Rapidly progressive interstitial lung disease with positive anti-MDA5 antibody as an immune-related complication of nivolumab: A case report.

Clinically amyopathic dermatomyositis (CADM) with a positive anti-MDA5 antibody titer is often associated with lethal rapidly progressive interstitial lung disease (RP-ILD). Despite the widespread use of immune checkpoint inhibitors (ICIs) in practice, there is no report of CADM with positive anti-MDA5 antibodies as their immune-related complication. We present a case of malignant mesothelioma who developed RP-ILD accompanied by distinct skin manifestations following the administration of nivolumab. Postmortem assessment of stored samples revealed a pre-existing positive titer of anti-MDA5 antibody, further augmented following ICI use, suggesting the possible value of serum screening for better risk stratification of this lethal complication.

Successful Treatment with High-dose Steroids for Acute Exacerbation of Idiopathic Pulmonary Fibrosis Triggered by COVID-19.

We herein report a case of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) triggered by COVID-19. An 87-year-old woman tested positive for COVID-19 on a polymerase chain reaction test, and computed tomography revealed ground-glass opacity (GGO) superimposed on a background pattern consistent with usual interstitial pneumonia. Considering these data, we diagnosed her with AE-IPF. She experienced worsening of dyspnea and expansion of the GGO. Therefore, we introduced high-dose steroids (methylprednisolone 250 mg/day for 3 days). After the treatment, the pulmonary infiltrates improved. She was discharged from our hospital without severe disability. High-dose steroids can be a viable treatment option for AE-IPF triggered by COVID-19.

Phase II Clinical Trial of Combination Therapy with Favipiravir and Methylprednisolone for COVID-19 with Non-Critical Respiratory Failure.

INTRODUCTION: The administration of systemic corticosteroids is a key strategy for improving COVID-19 outcomes. However, evidence is lacking on combination therapies of antiviral agents and systemic corticosteroids. The objective of this study was to investigate the efficacy and safety of the combination therapy of favipiravir and methylprednisolone in preventing respiratory failure progression in patients with COVID-19 and non-critical respiratory failure. METHODS: We conducted a multicenter, open-label, single-arm phase II study. The patients received favipiravir 3600 mg on the first day, followed by 1600 mg for a total of 10-14 days. Methylprednisolone was administered intravenously at 1 mg/ideal body weight (IBW)/day from days 1 to 5, followed by 0.5 mg/IBW/day from days 6 to 10 if clinically indicated. The primary endpoint was the proportion of patients requiring mechanical ventilation (MV) (including noninvasive positive pressure ventilation) or those who met the criteria for tracheal intubation within 14 days of the study treatment initiation (MVCTI-14). RESULTS: Sixty-nine patients were enrolled and underwent the study treatment. Of them, the MVCTI-14 proportion was 29.2% (90% confidence interval 20.1-39.9, p = 0.200). The proportion of patients who required MV or who died within 30 days was 26.2%, and 30-day mortality was 4.9%. The most significant risk factor for MVCTI-14 was a smoking history (odds ratio 4.1, 95% confidence interval 1.2-14.2). The most common grade 3-4 treatment-related adverse event was hyperglycemia, which was observed in 21.7%. CONCLUSION: The MVCTI-14 proportion did not reach a favorable level in the clinical trial setting with the threshold of 35%. However, the proportion of MV or death within 30 days was 26.6%, which might be close to the findings (28.1%) of the RECOVERY trial, which showed the efficacy of dexamethasone for patients with COVID-19 and non-critical respiratory failure. Further evaluation of this combination therapy is needed. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) identifier jRCTs041200025.

BK virus-associated viruria and viremia in a patient with lymphangioleiomyomatosis after lung re-transplantation: A case report and review of the literature on BK virus infection post-lung transplantation.

