Diagnostic accuracy of the interferon-gamma release assay in acquired immunodeficiency syndrome patients with suspected tuberculosis infection: a meta-analysis.

PURPOSE: The diagnostic accuracy of the interferon-gamma release assay (IGRA) in immunosuppressed patients remains unclear. METHODS: A systematic review and meta-analysis were performed for diagnostic test accuracy of IGRA in tuberculosis (TB) infection among people living with HIV (PLWHIV). Summary estimates of sensitivity and specificity were calculated using both univariate and bivariate models. RESULTS: The meta-analysis included 45 of the 1,242 first-screened articles. The total number of PLWHIV was 6,525; 3,467 had TB disease, including 806 cases of LTBI and 2,661 cases of active TB. The overall diagnostic odds ratio (DOR) of IGRA in the diagnosis of TB disease was 10.0 (95% confidence interval (CI) 5.59, 25.07), with an area under the curve (AUC) of 0.729. The DOR was better for QFT (14.2 (95%CI 4.359, 46.463)) than T-SPOT (10.0 (95%CI 3.866 26.033)). The sensitivity and specificity of QFT and T-SPOT were 0.663 (95%CI 0.471, 0.813), 0.867 (95%CI 0.683 0.942), and 0.604 (95%CI 0.481, 0.715), 0.862 (95%CI 0.654, 0.954), respectively, in the bivariate model. The sensitivity of IGRA in the diagnosis of LTBI was 0.64 (95%CI 0.61, 0.66). CONCLUSION: IGRA was useful in the diagnostic of TB disease in PLWHIV, and QFT showed a better tendency of DOR than T-SPOT. IGRA showed a limited effect to rule out LTBI in PLWHIV.

[Efficacy and Safety of Gefitinib as First-Line Chemotherapy for Elderly Patients with Advanced Non-Small Cell Lung Cancer(NSCLC)].

Epidermalgrowth factor receptor tyrosine kinase inhibitor(EGFR-TKI)is the first choice for the treatment of EGFR mutation- positive advanced non-small cell lung cancer(NSCLC). There have been few reports on the efficacy and safety of gefitinib in elderly patients with EGFR mutation-positive advanced NSCLC. We retrospectively assessed the efficacy and safety of gefitinib as first-line chemotherapy in 22 patients with advanced NSCLC aged 75 years or older and who were treated with gefitinib. The response rate was 81.8%, and the disease controlrate was 95.5%. The median progression-free survivaltime was 14.2 months, and the median survivaltime was 30.7 months. The common adverse events were skin toxicities(50.0%), liver dysfunction(18.2%), and diarrhea(18.2%). The dose of gefitinib was reduced in 36.3% of the patients, and the treatment of gefitinib was discontinued in 18.2% of the patients. Gefitinib is effective and safe for elderly patients with advanced NSCLC.

[A CASE OF SPINAL TUBERCULOSIS WITH NEUROPATHY AMELIORATED BY DRAINING A TUBERCULOUS ILIOPSOAS ABSCESS WITHOUT SPINAL SURGERY].

A 75-year-old woman was referred to our hospital after a health check-up disclosed abnormal shadows in the bilateral lungs. The patient was admitted to our hospital after being diagnosed with pulmonary tuberculosis. A physical examination showed a mass in the left inguinal area. Enhanced computed tomography revealed that the tuberculosis involved several regions including the lumber vertebrae, iliopsoas muscles, and left inguinal area. A therapeutic regimen consisting of INH, RFP, EB, and PZA was begun. Neuropathy in the lower extremities and dysuria indicated a spinal lesion, and spinal surgery was considered. However, the patient's history indicated that these symptoms were likely due to an iliopsoas abscess rather than a spinal lesion. This hypothesis was confirmed when the patient's symptoms improved with no sequelae after the abscess was drained. Our case demonstrates that spinal lesions as well as iliopsoas abscesses can cause neuropathy, and underscores the importance of obtaining a patient's history to correctly diagnose the disease and determine the appropriate treatment options.

[A case of antitubercular drug-induced toxic epidermal necrosis in a systemic lupus erythematosus patient during treatment for pulmonary tuberculosis].

