Findings from a discontinued clinical trial of favipiravir in high-risk patients with early-onset COVID-19.

INTRODUCTION: Favipiravir terminates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. Accordingly, early administration of favipiravir to SARS-CoV-2-infected coronavirus disease 2019 (COVID-19) patients may be expected to suppress disease progression. METHODS: A randomized double-blind placebo-controlled trial was conducted to demonstrate efficacy of favipiravir in reducing disease progression in patients with mild COVID-19. The participants were unvaccinated patients with comorbidities and at risk of progression to severe disease. Patients were enrolled within 72 h of disease onset and randomized to receive either favipiravir (1800 mg/dose on Day 1 followed by 800 mg/dose) or matching placebo twice daily for 10 days. The primary endpoint was the proportion of patients requiring oxygen therapy within 28 days of randomization. RESULTS: The trial was discontinued after enrolling 84 patients due to slower than anticipated enrollment caused by rapid uptake of SARS-CoV-2-vaccines and the emergence of the Omicron variant. Results from the 84 patients demonstrated no significant difference in all clinical outcomes. In post-hoc analyses, favipiravir treatment showed higher efficacy in patients within 48 h of onset. No deaths or severe adverse events were documented in the favipiravir group. Plasma concentrations of favipiravir from Day 2 onward were maintained above 40 µg/mL. CONCLUSIONS: Conducting clinical trials for pathogens like SARS-CoV-2 that rapidly accumulate mutations leading to altered disease characteristics carries significant risks unless it can be done in a short period. Therefore, it would be important to prepare the comprehensive clinical trial platform that can appropriately and promptly evaluate drugs even under a pandemic.

Antibody titers among healthcare workers for coronavirus disease 2019 at 6 months after BNT162b2 vaccination.

BACKGROUND: Antibody levels decrease substantially at 6 months after the BNT162b2 vaccine. The factors influencing titer of antibodies against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) among healthcare workers for coronavirus disease 2019 (COVID-19) is unclear. METHODS: We conducted a 6-month longitudinal prospective study in Japanese healthcare workers in a tertiary care hospital for COVID-19. Participants in the study were tested for the presence of anti-spike protein (SP) IgG antibodies before and at 1 and 6 months after the last vaccination dose. RESULTS: Among 1076 healthcare workers, 794 received the vaccine, and 469 entered the study. Five were infected with SARS-CoV-2 (none among COVID-19 section workers) by the end of the study and 451 participants were finally analyzed (mean age, 42.5 years; 27.3 % male; 18.8 % COVID-19 section workers). Median SP IgG index values were 0.0, 44.4, and 5.5 before and at 1 and 6 months after the last dose, respectively. Regression analysis revealed a negative correlation of SP IgG antibody levels with age (P < 0.0001), and higher levels in COVID-19 section workers (P = 0.0185) and in females (P = 0.0201). CONCLUSION: In healthcare workers at a COVID-19 hospital, IgG antibody titer was substantially lower at 6 months after receipt of the last dose of the BNT162b2 vaccine compared with that 1 month after the last dose, but was better preserved among younger participants, COVID-19 section workers and females.

A retrospective analysis of pembrolizumab plus chemotherapy versus pembrolizumab monotherapy for advanced or recurrent non-small cell lung cancer.

