Efficacy of Intrathecal Isoniazid and Steroid Therapy in Refractory Tuberculous Meningitis.

Tuberculous meningitis is an infectious disease with high mortality. Literature describing intrathecal therapy for tuberculous meningitis is scarce. We herein report a case of refractory tuberculous meningitis in a 52-year-old woman with underlying neuropsychiatric systemic lupus erythematosus. Despite systemic treatment with anti-tuberculosis drugs and dexamethasone, her meningeal irritation deteriorated. Intrathecal isoniazid and prednisolone administration was therefore initiated, and the symptoms of severe meningeal irritation improved along with head magnetic resonance imaging and cerebrospinal fluid findings. This case report highlights the efficacy of intrathecal isoniazid and steroid injections for refractory tuberculous meningitis, particularly in patients with severe meningeal irritation.

Decreased community-acquired pneumonia coincided with rising awareness of precautions before governmental containment policy in Japan.

The effectiveness of population-wide compliance to personal precautions (mask-wearing and hand hygiene) in preventing community-acquired pneumonia has been unknown. In Japan, different types of nonpharmaceutical interventions from personal precautions to containment and closure policies (CACPs, e.g. stay-at-home requests) were sequentially introduced from late January to April 2020, allowing for separate analysis of the effects of personal precautions from other more stringent interventions. We quantified the reduction in community-acquired pneumonia hospitalizations and deaths and assessed if it coincided with the timing of increased public awareness of personal precautions before CACPs were implemented. A quasi-experimental interrupted time-series design was applied to non-COVID-19 pneumonia hospitalization and 30-day death data from April 2015 to August 2020 across Japan to identify any trend changes between February and April 2020. We also performed a comparative analysis of pyelonephritis and biliary tract infections to account for possible changes in the baseline medical attendance. These trend changes were then compared with multiple indicators of public awareness and behaviors related to personal precautions, including keyword usage in mass media coverage and sales of masks and hand hygiene products. Hospitalizations and 30-day deaths from non-COVID-19 pneumonia dropped by 24.3% (95% CI 14.8-32.8) and 16.1% (5.5-25.5), respectively, in February 2020, before the implementation of CACPs, whereas pyelonephritis and biliary tract infections did not suggest a detectable change. These changes coincided with increases in indicators related to personal precautions rather than those related to contact behavior changes. Community-acquired pneumonia could be reduced by population-wide compliance to moderate precautionary measures.

Serological response to a third dose of SARS-CoV-2 vaccine according to previous infection history.

The IgG antibody titer against SARS-CoV-2 receptor binding protein (RBD) after mRNA vaccine were compared between those with and without previous infection (PI) for up to 48 weeks. Though sustained higher IgG-RBD were observed in the PI group after two doses of vaccines, both groups benefited from the booster shots of the third vaccine. This data supports the necessity of the booster shots to those with PI.

Evaluation of a Triage Checklist for Mild COVID-19 Outpatients in Predicting Subsequent Emergency Department Visits and Hospitalization during the Isolation Period: A Single-Center Retrospective Study.

Managing mild illness in COVID-19 and predicting progression to severe disease are concerning issues. Here, we investigated the outcomes of Japanese patients with mild COVID-19, and identified triage risk factors for further hospitalization and emergency department (ED) visits at a single tertiary hospital. A triage checklist with 30 factors was used. Patients recommended for isolation were followed up for 10 days for subsequent ED visits or hospital admission. Overall, 338 patients (median age, 44.0; 45% women) visited the clinic 5.0 days (median) after symptom onset. Thirty-six patients were immediately hospitalized following triage; others were isolated. In total, 72 non-hospitalized patients visited the ED during their isolation, and 30 were hospitalized after evaluation for oxygen desaturation. The median ED visit and hospitalization durations after symptom onset were 5.0 and 8.0 days, respectively. The checklist factors associated with hospitalization during isolation were age > 50 years, body mass index > 25 kg/m2, hypertension, tachycardia with pulse rate > 100/min or blood pressure > 135 mmHg at triage, and >3-day delay in hospital visit after symptom onset. No patients died. Altogether, 80% of patients with mild COVID-19 could be safely isolated at home. Age, BMI, underlying hypertension, date after symptom onset, tachycardia, and systolic blood pressure at triage might be related to later hospitalization.