A 48-year-old woman, who had been suffering from systemic lupus erythematosus for one year and receiving steroid therapy, was admitted to our hospital because of pulmonary tuberculosis. The tuberculosis was treated with INH, RFP, EB, and PZA after having doubled the dose of steroid, but terminated three weeks later due to the appearance of erythema exsudativum multiforme. Treatment was resumed with PZA, SM, and LVFX after resolution of the eruption. However, the addition of INH to the regimen provoked a recurrence of the eruption, which progressed rapidly to toxic epidermal necrolysis (TEN). Steroid pulse therapy stopped progression of the TEN, and treatment for tuberculosis was resumed. Although the choice of drug was rendered difficult by other adverse reactions, the patient was able to complete her tuberculosis treatment with RFP, EB, and TH. INH was most likely to be the offending agent in this case. Eruptions induced by antitubercular drugs are often seen, but there are few reports of severe toxic epidermal necrolysis.

Bochdalek Hernia Causing Sigmoid Colon Strangulation in an Elderly Patient.

Diaphragmatic hernia with bowel strangulation is a fatal condition requiring a prompt diagnosis. Bochdalek hernia is a common type of diaphragmatic hernia that rarely but occasionally occurs in adults. We herein report a case of Bochdalek hernia causing sigmoid colon strangulation in an elderly patient whose condition was initially misdiagnosed as empyema. The early diagnosis of strangulated bowel stemming from diaphragmatic hernia can be challenging because of its rarity and the nonspecificity of its symptoms. However, tracing the mesenteric arteries on computed tomography can enable a quick diagnosis.

[A case of severe Legionella pneumonia in which survival was achieved without sequelae with the use of extracorporeal membrane oxygenation (ECMO)].

A 54-year-old man presented with fever and dyspnea about a week before his admission. We diagnosed Legionella pneumonia from his chest X-ray imaging which showed bilateral lobe consolidation excluding the left upper lobe, and his sputum culture yielded Legionella pneumophilla serogroup 1. Combination therapy with levofloxacin and rifampin was started on admission. However, the patient developed severe acute respiratory distress syndrome (ARDS) and then extracorporeal membrane oxygenation (ECMO) was initiated on the 2nd day. His respiratory status gradually improved after that and he was weaned from ECMO on the 7th day. He was discharged without sequelae on the 36th day. The outcome suggests that use of ECMO should be considered for patients with severe Legionella pneumonia.

[A case of IgG4-positive inflammatory pseudotumor which rapidly resolved].

A 72-year-old man visited our hospital due to persistent cough, fever and weight loss. A chest X-ray film revealed a round tumor in the left lower lung field. A specimen obtained by transbronchial lung biopsy demonstrated histiocytic and lymphocytic infiltration in the alveolar space, with spindle myofibroblasts and plasmacytes in the interstitium, Those findings were consistent with inflammatory pseudotumor. Four weeks later, a chest X-ray film showed only scars of the primary lesion, and his symptoms resolved dramatically. He has had no recurrence of symptoms and pulmonary tumor since then. Although spontaneous remission is uncommon in inflammatory pseudotumor of the lung, there are several case reports about spontaneous remission of hepatic inflammatory pseudotumor and autoimmune pancreatitis, parts of IgG4-related sclerosing disease. Recently, inflammatory pseudotumor is thought to be IgG4-related sclerosing disease. We speculate that IgG4 may be associated with spontaneous remission of inflammatory pseudotumor of the lung, and we discuss this issue in relation to the pertinent literature.

Pleural effusion as a rare presentation of foreign body aspiration.

Unsuspected, non-asphyxiating, aspirated foreign body often masquerades as unresolved pneumonia, bronchiolitis or bronchial asthma. We report herein an 82-year-old, male patient with pleural effusion. Although the patient received the diagnosis of heart failure and treatment with diuretics, the pleural effusion remained, and a productive cough and a low-grade fever developed. Thoracentesis showed an exudative effusion, and chest computed tomography revealed a pill-like object in the right bronchus intermedius. The foreign body proved to be an iron pill, and the patient finally died from obstructive pneumonia due to severe mucosal damage caused by the pill. The present case emphasizes that foreign body aspiration may mimic not only respiratory but also cardiovascular diseases and should be suspected if the treatment of the initially diagnosed condition fails to ameliorate the patient's condition.

Serum alanine aminotransferase as an early marker of outcomes in patients receiving anti-PD-1 or anti-CTLA-4 antibody.