The BK virus (BKV) is a member of the polyomaviridae family of DNA viruses. BKV reactivates under a highly immunosuppressed state and causes renal dysfunction. In renal transplant patients, BKV infection leads to tubular impairment and loss of transplanted kidney grafts. However, few studies have reported on the relationship between BKV and lung transplantation. Adjustment of the dosage of immunosuppressants is needed in some cases, but the treatment method has not been established. Here, we report a case of BKV-associated viruria and viremia in a patient with lymphangioleiomyomatosis (LAM) after lung re-transplantation. A 44-year-old female refractory LAM patient who had undergone lung re-transplantation 3 months earlier was diagnosed with BKV-associated viruria and viremia. Urine cytology indicated decoy cells and the urine and serum polymerase chain reaction test was positive for BKV. As scheduled after re-transplantation surgery, immunosuppressive drugs were progressively reduced. This patient was considered to have experienced spontaneous BKV-associated viremia and viruria. Review of the literature suggested that 17%-42% of BKV-associated viruria cases have been reported after lung transplantation, but cases of BKV-associated nephropathy are rarely reported. Based on the present case, doctors involved in lung transplantation should monitor patients for BKV infection. Decoy cell monitoring by urine cytology is a useful screening method in the follow-up observation after lung transplantation. Early-stage interventions may prevent BKV-associated nephropathy even in patients who have developed BKV viremia, and sirolimus can be administered to patients with histories of BKV infection if they are carefully monitored.

Anti-PD-L1 peptide improves survival in sepsis.

BACKGROUND: Sepsis remains a leading cause of death in most intensive care units. Many deaths in sepsis are due to nosocomial infections in patients who have entered the immunosuppressive phase of the disorder. One cause of immunosuppression in sepsis is T-cell exhaustion mediated by programmed cell death-1 (PD-1) interaction with its ligand (PD-L1). Studies demonstrated that blocking the interaction of PD-1 with PD-L1 with knockout mice or inhibitory antibodies reversed T-cell dysfunction and improved sepsis survival. This study assessed the efficacy of a novel short-acting peptide (compound 8) that inhibits PD-1:PD-L1 signaling in a clinically relevant second-hit fungal sepsis model. METHODS: Mice underwent cecal ligation and puncture to induce peritonitis. Three days later, mice received intravenous injection of Candida albicans. Forty-eight hours after Candida infection, mice were treated with compound 8 or inactive peptide. The effect of Candida infection on expression of coinhibitory molecules, PD-1, and PD-L1 were quantitated by flow cytometry on CD4+ cells, CD8+ cells, natural killer (NK) cells, and natural killer T-cells (NKT). The effect of compound 8 on survival was also examined. RESULTS: Four days after fungal infection, PD-1 and PD-L1 expressions were markedly increased on CD4+, NK, and NKT cells in septic versus sham-operated mice (%PD-1 on CD4+, 11.9% versus 2.8%; and %PD-L1 on NKT, 14.8% versus 0.5%). Compared with control, compound 8 caused a 2-fold increase in survival from 30% to 60%, P < 0.05. CONCLUSIONS: Compound 8 significantly improved survival in a clinically relevant immunosuppressive model of sepsis. These results support immunoadjuvant therapy targeting T-cell exhaustion in this lethal disease.

Endothelial adhesion molecules and multiple organ failure in patients with severe sepsis.