BACKGROUND: Although clinical trials have investigated the addition of pembrolizumab to chemotherapy for non-small cell lung cancer, none have investigated the addition of chemotherapy to pembrolizumab. METHODS: We conducted a retrospective study of 71 NSCLC patients including 33 treated with pembrolizumab plus chemotherapy (combination therapy group) and 38 treated with pembrolizumab monotherapy (monotherapy group) from 1 May 2016 to 31 August 2020. RESULTS: Eleven of 33 (33.3%) patients in the combination therapy group and 37 of 38 (97.4%) patients in the monotherapy group had programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) ≥50%. Objective response rate (ORR) and median overall survival (OS) were not significantly different between the combination therapy group and monotherapy group (54.5% vs. 47.4, p = 0.637 and 16.6 vs. 27.0 months, p = 0.463). In patients with PD-L1 TPS ≥50%, ORR and median OS were not different between the combination therapy group and the monotherapy group (63.6% vs. 48.6%, p = 0.499 and not reached vs. 27.0 months, p = 0.976). Thirty-three (100%) patients experienced adverse events (AEs) in the combination therapy group and 32 (84.2%) in the monotherapy group. Treatment discontinuation at 1 year due to AEs occurred more frequently in the combination therapy group (45.2%) than in the monotherapy group (21.1%). CONCLUSION: There was no significant difference in ORR and OS between the two groups, and treatment discontinuation was more frequent in the combination group. A randomized controlled trial is needed to evaluate the addition of chemotherapy to pembrolizumab for first-line treatment in patients with PD-L1 TPS ≥50%.

Outcome and risk factor of immune-related adverse events and pneumonitis in patients with advanced or postoperative recurrent non-small cell lung cancer treated with immune checkpoint inhibitors.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with pre-existing respiratory diseases have been excluded in clinical trials of immune checkpoint inhibitor (ICI) therapy, and it is unknown whether the same degree of response can be expected as that in patients without pre-existing respiratory diseases and if they are associated with increased risk for various immune-related adverse events (irAEs) and ICI pneumonitis. This study aimed to evaluate predictive factors of clinical response, prognostic factors, risk factors of irAEs, and ICI pneumonitis in NSCLC patients with or without pre-existing respiratory diseases. METHODS: We conducted a retrospective study of 180 NSCLC patients who received ICI monotherapy of nivolumab, pembrolizumab, or atezolizumab from 1 January 2016 to 31 March 2019. RESULTS: A total of 119 patients had pre-existing respiratory diseases, including 20 with pre-existing idiopathic interstitial pneumonias (IIPs). A total of 85 patients experienced irAEs, of which ICI pneumonitis was the most frequent adverse event, occurring in 27 patients. Of the three patients who died from irAEs, all from ICI pneumonitis, two had pulmonary emphysema and one had pre-existing IIP. In multivariate analyses, irAEs were associated with objective response rate (ORR) and favorable OS, and IIPs were associated with increased risk for ICI pneumonitis. However, IIPs were not associated with low ORR or poor OS. CONCLUSIONS: Pre-existing IIPs were a risk factor for ICI pneumonitis. However, this study showed that ICI therapy can be offered to patients with pre-existing respiratory diseases with the expectation of the same degree of response as that in patients without pre-existing respiratory diseases. KEY POINTS: Significant findings of the study: Pre-existing IIPs were a risk factor for ICI pneumonitis, but objective response rate and prognosis of patients with IIPs were similar to those of other patients. WHAT THIS STUDY ADDS: In patients with pre-existing IIPs, ICI pneumonitis should be noted. However, ICI therapy can be offered to patients with pre-existing respiratory diseases with the expectation of the same degree of response as that in patients without pre-existing respiratory diseases.

Clinical course and findings of 14 patients with COVID-19 compared with 5 patients with conventional human coronavirus pneumonia.

OBJECTIVE: To clarify what future problems must be resolved and how clinical findings of SARS-CoV-2 infection differ from those of cHCoV infection. METHODS: Patients and Methods Clinical characteristics of 14 patients with laboratory-confirmed Coronavirus disease 2019 (COVID-19) and 5 patients with cHCoV pneumonia admitted to our institution and treated up to March 8, 2020, were retrospectively analyzed. RESULTS: On admission, 10 patients had pneumonia, 5 of whom had pulmonary shadows detectable only via computed tomography (CT). During hospitalization, another patient with no pulmonary shadows on admission developed pneumonia. In total, 11 (78.6%) of the 14 patients developed pneumonia, indicating its high prevalence in COVID-19. During hospitalization, the patients' symptoms spontaneously relapsed and resolved, and gastrointestinal symptoms were frequently found. C-reactive protein values showed correlation with the patients' clinical courses. Ritonavir/lopinavir were administered to 5 patients whose respiratory conditions worsened during admission, all of whom improved. However, the pneumonia in the 6 other patients improved without antivirals. None of the 14 patients died, whereas 5 other patients with cHCoV pneumonia were in respiratory failure on admission, and one patient (20%) died. CONCLUSION: Both SARS-CoV-2 and cHCoV can cause severe pneumonia. Problems for future resolution include whether antiviral agents administered in cases of mild or moderate severity can reduce the number of severe cases, and whether antivirals administered in severe cases can reduce mortality.

