Acute Hypertriglyceridaemia Caused by Tocilizumab in a Patient with Severe COVID-19.

Treatment with tocilizumab (TCZ) to block interleukin-6 (IL-6) signalling is predicted to mitigate cytokine release syndrome (CRS) caused by coronavirus disease 2019 (COVID-19). However, the adverse effects of TCZ on patients with COVID-19 remain unclear. We herein report a patient with COVID-19 treated with TCZ who developed acute hypertriglyceridaemia. Despite favipiravir treatment, acute respiratory distress syndrome developed in a 45-year-old patient with COVID-19; thus, TCZ was initiated. The triglyceride levels greatly increased after TCZ administration. Physicians should consider the negative impact of TCZ on the lipid profile in patients with COVID-19, although COVID-19-induced CRS itself may be an aggravating factor.

Comparison of two screening tests for HIV-Associated Neurocognitive Disorder suspected Japanese patients with respect to cART usage.

In this study, we demonstrated the pervasiveness of HIV-associated neurocognitive disorders (HAND) among a selection of Japanese patients as well as evaluated and compared the Mini Mental State Examination (MMSE) and the International HIV Dementia Scale (IHDS) for use as a screening tool among combination anti-retroviral therapy (cART)-naïve and cART experienced patients. The MMSE and the IHDS have both been used as HAND screening tests around the world with variable success. It has been reported the increased usage of cART the utility of these screening tests may have been diminished due to the decreased severity of impairment and the altered pattern of neurocognitive impairments in cART era HAND patients. It is therefore possible the MMSE and the IHDS may still be useful among cART-naïve patients even in the cART era. However, only one study has investigated and compared the screening results of the IHDS among cART-naïve and cART experienced patients. All HIV positive patients who visited, or were admitted, to the Ryukyu University Hospital between January 2009 and March 2014 were evaluated for inclusion. Selected patients (n = 49) had data without omission for all tests. The overall prevalence of HAND in our cohort was 44%. The area under the curve (AUC), for all subjects using the MMSE and the IHDS, were 0.60 and 0.69, respectively. However, the AUC among cART-naïve patients were 0.58 and 0.76 for the MMSE and the IHDS, respectively. Whereas, cART experienced patients had an AUC of 0.60 and 0.61, respectively. Overall, the MMSE demonstrated a poor screening ability for HAND, regardless of cART usage (the cut-off value of 27 had a Youden's J-Index of 0.1, in all groups). Alternatively, the IHDS was moderately useful for HAND screening among cART-naïve patients (the cut-off value of 11 had a Youden's J-Index of 0.4), but performed poorly as a screening test among cART experienced patients (the cut-off value of 11 had a Youden's J-Index of 0.1).

Evaluation of Anyplex™ II RV16 and RB5 real-time RT-PCR compared to Seeplex® RV15 OneStep ACE and PneumoBacter ACE for the simultaneous detection of upper respiratory pathogens.

This prospective study was performed to evaluate and compare the performance of the multiplex PCR Seeplex® assays and Anyplex™ II assays. From May 2014 until April 2016, a total of 247 respiratory samples were collected in Okinawa, Japan. Multiple respiratory pathogens were detected in 37% of patients with positive results. The most prevalent pathogens were influenza A virus and respiratory syncytial virus B. Despite minor differences in capabilities, both the Seeplex® assays and Anyplex™ II assays can be easily implemented in diagnostic or research laboratories to optimize the detection and management of respiratory pathogen induced diseases.

Etiological analysis and epidemiological comparison among adult CAP and NHCAP patients in Okinawa, Japan.