OBJECTIVE: To determine if serum levels of endothelial adhesion molecules were associated with the development of multiple organ failure (MOF) and in-hospital mortality in adult patients with severe sepsis. DESIGN: This study was a secondary data analysis of a prospective cohort study. SETTING: Patients were admitted to two tertiary intensive care units in San Antonio, TX, between 2007 and 2012. PATIENTS: Patients with severe sepsis at the time of intensive care unit (ICU) admission were enrolled. Inclusion criteria were consistent with previously published criteria for severe sepsis or septic shock in adults. Exclusion criteria included immunosuppressive medications or conditions. INTERVENTIONS: None. MEASUREMENTS: Baseline serum levels of the following endothelial cell adhesion molecules were measured within the first 72h of ICU admission: Intracellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), and Vascular Endothelial Growth Factor (VEGF). The primary and secondary outcomes were development of MOF (⩾2 organ dysfunction) and in-hospital mortality, respectively. MAIN RESULTS: Forty-eight patients were enrolled in this study, of which 29 (60%) developed MOF. Patients that developed MOF had higher levels of VCAM-1 (p=0.01) and ICAM-1 (p=0.01), but not VEGF (p=0.70) compared with patients without MOF (single organ failure only). The area under the curve (AUC) to predict MOF according to VCAM-1, ICAM-1 and VEGF was 0.71, 0.73, and 0.54, respectively. Only increased VCAM-1 levels were associated with in-hospital mortality (p=0.03). These associations were maintained even after adjusting for APACHE and SOFA scores using logistic regression. CONCLUSIONS: High levels of serum ICAM-1 was associated with the development of MOF. High levels of VCAM-1 was associated with both MOF and in-hospital mortality.

Interleukin-7 and anti-programmed cell death 1 antibody have differing effects to reverse sepsis-induced immunosuppression.

Sepsis remains a major cause of morbidity and mortality in most intensive care units. Protracted sepsis can evolve into a state of profound immunosuppression characterized by secondary infections, frequently with opportunistic-type pathogens. Immunoadjuvant therapy is currently being evaluated as a novel treatment for patients with sepsis. Two of the most promising immunoadjuvants are interleukin-7 (IL-7) and anti-programmed cell death 1 antibody (anti-PD-1). Both IL-7 and anti-PD-1 have been reported to boost host immunity and improve outcomes in patients with viral infections and cancer. The purpose of this study was to define the immunological mechanisms of action of IL-7 and anti-PD-1 in the two-hit sepsis model of cecal ligation and puncture followed by Candida albicans. In addition, we examined whether combined treatment with IL-7 and anti-PD-1 provided any additive beneficial effects in reversing immune dysfunction. The present findings demonstrated that IL-7 and anti-PD-1 had differing effects on innate and adaptive immune functions. Compared with anti-PD-1, IL-7 increased lymphocyte proliferation; expression of lymphocyte adhesion molecules, lymphocyte function-associated antigen 1, and very late antigen-4; interferon-γ production; and CD28 expression on splenic CD8 T cells. In contrast, anti-PD-1 seemed to have a greater effect on major histocompatibility complex class II expression on splenic macrophages and dendritic cells than IL-7. Combined treatment with IL-7 and anti-PD-1 produced additive effects on CD28 expression, lymphocyte proliferation, and splenic secretion of interferon-γ. In conclusion, the present study shows differences in immunomodulatory actions between IL-7 and anti-PD-1 and provides a potential rationale for combining IL-7 and anti-PD-1 in the therapy of sepsis.

Molecular epidemiological characteristics of Klebsiella pneumoniae associated with bacteremia among patients with pneumonia.

Some important virulence factors have been elucidated in Klebsiella pneumoniae infections. We investigated the relationship between virulence factors and multilocus sequence types (STs) and assessed the risk factors for bacteremia in patients with pneumonia due to K. pneumoniae. From April 2004 through April 2012, a total of 120 K. pneumoniae isolates from patients with pneumonia (23 with bacteremia and 97 without bacteremia) were collected from 10 medical institutions in Japan. Additionally, 10 strains of K. pneumoniae serotype K2 that were isolated >30 years ago were included in this study. These isolates were characterized using multilocus sequence typing (MLST), and the characteristics of their virulence factors, such as hypermucoviscosity phenotype and RmpA and aerobactin production between patients with and without bacteremia, were examined. MLST analysis was performed on the 120 isolates from patients with pneumonia, and some sequence type groups were defined as genetic lineages (GLs). GL65 was more prevalent among patients with bacteremia (21.7%) than in those without bacteremia (7.2%). The majority of the strains with serotype K2 were classified into GL14 or GL65, and rmpA and the gene for aerobactin were present in all GL65-K2 strains but absent in all GL14-K2 strains. In a multivariate analysis, the independent risk factors for bacteremia included GL65 (adjusted odds ratio [AOR], 9.46; 95% confidence interval [CI], 1.81 to 49.31), as well as neoplastic disease (AOR, 9.94; 95% CI, 2.61 to 37.92), immunosuppression (AOR, 17.85; 95% CI, 1.49 to 214.17), and hypoalbuminemia (AOR, 4.76; 95% CI, 1.29 to 17.61). GL65 was more prevalent among patients with bacteremia and was associated with the virulence factors of K. pneumoniae.