Changes in airway diameter and mucus plugs in patients with asthma exacerbation.

BACKGROUND: Airway obstruction due to decreased airway diameter and increased incidence of mucus plugs has not been directly observed in asthma exacerbation. We studied the changes in the inner diameter of the airway (Din) and the frequency of mucus plugs by airway generation in patients with asthma exacerbation. We compared these patients to those in a stable phase using high-resolution computed tomography (HRCT). METHODS AND FINDINGS: Thirteen patients with asthma were studied by HRCT during asthma exacerbation and in a stable period. The HRCT study was performed on patients who could safely hold their breath for a short while in a supine position 1 hour after initial treatment for asthma exacerbation. Using a curved multiplanar reconstruction (MPR) software, we reconstructed the longitudinal airway images and the images exactly perpendicular to the airway axis to measure the Din and mucus plugs from the second- (segmental) to sixth-generation bronchi in all segments of the lungs.The ratios of Din (exacerbation/stable) were 0.91(P = 0.016), 0.88 (P = 0.002), 0.83 (P = 0.001), 0.80 (P = 0.001), and 0.87 (NS) in the second-, third-, fourth-, fifth-, and sixth-generation bronchi, respectively. The percentages of airway obstruction due to mucus plugs were notably higher in the fourth- and fifth-generation bronchi (17.9%/18.1% in stable phase and 43.2%/45.9% in the exacerbation phase, respectively) than in the other generations of bronchi. CONCLUSIONS: Among the bronchi examined, the fourth- and fifth-generation bronchi were significantly obstructed during asthma exacerbation compared with the stable phase in terms of a decreased airway diameter and mucus plugs.

Diffuse alveolar hemorrhage caused by IgA deposition associated with multiple myeloma.

We report a man with diffuse alveolar hemorrhage caused by multiple myeloma who was diagnosed with the aid of bronchoalveolar lavage and transbronchial lung biopsy. Multiple myeloma should be considered as an important differential diagnosis in patients with diffuse alveolar hemorrhage, and bronchoscopy may help to differentiate the cause.

Restrictive ventilatory impairment improved by laminoplasty for ossification of the posterior longitudinal ligament.

We report a woman with severe restrictive ventilatory impairment because of respiratory muscle paralysis caused by ossification of the posterior longitudinal ligament (OPLL). Laminoplasty improved her respiratory function and quality of life. Cervical myelopathy including OPLL should be considered as an important differential diagnosis in patients with respiratory dysfunction.

Re-evaluation of the etiology and clinical and radiological features of community-acquired lobar pneumonia in adults.

OBJECTIVE: The aims of this study were to elucidate the frequency and etiology of community-acquired lobar pneumonia (CALP) and the clinical and radiological differences between CALP and tuberculous lobar pneumonia (TLP). PATIENTS AND METHODS: We retrospectively reviewed medical records of patients with community-acquired pneumonia (CAP) (n = 1032) and tuberculosis (n = 1101) admitted to our hospital. RESULTS: Sixty-nine (6.7%) patients with CAP and 23 (2.1%) with pulmonary tuberculosis developed CALP. Legionella species were the most common pathogen (27 patients, 39.1%), followed by Streptococcus pneumoniae (19 patients, 27.5%) and Mycoplasma pneumoniae (18 patients, 26.1%). Symptom duration was longer in the patients with TLP than in those with CALP. On chest radiographs, cavitation in the area of lobar pneumonia and nodular shadows were radiological findings predictive of TLP. High-resolution computed tomography showed cavitation in the area of lobar pneumonia, well-defined centrilobular nodules, and tree-in-bud sign to be the radiological findings predictive of TLP by multivariate logistic regression models. CONCLUSION: Common causes of CALP are Legionella species, S. pneumoniae, and M. pneumoniae. TLP should be considered in patients with lobar pneumonia, particularly in patients with long symptom duration, cavitation, and nodular shadows on chest radiographs, and cavitation, well-defined centrilobular nodules, and tree-in-bud sign on CT.

