Cryptogenic organizing pneumonia: clinical outcomes of 60 consecutive cases.

Background: Cryptogenic organizing pneumonia (COP) improves rapidly following corticosteroid treatment; however, relapse is common. Therefore, this retrospective observational study aimed to clarify the clinical outcomes of COP and identify the predictive factors for relapse. Methods: The laboratory findings, pulmonary function test results, computed tomography (CT) findings, and clinical outcomes of 60 consecutive COP patients treated at our institution between 2007 and 2013 were retrospectively reviewed. The clinical characteristics of COP patients who did and did not show improvement were compared to identify the predictive factors for relapse in patients showing improvement. Results: Forty-one patients showed improvement without relapsing (Group 1), whereas thirteen relapsed after showing improvement (Group 2). Six patients did not show any improvement (Group 3). The serum Krebs von den Lungen-6 (KL-6) levels in Group 3 were greater than those in Groups 1 and 2 (P=0.004). The incidence of traction bronchiectasis and reticular opacities in Group 3 was higher than that in Groups 1 and 2 (P=0.048 and P=0.006, respectively). The cut-off levels of C-reactive protein (CRP), blood neutrophil fraction (%neutrophils) and lymphocyte fraction (%lymphocytes) for predicting relapse were 6.84 mg/dL, 68.7% and 14.1% in Groups 1 and 2, respectively. The log-rank test revealed that high serum CRP levels (P<0.001), high %neutrophils (P=0.003) and low %lymphocytes (P=0.006) showed significant correlations with a shorter time to the first relapse episode. Conclusions: Chest CT findings depicting pulmonary fibrosis and high serum KL-6 levels were correlated with the non-improvement of COP. Blood test results indicating inflammatory reactions were correlated with relapse in patients with COP showing improvement.

Cytokine Release Syndrome with Relative Adrenal Insufficiency Induced by Ipilimumab and Nivolumab Combination Therapy for Clear Cell Renal Cell Carcinoma.

Combination therapy with ipilimumab and nivolumab is indicated for many types of cancers; however, several patients experience immune-related adverse events (irAEs). We herein report a case of cytokine release syndrome (CRS) in a 63-year-old woman with stage IV left clear cell renal cell carcinoma. Our patient developed CRS while taking prednisolone, 43 days after the start of ipilimumab and nivolumab administration. The patient was treated with steroid pulse therapy, which improved the symptoms of shock and respiratory failure. Increased vascular permeability and relative adrenal insufficiency are considered to be the main pathogeneses. The early administration of high-dose steroids is crucial as a replacement for corticosteroids.

Combination Therapy With Erlotinib and Ramucirumab in a Patient With Epidermal Growth Factor Receptor Mutation Positive Lung Adenocarcinoma and Interstitial Pneumonia: A Case Report.

Interstitial pneumonia often acts as a barrier to lung cancer treatment. We report the case of a 79-year-old man who was diagnosed with epidermal growth factor receptor (EGFR) mutation positive lung adenocarcinoma (T2aN0M0, stage ⅠB, EGFR exon 19 deletion), and was positive for anti-aminoacyl-tRNA synthetase antibodies with interstitial pneumonia. Metastasis in the right seventh rib was detected three months after surgical resection and radiation therapy was initiated. As recurrence was observed at both ends of the radiation field five months later, combination chemotherapy with erlotinib and ramucirumab was initiated. Approximately one year has passed since the start initiation of treatment, and acute exacerbation of interstitial pneumonia has not been observed during the follow-up period observation. The tumor has remained stable, indicating stable disease.

A Case of Takotsubo Cardiomyopathy Triggered by Asthma Exacerbation After mRNA-based Vaccination for COVID-19.

It is recommended to get the multiple coronavirus disease 2019 (COVID-19) vaccinations for almost all people including asthma patients. A 70-year-old Japanese woman with asthma experienced worsening of respiratory symptoms after the second dose of the mRNA-based COVID-19 vaccine BNT162b2. The patient had hypercapnic respiratory failure and cardiac-apex ballooning and was diagnosed with takotsubo cardiomyopathy induced by asthma exacerbation. Therapies for asthma exacerbation resulted in prompt improvement of respiratory failure and cardiac-apex ballooning. Our findings suggest that asthma patients are prone to exacerbations after receiving the COVID-19 vaccination; therefore, stratification of the patients at risk is required.

Exacerbation of Eosinophilic Granulomatosis With Polyangiitis After Administering Dupilumab for Severe Asthma and Eosinophilic Rhinosinusitis With Nasal Polyposis.