Immune-oncology (IO) drug therapy is effective against various types of cancer. Although several, potential, clinical predictive markers have been identified, none so far have proven reliable. Herein we evaluated changes in serum alanine aminotransferase (ALT), which is upregulated by the accumulation of activated CD8+T cells in the liver, as a potentially reliable predictive marker. We retrospectively analyzed 265 patients with advanced malignancies at three institutions between 2016 and 2019. The patients received IO drug therapy. We defined the ALT ratio (ALR) as the serum ALT value at baseline / the highest serum ALT during IO drug therapy, then determined whether the ALR correlated with the objective response rate or progression-free survival. The median follow-up was 3.1 months. We observed objective responses in 65 patients. The ALR ranged from 0.19 to 32.2 (median 1.5), and a significant ALR increase was observed in responders (p < 0.001). In receiver operating characteristic analysis, ALR = 1.55 had the highest sensitivity and specificity. The patients with ALR < 1.55 had a significantly poorer PFS than those with ALR ≥ 1.55. A high ALR was associated with a tumor response and good PFS in patients with advanced malignancies. The ALR based on activated cytotoxic T lymphocyte dynamics is therefore a reliable predictive marker.

Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy. METHODS: COVID-19 patients with moderate pneumonia (SpO2 ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO2), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions. RESULTS: A total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference (p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher. CONCLUSIONS: The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered. TRIAL REGISTRATION: Clinicaltrials.jp number: JapicCTI-205238.

Combined Small and Squamous Transformation in EGFR-mutated Lung Adenocarcinoma.

Histologic transformation has been described as an acquired mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We herein report the case of a woman with stage IV lung adenocarcinoma harboring EGFR exon 19 deletions who was initially treated with EGFR-TKIs; several cytotoxic chemotherapeutic regimens were used when resistance developed. A lymph node re-biopsy revealed histologic transformation of the tumor to combined small-cell lung cancer and squamous cell carcinoma with retained EGFR exon 19 deletions. Following sequential chemotherapy appropriate for transformed histology, a clinical response was achieved.

Risk factors for post-bronchoscopy pneumonia: a case-control study.

The bronchoscopy, though usually safe, is occasionally associated with complications, such as pneumonia. However, the use of prophylactic antibiotics is not recommended by the guidelines of the British Thoracic Society. Thus far there are few reports of the risk factors for post-bronchoscopy pneumonia; the purpose of this study was to evaluate these risk factors. We retrospectively collected data on patients in whom post-bronchoscopy pneumonia developed from the medical records of 2,265 patients who received 2666 diagnostic bronchoscopies at our institution between April 2006 and November 2011. Twice as many patients were enrolled in the control group as in the pneumonia group. The patients were matched for age and sex. In total, 37 patients (1.4%) had post-bronchoscopy pneumonia. Univariate analysis showed that a significantly larger proportion of patients in the pneumonia group had tracheobronchial stenosis (75.7% vs 18.9%, p < 0.01) and a final diagnosis of primary lung cancer (75.7% vs 43.2%, p < 0.01) than in the control group. The pneumonia group tended to have more patients with a history of smoking (83.8% vs 67.1%, p = 0.06) or bronchoalveolar lavage (BAL) (4.3% vs 14.9%, p = 0.14) than the control group. In multivariate analysis, we found that tracheobronchial stenosis remained an independent risk factor for post-bronchoscopy pneumonia (odds ratio: 7.8, 95%CI: 2.5-24.2). In conclusion, tracheobronchial stenosis was identified as an independent risk factor for post-bronchoscopy pneumonia by multivariate analysis in this age- and sex- matched case control study.

Ultrasensitive enzyme-linked immunosorbent assay for the detection of MPT64 secretory antigen to evaluate Mycobacterium tuberculosis viability in sputum.

