care in that phenotype. Non-inflammatory and mild cases of DPP-4i-BP may resolve spontaneously with supportive care, including the discontinuation of DPP-4i and no oral corticosteroid therapy.

Herpes zoster in lung cancer patients treated with PD-1/PD-L1 inhibitors.

Background: Herpes zoster (HZ) occurs mostly in elderly and immunocompromised individuals. Immune reconstitution may be associated with the pathogenesis of HZ. As immune checkpoint inhibitor (ICI) treatment amplifies the immune response, use of ICI may increase the incidence of HZ. There have been few studies of HZ in lung cancer patients treated with ICI. This study was performed to investigate the frequency of HZ in lung cancer patients who received ICI or cytotoxic chemotherapeutic agents. Methods: We searched the electronic medical records for lung cancer patients receiving anticancer drug therapy at our hospital, who developed HZ between April 2011 and June 2020. Results: The review identified 80 patients with a history of ICI treatment (ICI group) and 356 who had been treated with cytotoxic chemotherapeutic agents alone (non-ICI group). Among the 20 patients who developed HZ, 4 (5.0%) belonged to the ICI group and 16 (4.5%) to the non-ICI group (P=0.782). After exclusion of patients aged 65 years and older, to avoid effects of advanced age on the results, the ICI and non-ICI groups consisted of 24 and 81 patients, respectively. In total, 3 of the 24 patients (12.5%) in the ICI group and 1 of the 81 (1.2%) patients in the non-ICI group developed HZ (P=0.0365). Conclusions: There was no significant difference in the rate of HZ between lung cancer patients treated with ICI and those treated with cytotoxic chemotherapy alone. However, patients younger than 65 years treated with ICI might be at increased risk of HZ. Because this is a retrospective small study, further prospective observational studies are needed.

Role of pro-inflammatory cytokines in the pathophysiology of herpes simplex virus superinfection in Darier's disease.

Darier's disease (DD) and Hailey-Hailey disease (HHD), belonging to a hereditary acantholytic dermatosis caused by mutations in ATP2A2 and ATP2C1, respectively, are easily affected by eczema herpeticum (EH) induced by mostly herpes simplex virus (HSV) superinfection. However, the mechanisms by which those patients with DD or HHD are susceptible to HSV are not well elucidated. Here, we experienced two cases with DD, including three episodes of the exacerbation of DD after the development of severe EH. We serially measured serum cytokines before and after the development of EH and DD in these patients. Furthermore, we analyzed the effect of pro-inflammatory cytokines on the mRNA expression of ATP2A2 and ATP2C1, and HSV growth. The timing of EH onset in these patients was coincident with the increase in serum interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels. Moreover, the exacerbation of DD occurred in the non-lesional skin of EH after EH remission (mean 24 days, ranging 15-30 days after EH onset). IL-6 and TNF-α enhanced HSV-1 growth, and ATP2A2 and ATP2C1 mRNA levels were downregulated by IL-6 stimulation in cultured differentiated keratinocytes. Increased pro-inflammatory cytokines IL-6 and TNF-α lead to development of severe EH lesions via accentuation of HSV growth. IL-6 acts as an exacerbating factor of DD and HHD by downregulating the expression of responsible genes.

Varicella Zoster Virus-Associated Meningitis as a Rebound Varicella Zoster Disease after Antiviral Discontinuation.

Varicella zoster virus (VZV)-associated meningitis is usually progressive and can be fatal, and early diagnosis and aggressive treatment with intravenous antivirals such as acyclovir (ACV) are required in immunocompromised patients. Patients receiving corticosteroids and immunosuppressive therapy have a significantly higher risk of VZV-associated meningitis. In this report, we describe an unusual case of herpes zoster (HZ) in a young woman who was first diagnosed during tapering of prednisone for dermatomyositis. The skin lesions affected the left L2 and L3 dermatomes, which is unusual in VZV-associated meningitis. Despite showing a good rapid response to antivirals, she developed VZV-associated meningitis immediately after discontinuation of ACV. This phenomenon is often called rebound VZV reactivation disease and occurs after discontinuation of antivirals. This case was notable in that the affected dermatomes were distant from the cranial nerves. Thus, progression of HZ to VZV reactivation-associated meningitis can occur even in appropriately treated HZ patients. Continuation of antivirals beyond 1 week in patients on immunosuppressive therapy may be associated with a decreased risk of severe rebound VZV disease, such as VZV-associated meningitis.

Detection of multinucleated giant cells in differentiated keratinocytes with herpes simplex virus and varicella zoster virus infections by modified Tzanck smear method.

