Evaluation of Line Immunoassay to Detect HTLV-1 Infection in an Endemic Area, Southwestern Japan; Comparison with Polymerase Chain Reaction and Western Blot.

BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) has been recognized as a cause of adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis, and HTLV-1-associated uveitis. HTLV-1 infection is normally detected by screening for HTLV-1 antibodies, and positive samples are confirmed by Western blot (WB). However, WB fails to confirm some samples that were positive for HTLV-1 antibodies on screening. Line immunoassay (LIA) is commonly used in Europe and Brazil, but not in Japan. Therefore, we evaluated the performance of LIA as a method of confirming HTLV-1 antibodies using samples in Japan. METHODS: LIA was compared with polymerase chain reaction (PCR) and WB using 50 negative and 70 positive samples tested by chemiluminescent enzyme immunoassay (CLEIA) in Miyazaki, Japan, an HTLV-1 endemic area. LIA (INNO-LIA HTLVI/II Score) and WB (Problot HTLV-I) were performed according to the manufacturer's instructions. Real-time PCR for HTLV-1 pX region was performed using DNA derived from white blood cells. The samples that tested negative by real-time PCR were further tested by nested PCR. RESULTS: All 50 CLEIA negative samples were determined to be negative by LIA and PCR. Of the 70 positive samples, 66 tested positive by both of LIA and PCR. Three samples tested negative by LIA and PCR, and the remaining sample (PCR negative) showed non-specific staining in LIA and WB. WB showed more indeterminate results than LIA. Gp21 antibody in LIA demonstrated a high ability to discriminate between positive and negative PCR results. Furthermore, the degree of gp21 antibody reaction by LIA showed correlation with HTLV-1 proviral loads (PVLs). CONCLUSIONS: Our results indicate that LIA performs well in confirming HTLV-1 seropositivity by showing a low incidence of indeterminate results and good agreement with PCR using samples in Japan, although the number of samples tested was small. In addition, semi-quantitative antibody titer to gp21 correlated well with HTLV-1 PVLs. Further study including larger samples is necessary to determine the positioning of LIA for HTLV-1 detection in Japan.

Possible Case of Novel Spotted Fever Group Rickettsiosis in Traveler Returning to Japan from India.

A 60-year-old woman experienced fever, headache, rash, and altered vision after returning to Japan from India. Testing detected elevated antibody titers to spotted fever group rickettsia; PCR on blood yielded positive results for the rickettsial outer membrane protein A gene. We isolated a unique rickettsial agent and performed a full-genome analysis.

Severe fever with thrombocytopenia syndrome with myocardial dysfunction and encephalopathy: A case report.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in China, Korea and Japan caused by a novel bunyavirus, SFTS virus (SFTSV). Although central nervous system manifestations are common in SFTS patients, the pathogenesis has not been elucidated; and there are few reports of myocardial dysfunction. Here we report an elderly Japanese patient with reversible myocardial dysfunction and encephalopathy. A previously healthy 65-year-old male engaged in forestry got a tick bite and developed fever and fatigue in 3 days. Three days after onset, he presented to a local hospital where the diagnosis of SFTS with hemophagocytotic syndrome was made. The blood test showed leukopenia and thrombocytopenia as well as elevated levels of alanine aminotransferase and aspartate aminotransferase. Marked hemophagocytosis was found on bone marrow smear. Peripheral blood was positive for SFTSV gene by reverse-transcription polymerase chain reaction. On day 7, the patient was transferred to our hospital. We observed disturbance of consciousness, Kernig sign and myoclonus to face and limbs. Decreased blood flow of whole cerebral cortex was detected by single photon emission computed tomography (SPECT). Chest X-ray revealed cardiomegaly and electrocardiography (ECG) showed abnormal T waves. These data suggested acute encephalopathy and myocardial dysfunction. We treated him with corticosteroid and blood transfusion, which resulted in the complete recovery of the above abnormal symptoms and laboratory data including the findings in SPECT and ECG in about a month. This case demonstrated transient myocardial dysfunction and encephalopathy can occur in addition to typical clinical manifestation of SFTS.

Unusual cystic hamartomatous lung lesion with clinical manifestation of subpleural bullae in a woman of reproductive age: A case report.