Clinical Differentiation of Severe Fever with Thrombocytopenia Syndrome from Japanese Spotted Fever.

Severe fever with thrombocytopenia syndrome (SFTS) and Japanese spotted fever (JSF; a spotted fever group rickettsiosis) are tick-borne zoonoses that are becoming a significant public health threat in Japan and East Asia. Strategies for treatment and infection control differ between the two; therefore, initial differential diagnosis is important. We aimed to compare the clinical characteristics of SFTS and JSF based on symptomology, physical examination, laboratory data, and radiography findings at admission. This retrospective study included patients with SFTS and JSF treated at five hospitals in Nagasaki Prefecture, western Japan, between 2013 and 2020. Data from 23 patients with SFTS and 38 patients with JSF were examined for differentiating factors and were divided by 7:3 into a training cohort and a validation cohort. Decision tree analysis revealed leukopenia (white blood cell [WBC] < 4000/µL) and altered mental status as the best differentiating factors (AUC 1.000) with 100% sensitivity and 100% specificity. Using only physical examination factors, absence of skin rash and altered mental status resulted in the best differentiating factors with AUC 0.871, 71.4% sensitivity, and 90.0% specificity. When treating patients with suspected tick-borne infection, WBC < 4000/µL, absence of skin rash, and altered mental status are very useful to differentiate SFTS from JSF.

Long-term impact of pneumococcal conjugate vaccines for children on adult pneumococcal pneumonia in Japan: Two multicenter observational studies from 2011 to 2020.

BACKGROUND: Pediatric pneumococcal conjugate vaccines (PCVs) introduction has directly and indirectly reduced pneumococcal pneumonia and invasive disease caused by PCV-covered serotypes among children and adults globally. In Japan, both PCV7 and PCV13 were introduced into the national immunization program (NIP) for children in 2013. However, the long-term impact of PCV use in children on adult pneumococcal pneumonia in Japan remains unclear. METHODS: We assessed serotypes isolated from adult pneumococcal pneumonia patients (in- and outpatients) in two multicenter observational studies in Japan: 2011-2014 and 2016-2020. The latter study period was divided into two periods to evaluate changes after PCV introduction in children. The Quellung reaction was used to determine serotypes. We evaluated trends of individual and vaccine-covered serotypes over three periods and assessed the difference in changes by patient group before and after the introduction of pediatric PCVs. RESULTS: A total of 650 patients were enrolled: 224, 322, and 104 in 2011-2014, 2016-2017, and 2018-2020, respectively. The median age was 73 years; 59.7% (388/650) were male; 86.9% (565/650) had comorbidities; and 10.2% (66/650) were nursing-home residents. The proportion of PCV13 serotypes decreased from 52.7% in 2011-2014 to 30.4% in 2016-2017 (p <0.001) after PCV13 introduction for children. However, PCV13, PCV15, and PCV20 serotypes still accounted for 38.5, 43.3, and 59.6% of total pneumococcal pneumonia in 2018-2020, respectively. Decline of PCV13 serotypes was more marked in patients aged ≥65 (-23.5%; p <0.001) than those aged <65 (-12.3%; p = 0.104) from 2011-2014 to 2016-2020. The proportion of PPSV23 non-PCV13 serotypes didn't change over time. CONCLUSIONS: The proportion of adult pneumococcal pneumonia caused by PCV13 serotypes in Japan declined after pediatric PCVs introduction into NIP, possibly due to indirect effects of pediatric PCVs. However, use of new PCVs in Japanese adults may potentially prevent additional pneumococcal pneumonia cases. Now, pneumococcal vaccination strategy for older adults requires discussion.

Clinical and microbiological characteristics and challenges in diagnosing infected aneurysm: a retrospective observational study from a single center in Japan.