BACKGROUND: Etiological epidemiology and diagnosis are important issues for CAP and NHCAP. Despite the availability of effective therapies, significant morbidity and mortality ensues. METHODS: We retrospectively analyzed the etiology of 200 pneumonia patients at the University of the Ryukyus Hospital. Patients were categorized into CAP (n = 97) or NHCAP (n = 103), according to the Japanese Respiratory Society guidelines. Diagnoses were made using clinical tests including, Gram stain, bacterial culture, serum and urinary tests. RESULTS: Pathogens were detected in 71% of patients, and identified as the source of infection in 52% (104/200). The majority of patients suffered from Streptococcus pneumoniae (32/200), Haemophilus influenzae (22/200), and Moraxella catarrhalis (16/200). Gram stain guided pathogen-oriented therapy decisions for 38 of 96 patients with unknown pathogens. Atypical pathogens were only diagnosed in CAP patients (n = 5). Severity of pneumonia was related to male sex (p = 0.006), and preexisting conditions, such as chronic heart failure (p < 0.001) and COPD (p < 0.001). Risk factors associated with increased length of stay included chronic heart failure, chronic renal failure, other pulmonary diseases and diabetes. Mortality for NHCAP patients was associated with lung cancer and bronchiectasis. CAP patients were more frequently admitted during winter months, while NHCAP patients were admitted during all other seasons. Seasonal patterns for individual pathogens could not be determined. CONCLUSION: Gram staining remains useful to guiding diagnostics. Pathogens affecting CAP and NHCAP patients were not significantly different; as such, attention should be focused on the management of underlying conditions. Clinical outcomes were not affected by guideline discordant therapy.

The clinical and phylogenetic investigation for a nosocomial outbreak of respiratory syncytial virus infection in an adult hemato-oncology unit.

Although many reports have already shown RSV outbreaks among hemato-oncology patients, genomic studies detecting similar RSV strains prior to an outbreak in the hospital are rare. In 2014, the University of the Ryukyus hospital hemato-oncology unit experienced, and successfully managed, a respiratory syncytial virus (RSV) nosocomial outbreak. During the outbreak investigation, genotyping and phylogenetic analysis was used to identify a potential source for the outbreak. Nasopharyngeal swabs were tested for RSV using three tests: (1) rapid antigen test (RAT); (2) reverse transcriptase polymerase chain reaction (PCR); or (3) quantitative PCR (RT-qPCR); a positive PCR reaction was considered a confirmed case of RSV. Phylogenetic analysis of the G protein was performed for outbreak and reference samples from non-outbreak periods of the same year. In total, 12 confirmed cases were identified, including 8 hemato-oncology patients. Patient samples were collected weekly, until all confirmed RSV cases returned RSV negative test results. Median time of suspected viral shedding was 16 days (n = 5, range: 8-37 days). Sensitivity and specificity of the RAT compared with RT-qPCR were 30% and 91% (n = 42). Phylogenetic analysis revealed nine genetically identical strains; eight occurring during the outbreak time period and one strain was detected 1 month prior. A genetically similar RSV detected 1 month before is considered one potential source of this outbreak. As such, healthcare providers should always enforce standard precautions, especially in the hemato-oncology unit.

An Autopsy Case of Two Distinct, Acquired Drug Resistance Mechanisms in Epidermal Growth Factor Receptor-mutant Lung Adenocarcinoma: Small Cell Carcinoma Transformation and Epidermal Growth Factor Receptor T790M Mutation.

We herein describe the case of a 63-year-old man who died from relapsed epidermal growth factor receptor gene (EGFR) exon 19 deletion lung adenocarcinoma treated with erlotinib. According to the autopsy results, he was confirmed to have small cell carcinoma without the EGFR T790M mutation in his pancreas and left kidney metastatic specimens, while the adenocarcinoma metastatic lesion in his right kidney had the EGFR T790M mutation; both retained the somatic EGFR exon 19 deletion. We herein report an autopsy case of resistance to an EGFR tyrosine kinase inhibitor via small cell carcinoma transformation and the EGFRT790M mutation in separate metastatic organs.

Implementation of bronchoalveolar lavage using a high-flow nasal cannula in five cases of acute respiratory failure.