Allergic Bronchopulmonary Mycosis Due to Schizophyllum commune Treated Effectively with Voriconazole.

A 63-year-old woman presented to our hospital for cough, sputum, and abnormal shadows on chest X-ray. Schizophyllum commune was isolated from mucous plugs. Positive specific IgE and IgG against the fungi, elevated serum IgE, and mucous plugs with typical histologic findings of allergic bronchopulmonary mycosis (ABPM) led to the diagnosis of ABPM due to S. commune. We initially administered itraconazole unsuccessfully. Changing the antifungal agent to voriconazole resulted in improvement of the symptoms and chest imaging findings. Her ABPM has not relapsed for two years since the cessation of voriconazole, which was administered for one year.

Grade 4 asbestosis does not extend directly from the respiratory bronchiole to the peripheral lung.

AIMS: To confirm whether or not grade 4 asbestosis progresses from the respiratory bronchiole to the peripheral lung. METHODS AND RESULTS: We examined retrospectively the autopsy or lobectomy specimens from 31 cases (29 males; mean age 64 years) satisfying the pathological criteria of grade 4 asbestosis. Asbestos bodies (ABs) were quantified in samples of dissolved lung and in tissue preparations on glass slides. Respiratory bronchiolar lesions were graded as 0, 1 and ≥2. Grade 4 asbestosis was subdivided into an atelectatic induration (AI) and usual interstitial pneumonia pattern (UIP pattern). Five, 10, and 16 cases had grades 0, 1 or ≥2 lesions, respectively, with mean respective numbers of ABs in dissolved lung of 117 000/g dry lung, 468 000/g and 968 000/g; and in specimens on glass slides of seven ABs/cm2 of tissue slice, 34 ABs /cm2 and 195 ABs /cm2 . The differences were significant. Fifteen and 16 cases showed AI and UIP patterns, respectively, with mean respective numbers of ABs in dissolved lung of 1 006 000/g dry lung and 354 000/g, and 186 and 56 ABs/cm2 on glass slides. The differences were significant. AI patterns originated in subpleural lobules or subpleural zonal areas and UIP patterns originated in subpleural, peripheral lobules. CONCLUSIONS: Grade 4 asbestosis does not start in the respiratory bronchiole. The presence of a grade 1 lesion is not required for the diagnosis of grade 4 asbestosis.

Smoking history and emphysema in asthma-COPD overlap.

BACKGROUND: Emphysema is a distinct feature for classifying COPD, and smoking history (≥10 pack-years) is one of several newly proposed criteria for asthma-COPD overlap (ACO). We studied whether or not a smoking history (≥10 pack-years) and emphysema are useful markers for classifying ACO and differentiating it from asthma with chronic airflow obstruction (CAO). METHODS: We retrospectively studied the mortalities and frequencies of exacerbation in 256 consecutive patients with ACO (161 with emphysema and 95 without emphysema) who had ≥10 pack-years smoking history, 64 asthma patients with CAO but less of a smoking history (<10 pack-years) and 537 consecutive patients with COPD (452 with emphysema and 85 without emphysema) from 2000 to 2016. In the patients with emergent admission, the causes were classified into COPD exacerbation, asthma attack, and others. RESULTS: No asthma patients with CAO had emphysema according to computed tomography findings. The prognoses were significantly better in patients with asthma and CAO than in those with ACO and COPD and better in those with ACO than in those with COPD. In both ACO and COPD patients, the prognoses were better in patients without emphysema than in those with it (P=0.027 and P=0.023, respectively). The frequencies of emergent admission were higher in COPD patients than in ACO patients, and higher in patients with emphysema than in patients without emphysema. ACO/emphysema (+) patients experienced more frequent admission due to COPD exacerbation (P<0.001), while ACO/emphysema (-) patients experienced more frequent admission due to asthma attack (P=0.014). CONCLUSION: A smoking history (≥10 pack-years) was found to be a useful marker for differentiating ACO and asthma with CAO, and emphysema was a useful marker for classifying ACO. These markers are useful for predicting the overall survival and frequency of exacerbation.