BACKGROUND: It is challenging to diagnose infected aneurysm in the early phase. This study aimed to describe the clinical and microbiological characteristics of infected aneurysm, and to elucidate the difficulties in diagnosing the disease. METHODS: Forty-one cases of infected aneurysm were diagnosed in Nagasaki University Hospital from 2005 to 2019. Information on clinical and microbiological characteristics, radiological findings, duration of onset, and type of initial computed tomography (CT) imaging conditions were collected. Factors related to diagnostic delay were analyzed by Fisher's exact test for categorical variables or by the Wilcoxon rank-sum test for continuous variables. RESULTS: Pathogens were identified in 34 of 41 cases; the pathogens were Gram-positive cocci in 16 cases, Gram-negative rods in 13 cases, and others in five cases. Clinical characteristics did not differ in accordance with the identified bacteria. At the time of admission, 16 patients were given different initial diagnoses, of which acute pyelonephritis (n = 5) was the most frequent. Compared with the 22 patients with an accurate initial diagnosis, the 19 initially misdiagnosed patients were more likely to have been examined by plain CT. The sensitivities of plain CT and contrast-enhanced CT were 38.1% and 80.0%, respectively. CONCLUSIONS: In cases of infected aneurysm, diagnostic delay is attributed to non-specific symptoms and the low sensitivity of plain CT. Clinical characteristics of infected aneurysm mimic various diseases. Contrast-enhanced CT should be considered if infected aneurysm is suspected.

A multicenter non-randomized, uncontrolled single arm trial for evaluation of the efficacy and the safety of the treatment with favipiravir for patients with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is a bunyavirus infection with high mortality. Favipiravir has shown effectiveness in preventing and treating SFTS virus (SFTSV) infection in animal models. A multicenter non-randomized, uncontrolled single arm trial was conducted to collect data on the safety and the effectiveness of favipiravir in treatment of SFTS patients. All participants received favipiravir orally (first-day loading dose of 1800 mg twice a day followed by 800 mg twice a day for 7-14 days in total). SFTSV RT-PCR and biochemistry tests were performed at designated time points. Outcomes were 28-day mortality, clinical improvement, viral load evolution, and adverse events (AEs). Twenty-six patients were enrolled, of whom 23 were analyzed. Four of these 23 patients died of multi-organ failure within one week (28-day mortality rate: 17.3%). Oral favipiravir was well tolerated in the surviving patients. AEs (abnormal hepatic function and insomnia) occurred in about 20% of the patients. Clinical symptoms improved in all patients who survived from a median of day 2 to day10. SFTSV RNA levels in the patients who died were significantly higher than those in the survivors (p = 0.0029). No viral genomes were detectable in the surviving patients a median of 8 days after favipiravir administration. The 28-day mortality rate in this study was lower than those of the previous studies in Japan. The high frequency of hepatic dysfunction as an AE was observed. However, it was unclear whether this was merely a side effect of favipiravir, because liver disorders are commonly seen in SFTS patients. The results of this trial support the effectiveness of favipiravir for patients with SFTS.

Impact of the pediatric 13-valent pneumococcal conjugate vaccine on serotype distribution and clinical characteristics of pneumococcal pneumonia in adults: The Japan Pneumococcal Vaccine Effectiveness Study (J-PAVE).

BACKGROUND: The pediatric 13-valent pneumococcal conjugate vaccine (PCV13) was included in the pediatric immunization programme in Japan in late 2013. The impact of vaccination on the serotype distribution and clinical characteristics of pneumococcal pneumonia has not been described. METHODS: The first phase of this multicentre prospective study was conducted at community-based hospitals in Japan from 2011 to 2014. The second phase was conducted from 2016 to 2017. Pneumococcal isolates and clinical data were collected from patients with community-acquired pneumonia who were ≥15 years of age. Patients were classified by pneumococcal serotype to PCV13 serotype, 23-valent pneumococcal polysaccharide vaccine (PPV23) non-PCV13 serotype, and non-vaccine serotype. RESULTS: A total of 484 patients were enrolled, 241 in the first phase and 243 in the second. The proportion of PCV13 serotypes decreased from 53% to 33% (p < 0.001), whereas PPV23 non-PCV13 serotypes did not change (p = 0.754). PCV13 serotypes were associated with increased risk of elevated blood urea nitrogen (adjusted odds ratio 2.49; 95% confidence interval: 1.49-4.16) and hospitalization (adjusted odds ratio 1.74; 95% confidence interval: 1.02-2.95). These associations were not observed in patients with PPV23 non-PCV13 serotypes. CONCLUSIONS: The occurrence of pneumococcal pneumonia caused by vaccine-covered serotypes dramatically decreased following the introduction of pediatric PCV13. The PCV13 serotypes were associated with pneumonia severity.

