Hidetoshi Igari

Chronic pulmonary complications associated with toxic epidermal necrolysis: Report of a severe case with anti‐Ro/SS‐A and a review of the published work

Patients with toxic epidermal necrolysis (TEN) have been known to have various complications. Though pulmonary complications are often observed, they usually show an acute form; however, chronic complications are quite rare and little is known about either their incidences or clinical manifestations. We herein report a 33‐year‐old man who presented with chronic pulmonary complications after a recovery from TEN. At the onset of TEN, he had severe respiratory failure and artificial ventilation was instituted. Despite being extubated successfully, respiratory failure reappeared 1 month later. A diagnosis of chronic bronchitis with severe obstructive ventilatory impairment and bronchiectasis was made and he was treated with steroids, bronchodilators and antibiotics, however, he died 1.5 years after the onset of TEN. There have been 13 reported cases of chronic pulmonary complications with TEN or Stevens–Johnson syndrome (SJS) in the English published work. Such cases are usually classified into chronic bronchitis/bronchiolitis with obstructive change (including bronchiolitis obliterans and bronchiolitis obliterans organizing pneumonia), respiratory tract obstruction and bronchiectasis. Approximately 40% of all such patients die while the surviving continue to suffer from these complications because no curative therapy yet exists. As a result, the prognosis seems to be poor. The relationship between TEN and these chronic pulmonary complications remains to be elucidated. Interestingly, our patient was asymptomatically anti‐Ro/SS‐A positive at the onset of TEN. In addition, eccrine gland involvement and an extremely high level of serum salivary amylase were observed at the onset of TEN, furthermore, Sjögren‐like symptoms occurred after recovery from TEN. These findings suggested that the Sjögren‐like autoimmune abnormalities induced by anti‐Ro/SS‐A correlated with the development of chronic pulmonary complications in our patient.

Role of EDRF in pulmonary circulation during sustained hypoxia.

The pulmonary artery pressure (PAP) response to hypoxia is characterized by an initial vasoconstriction followed by vasodilation. Pulmonary vessels can release endothelium-derived relaxing factor (EDRF), which is considered to be nitric oxide (NO), but the role of EDRF in the regulation of normal and hypoxic pulmonary vascular tone is still uncertain. We designed this study to address the in vivo role of EDRF in vasodilation during sustained hypoxia. We studied the effects of an EDRF-synthesis inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), on the pulmonary vascular response to sustained hypoxia (10% O2, 20 min) in normoxic (N) and chronically hypoxic (CH) rats. Biphasic PAP response was observed in N rats, whereas PAP was unchanged in CH rats during sustained hypoxic exposure. The L-NAME-induced PAP increase during normoxia was greater in CH than in N rats, suggesting that basal EDRF plays an important role in attenuating the severity of pulmonary hypertension in CH rats. Administration of L-NAME increased the initial increment in PAP by acute hypoxia and shifted the PAP response upward throughout sustained hypoxia, while still showing the biphasic pattern, in N rats. In contrast, PAP increased acutely and remained elevated with little recovery in the late phase in CH rats. The inducible NO synthase messenger RNA (mRNA) expression and protein showed greater increases in the lungs of CH than in N rats. These results suggest that EDRF release during sustained hypoxia may partly contribute to the roll-off in PAP response during sustained hypoxia in N rats, and that augmented EDRF may prevent a further increase in PAP during chronic hypoxia.

Comparison between concentrations of amphotericin B in infected lung lesion and in uninfected lung tissue in a patient treated with liposomal amphotericin B (AmBisome)

Generally, the primary lesion of a mold infection is in the airway, an extravascular site. Therefore, the antifungal drug concentration at the actual tissue lesion of a mold infection is as important as in the blood compartment. Although our antifungal armamentarium has expanded recently, polyenes are still often needed in clinical practice because of their potent fungicidal activity and the rarity of resistance. Nevertheless, the distribution of amphotericin B (AmB) in infected lung tissue has not yet been evaluated. Using high-performance liquid chromatography analysis, we determined the concentrations of AmB in plasma and infected and uninfected tissues of resected lung simultaneously, in a patient with pulmonary aspergillosis treated with liposomal amphotericin B (L-AmB). The AmB concentration in the infected lesion of the lung was approximately 5.2 times higher than that in plasma and 3.7 times higher than in uninfected lung tissue. L-AmB accumulated in the infected lesion of the lung at a higher concentration. Although our data are from only one patient, they may be useful in helping to develop better strategies for the use of L-AmB against pulmonary fungal infections.