Clinical Characteristics of Influenza-Associated Pneumonia of Adults: Clinical Features and Factors Contributing to Severity and Mortality.

Background: Pneumonia is a major complication of influenza that contributes to mortality. Clinical characteristics and factors of influenza virus contributing to the severity and mortality of pneumonia have not been fully elucidated. Objective: The objective was to clarify clinical characteristics and factors contributing to the severity and mortality of influenza-associated pneumonia (flu-p). Methods: We retrospectively analyzed patients with flu-p. Results: From December 1999 to March 2016, 210 patients with a median age of 69 (range, 17 to 92) years with flu-p based on positive rapid antigen tests, increased antibody titers of paired sera, or positive results of reverse transcription polymerase chain reaction were admitted to our institution. A multivariate analysis found that advanced age (≥ 65 years), pneumonia subtypes (unclassified), diabetes mellitus, and acute kidney injury complicated with flu-p were independent factors associated with disease severity, whereas pneumonia subtypes (mixed viral and bacterial pneumonia and unclassified), healthcare-associated pneumonia, acute kidney injury complicated with flu-p, and severity on admission (severe) were independent factors associated with non-survival. Conclusion: The clinical characteristics of flu-p are varied, and the contribution of several factors to the severity and mortality of flu-p suggest their importance in either preventing flu-p or managing flu-p after it develops.

How many instructions are required to correct inhalation errors in patients with asthma and chronic obstructive pulmonary disease?

In the treatment of asthma and chronic obstructive pulmonary disease (COPD), errors in handling and wrong techniques in using inhalation devices are associated with poor disease control. The aim of this study was to evaluate the number of instructions that are necessary to minimize errors in using pressurized metered-dose inhaler (pMDI), soft mist inhaler (SMI), and dry powder inhaler (DPI). Among 216 patients with asthma (n = 135) and COPD (n = 81), we studied 245 cases that used different types of inhalation devices. After initial guidance, 145 of 245 cases (59%) made at least one error that could affect efficacy. For every device, at least three instructions were required to achieve entirely no errors or less than 10% errors in total. The most common error on the use of pMDI was device handling, whereas that of DPI was inhalation manner. Both errors were associated with low peak flow rate. In both patients with asthma and in patients with COPD, the most common error was inhalation manner. We concluded that it is necessary to repeat at least three times of instructions to achieve effective inhalation skills in both asthma and COPD patients.

Development of myasthenia gravis 8 years after interstitial lung disease associated with antisynthetase (anti-EJ antibody) syndrome.

Patients with antisynthetase-positive interstitial lung disease (ILD) alone sometimes develop myositis during follow-up, but myasthenia gravis (MG) overlapping on antisynthetase syndrome is unusual. A 56-year-old woman with ILD and anti-EJ antibody treated for 8 years developed MG. Physicians should consider myositis and MG when patients develop muscle symptoms during follow-up.

Risk factors for the severity and mortality of pneumococcal pneumonia: Importance of premorbid patients' performance status.

Comorbidity is known to be associated with the severity and mortality of pneumonia. The severity of each underlying disease varies, and performance status, which is known to be a prognostic factor of malignant diseases, reflects the overall patient condition as affected by his/her comorbidity and underlying diseases of various severity. We investigated whether premorbid patients' performance status is associated with the severity and mortality of pneumococcal pneumonia. This retrospective study assessed these factors in hospitalized patients suffering from pneumococcal pneumonia from 2002 to 2015. We included 424 patients aged 68.9 ± 14.1 years in the study, of which 68.9% were men. A multivariate analysis found that advanced age (≥65 years), diabetes mellitus, and poor performance status were independent factors associated with severity, whereas old pulmonary tuberculosis, poor performance status, pneumococcal bacteremia, and severe pneumonia were independent factors that were associated with non-survival. Poor performance status was associated with the severity and mortality of pneumococcal pneumonia.