Pulmonary hamartoma is a common benign lung disorder, and most cases show solid nodules. Here, we documented the clinicopathological features of a growing, bulla-like, multilocular hamartomatous lung lesion in a woman of reproductive age. To the best of our knowledge, this disorder has not been reported in the literature to date. An asymptomatic 29-year-old Japanese woman with no significant past medical history was referred to our institution for surgical treatment of a bullous lesion in the right upper lobe because the pulmonary lesion had enlarged to multilocular cysts, including a giant bulla, within 1 year, leading to compression of the right lung. The bullous lesion, which was projected from the apex of the lung via a narrow stalk, showed nonemphysematous, multiloculated tissue. The wall mimicked a bronchiolar structure with ciliated, nonatypical epithelium and layers of nonatypical spindle cells that were positive for smooth muscle markers and sex steroid hormone receptors. No cartilage was included in the lesion. We believe that this may be a novel form of hamartoma. This disorder may be included in a differential diagnosis of subpleural bullous diseases in women of reproductive age.

Use of anti-tumor necrosis factor biologics in the treatment of rheumatoid arthritis does not change human T-lymphotropic virus type 1 markers: a case series.

Anti-tumor necrosis factor (anti-TNF) biologics are effective in the treatment of rheumatoid arthritis (RA); however, it is still not clear whether this treatment promotes the development of malignancies such as lymphoma. Human T-lymphotropic virus type 1 (HTLV-1), which is a causative agent of adult T-cell lymphoma (ATL), is prevalent in Japan. Many HTLV-1-positive patients with RA are assumed to exist; however, there have thus far been no reports on the effect of anti-TNF biologics on HTLV-1-positive patients. We analyzed the response to treatment with anti-TNF biologics and change of HTLV-1 markers in two cases of RA. The two cases showed no response based on the European League Against of Rheumatism response criteria 60-96 weeks after administration of anti-TNF biologics (infliximab and etanercept). No signs of ATL were observed and HTLV-1 markers, such as proviral load and clonality of HTLV-1-infected cells, showed no significant change in either of two cases. Therefore, treatment with anti-TNF biologics did not induce activation of HTLV-1, although the effect on RA was not as effective as in HTLV-1-negative patients in this limited study. Further long-term study with a greater number of patients is necessary to clarify the safety and efficacy of anti-TNF biologics in HTLV-1-positive patients with RA.

[Ten-year questionnaire survey on adult asthma patients in Miyazaki Prefecture, Japan].

OBJECTIVES: To decrease the number of asthma deaths occurring in Miyazaki Prefecture in Japan by promoting guideline-based treatment through the bronchial asthma forum. METHODS: A self-completed questionnaire survey of adult asthma patients was conducted in Miyazaki Prefecture during the same season for 10 consecutive years from 1999 to 2008. RESULTS: A total of 7899 responses were collected from medical institutions throughout the prefecture. In the course of 10 years, the doses of the drugs used for long-term management, including inhaled steroids, long-acting inhaled ß2-stimulants, and leukotriene receptor antagonists, increased year after year. Consequently, the frequency of asthma symptoms declined and there was a decrease in the use of short-acting inhaled ß2-stimulants, parenteral aminophylline, and slow-release theophylline preparations in response to this trend. Prescription rate of inhaled steroids and patients satisfaction was higher in the facilities of specialists than non-specialists. In patients with rhinitis symptoms, asthma was improved by concurrently treating both rhinitis and asthma in the survey of 2008. CONCLUSIONS: Asthma treatment based on the guideline was increasing in Miyazaki Prefecture, and this may have resulted in the improvement of asthma symptoms, increased patient satisfaction, and more importantly, a decrease in the number of asthma deaths.

Proviral loads of human T-lymphotropic virus Type 1 in asymptomatic carriers with different infection routes.