Eosinophilic granulomatosis with polyangiitis (EGPA) refers to systemic vasculitis in patients with bronchial asthma and eosinophilic rhinosinusitis. Dupilumab has been approved for the treatment of asthma, eosinophilic rhinosinusitis, and atopic dermatitis. A man in his 50s with a history of asthma and eosinophilic rhinosinusitis with nasal polyposis developed high fever and dyspnea while undergoing dupilumab treatment. Laboratory examinations identified hypereosinophilia. Chest radiography and computed tomography revealed right-sided tracheal dislocation, extensive consolidation, and ground-glass opacities with traction bronchiectasis. Evidence of interstitial pneumonia, eosinophilia, and increased eosinophil counts in the bronchoalveolar lavage fluid was observed. We diagnosed the patient with EGPA and administered corticosteroids, which improved his symptoms and radiographic signs. Although the relationship between EGPA and dupilumab treatment is unclear, EGPA may have been exacerbated by dupilumab in this case. Therefore, when administering dupilumab to patients with partial symptoms of EGPA, care should be taken to monitor for adverse symptom development and exacerbation.

Non-small Cell Lung Cancer With Proto-Oncogene B-Raf V600E Presenting a Distinctive Clinical Course: A Case Report.

Cases of proto-oncogene B-Raf (BRAF) V600E mutation are rare, accounting for 1%-4% of non-small cell lung cancers (NSCLCs), and its clinical features remain unclear. Here, we report a case of BRAF mutation-positive lung adenocarcinoma with an atypical clinical course and long-term survival. The patient was a 63-year-old female nonsmoker who was diagnosed with stage IA adenocarcinoma after surgical resection. Five years after the surgery, cancer recurred and was treated with various cytotoxic anticancer agents. During the course of treatment, the patient was found to be BRAF V600E mutation-positive and was treated with molecular-targeted drugs. Although multiple brain, subcutaneous, and tonsillar metastases appeared, the progression was significantly slower, and the patient survived for 14 years and three months after the diagnosis. There have been few case reports of long-term survival in BRAF-positive lung cancer, and more cases need to be accumulated in the future to gather more information. Based on this case, we speculate that sensitivity to cytotoxic anticancer agents such as pemetrexed (PEM) and maintenance of performance status (PS), in addition to molecular-targeted agents, are important for long-term survival.

Successful treatment of paraneoplastic pemphigus and bronchiolitis obliterans associated with follicular lymphoma with obinutuzumab and bendamustine.

We herein report the rare case of a 72-year-old female who presented with paraneoplastic pemphigus (PNP) and bronchiolitis obliterans (BO) associated with follicular lymphoma (FL), who was successfully treated with obinutuzumab (GA101; G) and bendamustine (B). The patient had severe erosive stomatitis and bilateral conjunctival hyperemia that persisted for more than 6 months. A huge mass was found in the abdominal cavity, and a biopsy revealed grade 1 FL (stage IV). Based on a lip biopsy result, the patient was diagnosed with PNP associated FL. The patient received bendamustine and obinutuzumab (BG) chemotherapy and FL and PNP responded very well, but BO was additionally associated during the course of BG. BO progressed without exacerbation as BG therapy progressed to a 2 year maintenance therapy with G, and combination of azithromycin, inhaled bronchodilator therapy, and corticosteroid. She was followed up at the outpatient department with no pulmonary function decline or FL and PNP recurrence. Our case suggests that BG could be a promising treatment option for PNP and BO.

Prolonged persistence of SARS-CoV-2 infection during A+AVD therapy for classical Hodgkin's lymphoma: A case report.

We describe a case of coronavirus disease 2019 (COVID-19) in a patient with mixed cellularity classical Hodgkin lymphoma (cHL) undergoing brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) therapy. A 43-year-old man presented to our hospital with a complaint of fever, for which he was diagnosed with COVID-19 after a positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and antiviral therapy with favipiravir and ciclesonide was started subsequently. The fever persisted for the first few days of treatment, but his respiratory status was stable, and he became asymptomatic and afebrile on day 9. Although the PCR tests remained positive, he met the updated discharge criteria of the World Health Organization (WHO) on day 12. However, his fever recurred, and his condition worsened on day 16. A chest X-ray showed a new opacity. It is likely that favipiravir and ciclesonide treatment probably did not completely eliminate the virus in the patient, and therefore the infection persisted. We added remdesivir from day 21, and the improvement was remarkable. He was discharged on day 29 after two consecutive PCR test results were negative. PCR tests are not mandatory for the updated WHO discharge criteria. However, even after antiviral therapy, COVID-19 patients with hematologic malignancies may have prolonged active infection with impaired viral excretion. Depending on the background disease and comorbidities, there may be some patient populations for whom it is not appropriate to simply comply with the current discharge criteria. Therefore, more emphasis may be needed on PCR examinations.

