Takenobu Yamamoto

Sunflower seed allergy is uncommon, and reports of severe systemic reactions, such as anaphylaxis, are limited, particularly in Japan where sunflower seeds are not routinely consumed. A 38‐year‐old woman developed throat discomfort, dyspnea, and generalized urticaria within minutes of ingesting cookies containing sunflower seeds and was diagnosed with anaphylaxis. Her medical history included bronchial asthma and pollinosis caused by Japanese cedar and cypress. Skin prick testing (SPT) showed a strong positive (4+) reaction to sunflower seeds, while the results were negative for mugwort, cashew nut, and macadamia nut. Basophil activation testing (BAT) demonstrated marked upregulation of CD203c expression on basophils in response to sunflower seed extract, with an activation rate of 50.6% at 10 μg/mL, whereas the positive and negative controls showed activation of 34.5% and 1.8%, respectively. Serum analysis in immunoblotting revealed immunoglobulin E (IgE) binding to both the precursor and mature forms of 2S albumin, as well as to a novel 60 kDa antigen in sunflower seed and pollen extracts. Long‐term exposure to sunflower seeds during childhood and adolescence while keeping birds may suggest sensitization via inhalation or skin contact rather than through oral ingestion or cross‐reactivity with related pollens. 2S albumins are seed storage proteins found in high concentrations in several nuts and seeds and are major allergens capable of causing severe systemic reactions due to their resistance to heat processing and digestive enzymes. For the diagnosis and severity assessment of sunflower seed allergy, immunoblotting to detect IgE reactivity to 2S albumin is essential in addition to SPT and BAT. Detection of IgE antibodies against antigens of identical molecular weight in both sunflower seeds and pollen indicates the presence of shared antigens, suggesting that caution is necessary not only for sunflower seed ingestion but also for exposure to pollen.

Panton‐Valentine leukocidin (PVL) is a toxin generally produced by community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA) that is cytotoxic to neutrophils. USA300 is a virulent epidemic PVL‐producing MRSA clone; it is increasing. Recently, ΨUSA300, a deleted mutant of USA300, has been identified in Japan. However, reports on the clinical and epidemiological characteristics of PVL‐producing MRSA strains, including USA300 and ΨUSA300, remain limited. We included 65 patients who visited our dermatology clinic between January 2020 and May 2024 with skin and soft tissue infections in which CA‐MRSA was detected. Clinical information, antimicrobial susceptibility, PVL production, and MRSA strains were analyzed.PVL, found in 70.8% of patients with CA‐MRSA infection, was more common in younger patients (median age: 34 years) without underlying diseases and was more likely to present with deep‐seated pyoderma (DSP), relapse of clinical symptoms, and intra‐familial outbreaks, with a sepsis‐related complication rate of 4.3%. Patients with PVL‐nonproducing MRSA were anemic and had renal dysfunction. USA300 accounted for 54.3% of the PVL‐producing CA‐MRSA, and 32.0% of USA300 strains were the ΨUSA300 variant. All PVL‐producing CA‐MRSA strains were susceptible to rifampicin and minocycline, whereas most remained susceptible to sulfamethoxazole trimethoprim and fosfomycin. All USA300 strains, including ΨUSA300 strains, were susceptible to gentamicin, whereas 44.4% of PVL‐producing non‐USA300 strains were susceptible.PVL‐producing CA‐MRSA infections commonly present with clinical manifestations of DSP, relapse of clinical symptoms, and intra‐familial outbreaks in younger individuals without underlying diseases and, rarely, with sepsis‐related complications. The increased incidence of USA300 and ΨUSA300 strains in Japan, without differences in age, sex, clinical characteristics, clinical recurrence, intra‐familial outbreaks, and susceptibility to antibiotics, raises concerns regarding the possibility of the global spread of these infections. Given the susceptibility of these strains to gentamicin, nasal application of gentamicin may be a potential strategy to prevent intra‐familial outbreaks and the recurrence of USA300 strains, including ΨUSA300.

The concept of immune reconstitution inflammatory syndrome (IRIS) has recently been applied to patients with non‐HIV infection with immune fluctuations. However, quantitative criteria to diagnose non‐HIV IRIS have not been established. Similarly, immune‐related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) are also caused by immune fluctuations. No study has directly compared the immunological indicators of non‐HIV IRIS and irAEs. Thus, we investigated whether irAEs can be included in non‐HIV IRIS. We aimed to search for diagnostic biomarkers for non‐HIV IRIS and to compare the immunopathogenesis of non‐HIV IRIS and irAEs based on immunological indicators. We selected drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) and dipeptidyl peptidase‐4 inhibitor‐associated bullous pemphigoid (DPP4i‐BP) as underlying diseases of non‐HIV IRIS. Blood cell counts, cytokines or chemokines, and herpesvirus‐derived DNA in saliva were quantified and compared between IRIS/irAE‐positive and ‐negative as well as non‐HIV IRIS and irAEs groups. The DPP4i‐BP group had a shorter incubation time to IRIS onset than the DIHS/DRESS group; the irAE group had a longer incubation time than the DIHS/DRESS group. A higher neutrophil‐to‐lymphocyte ratio and serum interferon gamma inducible protein 10 levels could be potential biomarkers of IRIS and irAEs onset; however, no useful cut‐off values for diagnosis were indicated. Meanwhile, the transition of regulatory T cells (Tregs) from the baseline to the onset of IRIS or irAEs differed between IRIS in DIHS/DRESS and irAEs. Only the DIHS/DRESS group showed an increase of Epstein‐Bar virus (EBV) ( p < 0.0001) and human herpesvirus 6 ( p < 0.05) positivity in saliva at the onset of IRIS compared to that at baseline. Although non‐HIV IRIS and irAEs have a small number of common immunological indicators, the dynamics of Tregs, cytokines, or chemokines and positivity of herpesvirus‐derived DNA in saliva differ, suggesting that non‐HIV IRIS and irAEs should remain as separate entities.