Accuracy of High-Throughput Nanofluidic PCR-Based Pneumococcal Serotyping and Quantification Assays Using Sputum Samples for Diagnosing Vaccine Serotype Pneumococcal Pneumonia: Analyses by Composite Diagnostic Standards and Bayesian Latent Class Models.

The lack of reliable diagnostic tests for detecting vaccine serotype pneumococcal pneumonia (VTPP) remains a challenging issue in pneumococcal vaccine studies. This study assessed the performances of high-throughput nanofluidic PCR-based pneumococcal serotyping and quantification assay methods using sputum samples (the nanofluidic sputum quantitative PCR [Sp-qPCR] assay) to diagnose 13-valent pneumococcal conjugate VTPP compared with the performance of the serotype-specific urinary antigen detection (UAD) assay using urine samples. Adult pneumonia patients from Japan were enrolled in this study between September 2012 and August 2014. Sputum samples were subjected to the nanofluidic Sp-qPCR assay, quantitatively cultured, and serotyped by the Quellung reaction (SpQt). Urine samples were tested by the UAD method. The diagnostic performances of these tests were assessed using composite reference standards and Bayesian latent class models (BLCMs). Among 244 total patients, 27 (11.1%) tested positive with the UAD assay, while 16 (6.6%) and 34 (13.9%) tested positive with the SpQt and nanofluidic Sp-qPCR assays, respectively, with a cutoff value of ≥104 DNA copies/ml, which showed the maximum value of the Youden index. Using BLCMs, the estimated prevalence for VTPP was 12.9%, and the nanofluidic Sp-qPCR assay demonstrated the best performance (sensitivity, 90.2%; specificity, 96.9%), followed by UAD (sensitivity, 75.6%; specificity, 97.9%) and SpQt (sensitivity, 45.8%; specificity, 99.5%). However, when a higher cutoff value of ≥107 DNA copies/ml was applied, the performance of UAD became comparable to that of Sp-qPCR. The vaccine serotype-specific pneumococcal DNA load in sputum among UAD-positive patients was 3 logs higher than that among UAD-negative patients (P = 0.036). The nanofluidic Sp-qPCR assay may be accurate and useful for detecting VTPP among adults.

A case series of histoplasmosis patients with elevated serum soluble interleukin-2 receptor levels.

Histoplasmosis is a common endemic mycosis that is usually asymptomatic but occasionally results in severe illness. Histoplasmosis and its causative agent, Histoplasma capsulatum, are found worldwide but rarely in Japan. In recent years, however, the number of histoplasmosis patients in Japan has increased. In addition, to our knowledge, there are no previous reports of increased serum soluble interleukin-2 receptor (sIL-2R) levels in patients with histoplasmosis. We report a case series of histoplasmosis in three Japanese temporary workers in Manzanillo, Mexico. All three patients developed a persistent high fever and general fatigue. Laboratory tests showed increased C-reactive protein levels and mild liver dysfunction. All patients also showed increased soluble interleukin-2 receptor (sIL-2R) levels. Chest computed tomography revealed multiple nodules in both lung fields. All patients were positive for serum anti-Histoplasma antibodies, and two patients were positive for Histoplasma on polymerase chain reaction tests. After treatment that included antifungals, their conditions gradually improved and laboratory data normalized. Although one patient developed respiratory failure, this patient recovered with antifungal therapy in combination with methylprednisolone. Serum sIL-2R levels in all patients gradually declined to normal levels, indicating their recovery from Histoplasma infection. From our experience with these patients, sIL-2R levels may be a useful biomarker for patients with histoplasmosis.