Resumption/efficacy and safety of an azithromycin-containing regimen against Mycobacterium avium complex lung disease in patients who experienced adverse effects with a clarithromycin-containing regimen.

BACKGROUND: Antibiotic therapy, including clarithromycin (CLR), has been widely used for the management of Mycobacterium avium complex (MAC) lung disease in clinical settings. When patients develop adverse events (AEs) during CLR-based treatment, the treatment regimen is modified or chemotherapy itself is discontinued. The need for alternative macrolide treatment strategies is emphasized due to the high rate of AEs possibly caused by CLR. Thus, the current study aimed to examine the efficacy and safety of azithromycin (AZM) in patients with MAC lung disease whose treatment was switched from CLR to AZM. METHODS: We performed a retrospective study of patients with MAC lung disease. The inclusion criteria were as follows: (1) patients who experienced AEs during treatment with antibiotics, including CLR, between December 2012 and November 2017, and (2) those who had antimicrobial therapy that was switched from CLR to AZM. The efficacy and safety of AZM during the clinical course of the disease after switching the regimen from CLR to AZM were investigated. RESULTS: Antibiotic therapy was switched in 31 patients who presented with AEs including drug-induced fever, rash, dysgeusia, liver dysfunction, and neutropenia during treatment with CLR-containing regimens. After switching to AZM, the median duration of treatment was 1286 (364-4615) days. During follow-up, 13 patients had a negative conversion of sputum culture. CONCLUSIONS: AZM may be safe and effective for patients with MAC lung disease who have difficulty tolerating CLR. In patients who experienced AEs possibly caused by CLR, switching from CLR to AZM might be an appropriate strategy.

A case of non-small cell lung cancer with danazol-dependent aplastic anemia induced by pembrolizumab.

Programmed cell death protein 1 immune checkpoint inhibitor is an effective treatment for non-small cell lung cancer. Although hematological immune-related adverse events induced by antiprogrammed-cell-death-protein-1 immunotherapy have been reported, they are rare, and there remain many unknowns. We report the case of a 77-year-old woman with non-small cell lung cancer and pembrolizumab-induced danazol-dependent aplastic anemia. Sixteen days after she received pembrolizumab with carboplatin and pemetrexed as first-line treatments, she developed pancytopenia, including severe thrombocytopenia (1 × 109/L) with oral bleeding, epistaxis, and systemic purpura. We initially diagnosed immune-related thrombocytopenia based on an elevated level of platelet-associated immunoglobulin G (922ng/107 cells), but her thrombocytopenia was refractory to prednisolone (1mg/kg) and thrombopoietin receptor agonists. We eventually diagnosed aplastic anemia based on the findings of bone marrow hypoplasia. Treatment with cyclosporine and danazol 300mg (7.5mg/kg) was initiated. Eighteen days later, her blood cell count increased, and we reduced danazol to 100mg. Twenty-four days after the reduction of danazol, her platelet count dropped again to 14 × 109/L; subsequently, increasing danazol improved her platelet count in a few days. Although aplastic anemia was recovered, she died owing to lung cancer progression. In this case, the thrombocytopenia was noticeable initially; however, pancytopenia appeared a month later, and we diagnosed her with aplastic anemia. Platelet counts improved rapidly with the use of danazol. No effective treatment has yet been established for aplastic anemia induced by antiprogrammed-cell-death-protein-1 immunotherapy, but our case suggests that danazol is an effective therapy.

High levels of anti-SSA/Ro antibodies in COVID-19 patients with severe respiratory failure: a case-based review : High levels of anti-SSA/Ro antibodies in COVID-19.

We treated two patients with severe respiratory failure due to coronavirus disease 2019 (COVID-19). Case 1 was a 73-year-old woman, and Case 2 was a 65-year-old-man. Neither of them had a history of autoimmune disease. Chest computed tomography scans before the antiviral therapy showed bilateral multiple patchy ground-glass opacities (GGO) consistent with COVID-19 pneumonia. The GGO regressed over the course of the antiviral treatment; however, new non-segmental patchy consolidations emerged, which resembled those of interstitial lung disease (ILD), specifically collagen vascular disease-associated ILD. We tested the patients' sera for autoantibodies and discovered that both patients had high anti-SSA/Ro antibody titers. In Case 1, the patient recovered with antiviral therapy alone. However, in Case 2, the patient did not improve with antiviral therapy alone but responded well to corticosteroid therapy (methylprednisolone) and made a full recovery. The relationship between some immunological responses and COVID-19 pneumonia exacerbation has been discussed previously; our discovery of the elevation of anti-SSA/Ro antibodies suggests a contribution from autoimmunity functions of the immune system. Although it is unclear whether the elevation of anti-SSA/Ro antibodies was a cause or an outcome of aggravated COVID-19 pneumonia, we hypothesize that both patients developed aggravated the COVID-19 pneumonia due to an autoimmune response. In COVID-19 lung injury, there may be a presence of autoimmunity factors in addition to the known effects of cytokine storms. In patients with COVID-19, a high level of anti-SSA/Ro52 antibodies may be a surrogate marker of pneumonia severity and poor prognosis.