Prospective analysis of efficacy and safety of an individualized-midazolam-dosing protocol for sedation during prolonged bronchoscopy.

BACKGROUND: Newer more advanced techniques in bronchoscopy may require longer procedure times, although a standard protocol for sedation during prolonged bronchoscopy has not yet been defined. METHODS: We designed a prospective, non-randomized, single-arm study (UMIN trial number 000003971) using patient questionnaires and vital sign monitoring to assess the efficacy and safety of a standardized midazolam dosing protocol based on gender and age for use during bronchoscopy. The loading dose of midazolam was 0.075mg/kg for men ≤65 years old and women ≤70 and 0.05mg/kg for men ≥66 years and women ≥71 years, with subsequent doses of one-half the loading dose to be administered every 20min. The primary endpoint was tolerability and secondary endpoints included anxiety and recall of procedure, willingness to undergo repeat procedure, and complications. Safety was evaluated in terms of monitored changes in blood pressures, ECG, oxygen saturation, and CO2 content in expiration during the procedure. RESULTS: A total of 204 patients were included in the study. Overall, 163 patients (79.9%) reported "no distress" during the procedure, 185 patients (90.7%) reported "no anxiety," and 175 (85.8%) replied that they would accept a repeat procedure, if necessary. The mean minimum oxygen saturation was 90.2% and the mean maximum expiratory CO2 level was 37.7mmHg. There were no serious complications related to the protocol. CONCLUSIONS: The midazolam dosing protocol examined in this study was safe and effective. It is simple, and it could easily be translated to routine clinical practice.

Endobronchial ultrasound transbronchial needle aspiration in older people.

AIM: The usefulness and safety of endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) have been established recently, but no study has evaluated whether or not aging increases the risk of the procedure. In the present study, we aimed to assess the usefulness and safety of EBUS-TBNA in older patients. METHODS: The medical records and database of 109 patients who received EBUS-TBNA between 2008 and 2011 at Nagoya University Hospital, Nagoya, Japan were reviewed retrospectively. All patients underwent bronchoscopy under light sedation with midazolam. A total of 34 patients were aged 70 years or older (the older group) and 75 were aged 69 years or younger (the younger group). We analyzed patients' characteristics, changes of clinical parameters, usage doses of midazolam and lidocaine, procedure duration, geographic data of biopsied lymph nodes, diagnostic yield, and complications in both groups. RESULTS: There were more comorbidities in the older group. Four patients (11.8%) in the older group had poor performance status (2-3). Systolic blood pressure at baseline was significantly higher in the older group. There were no statistical differences between the two groups in some clinical parameters (minimum oxygen saturation [SpO2 ], reduction in SpO2 , maximum oxygen supplementation, elevation of systolic blood pressure, increase of heart rate) during the procedure. Diagnostic performance in older patients was similar to that found in younger patients. There was no difference in the frequency of complications between both groups. CONCLUSION: Safety and usefulness of EBUS-TBNA in older people were comparable with those in younger people.

Clinical characteristics of Pneumocystis pneumonia in non-HIV patients and prognostic factors including microbiological genotypes.