In recent clinical practice, high-flow nasal cannula (HFNC) therapy has been used to improve oxygenation in adults with acute respiratory failure (ARF). However, bronchoscopy using HFNC in ARF has not yet been reported. Herein, we describe 5 cases of ARF where bronchoalveolar lavage (BAL) was employed successfully using an HFNC. We were able to discontinue or reduce the HFNC fraction of inspired oxygen (FiO2) 30 min after completion of the bronchoscopy. Only 1 patient needed non-invasive positive pressure ventilation for 16 h after bronchoscopy. The HFNC may be a useful tool for ARF patients who require bronchoscopy.

Pure red cell aplasia induced by lamivudine without the influence of zidovudine in a patient infected with human immunodeficiency virus.

We herein report the case of a patient with human immunodeficiency virus infection and acquired immune deficiency syndrome who was diagnosed with drug-induced pure red cell aplasia consequent to lamivudine treatment. The patient was admitted to our hospital for treatment of increasing shortness of breath following physical effort. Upon admission, routine blood tests revealed a hemoglobin level of 7.6 g/dL and a hematocrit proportion of 21.2%, with normal leukocyte and platelet counts. After stopping the lamivudine treatment, the patient's hemoglobin concentration and hematocrit level returned to normal. A bone marrow examination showed an exclusive reduction in erythrocyte formation. This case indicates that lamivudine can induce severe anemia without the influence of zidovudine.

Clinicopathological findings of four cases of pure influenza virus A pneumonia.

OBJECTIVE: The purpose of this study was to perform clinicopathological evaluations of patients with pure influenza A virus pneumonia. METHODS: We performed clinicopathological analyses of four cases of pure influenza A virus pneumonia. Patients Among the four cases, three were caused by the pandemic (H1N1) 2009 virus. Three patients were analyzed during autopsy, and one underwent transbronchial lung biopsy. RESULTS: We suggest that the interval between influenza virus A pneumonia onset and our analysis affected the pathological findings. Diffuse alveolar damage was observed during the acute phase. After ten days, organizing pneumonia and marked proliferation of premature type II alveolar epithelium were observed. Clinically, intra-alveolar hemorrhage was observed in two patients. Pathologically, hyaline membrane formation and intra-alveolar hemorrhage were observed in all cases. CONCLUSION: Severe epithelial damage was determined as the main mechanism of respiratory failure caused by influenza A virus pneumonia.

The prevalence of airway obstruction among Japanese HIV-positive male patients compared with general population; a case-control study of single center analysis.

BACKGROUND AND OBJECTIVE: Previous studies have suggested that human immunodeficiency virus (HIV) infection and/or the airway colonization of Pneumocystis jirovecii (Pcj) impact on the progression of airway obstruction, such as chronic obstructive pulmonary disease (COPD). This study was aimed to evaluate the relationship between HIV infection, airway colonization of Pcj and airway obstruction in Japanese male patients. METHODS: Case-control study of 49 HIV-positive and 257 HIV-negative men were enrolled in this study. Airway obstruction was determined by spirometry. Cigarette smoking was determined by a self report. Laboratory data were obtained from medical records. Among HIV positive patients, the airway colonization of Pcj was evaluated by induced sputum using the real time polymerase chain reaction method. RESULTS: Forty-eight out of 49 (97.9%) HIV-positive patients received antiretroviral therapy, and their median CD4 cell counts were 491/µL (79-935). The prevalence of airway obstruction as determined by spirometry was 10.2% (5/49) in HIV-positive subjects and 2.4% (5/208) in HIV-negative subjects (p = 0.024). Compared with the control group, HIV-positive patients were significantly younger (median age 44 vs 40, p = 0.019). After adjusting for age, pack-years of smoking, HIV infection was an independent risk factor for airway obstruction (OR; 10.93, 95%CI 1.99-60.1, p = 0.006). None of patient was detected the airway colonization of Pcj. CONCLUSIONS: HIV infection was an independent risk factor for airway obstruction regardless of airway colonization of Pcj. Health-care providers should be aware of the increased likelihood of airway obstruction among HIV-positive patients.