High human T-lymphotropic virus Type 1 (HTLV-1) proviral DNA load (PVL) has been reported to be one risk factor for the development of adult T-cell leukemia/lymphoma (ATL). ATL is also believed to develop in HTLV-1 carriers who acquire infection perinatally. ATL cells have been reported to frequently harbor defective provirus. In our study, PVLs for three different regions of HTLV-1 provirus (5'LTR-gag, gag and pX) were measured in 309 asymptomatic carriers with different infection routes. PVLs for the pX region in 21 asymptomatic carriers with maternal infection was significantly higher than in 24 carriers with spousal infection. Among 161 carriers with relatively high pX PVLs (equal to or greater than 1 copy per 100 peripheral blood mononuclear cells), 26 carriers (16%) had low gag PVL/pX PVL (less than 0.5) and four (2%) had low 5'LTR-gag PVL/pX PVL (less than 0.5). Low gag PVL/pX PVL ratio, which reflects deficiency and/or polymorphism of HTLV-1 proviral DNA sequences for the gag region, was also associated with maternal infection. These data suggest that HTLV-1 carriers with maternal infection tend to have high PVLs, which may be related to provirus with deficiency and/or the polymorphism of proviral DNA sequences. In addition, there is a possibility that this ratio may be used as a tool to differentiate the infection routes of asymptomatic HTLV-1 carriers, which supports the need for a large scale study.

[Impact of the Antimicrobial Stewardship Team Intervention Focusing on Changes in Prescribing Trends and the Rate of Carbapenem-resistant P. aeruginosa].

Antimicrobial stewardship (AS) intervention strategy is a critical process in promoting appropriate antibiotic use, thus preventing unnecessarily prolonged therapy and reducing antimicrobial resistance (AMR). Although limiting unnecessary carbapenem use by AS intervention is speculated to reduce AMR, there is a lack of specific data on the efficacy of AS team (AST) intervention regarding carbapenem-resistant Pseudomonas aeruginosa (CRPA). Consequently, this study aimed to evaluate the impact of our AS strategy on carbapenem use and CRPA. The AS intervention strategy was launched in July 2017 and consisted of daily audits and feedback on carbapenem use. We evaluated the 4-year prescription trend, including the rate of switching to other antimicrobials, and the rate of CRPA and the days of therapy required prior to and after the beginning of the AST intervention. The rate of switching to narrow-spectrum antibiotics and the discontinuation of carbapenem treatment were significantly higher in the pre-intervention period compared with the post-intervention period. (7.0% vs. 14.5%; p<0.001; 54.1% vs. 50.9%; p=0.027). However, there were no significant differences in the rate of CRPA prior to and after the beginning of the AST intervention. Furthermore, there was no correlation found between consumption and resistance rate (Pearson's r=0.123). Our results suggest that it is extremely important for AST to promote de-escalation and reduce unnecessary use, while the combination of process and outcome indicators other than antimicrobial consumption and resistance rate are required for the evaluation of the AS programs.

[A case of intubation granuloma treated with steroid inhalation].

A 36-year-old woman was given a diagnosis of hemophagocytic syndrome associated with systemic lupus erythematosus, and was treated with high-dose methylprednisolone and etoposide. She needed endotracheal intubation for mechanical ventilation because of respiratory failure. She developed hoarseness and stridor 69 days after extubation. A pedunculated mass under her glottis was observed by the laryngoscopy. Development of a laryngeal granuloma due to long-term contact with the endotracheal tube was considered, although she was continuously given oral prednisolone (22.5 mg/day) even after extubation. She was treated with inhalation of fluticasone propionate and her symptoms, e.g. hoarseness, decreased. Disappearance of the polypoid lesion was seen on day 26. A laryngeal granuloma due to intubation developed, even with the systemic administration of steroids; but it was successfully treated with steroid inhalation.

[Overwhelming postsplenectomy infection 22 years after splenectomy].

A 25-year-old man undergoing splenectomy at 3 years of age to treat idiopathic thrombocytopenic purpura but no history of Streptococcus pneumonia vaccination, and reporting high fever, nausea, and headache developed purpura, confusion, and hypotension the next day and was admitted. Detailed examination showed disseminated intravascular coagulation and multiple-organ dysfunction. Chest X-ray and computed tomography (CT) showed pneumonia and pleural effusion. Blood culture was positive for S. pneumoniae. Gram staining of sputa yielded numerous white blood cells and gram-negative rods, and sputa culture was positive for Pasteurella multocida and Haemophilus influenzae. The medical history and presence of these organisms yielded a diagnosis of overwhelming postsplenectomy infection (OPSI), and the patient responded to treatment with a combination of benzylpenicillin, cefotaxime, and meropenem. This case suggests that patients with a history of splenectomy may benefit from vaccination for S. pneumoniae and adequate education on OPSI.