BACKGROUND: The number of patients with non-HIV Pneumocystis pneumonia (PCP) is increasing with widespread immunosuppressive treatment. We investigated the clinical characteristics of non-HIV PCP and its association with microbiological genotypes. METHODS: Between January 2005 and March 2010, all patients in 2 university hospitals who had been diagnosed with PCP by PCR were enrolled in this study. Retrospective chart review of patients, microbiological genotypes, and association with 30-day mortality were examined. RESULTS: Of the 82 adult patients investigated, 50 patients (61%) had inflammatory diseases, 17 (21%) had solid malignancies, 12 (15%) had hematological malignancies, and 6 (7%) had received transplantations. All patients received immunosuppressive agents or antitumor chemotherapeutic drugs. Plasma (1→3) ß-D-glucan levels were elevated in 80% of patients, and were significantly reduced after treatment in both survivors and non-survivors. However, ß-D-glucan increased in 18% of survivors and was normal in only 33% after treatment. Concomitant invasive pulmonary aspergillosis was detected in 5 patients. Fifty-six respiratory samples were stored for genotyping. A dihydropteroate synthase mutation associated with trimethoprim-sulfamethoxazole resistance was found in only 1 of the 53 patients. The most prevalent genotype of mitochondrial large-subunit rRNA was genotype 1, followed by genotype 4. The most prevalent genotype of internal transcribed spacers of the nuclear rRNA operon was Eb, followed by Eg and Bi. Thirty-day mortality was 24%, in which logistic regression analysis revealed association with serum albumin and mechanical ventilation, but no association with genotypes. CONCLUSIONS: In non-HIV PCP, poorer general and respiratory conditions at diagnosis were independent predictors of mortality. ß-D-glucan may not be useful for monitoring the response to treatment, and genotypes were not associated with mortality.

Second-line weekly paclitaxel in resistant or relapsed non-small cell lung cancer treated with docetaxel and carboplatin: a multi-center phase II study.

We conducted a phase II trial to evaluate the safety and efficacy of weekly paclitaxel in patients with resistant or relapsed non-small cell lung cancer (NSCLC) treated with docetaxel and carboplatin. Thirty-two NSCLC patients at a median age of 58.0 years (range 33-75) were enrolled. The Eastern Cooperative Oncology Group performance status scores (0/1/2) were 18/9/5, respectively. The majority of patients had adenocarcinoma (84%) and stage IV disease (81%). The response rate for the first-line chemotherapy was 28%. Paclitaxel was administered at a dose of 80 mg/m(2) as an intravenous infusion 60 min weekly for 6 consecutive weeks of an 8-week cycle. All patients were assessable for response and toxicity. The median number of cycles administered was two (range 1-8), and the overall response rate was 15.6%. The median survival time (MST) was 10.6 months (95% CI=8.2-12.5), while the 1-year survival rate was 37.5%, and the median progression-free survival was 4.9 months (95% CI=3.0-7.1). Hematological toxicities (grade 3 or 4) were observed in 15 patients (46.9%) with leukopenia, and in 4 (12.5%) with anemia. Non-hematological toxicity was generally mild, though grade 3 anorexia was observed in 3 patients (9.3%). No treatment-related deaths were observed. In conclusion, second-line weekly paclitaxel is effective in NSCLC patients treated with docetaxel plus carboplatin and is associated with a tolerable toxicity profile.

[A case of Langerhans cell histiocytosis which resolved only on smoking cessation].

We report a case with Langerhans cell histiocytosis appearing as an extra-pleural tumor. A 20-year-old man was transferred to our hospital because of right chest pain and fever. His chest X-ray showed an extra-pleural mass and chest CT scan showed a mass lesion with right 7th rib fracture. 67Gallium and bone scintigram showed uptake at the same site. We performed a CT-guided puncture biopsy. Pathological findings of the specimen showed diffuse proliferation of histiocytoid cells with some eosinophils. The histiocytes were positive for S-100 protein and CD1a on immunohistochemical stain. Langerhans cell histiocytosis was diagnosed. There was no other involvement of the disease except the rib. The tumor resolved only with smoking cessation and no recurrence was observed during the follow-up period. An association between smoking and progressions of the rib disease was suggested.