Use of Corticosteroids for Urinary Tuberculosis Patients at Risk of Developing Ureteral Obstruction.

A 77-year-old man with urinary tuberculosis developed post renal anuria two days after starting an anti-tuberculosis drug regimen. He had bilateral hydronephrosis, and his right kidney was radiologically diagnosed to be non-functioning. A transurethral catheter was placed in the left ureter. No improvement in the ureteral stricture was noted during the initial three weeks of treatment; however, the stricture did thereafter improve after the commencement of oral prednisolone. In cases of urinary tuberculosis, ureteral stricture can deteriorate and result in ureteral obstruction during anti-tuberculosis treatment. Pre-emptive administration of corticosteroids may be beneficial for preventing such stricture in patients with a pre-existing ureteral lesion.

Outcome of surgical management for active mitral native valve infective endocarditis: a collective review of 57 patients.

OBJECTIVE: At our institutions, mitral valve vegetation with a high risk for embolism is surgically treated as soon as possible to maintain the quality of life of patients, and valve repair has been actively performed. We reviewed the surgical outcome for active mitral infective endocarditis (AMIE) following this treatment policy. METHODS: Fifty-seven patients underwent surgery for native AMIE between April 1999 and December 2012 (repair 36, replacement 21). We retrospectively investigated the risk factors for in-hospital death, the prognosis of patients with cerebral infarction, and the short- and long-term outcomes of valve repair and replacement. RESULTS: The preoperative conditions and the intraoperative findings in the replacement group were more complicated. But, no significant differences were observed in in-hospital mortality, 4-year survival, or 4-year reoperation-free rate between the groups (repair 8, 88.2, and 92.4%; replacement 9, 90.5, and 94.7%, respectively). The incidence of postoperative cardiac-related events including heart failure, thromboembolism, and major bleeding was higher in the replacement group. Although our study failed to identify predictors of in-hospital mortality, uncontrolled and nosocomial infections were responsible for high in-hospital mortality of 17 and 33%, respectively. Nine patients with symptomatic non-hemorrhagic cerebral infarction underwent early surgery within 2 weeks of the onset of stroke (median maximum infarct diameter and volume: 18.2 mm and 0.72 cm(3), respectively). No patients had severe hemorrhagic conversion. CONCLUSION: Mitral valve repair is appropriate to prevent postoperative cardiac-related events. Reducing in-hospital mortality due to uncontrolled infection remains challenging. Early surgery may be reasonable for patients with small non-hemorrhagic infarction.

The relationship between biofilm formations and capsule in Haemophilus influenzae.

To evaluate the biofilm formation of non-typeable Haemophilus influenzae (NTHi) and H. influenzae type b (Hib) clinical isolates, we conducted the following study. Serotyping and polymerase chain reaction were performed to identify ß-lactamase-negative ampicillin (ABPC)-susceptible (BLNAS), ß-lactamase-negative ABPC-resistant (BLNAR), TEM-1 type ß-lactamase-producing ABPC-resistant (BLPAR)-NTHi, and Hib. Biofilm formation was investigated by microtiter biofilm assay, as well as visually observation with a scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) in a continuous-flow chamber. As a result, totally 99 strains were investigated, and were classified into 4 groups which were 26 gBLNAS, 22 gBLNAR, 28 gBLPAR-NTHi and 23 Hib strains. The mean OD600 in the microtiter biofilm assay of gBLNAS, gBLNAR, gBLPAR-NTHi, and Hib strains were 0.57, 0.50, 0.34, and 0.08, respectively. NTHi strains were similar in terms of biofilm formations, which were observed by SEM and CLSM. Five Hib strains with the alternated type b cap loci showed significantly increased biofilm production than the other Hib strains. In conclusion, gBLNAS, gBLNAR, and gBLPAR-NTHi strains were more capable to produce biofilms compared to Hib strains. Our data suggested that resistant status may not be a key factor but capsule seemed to play an important role in H. influenzae biofilm formation.