OBJECTIVES: This study examined Mycobacterium tuberculosis (MTB)-secreted MPT64 as a surrogate of bacterial viability for the diagnosis of active pulmonary TB (PTB) and for follow-up treatment. METHODS: In this proof-of-concept prospective study, 50 PTB patients in the Tokyo metropolitan region, between 2017 and 2018, were consecutively included and 30 healthy individuals were also included. Each PTB patient submitted sputum on days 0, 14 and 28 for diagnosis and follow-up, and each healthy individual submitted one sputum sample. The following were performed: smear microscopy, Xpert MTB/RIF, MGIT and solid culture, and MPT64 detection on the sputum samples. Ultrasensitive ELISA (usELISA) was used to detect MPT64. The receiver operating characteristic analyses for diagnosis and follow-up revealed the optimal cut-off value of MPT64 absorbance for detecting culture positivity at multiple intervals. RESULTS: The sensitivity of MPT64 for diagnosing PTB was 88.0% (95% CI 75.7-95.5) and the specificity was 96.7% (95% CI 82.8-99.9). The specificity of MPT64 for predicting negative culture results on day 14 was 89.5% (95% CI 66.9-98.7). The sensitivity of MPT64 for predicting positive culture results on day 28 was 81.0% (95% CI 58.1-94.6). CONCLUSIONS: This study revealed that MPT64 is useful for diagnosing active PTB in patients and predicting treatment efficacy at follow-up.

Novel method for sputum induction using the Lung Flute in patients with suspected pulmonary tuberculosis.

BACKGROUND AND OBJECTIVE: The Lung Flute is a small self-powered audio device that generates sound waves, which vibrate in tracheobronchial secretions. This was a preliminary trial to evaluate the usefulness of the Lung Flute for sputum sampling in patients suspected of pulmonary tuberculosis (TB). METHODS: Thirty-four patients who were not expectorating sputum, but for whom sputum examination was required for the differential diagnosis of TB or other diseases, were enrolled in the study. Patients were instructed to blow out fast and hard through the Lung Flute and to repeat this for a total 20 sets of two blows each. RESULTS: Using the Lung Flute, sputum samples were collected within 10 or 20 min from 30 of 34 patients (88%). The device permitted a rapid diagnosis of TB in seven of 15 confirmed TB cases. In three patients acid-fast bacillus smears were positive. In four patients acid-fast bacillus smears were negative, but PCR tests for TB were positive. Hyperventilation-related symptoms occurred in three patients. CONCLUSIONS: The application of the Lung Flute may represent a promising technique for the rapid diagnosis of pulmonary TB.

[A case of sternoclavicular joint tuberculosis with renal failure due to rifampicin].

A 79-year-old man was admitted to a previous hospital complaining of left precordial swelling. Chest CT scan showed destruction of left sternoclavicular joint and a mass of 5 cm in diameter. Needle biopsy was performed and the diagnosis of sternoclavicular joint tuberculosis was made on the basis of presence of M. tuberculosis in the specimen. The patient was treated with isoniazid, ethambutol, rifampicin, and pyrazinamid but he developed renal failure. Then, he was transferred to our hospital. All medications were suspended because of the possibility of the side effect of drugs. We performed renal biopsy and histopathological examination revealed interstitial nephritis and minimal-change glomerulonephritis. From the result of examination, we considered interstitial nephritis was due to rifamicin. The treatment with 50 mg/day of prednisolone and isoniazid, ethambutol, and levofloxacin was administrated and renal failure and precordial mass were improved. Tuberculous arthritis usually affect hip and knee joint and sternoclavicular joint involvement is very rare.

[A cluster of paragonimiasis westermani infections in Thai immigrants].

We report a cluster of infections in four female Thai immigrants aged between 35 and 49 years who developed paragonimiasis westermani within 16 months of ingesting freshwater crabs purchased from a market in Japan. Their symptoms included cough, bloody sputum, chest pain, and dyspnea. Radiographic and CT findings comprised pleural effusion, pneumothorax, air-space consolidation, and nodular opacities. Paragonimus eggs were identified in the feces of one patient, and in the pleural effusion and the bronchoalveolar lavage fluid (BALF) of another. All diagnoses of paragonimiasis westermani were established by enzyme-linked immunosorbent assay (ELISA) of their serum. Paragonimiasis is a re-emerging disease in Japan. Moreover, since the number of immigrant patients is increasing, it is necessary to pay attention to infectious diseases resulting from their eating habits as well as imported diseases.

Tertiary lymphoid organs in the inflammatory myopathy associated with PD-1 inhibitors.