Increased expression of HBZ and Foxp3 mRNA in bronchoalveolar lavage cells taken from human T-lymphotropic virus type 1-associated lung disorder patients.

OBJECTIVE: Human T-lymphotropic virus type 1 (HTLV-I) causes adult T-cell leukemia/lymphoma (ATLL), and is associated with chronic inflammatory diseases, including inflammatory pulmonary diseases. HTLV-I bZIP factor (HBZ), which is expressed in all adult T-cell leukemia cells, plays a critical role in the development of lymphoma and systemic inflammation. HTLV-I is harbored by CD4(+) T cells that express forkhead box P3 (Foxp3), and HBZ interacts with Foxp3. This study investigated the chest computed tomography (CT) findings and expression of HBZ and Foxp3 in the bronchoalveolar lavage (BAL) cells from patients with HTLV-I-associated lung disorders. METHODS: CT scans obtained from 37 patients (10 men and 27 women, aged 37-77 years) with HTLV-I-associated lung disorders were retrospectively evaluated. The expression levels of HBZ and Foxp3 mRNA in BAL cells and the levels of inflammatory cytokines in the BAL fluid (BALF) from patients were compared with those in control subjects. RESULTS: CT scans frequently revealed a diffuse panbronchiolitis (DPB)-like pattern, along with a nonspecific interstitial pneumonia (NSIP) pattern. An analysis of the BALF revealed lymphocytosis and increased expression of HBZ mRNA in patients with HTLV-I-associated lung disorders. The expression of Foxp3 mRNA positively correlated with the percentages of lymphocytes present in the BALF. The inflammatory cytokine and IL-10 levels were significantly increased in the BALF from patients with HTLV-I-associated lung disorders. CONCLUSION: The NSIP pattern may be a manifestation of pulmonary involvement in HTLV-I-infected patients, as is the DPB-like pattern. HBZ and Foxp3 likely have a role in the development of lung inflammation.

Fucoidan enhances intestinal barrier function by upregulating the expression of claudin-1.

AIM: To evaluate the protective effects of fucoidan on oxidative stress-induced barrier disruption in human intestinal epithelial cells. METHODS: In Caco-2 cell monolayer models, the disruption of barrier function by oxidative stress is mediated by H2O2. The integrity of polarized Caco-2 cell monolayers was determined by measuring the transepithelial resistance (TER) and permeability was estimated by measuring the paracellular transport of FITC-labeled 4-kDa dextran (FD4). The protective effects of fucoidan on epithelial barrier functions on polarized Caco-2 cell monolayers were evaluated by TER and FD4 flux. The expression of tight junction (TJ) proteins was assessed using reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining. RESULTS: Without H2O2 treatment, fucoidan significantly increased the TER compared to control (P < 0.05), indicating a direct enhancement of intestinal epithelial barrier function. Next, H2O2 disrupted the epithelial barrier function in a time-dependent manner. Fucoidan prevented the H2O2-induced destruction in a dose-dependent manner. Fucoidan significantly decreased H2O2-induced FD4 flux (P < 0.01), indicating the prevention of disruption in paracellular permeability. RT-PCR showed that Caco-2 cells endogenously expressed claudin-1 and -2, and occludin and that H2O2 reduced the mRNA expression of these TJ proteins. Treatment with fucoidan attenuated the reduction in the expressions of claudin-1 and claudin-2 but not occludin. Immunofluorescence staining revealed that the expression of claudin-1 was intact and high on the cell surface. H2O2 disrupted the integrity of claudin-1. Treatment with fucoidan dramatically attenuated the expression of claudin-1. CONCLUSION: Fucoidan enhanced intestinal epithelial barrier function by upregulating the expression of claudin-1. Thus, fucoidan may be an appropriate therapy for the treatment of inflammatory bowel diseases.

Depression of local cell-mediated immunity and histological characteristics of disseminated AIDS-related Mycobacterium avium infection after the initiation of antiretroviral therapy.