Herpes simplex virus (HSV) and varicella zoster virus (VZV) infections induce the formation of intraepidermal vesicles containing acantholytic cells and multinucleated giant cells in the skin. The Tzanck smear is most commonly used to diagnose cutaneous herpetic infections, but it leads to many false-positive and -negative results. This study aimed at establishing a method detecting much larger multinucleated giant cells using the Tzanck smear because these cells characterize the viral cytopathic effect in skin infections. Morphological changes were analyzed among several layers of keratinocytes with HSV- or VZV-related cutaneous lesions, clinically and in vitro. We compared the sensitivity of the Tzanck smear to detect large acantholytic cells using both the removed roof tissue part (our approach) and the floor of the lesion (conventional approach) of a fresh vesicle. Large acantholytic cells were detected 2.0-times more frequently in the removed roof tissue part of the vesicle than in the floor of the lesion. Round cells were much larger in the removed roof tissue part of the vesicle corresponding to the granular or prickle layer of the epidermis than in its floor of the lesion corresponding to the basal or prickle layer with the Tzanck smear. Differentiated cultured keratinocytes formed multinucleated giant cells by cell-to-cell fusion with resolution of cell membrane with VZV infection. Differentiated keratinocytes promote multinucleated giant cell formation by cell-to-cell fusion with HSV-1 or VZV infection. To increase the sensitivity, the Tzanck smear should be prepared from the removed roof tissue part of a fresh vesicle to detect multinucleated giant cells in herpetic infections.

Severe oral stomatitis due to reactivation of herpes simplex virus type 1 in a methotrexate-treated patient with dermatomyositis.

We herein report a case of a 79-year-old Japanese woman who developed severe oral stomatitis during methotrexate (MTX) treatment for dermatomyositis. She had been treated with MTX (12 mg/week) and prednisolone (5 mg/day) for dermatomyositis for 4 years. She developed painful stomatitis, fever, and pancytopenia. Initially, her symptoms were suspected to be caused by mucosal toxicity of MTX. Therefore, the drug was discontinued, and leucovorin was administered. However, oral stomatitis worsened in a few days, resulting in intolerance of oral ingestion due to severe pain. Polymerase chain reaction revealed the presence of herpes simplex virus type 1 (HSV-1) in oral erosive lesions, and blood examination was positive and negative for anti-HSV IgG and anti-HSV IgM, respectively. Therefore, HSV-1 reactivation-induced oral stomatitis was diagnosed, and acyclovir treatment was started, which promptly improved oral stomatitis. HSV-1 reactivation is usually asymptomatic or results in localized vesicular lesions at the mucocutaneous junction of the lips in immunocompetent individuals. Our case illustrates that HSV-1 reactivation induces severe stomatitis in patients treated with low-dose MTX for autoimmune diseases, not just in those with severe immunosuppressive conditions. Of note, HSV-1 reactivation-induced stomatitis is a diagnostic challenge, especially during MTX treatment.

Hypercalcemia Associated with Extramammary Paget's Disease.

Hypercalcemia of malignancy occurs in up to one third of patients at some point during the course of their advanced stage. The majority of them is caused by humoral hypercalcemia of malignancy due to systemic secretion of parathyroid hormone-related protein (PTHrP) by tumor cells. Extramammary Paget's disease is a slow-growing cutaneous malignancy commonly limited to the epidermis of the anogenital region, but rarely becomes invasive and metastatic to distant sites. Herein, we report a 70-year-old male patient with metastatic extramammary Paget's disease. He consulted our hospital with altered consciousness and tumor in his genital area. Physical examination revealed erythematous plaque with a tumor on the scrotum and perineum. It was diagnosed as extramammary Paget's disease (multiple liver metastases and multiple lymph node metastases by skin biopsy and image examination). Increases in serum-corrected calcium and PTHrP-intact levels (15.3 mg/dL and 66.1 pg/L, respectively) were confirmed. PTHrP immunohistochemistry showed positive staining in the tumor cells. We diagnosed humoral hypercalcemia of malignancy. We treated hypercalcemia with saline, furosemide, zoledronic acid, and elcatonin. Regarding the local control of the tumor, 30 Gy/10 Fr electron beam therapy was performed. However, treatment with zoledronic acid was only temporally effective to correct hypercalcemia, and an increased serum calcium level developed again. Concurrently, the liver metastases were rapidly enlarged, and his general condition gradually deteriorated. The patient died on day 55. When patients with extramammary Paget's disease show unconsciousness, serum calcium level should be measured and PTHrP-producing tumor distinguished.