BACKGROUND: Programmed cell death 1 inhibitors have revolutionized therapy for cancer by their outstanding effectiveness. However, they may cause adverse effects, among which inflammatory myopathy is one of the most disabling. To elucidate its mechanism, we analysed muscle biopsies and compared them with other inflammatory myopathies. METHODS: Muscle biopsies from three patients with inflammatory myopathy after treatment with PD-1 inhibitors for cancer were subjected to immunohistochemical and ultrastructural analyses to localize CD8+ cytotoxic cells and markers of lymphoid follicles. For comparison, two cases of polymyositis and one of juvenile dermatomyositis were examined. RESULTS: Nearly identical pathological features were observed in the three cases. In the island-like foci of inflammation, muscle fibers were undergoing degeneration. CD8+ cytotoxic T cells, macrophages, CD4+ cells, and B cells were observed in the foci. CD8+ cells were seen outside and inside the basal lamina of non-necrotic muscle fibers. Lymphoid follicle-like structures with CD21+ follicular dendritic cells were present. The blood vessels in the foci showed features consistent with the high endothelial venules, on which their markers, PNAd and CCL21, were expressed. In polymyositis, blood vessels stained only faintly for PNAd and CCL21, while in juvenile dermatomyositis, in which tertiary lymphoid follicle-like structure was reported in the past, they stained positively. CONCLUSIONS: In inflammatory myopathy associated with PD-1 inhibitors, CD8+ cells appear to predominantly destruct muscle fibers. The presence of lymphoid follicle-like structures and expression of PNAd and CCL21 on the endothelial cells suggest the tertiary lymphoid organs are formed, and involved in the leakage of lymphocytes. Thus, in the three cases examined, formation of the tertiary lymphoid organs is likely to play an important role in genesis of the PD-1 myopathy.

A Case Series of Acute Kidney Injury During Anti-tuberculosis Treatment.

Objective The standard anti-tuberculosis (TB) regimen occasionally causes acute kidney injury (AKI). The major etiology is rifampicin-induced acute interstitial nephritis. However, the standard management of AKI induced by anti-TB drugs has yet to be established. Methods We retrospectively reviewed patients with TB who developed AKI after starting standard anti-TB treatment between 2006 and 2016 at a single TB center. The clinical characteristics and the management are described. Results Among 1,430 patients with active TB, 15 (1.01%) developed AKI. The mean age (standard deviation) was 61 years (18). The median (interquartile range) time to AKI development was 45 days (21-54 days). The median serum creatinine level before anti-TB treatment was 0.7 mg/dL (0.5-1.4 mg/dL), whereas the median peak serum creatinine level after AKI onset was 4.0 mg/dL (3.08-5.12 mg/dL). Five patients (33.3%) were pathologically confirmed as having acute interstitial nephritis (AIN), and 7 patients (46.7%) had a clinical diagnosis of the disease. All anti-TB drugs were stopped, and steroids were administered to 5 (100%) patients with pathologically confirmed AIN and 3 (42.8%) patients with clinically diagnosed AIN. The renal function was normalized in 12 patients (80.0%) after restarting anti-TB treatment without rifampicin (n=12) or isoniazid (n=1). Two patients died due to severe renal failure after restarting rifampicin. Conclusion Rifampicin is the leading cause of AKI. Levofloxacin may be an alternative to rifampicin thanks to its safety and potency. Restarting anti-TB treatment without rifampicin and short-term steroid administration may be a feasible management for AKI.

TAFRO syndrome: current perspectives.

Multicentric Castleman's disease (MCD), a distinct subtype of Castleman's disease, is a rare, nonneoplastic, lymphoproliferative disorder. Patients with MCD present with systemic symptoms and multiple lymphadenopathy. Lymph node biopsy is necessary for the diagnosis of various histological MCD patterns including hyaline vascular, plasma cell, and mixed types. Human herpesvirus 8 (HHV8) infection was identified as an important etiology of MCD among immunocompromised patients such as those positive for human immunodeficiency virus. Although HHV8-negative MCD was reported in immunocompetent patients, the underlying etiology remains unknown. Several experts speculate that MCD in immunocompetent patients might be due to proinflammatory hypercytokinemia because of infection by a virus other than HHV8, inflammation, or neoplastic disease. In 2010, a distinct variant of HHV8-negative MCD reported in Japan was characterized by thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (TAFRO). Recent case reports and a systematic review suggest that TAFRO syndrome might have a unique pathogenesis among HHV8-negative MCD variants. This review introduces TAFRO syndrome as a subtype of HHV8-negative MCD and offers an overview of the current perspectives on this syndrome.