OBJECTIVE: The aim of the present study was to examine the immunohistological characteristics of disseminated Mycobacterium avium infection after the initiation of antiretroviral therapy (ART) for acquired immunodeficiency syndrome (AIDS). METHODS: We histologically investigated five autopsied AIDS patients with systemic M. avium infection. RESULTS: The inflammatory cell composition in the affected tissues was assessed using immunohistochemistry. The celiac lymph nodes and intestinal canal were the most commonly involved organs in the AIDS cases. The most common histological feature was unstructured aggregation of histiocytes. Immunohistochemistry revealed depression of CD4(+), CD8(+) and CD57(+) cells in the gut lamina propria and mesenteric lymph nodes. CONCLUSION: These findings suggest that local cell-mediated immunity is depressed in affected tissues and that the primary histological feature is poor organization of granulomas in mycobacterial lesions, despite the administration of adequate ART.

[A case of pleural tuberculoma with new pulmonary infiltration during anti-tuberculosis therapy].

A 61-year-old woman who had received treatment for tuberculous pleurisy for 2 months visited our outpatient clinic. Chest computed tomography (CT) showed the presence of a lens-shaped pleural mass with pulmonary infiltration, despite the decreased pleural effusion. Two weeks later, chest CT showed an increase in the size of the mass and expansion of the intrapulmonary shadow. Percutaneous CT-guided lung biopsy was performed, and histopathological examination revealed granulomatous inflammation without caseous necrosis or acid-fast bacilli. Sputum culture was negative for acid-fast bacilli. Anti-tuberculosis medication was continued, and the lesions eventually resolved. These lesions were diagnosed as pleural tuberculomas, and the intrapulmonary infiltration was considered to be due to the paradoxical worsening of the patient's condition.

Acquired immune-deficiency syndrome with focal onset of Mycobacterium avium infection displaying a histological/genetic pattern of disseminated mycobacteria.

A 66-year-old man with human immunodeficiency virus (HIV) infection was admitted for treatment of Pneumocystis pneumonia. Upon admission, a tumor mass adjacent to the thoracic descending aorta was revealed on computed tomography. Histology revealed an exudative granuloma with histiocytes packed with numerous acid-fast bacilli. Mycobacterium avium was isolated from the tissue. A genetic examination of the isolates demonstrated this strain to be located in the cluster consisting of strains that cause systemic infection. The patient's baseline CD4+ cell count was 9/µL and the HIV-RNA viral load was 43,800 copies/mL. This case suggests the possibility of a localized onset of disseminated M. avium infection.

Diagnosis of intestinal tuberculosis using a monoclonal antibody to Mycobacterium tuberculosis.

AIM: To investigate the utility of immunohistochemical (IHC) staining with an antibody to Mycobacterium tuberculosis (M. tuberculosis) for the diagnosis of intestinal tuberculosis (TB). METHODS: We retrospectively identified 10 patients (4 males and 6 females; mean age = 65.1 ± 13.6 years) with intestinal TB. Clinical characteristics, including age, gender, underlying disease, and symptoms were obtained. Chest radiograph and laboratory tests, including sputum Ziehl-Neelsen (ZN) staining, M. tuberculosis culture, and sputum polymerase chain reaction (PCR) for tubercle bacilli DNA, as well as Tuberculin skin test (TST) and QuantiFERON-TB gold test (QFT), were examined. Colonoscopic records recorded on the basis of Sato's classification were also reviewed, in addition to data from intestinal biopsies examined for histopathological findings, including hematoxylin and eosin staining, and ZN staining, as well as M. tuberculosis culture, and PCR for tubercle bacilli DNA. For the present study, archived formalin-fixed paraffin-embedded (FFPE) intestinal tissue samples were immunohistochemically stained using a commercially available species-specific monoclonal antibody to the 38-kDa antigen of the M. tuberculosis complex. These sections were also stained with the pan-macrophage marker CD68 antibody. RESULTS: From the clinical data, we found that no patients were immunocompromised, and that the main symptoms were diarrhea and weight loss. Three patients displayed active pulmonary TB, six patients (60%) had a positive TST, and 4 patients (40%) had a positive QFT. Colonoscopic findings revealed that all patients had type 1 findings (linear ulcers in a circumferential arrangement or linear ulcers arranged circumferentially with mucosa showing multiple nodules), all of which were located in the right hemicolon and/or terminal ileum. Seven patients (70%) had concomitant healed lesions in the ileocecal area. No acid-fast bacilli were detected with ZN staining of the intestinal tissue samples, and both M. tuberculosis culture and PCR for tubercle bacilli DNA were negative in all samples. The histopathological data revealed that tuberculous granulomas were present in 4 cases (40%). IHC staining in archived FFPE samples with anti-M. tuberculosis monoclonal antibody revealed positive findings in 4 patients (40%); the same patients in which granulomas were detected by hematoxylin and eosin staining. M. tuberculosis antigens were found to be mostly intracellular, granular in pattern, and primarily located in the CD68(+) macrophages of the granulomas. CONCLUSION: IHC staining with a monoclonal antibody to M. tuberculosis may be an efficient and simple diagnostic tool in addition to classic examination methods for the diagnosis of intestinal TB.