Deep‐seated dermatomycosis is a rare disease that is often caused by trauma and/or systemic immunodeficiency. We describe a case of chromoblastomycosis complicated by hyalohyphomycosis that occurred simultaneously at different sites. A 92‐year‐old Japanese man who had been taking oral prednisolone for an IgG4‐related respiratory disease visited our clinic. He developed brownish plaques with grayish‐white scales with pseudo‐carcinomatous hyperplasia and numerous brownish muriform cells developing in the dermis of his right hand, and multiple painful abscesses with pustules and papules and numerous hyphae within and around the histiocytes in the dermis of his right lower leg. Upon skin tissue culture and DNA sequencing, Exophiala xenobiotica and Scedosporium apiospermum were detected separately. He had severe cellular immunodeficiency indicated by low levels in the phytohemagglutinin (PHA)‐stimulated lymphocyte transformation test (LTT) and serum interferon‐gamma (IFN‐γ), although his humoral immunity was normal. The patient died of bacterial pneumonia, despite antifungal drug treatment for 2 months. IFN‐γ producing type 1 T helper (Th1) cells play an important role in the defense against fungal infections, however, corticosteroids specifically suppress Th1 cell responses and promote the induction of fungal infection. Measurement of PHA‐stimulated LTT and serum IFN‐γ may be useful in determining the severity and prognosis of deep‐seated dermatomycosis in patients undergoing corticosteroid treatment.

Amenamevir is an oral once‐daily antiherpesvirus drug that can be administered without dose adjustment in patients with impaired renal function. There are currently no clinical data on immunocompromised patients with herpes zoster treated with amenamevir. Therefore, an exploratory study of the efficacy and safety of amenamevir against herpes zoster in patients with immunosuppression was conducted. Inclusion criteria included patients with acute herpes zoster receiving immunosuppressive drugs or those with malignant tumors or autoimmune diseases. Twenty‐four patients were included and received amenamevir (400 mg once daily after meals) for up to 14 days. The primary end point of overall improvement in skin symptoms 7 days after treatment initiation (day 7) was 58.3% for “markedly improved” and 20.8% for “improved.” The combined improvement rate was 79.2% (95% confidence interval, 57.8–92.9), and 20.8% of patients experienced “worsened” symptoms. The secondary end points of overall improvement in skin symptoms on day 14 and day 28 were 95.7% and 100%, respectively. The skin symptoms progressed during treatment, peaking on day 7, and then began to heal. By Kaplan–Meier estimation, the median periods to complete crusting and healing were both day 14. There were five adverse events with a possible causal relationship to amenamevir (bacterial skin infection, anemia, hyponatremia, headache, and abnormal liver function) in one of the 24 patients. Although the bacterial skin infection was severe, all events in this patient were reported to be either recovered or recovering. These findings indicate that amenamevir can be effective and safe in immunocompromised patients with herpes zoster. However, as worsening can happen around day 7, it is necessary to carefully monitor such patients and switch to other therapies such as intravenous acyclovir if necessary.Clinical trial identifier: Japan Registry of Clinical Trials jRCTs031190208.

Herpes zoster (HZ) rarely results in later death, but predictive biomarkers for mortality necessitates further elucidation. To investigate immune dynamics prior to HZ event, risk factors for HZ onset, and immune status at initial HZ. 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. 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. The study had small population size, varying age distribution, and retrospective nature. The pre-onset data might have been exaggerated. 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.

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 mu g/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.

Background: The prognosis of dipeptidyl peptidase‐4 inhibitor‐associated bullous pemphigoid (DPP‐4i‐BP) is variable, with some cases showing spontaneous remission after drug cessation and others showing worsening BP or developing infectious complications, termed infectious immune reconstitution inflammatory syndrome (IRIS), after DPP‐4i cessation. We recently demonstrated that the neutrophil‐to‐lymphocyte ratio measured at baseline and during treatment predicts the eventual development of infectious IRIS.Objectives: To identify key molecular immune parameters that correlate with, and potentially shape, subsequent immune responses after DPP‐4i cessation.Methods: This retrospective observational study examined DPP‐4i‐BP patients who were treated at our hospital for 4 years. Patients selected for this study were those who developed BP after initiation of DPP‐4i and were followed up at least 90 days after DPP‐4i cessation, if information and the relevant parameters were available from the medical records. The patients were divided into two cohorts: a spontaneous remission group and an exacerbation group showing worsening BP or developing infectious IRIS. Serum cytokine/chemokine levels were determined using a multiplex biometric immunoassay.Results: Serum levels of eotaxin and interferon (IFN)‐α/γ before DPP‐4i cessation were significantly higher in the remission group (161.6 [standard error 21.9] pg/mL and 14.4 [4.8]/9.2 [4.6] pg/mL, respectively) than in the exacerbation group (51.1 [standard error 9.8] pg/mL and 1.6 [1.6]/1.0 [0.5] pg/mL, respectively, p < 0.005). Importantly, regarding changes in cytokine/chemokine levels before and after cessation of DPP‐4i, increasing levels of IFN‐α/γ, interleukin‐10, and interleukin‐1RA following drug cessation were associated with the subsequent development of infectious IRIS.Conclusions: As observed in patients with coronavirus disease 2019, if the production of IFN‐α/γ and eotaxin occurs early and intense enough before DPP‐4i cessation, virus reactivation as a manifestation of infectious IRIS can be prevented. If not, exuberant virus‐related inflammatory reactions would ensue, as observed in a cytokine storm.