Comparison of specificities between two interferon-gamma release assays in Japan.

We compared the specificities of two interferon-gamma release assays (IGRAs), T-SPOT®.TB (T-SPOT) and the QuantiFERON®-TB Gold In-Tube (QFT-GIT) assay, in strictly selected subjects with a low risk of tuberculosis (TB) infection in a Japanese population. Of 111 subjects who were mostly bacille Calmette-Guérin vaccinated, one was positive using both assays and 110 were negative, using international cut-off values. Although several meta-analyses report that QFT-GIT has higher specificity than T-SPOT, our study demonstrates that the specificity of both assays is equally high in a population with a truly low risk of TB infection.We compared the specificities of two interferon-gamma release assays (IGRAs), T-SPOT®.TB (T-SPOT) and the QuantiFERON®-TB Gold In-Tube (QFT-GIT) assay, in strictly selected subjects with a low risk of tuberculosis (TB) infection in a Japanese population. Of 111 subjects who were mostly bacille Calmette-Guérin vaccinated, one was positive using both assays and 110 were negative, using international cut-off values. Although several meta-analyses report that QFT-GIT has higher specificity than T-SPOT, our study demonstrates that the specificity of both assays is equally high in a population with a truly low risk of TB infection.

Immunogenicity of a monovalent pandemic influenza A H1N1 vaccine in health‐care workers of a university hospital in Japan

A phase III observational study evaluating a single‐dose of an inactivated, split‐virus, unadjuvanted AH1pdm vaccine in HCW was conducted. A safe and effective vaccine was needed after the emergence of AH1pdm in April 2009. We analyzed the immunogenicity and safety of the vaccine. A total of 409 subjects were enrolled and given 15 μg hemagglutinin antigen by s.c. injection. Antibody titers were measured using hemagglutination‐inhibition antibody assays before vaccination and 28 days after. The co‐primary immunogenicity end‐points were the proportion of subjects with antibody titers of 1:40 or more, the proportion of subjects with either seroconversion or a significant increase in antibody titer, and the factor increase in geometric mean titer. We collected 389 pair samples. Antibody titers of 1:40 or more were observed in 148 of 389 subjects (38.0%, 95% CI: 33.2–42.9). The immunogenicity was also confirmed in other end‐points, but was not sufficient and was lower than in previous reports. A total of 96 of adverse events was reported: 51 local events and 57 systemic events. There were 12 subjects with both local and systemic events. Nearly all events were mild to moderate except in four subjects. A single 15‐μg dose of AH1pdm vaccine did not induce sufficient immunogenicity in HCW, with mild‐to‐moderate vaccine‐associated adverse events. We need to consider further improvement of the AH1pdm vaccine program in HCW for the prevention of nosocomial infection, as well as for the benefit of HCW.

Gene Expression Profiling of Polymorphonuclear Leukocytes Treated with the Culture Filtrate of Aspergillus fumigatus and Gliotoxin