Active infective endocarditis due to Erysipelothrix rhusiopathiae: zoonosis caused by vancomycin-resistant gram-positive rod.

A 42-year-old female who was a voluntary worker in a school for handicapped children was referred to us for surgery for active infective endocarditis. Trans-esophageal echocardiography showed 2 large mobile vegetations on the aortic valve and severe aortic regurgitation. Aortic valve replacement was performed to prevent septic embolism and deterioration of congestive heart failure. The empiric therapy with vancomycin, ampicillin, and gentamycin was initiated because a pathogen was not identified. But Erysipelothrix rhusiopathiae (gram-positive rod) was isolated on the 4th day after surgery. The target therapy with penicillin G and clindamycin was started and continued for 4 weeks after surgery. The inflammatory parameters improved steadily and the patient was discharged on the 36th day after surgery. Infective endocarditis due to gram-positive rods can be easily mistaken for streptococci or dismissed as a skin contamination. But, E. rhusiopathiae endocarditis should be considered in the differential diagnosis.

Transbronchial biopsy using endobronchial ultrasonography with a guide sheath increased the diagnostic yield of peripheral pulmonary lesions.

OBJECTIVE: The advantage of transbronchial biopsy (TBB) using endobronchial ultrasonography (EBUS) with a guide sheath (GS) over TBB without EBUS guidance was investigated in this study. MATERIALS AND METHODS: A retrospective chart review was conducted at Nagasaki University Hospital, Japan. Data were collected from all cases of peripheral pulmonary lesions (PPLs) undergoing either EBUS-GS-guided TBB or TBB without EBUS guidance in our department from December 2003 through November 2009. The diagnostic yield in each group was compared, after adjustment for other factors. RESULTS: In total 110 PPLs were investigated in 102 patients: 65 (59.1%) were examined with EBUS-GS-guided TBB (EBUS-GS group) and 45 (40.9%) were TBB without EBUS guidance (non-EBUS group). Both procedures were performed under x-ray fluoroscopy. Basic characteristics were similar between the two groups. Of all EBUS examined lesions, 53 (81.5%) were visualized by EBUS. The diagnostic yields in EBUS-GS group and non-EBUS group were 64.6% and 46.7%, respectively (p=0.08). Adjusting for size and location of lesions, the yield of EBUS-GS guidance was 1.46 (95% confidence interval 1.03 to 2.05) times higher than without EBUS guidance. When the lesion was visualized by EBUS, the diagnostic yield ratio was further increased to 1.63 (95% CI 1.16 to 2.27). CONCLUSION: EBUS-GS-guided TBB demonstrates a higher diagnostic yield than TBB without EBUS guidance.

[A case of pacemaker-lead infection by linezolid-resistant methicillin-resistant Staphylococcus aureus in a hemodialysis patient].

A 76-year-old woman undergoing hemodialysis and having a permanent pacemaker during care elsewhere developed a shunt infection with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Vancomycin (VCM) and other antimicrobial agents were not effective even after her artificial shunt vessel was removed. Linezolid (LZD) was administered for 56 days to resolve fever. MRSA was detected repeatedly in blood culture for 7 months except while LZD was being administered, so she was referred to our hospital for further investigation and treatment. Blood culture isolated 3 MRSA strains, all having a minimum inhibitory concentration (MIC) of LZD above 16 microg/mL while that of VCM varied at 24 microg/mL. Based on these findings, combined VCM, rifampicin, and arbekacin therapy was started but did not resolve the MRSA bacteremia problem. Transesophageal echocardiography showed flat vegetation around the pacemaker lead passing through the tricuspid valve. Based on strongly suspected pacemaker-lead infection, the pacemaker system was removed by heart surgeons using radiographic imaging on day 16 after admission. Her blood culture then became negative. She was returned to the previous hospital on day 66 after admission, where combination antibiotic therapy was continued for about one month. MRSA was not detected again after pacemaker system removal.