The aim of the measurement of Epstein-Barr virus DNA in hydroa vacciniforme and hypersensitivity to mosquito bites.

Epstein-Barr virus (EBV) DNA load in the blood increases in posttransplant lymphoproliferative disorders and chronic active EBV infection. In this report, we analyzed the EBV DNA load in the peripheral blood mononuclear cells (PBMCs) and plasma of patients with hydroa vacciniforme (HV) and/or hypersensitivity to mosquito bites (HMB) to understand the clinical significance of EBV DNA load. All 30 patients showed high DNA loads in the PBMCs over the cut-off level. Of 16 plasma samples, extremely high in two samples obtained from patients with hemophagocytic lymphohistiocytosis (HLH). The amount of cell-free DNA in plasma was correlated to the serum levels of lactate dehydrogenase and inversely correlated to platelet counts. These results indicate that the EBV DNA load in PBMCs can provide one of the diagnostic indicators for HV and HMB and marked elevation of cell-free EBV DNA in plasma might be related to cytolysis such as that observed in HLH.

Hydroa vacciniforme: a distinctive form of Epstein-Barr virus-associated T-cell lymphoproliferative disorders.

Hydroa vacciniforme (HV) is a cutaneous subset of Epstein-Barr virus (EBV)-associated T/NK lymphoproliferative disorders (LPDs). Our previous case series study clearly showed a clinical spectrum of EBV-associated T/NK LPDs including HV, hypersensitivity to mosquito bites (HMB), chronic active EBV infection (CAEBV), and hemophagocytic lymphohistiocytosis (HLH). Patients with HV are divided into two groups: a benign subtype designated "classic HV" (cHV) and more serious systemic HV (sHV), also called "HV-like LPD" in the 2017 World Health Organization (WHO) classification. Patients with cHV usually have an increased number of EBV-infected γδT cells and patients with sHV without HMB are further classified into two groups: γδT-cell- and αßT-cell-dominant types. Patients with HMB, with or without HV-like eruptions, have an increased number of EBV-infected NK cells in the blood. Patients with cHV and γδT-cell-dominant sHV show a favourable prognosis, but the other subtypes such as αßT-cell-dominant sHV and HMB have a poor prognosis with mortality rates of 11.5 and 3.51 per 100 person-years, respectively. In addition to the clinical subtypes and the dominant lymphocyte subsets, the poor prognostic indicators include onset age over nine years and expression of the reactivation marker, BZLF1 mRNA. No prognostic correlation has been reported for anti-EBV antibody titres or EBV DNA load. The clinical subtypes and their prognostic factors should be considered for therapeutic interventions.

Cell-to-cell transmission of HSV-1 in differentiated keratinocytes promotes multinucleated giant cell formation.

BACKGROUND: Herpes simplex virus (HSV) infection in the skin causes small grouped vesicles characterized by acantholytic cells and multinucleated giant cells (MGCs). Although viral factors have been studied as fusion proteins, little is known how the differentiation status of keratinocytes is involved in the formation of MGCs by HSV-1 infection. OBJECTIVE: As the human epidermis is composed of several layers of keratinocytes that undergo terminal differentiation, we aimed to elucidate whether the differentiation status of keratinocytes affects viral entry, propagation, cell-to-cell transmission of HSV-1, and MGC formation. METHODS: HaCaT cells and normal human epidermal keratinocytes were cultured in either low- or high-Ca2+ medium. After HSV-1 infection, cellular morphology, viral propagation, and expression of cytoskeletal and intercellular adhesion molecules were examined sequentially. Viral entry, replication, and expression of HSV receptors were analyzed. Cell-to-cell transmission and fusion after HSV-1 infection was evaluated using the Cell Tracker™ Red CMTPX dye system. RESULTS: Keratinocytes in high-Ca2+ medium formed MGCs, but those in low-Ca2+ medium formed single nuclear round cells in response to HSV-1 infection. HSV-1 entered the keratinocytes more effectively in low-Ca2+ than in high-Ca2+ medium, although transcripts of HSV receptors were comparable in both conditions. HSV-1 could replicate more efficiently in high-Ca2+ than in low-Ca2+ medium. A cell-to-cell fusion assay showed that HSV-1-infected and adjacent-uninfected keratinocytes were involved in MGCs in high-Ca2+ but not in low-Ca2+ medium. CONCLUSION: Differentiated keratinocytes promote MGC formation by cell-to-cell fusion with resolution of cell membrane and cell-to-cell transmission of HSV-1 from infected keratinocytes to neighboring uninfected keratinocytes.