[A case of disseminated nontuberculous mycobacteriosis during purpura associated with hypergammaglobulinemia and hepatitis type C].

A 74-year-old woman with hepatitis due to hepatitis C virus followed up using oral predonisolone (3 mg/day) for two years because of hypergammaglobulinemia-associated purpura reported fever and lumbago in February 2005. Upon admission in June, she was found in chest-computed tomography to have atelectasia in the right middle lung lobe and a nodule with a cavity in the right lower lobe. She tested positive for tuberculous glycolipid antibody. Gallium scintigraphy showed an abnormal accumulation in the lower lumbar vertebra. Magnetic resonance imaging showed abnormal enhancement at L4, L5, and their intervertebral disc. Mycobacterium intracellulare (M. intracellulare) was detected in blood culture, bronchoalveolar lavage, and a biopsy specimen from the intervertebral disc, yielding a diagnosis of disseminated nontuberculous mycobacteriosis (NTM) due to M. intracellulare. She was treated with clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP), but EB and RFP were discontinued due to of the fever they induced. She was then treated with a combination of CAM, levofloxacin, and streptomycin and followed up as an out patient. Based on case reports of disseminated NTM infection in Japan, the prognosis is poor and a protocol must be established for its treatment.

Epidemiology and risk factors for mortality in bloodstream infections: A single-center retrospective study in Japan.

BACKGROUND: Few published data are available on the morbidity and mortality of bloodstream infections (BSIs) in Japan. We sought to investigate the epidemiology of BSIs, the involvement of antimicrobial resistance, and the factors that influence patient prognosis. METHODS: This single-center study retrospectively evaluated patients who were found to have positive blood cultures at a tertiary teaching hospital between January 2012 and December 2016. RESULTS: A total of 2,105 patients with BSIs were included; 1,786 survived and 319 died, and the 30-day mortality rate was 15.2% over the 5-year study period. BSIs caused by yeasts were independently associated with 30-day mortality. The 30-day mortality rate of BSIs caused by extended-spectrum beta lactamase-producing gram-negative bacteria was significantly higher than that of BSIs caused by nonproducing bacteria. DISCUSSION: The differences in mortality may be caused by differences in the distribution of pathogens and in the delivery of health care. CONCLUSIONS: This study reported epidemiology and antimicrobial resistance data of BSIs in Japan and identified several risk factors associated with 30-day mortality. National surveillance of BSIs is required in Japan for comparison with other countries.

[Mycoplasma pneumonia of identical twin sisters with different clinical courses depending on the treatment].

Mycoplasma pneumoniae (M. pneumoniae) pneumonia is a common disease which usually shows a good prognosis, however, it can develop a very serious state such as respiratory distress syndrome. We experienced 2 cases with M. pneumoniae pneumonia from identical twin sisters. Case 1, who was 22 years-old and was the senior sister of the twin, complained of fever and cough on August 1st, 1999. Her chest radiograph revealed consolidation in the right lung. When she was admitted to our hospital on August 11, she revealed severe hypoxemia and the titer to M. pneumoniae was markedly elevated. She was diagnosed as M. pneumoniae pneumonia with acute respiratory distress syndrome and treated with clarithromycin and methylprednisolone. Although it was necessary for her to be in the intensive care unit for 8 days, her condition gradually improved and was discharged on the 30th of September. Case 2, who was the younger sister of Case 1, complained cough and fever on August 21, 1999. Her chest radiograph showed consolidation in the left lung. She was treated by sparfloxacin because the intrafamilial infection of M. pneumoniae was most likely. The diagnosis was confirmed by the increased antibody-titer to M. pneumoniae later. There have been several reports that hyperimmune reaction may be related with the worse course of M. pneumoniae pnuemonia. However, the clinical courses of twin sisters, who should be very similar in their immune response to the same antigen, were very different from each other. The time of administration of effective antibiotics seemed to be a crucial factor to determine their courses. These results emphasized the importance of early diagnosis of the patients with M. pneumoniae pneumonia and the adequate chemotherapy to prevent developing severe respiratory failure.

Treatment with anti­tumor necrosis factor biologic agents in human T lymphotropic virus type I­positive patients with rheumatoid arthritis.