Distribution of mycobacterial antigen based on differences of histological characteristics in pulmonary Mycobacterium avium infectious diseases--consideration of the extent of surgical resection from the pathological standpoint.

Quantitative assessment of mycobacterial antigens is very important to determine the surgical indication, as well as the area of resection for pulmonary Mycobacterium avium complex (MAC) infectious disease. However, at present, pathological assessment is only possible as a postoperative examination. We performed quantitative evaluation of mycobacterial antigens using lung tissues with MAC pulmonary infection obtained from surgical resection. The distribution of mycobacterial antigens was evaluated by immunohistochemical staining with monoclonal antibody for mycobacteria. In exudative reactions, many monocyte-lineage cells containing mycobacterial antigens were observed in alveoli, whereas the quantity of mycobacterial antigens was extremely decreased in proliferative reactions. Epithelioid cells or multinucleated giant cells contained mycobacterial antigens in necrotic granulomas. In solitary nodules with central necrosis, mycobacterial antigens were frequently observed, whereas they were rarely observed in solitary nodules without caseous necrosis. Mycobacterial antigens were not observed in the epithelial layer of bronchioles in any cases, although proliferative granulomas were notably observed in the developed lymphoid follicles in subepithelial lesions of bronchiole. Thus, exudative reactions or nodules with caseous necrosis indicate the possibility of numerous mycobacteria remaining in the pulmonary focus. Therefore, intraoperative histological assessment may help in the determination of the area of surgical resection. This is the first study to quantitatively evaluate mycobacterial antigens according to histological characteristics in MAC pulmonary disease.

Role of neuraminidase inhibitor chemoprophylaxis in controlling nosocomial influenza: an observational study.

BACKGROUND: An influenza outbreak might result in disruption of services at acute care setting hospitals. OBJECTIVES: In this study, we retrospectively evaluated the use of neuraminidase inhibitor chemoprophylaxis for prevention of nosocomial spread of influenza in a university hospital. PATIENTS/METHODS: During the 3-year study period, 202 index cases of influenza [30 hospitalized patients and 172 healthcare workers (HCW)] and 762 individuals who had had close contact with the index cases (248 hospitalized patients and 514 HCW) were identified. Of these contacts, 416 received neuraminidase inhibitor chemoprophylaxis. RESULTS: When both the index cases and the close contacts were hospitalized patients, the incidence of influenza was lower among the close contacts who received chemoprophylaxis than among those who did not (odds ratio, 0.07; confidence interval, 0.01-0.49; P = 0·012). In contrast, when the index cases were HCW, the incidence of influenza was not different between close contacts who did or did not receive chemoprophylaxis. CONCLUSIONS: This study suggests that chemoprophylaxis might be useful to prevent nosocomial spread of infection between hospitalized patients.