Single-Center Noninferiority Randomized Trial on the Efficacy and Safety of Low- and High-Dose Rush Oral Milk Immunotherapy for Severe Milk Allergy.

INTRODUCTION: Oral immunotherapy (OIT) has been reported to be effective but associated with a risk of severe symptoms. Thus, an OIT method with decreased risk is required. OBJECTIVES: We aimed to evaluate the efficacy and safety of low- and high-dose OIT regimens in children with severe milk allergy. METHODS: Overall, 33 participants (median age, 9 years; median final dose of the milk oral food challenge [OFC], 2 mL) were included. The participants were randomly assigned to groups that received either a low (20 mL; n = 19) or high (100 mL; n = 14) maintenance target dose of OIT. The dose was gradually increased to the target dose in the rush escalation phase and was then maintained daily at home. The primary endpoint was the final OFC dose at 6 months of OIT. Adverse events during OIT were evaluated. RESULTS: The final OFC dose after OIT was significantly higher than that before OIT in both groups (low-dose, p = 0.000; high-dose, p = 0.006), but there was no significant difference in the final OFC dose between the 2 groups (p = 0.767). In the maintenance phase, the high-dose group had significantly more severe symptoms than did the low-dose group (0.5%, 11/2,355 total intake events vs. 0.1%, 4/3,230 total intake events; p = 0.018). CONCLUSIONS: An equally increased dose effect was observed for maintenance OIT doses of 20 and 100 mL in children with severe milk allergy. The risk of severe symptoms in the maintenance phase was lower in the low-dose group. A low-dose OIT regimen is recommended for severe milk allergy.

Bacterial population kinetics in heteroresistant Mycobacterium tuberculosis harbouring rare resistance-conferring mutations in gyrA and rpoB imply an epistatic interaction of mutations in a pre-XDR-TB patient.

OBJECTIVES: Bacterial population kinetics of strains harbouring drug resistance-conferring mutations within a patient often show cryptic resistance in clinical practice. We report a case that showed emergence and dominance of Mycobacterium tuberculosis with uncommon rpoB and gyrA mutations, followed by an rpoC compensatory mutation, during treatment. METHODS: A pre-XDR-TB patient showed heteroresistance to rifampicin and levofloxacin during treatment as a result of intermittent self-cessation. WGS was applied to investigate intra-host strain composition using five pairs of isolates from sputum samples. RESULTS: The subclone in this study possessed rare mutations conferring resistance to rifampicin (rpoB V170F) and levofloxacin (gyrA S91P) and it rapidly outcompeted other subclones during treatment that included levofloxacin but not rifampicin (<7 days). The high-probability compensatory mutation rpoC V483A also emerged and became dominant subsequent to the rpoB V170F mutation. CONCLUSIONS: To the best of our knowledge, this is the first case showing the emergence of such a rare variant that dominated the population within a patient during treatment of TB.

Characteristics and prognosis of interstitial pneumonias complicated with pneumomediastinum.

BACKGROUND: The clinical characteristics and prognostic impact of complication with pneumomediastinum in patients with interstitial pneumonias (IPs) are not well studied due to the relatively limited nature of available reports. The purpose of this study was to clarify the characteristics and prognostic factors of IPs complicated with pneumomediastinum. METHODS: Consecutive patients with IPs complicated with pneumomediastinum detected by computed tomography (CT) between July 1, 2011, and April 30, 2014 were retrospectively reviewed. Clinical data including symptoms associated with pneumomediastinum, laboratory data, lung function tests, treatments, and mortality were collected from medical records. RESULTS: Forty-five patients (25 males, 20 females), including 32 with idiopathic IP (IIPs) and 13 connective tissue disease-associated interstitial lung diseases (CTD-ILDs) were identified. The median age of onset of pneumomediastinum was 72 years (interquartile range [IQR] 68-79 years). The most common symptom associated with occurrence of pneumomediastinum was appearance or worsening of dyspnoea. No specific treatment was performed for most (84%) of the cases. The median period between occurrence and improvement of pneumomediastinum was 29 days (IQR 5-69 days). Multivariate analysis revealed that IIPs and no improvement of pneumomediastinum were associated with poor prognosis. CONCLUSIONS: Patients with IIPs complicated with pneumomediastinum and those without improvement of pneumomediastinum had poor prognosis.