OBJECTIVE: To investigate the response to and safety of anti­tumor necrosis factor (anti-TNF) therapy in human T lymphotropic virus type I (HTLV-I)­positive patients with rheumatoid arthritis (RA). METHODS: Therapeutic response was evaluated in 10 HTLV-I­positive and 20 HTLV-I­negative patients with RA (sex and age matched) at 3 months after the beginning of anti-TNF therapy using the European League Against Rheumatism improvement criteria. As secondary end points, the discontinuation rate of anti-TNF therapy and its safety, especially the development of adult T cell leukemia (ATL), were evaluated over a 2-year period. RESULTS: Significantly higher baseline levels of C-reactive protein (CRP) were observed in HTLV-I­positive patients than in HTLV-I­negative patients (P = 0.0003). The response rate to anti-TNF therapy was lower in HTLV-I­positive patients than in HTLV-I­negative patients. The median CRP level, erythrocyte sedimentation rate, and Disease Activity Score in 28 joints at 3 months after anti-TNF treatment in HTLV-I­positive patients were significantly higher than in HTLV-I­ negative patients (P = 0.003, P = 0.03, and P = 0.003, respectively). The discontinuation rate due to insufficient response was significantly higher in HTLV-I­positive patients than in HTLV-I­negative patients (P = 0.013). During the 2-year observation period, no patients developed ATL. CONCLUSION: These data suggest that HTLV-I­positive patients with RA had higher inflammation and greater resistance to anti-TNF treatment than HTLV-I­negative patients. Further study is necessary to determine whether HTLV-I infection should be measured when anti-TNF agents are administered to patients with RA, especially in areas were HTLV-I is endemic.

Crystalglobulinemia with fulminant course with cylinder-like bodies on peripheral blood smear.

A 63-year-old woman presented to our hospital with fever, purpura and pain in both legs and died 4 days after admission. Her blood smear and skin biopsy showed cylinder-like bodies (20×120 µm). She was diagnosed to have monoclonal gammopathy (IgG, lambda type). An autopsy revealed cylinder-like bodies in the vasculature of various organs. We noted a proliferation of atypical plasma cells in her bone marrow, suggesting pre-existing myeloma. Crystalglobulinemia is a rare manifestation of hypergammaglobulinemia that can cause multiple embolisms of the small vessels, and this resulted in the patient's fulminant course. The identification of cylinder-like bodies in the peripheral blood may help in reaching a diagnosis in such cases.

Improvement of rheumatoid arthritis and autoimmune hepatitis in a patient treated with the tumor necrosis factor inhibitor, etanercept.

We report a case of rheumatoid arthritis (RA) with autoimmune hepatitis (AIH) and Sjogren syndrome (SjS) that was treated with the tumor necrosis factor (TNF) inhibitor, etanercept (ETN). Both RA activity and transaminase levels improved as a result of treatment. Follow-up liver biopsy showed improvement of hepatitis. Although the efficacy of anti-TNF for RA patients with AIH remains controversial, this case suggests that treatment with ETN may result in a favorable clinical course in a certain subset of patients with RA and AIH.

Leukocytapheresis (LCAP) decreases the level of platelet-derived microparticles (MPs) and increases the level of granulocytes-derived MPs: a possible connection with the effect of LCAP on rheumatoid arthritis.

Microparticles (MPs) are believed to play an important role in inflammatory diseases such as rheumatoid arthritis (RA). Leukocytapheresis (LCAP) is one of the options available for the treatment of RA. We analyzed the levels of MPs in RA, by flow cytometry, especially in relation to the effect of LCAP. Twenty female patients with RA were recruited into this study. Six of the 20 patients with RA further received LCAP. Plasma levels of platelet-derived MPs were high in patients with RA and are correlated with disease activity. LCAP significantly improved RA in all six patients. The numbers of platelet-derived MPs significantly decreased after the first session of LCAP, which was probably due to direct removal by LCAP. Mean numbers of platelet-derived MPs after four sessions of LCAP markedly decreased. The numbers of granulocyte-derived MPs, which are suggested to have an anti-inflammatory effect, were markedly increased after the first session of LCAP. These data suggest that removal of platelet-derived MPs and increase of granulocyte-derived MPs are novel mechanisms of LCAP as effective treatment in RA.