Pathogens of the Aspergillus species are frequently seen in deep‐seated mycoses. We previously demonstrated that the culture filtrate of Aspergillus fumigatus (CF) has immunosuppressive effects on polymorphonuclear leukocytes (PMNs), which act as the main phagocytes to hyphae of Aspergillus fumigatus (A. fumigatus). But little is known about the gene expression profiles involved in it. Therefore we investigated the changes in gene expression in human PMNs treated with CF or gliotoxin at two time points, using microarray analysis. CF and gliotoxin changed the expression of 548 and 381 genes, respectively. Only 51 genes showed the same expression patterns with the two stimulants, and CF‐induced changes in gene expression occurred comparatively earlier than those induced by gliotoxin. Among 31 genes encoding apoptosis, which were up‐ or down‐regulated in this assay, only 3 genes were similarly changed by both kinds of stimulation. Apoptosis was detected and quantified using two apoptosis assays. CF and gliotoxin changed the expessions of only 3 out of 19 regulated genes related to inflammatory mediators and receptors similarly. The up‐regulation of the gene encoding annexin 1 (ANXA1), which is known to be involved in extravasation and apoptosis of neutrophils, may play a role in the immunosuppressive effect of A. fumigatus. The difference in expression changes between CF and gliotoxin is presumed to be caused by the interaction among the components of CF and therefore the interaction is an area of interest for further investigation.

Role of carotid body in pressure response of pulmonary circulation in rats.

We investigated how signals arising from peripheral chemoreceptors could affect pulmonary vasculature in rats. Effects of the hypoxic exposure (10%) on mean pulmonary arterial pressure (mPAP), abdominal aortic flow (Q) and the estimated total pulmonary vascular resistance (mPAP/Q) were determined in anesthetized, artificially ventilated, carotid sinus nerve intact or chemodenervated rats. The pressor response of PAP to hypoxia seen in intact rats changed to the depressor response after chemodenervation. Hypoxia elicited a decrease in Q and an increase in mPAP/Q in both intact and chemodenervated rats. Selective carotid body stimulation by the intra-carotid injection of sodium cyanide (NaCN) in normoxia elicited an immediate but transient increase in PAP and Q before and after bilateral vagotomy. The peak change in PAP slightly preceded that in Q. These responses to NaCN were completely abolished by chemodenervation. These results indicate that the immediate chemoreflex contributes to the short-term regulation of pulmonary vasculature in rats.

Immunogenicity of a Monovalent Pandemic Influenza A H1N1 Virus Vaccine with or without Prior Seasonal Influenza Vaccine Administration

ABSTRACT The immunogenicity of pandemic influenza A H1N1 virus (A/H1pdm) vaccine might be modified by prior seasonal trivalent influenza vaccine (sTIV) administration. We conducted a retrospective analysis of immunogenicity of 243 health care workers (number of sTIV-positive [sTIV+] subjects, 216; number of sTIV− subjects, 27) by hemagglutination inhibition. There was no significant difference in the ratios of antibody titers of ≥40 (41.2% versus 48.1%; P = 0.49) and fold increases in geometric mean titer (3.8 versus 4.5; P = 0.37). sTIV injected 7 to 10 days prior to A/H1pdm vaccine administration did not interfere with the immunogenicity of the latter.

Quality control in QuantiFERON-TB gold in-tube for screening latent tuberculosis infection in health care workers

QuantiFERON-TB gold in-tube has been used for screening latent tuberculosis infection in newly employed health care workers in Japan. There have been a few studies concerning quality control. We retrospectively analysed QuantiFERON-TB gold in-tube results in a hospital in Japan. Interferon-γ values in three blood collection tubes for QuantiFERON-TB gold in-tube were analysed in association with the positivity rate. The data set consisted of health care workers aged 20-29 years during the 7 years between 2010 and 2016. The yearly QuantiFERON-TB gold in-tube positivity rate was 0.9%, 16.4%, 3.0%, 39.3%, 2.8%, 0.9% and 1.5%, and was extremely high in 2011 and 2013. The interferon-γ values in the tuberculosis antigen tube were elevated in these two years, as indicated by higher median and wider interquartile range. The interferon-γ value in the negative control tube was also higher in 2011. The higher interferon-γ values in collection tubes (tuberculosis antigen tube and/or negative control tube) resulted in higher QuantiFERON-TB gold in-tube positivity rate. The distribution of interferon-γ in tuberculosis antigen tube and negative control tube, as evaluated by median and interquartile range, proved to be an effective index for the quality control of QuantiFERON-TB gold in-tube.