Carcinoembryonic antigen and CYFRA 21-1 responses as prognostic factors in advanced non-small cell lung cancer.

BACKGROUND: It is unclear whether changes in serum tumor marker expression post-treatment are of prognostic value. We investigated the associations between changes in serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) after first-line treatment and overall survival (OS) in non-small cell lung cancer (NSCLC). METHODS: Advanced NSCLC patients (April 2010 to December 2015) with elevated serum CEA or CYFRA 21-1 were included. The associations between tumor marker changes after treatment initiation and OS were analyzed. RESULTS: Ninety-six and 55 patients were CEA- and CYFRA 21-1-positive, respectively. The serum CEA response at 4 months and CYFRA 21-1 responses at 1 and 4 months were significantly associated with OS in the univariate analyses (P=0.025, P=0.016 and P<0.001, respectively). Moreover, in the multivariate analyses, serum CYFRA 21-1 response at 4 months was significantly associated with improved OS (P=0.038). CONCLUSIONS: In NSCLC patients, serum CEA and CYFRA 21-1 responses after treatment initiation may predict longer OS.

Prognostic impact of pleural effusion in EGFR-mutant non-small cell lung cancer patients without brain metastasis.

BACKGROUND: In epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), brain metastasis is known as a poor prognosis factor. However, prognostic factors in the patients without brain metastasis remain unclear. In this study, we aimed to clarify the differences between metastatic site and prognosis in common EGFR-mutant NSCLC patients without brain metastasis. METHODS: Chemotherapy-naïve, advanced EGFR-mutant NSCLC patients without brain metastasis diagnosed between January 2010 and March 2016 were enrolled. We evaluated prognosis according to the presence or absence of bone metastases, liver metastasis, and pleural effusion. RESULTS: A total of 50 EGFR-mutant NSCLC patients without brain metastasis were enrolled. The median progression-free survival and overall survival were significantly shorter in patients with pleural effusion than in those patients without (progression-free survival 7.0 months, 95% confidence interval [CI] 3.7-13.0 vs. 13.0 months, 95% CI 9.1-21.7, hazard ratio [HR] 2.29, 95% CI 1.11-4.73, P = 0.020; overall survival 19.5 months, 95% CI 5.7-28.8 vs. 55.3 months, 95% CI 24.0-not evaluable, HR 3.00, 95% CI 1.35-6.68, P = 0.005). Pleural effusion was an independent factor of poor prognosis for progression-free survival (HR 3.44, 95% CI 1.50-7.88, P = 0.003) and overall survival (HR 2.34, 95% CI 1.00-5.44, P = 0.049). CONCLUSION: Pleural effusion might be a poor prognosis factor for advanced EGFR-mutant NSCLC patients without brain metastasis treated with first-generation EGFR-tyrosine kinase inhibitors. Further precision medicine according to the metastatic site is required.

BK virus pneumonia following stem cell transplantation against diffuse large B-cell lymphoma.

The patient, a 70-year-old woman with diffuse large B-cell lymphoma (DLBCL), developed haemorrhagic cystitis associated with the BK virus (BKV) and adenovirus type 11. Moreover, chest computed tomography showed ground-glass opacity (GGO) in the bilateral upper lobe, and we performed bronchoalveolar lavage (BAL). The BKV DNA load was elevated not only in blood but also in BAL fluid (BALF), leading to the diagnosis of BKV pneumonia. After administering cidofovir, the respiratory symptoms and GGO abated. Therefore, detection of BKV DNA in BALF is useful for diagnosing BKV pneumonia. The patient with DLBCL developed BKV pneumonia. We performed BAL, and BKV DNA load was elevated on BALF. The detection of BKV DNA in BALF is useful for diagnosing BKV pneumonia.

Pulmonary pleomorphic carcinoma with pseudoprogression during nivolumab therapy and the usefulness of tumor markers: A case report.

Pseudoprogression was reported as one of the unconventional responses during immune checkpoint inhibitor therapy. A 70-year-old man with pulmonary pleomorphic carcinoma received nivolumab therapy. Pleural effusion and pulmonary metastasis increased, however then shrank and serum cytokeratin 19 fragment levels decreased. Serum tumor marker might help to distinguish pseudoprogression.