Acute ischaemic lung injury due to pulmonary vascular obstruction.

AIMS: We have encountered cases of a distinctive myxomatous alveolar wall thickening around pulmonary infarctions, and have termed it 'acute ischaemic lung injury' (AILI). In this study we determined if pulmonary infarction is the only cause of AILI and have elucidated its histological features. METHODS AND RESULTS: We examined 2941 cases that underwent lobectomy, surgical lung biopsies for nodular lesions or autopsies between 1994 and 2014. Cases were divided into pulmonary infarction and non-infarction groups. The histological features of AILI sought were lobule-based alveolar wall thickening (myxomatous or fibrous) with epithelial metaplasia and negligible inflammation. In order to characterize AILI further, we performed immunohistochemical staining using several antibodies. Thirty-four of 69 cases in the infarction group (mean age 57.1 years, 30 males) had AILI, whereas only one (but with vascular obstruction) of the remaining 2872 in the non-infraction group had AILI. AILI was located around infarctions. Separation of the epithelial and endothelial basement membranes of the alveolar wall was observed in 75% of cases. CONCLUSIONS: AILI is associated almost exclusively with lung infarction, caused presumably by vascular obstruction. We consider AILI to represent a distinct lung lesion other than pulmonary haemorrhage and infarction.

Combined Allergic Bronchopulmonary Aspergillosis and Eosinophilic Granulomatosis with Polyangiitis: Three Cases and a Review of the Literature.

Previous reports of combined allergic bronchopulmonary mycosis (ABPM) and eosinophilic granulomatosis with polyangiitis (EGPA) are limited; however, among 41 cases of ABPM and 18 cases of EGPA treated at our hospital, we experienced three cases of combined ABPM and EGPA. In two of these cases, the diagnosis of EGPA preceded that of ABPM, however, one of the two cases had already shown findings suggestive of ABPM, such as mucous plugs and central bronchiectasis, at the time of the diagnosis of EGPA. In six previously reported cases of combined ABPM and EGPA, ABPM preceded EGPA in four cases. In the other two cases in which EGPA was diagnosed before or simultaneously with ABPM, findings suggestive of ABPM had been detected when EGPA was diagnosed, which suggests that sensitization to fungi resulting in ABPM may play an important role in the development of EGPA. Careful attention should therefore be paid to the possibility that these diseases may coexist during the course of either disease.

COPD assessment test and severity of airflow limitation in patients with asthma, COPD, and asthma-COPD overlap syndrome.

OBJECTIVE: The COPD assessment test (CAT) consists of eight nonspecific scores of quality of life. The aim of this study was to compare the health-related quality of life and severity of airflow limitation in patients with asthma, COPD, and asthma-COPD overlap syndrome (ACOS) using the CAT. METHODS: We examined CAT and lung functions in 138 patients with asthma, 99 patients with COPD, 51 patients with ACOS, and 44 patients with chronic cough as a control. The CAT score was recorded in all subjects, and the asthma control test was also administered to patients with asthma and ACOS. The CAT scores were compared, and the relationships between the scores and lung function parameters were analyzed. RESULTS: The total CAT scores and scores for cough, phlegm, and dyspnea were higher in patients with ACOS than in patients with asthma and COPD. The total CAT scores were correlated with the percent predicted forced expiratory volume in 1 second only in patients with COPD. The total CAT scores and dyspnea scores adjusted by the percent predicted forced expiratory volume in 1 second were higher in patients with ACOS than in patients with COPD and asthma. The CAT scores and asthma control test scores were more closely correlated in patients with ACOS than in patients with asthma. CONCLUSION: Patients with ACOS have higher disease impacts and dyspnea sensation unproportional to the severity of airflow limitation.