Cough and sputum in long COVID are associated with severe acute COVID-19: a Japanese cohort study.

BACKGROUND: Multiple prolonged symptoms are observed in patients who recover from acute coronavirus disease 2019 (COVID-19), defined as long COVID. Cough and sputum are presented by patients with long COVID during the acute and post-acute phases. This study aimed to identify specific risk factors for cough and sputum in patients with long COVID. METHODS: Hospitalized patients with COVID-19 aged 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. RESULTS: At the 3-, 6-, and 12-month follow-ups, there were no differences in the incidence rates of wet and dry coughs. In contrast, the proportion of patients presenting sputum without coughing increased over time compared to those with sputum and coughing. Univariate analyses of cough and sputum at all follow-up visits identified intermittent mandatory ventilation (IMV), smoking, and older age as risk factors for prolonged symptoms. At the 12-month follow-up, persistent cough and sputum were associated with the characteristics of severe COVID-19 based on imaging findings, renal and liver dysfunction, pulmonary thromboembolism, and higher serum levels of LDH, KL-6, and HbA1C. The Kaplan-Meier curves showed that the severity of acute COVID-19 infection was correlated with prolonged cough and sputum production. Multivariable logistic regression analysis showed that IMV ventilator management were independent risk factors for prolonged cough and sputum at 12 months. CONCLUSIONS: In a Japanese population with long COVID, prolonged cough and sputum production were closely associated with severe COVID-19. These findings emphasize that a preventive approach including appropriate vaccination and contact precaution and further development of therapeutic drugs for COVID-19 are highly recommended for patients with risk factors for severe infection to avoid persistent respiratory symptoms.

Impact of respiratory bacterial infections on mortality in Japanese patients with COVID-19: a retrospective cohort study.

BACKGROUND: Although cases of respiratory bacterial infections associated with coronavirus disease 2019 (COVID-19) have often been reported, their impact on the clinical course remains unclear. Herein, we evaluated and analyzed the complication rates of bacterial infections, causative organisms, patient backgrounds, and clinical outcome in Japanese patients with COVID-19. METHODS: We performed a retrospective cohort study that included inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021) and obtained demographic, epidemiological, and microbiological results and the clinical course and analyzed the cases of COVID-19 complicated by respiratory bacterial infections. RESULTS: Of the 1,863 patients with COVID-19 included in the analysis, 140 (7.5%) had respiratory bacterial infections. Community-acquired co-infection at COVID-19 diagnosis was uncommon (55/1,863, 3.0%) and was mainly caused by Staphylococcus aureus, Klebsiella pneumoniae and Streptococcus pneumoniae. Hospital-acquired bacterial secondary infections, mostly caused by Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, were diagnosed in 86 patients (4.6%). Severity-associated comorbidities were frequently observed in hospital-acquired secondary infection cases, including hypertension, diabetes, and chronic kidney disease. The study results suggest that the neutrophil-lymphocyte ratio (> 5.28) may be useful in diagnosing complications of respiratory bacterial infections. COVID-19 patients with community-acquired or hospital-acquired secondary infections had significantly increased mortality. CONCLUSIONS: Respiratory bacterial co-infections and secondary infections are uncommon in patients with COVID-19 but may worsen outcomes. Assessment of bacterial complications is important in hospitalized patients with COVID-19, and the study findings are meaningful for the appropriate use of antimicrobial agents and management strategies.

Diagnostic and prognostic biomarkers for progressive fibrosing interstitial lung disease.

No biomarkers have been identified in bronchoalveolar lavage fluid (BALF) for predicting fibrosis progression or prognosis in progressive fibrosing interstitial lung disease (PF-ILD). We investigated BALF biomarkers for PF-ILD diagnosis and prognosis assessment. Overall, 120 patients with interstitial pneumonia who could be diagnosed with PF-ILD or non PF-ILD were enrolled in this retrospective study. PF-ILD was diagnosed according to Cottin's definition. All patients underwent bronchoscopy and BALF collection. We evaluated blood and BALF parameters, high-resolution computed tomography (HRCT) patterns, and spirometry data to identify factors influencing PF-ILD diagnosis and prognosis. On univariate logistic analysis, age, sex, the BALF white blood cell fraction (neutrophil, lymphocyte, eosinophil, and neutrophil-to-lymphocyte ratio), BALF flow cytometric analysis (CD8), and an idiopathic pulmonary fibrosis/usual interstitial pneumonia pattern on HRCT were correlated with PF-ILD diagnosis. Multivariate logistic regression analysis revealed that sex (male), age (cut-off 62 years, area under the curve [AUC] 0.67; sensitivity 0.80; specificity 0.47), white blood cell fraction in BALF (NLR, neutrophil, and lymphocyte), and CD8 in BALF (cut-off 34.2; AUC 0.66; sensitivity, 0.74; specificity, 0.62) were independent diagnostic predictors for PF-ILD. In BALF, the NLR (cut-off 8.70, AUC 0.62; sensitivity 0.62; specificity 0.70), neutrophil count (cut-off 3.0, AUC 0.59; sensitivity 0.57; specificity 0.63), and lymphocyte count (cut-off 42.0, AUC 0.63; sensitivity 0.77; specificity 0.53) were independent diagnostic predictors. In PF-ILD patients (n = 77), lactate dehydrogenase (cut-off 275, AUC 0.69; sensitivity 0.57; specificity 0.78), Krebs von den Lungen-6 (cut-off 1,140, AUC 0.74; sensitivity 0.71; specificity 0.76), baseline forced vital capacity (FVC) (cut-off 1.75 L, AUC 0.71; sensitivity, 0.93; specificity, 0.46), and BALF neutrophil ratio (cut-off 6.0, AUC 0.72; sensitivity 0.79; specificity 0.80) correlated with death within 3 years. The BALF cellular ratio, particularly the neutrophil ratio, correlated with the diagnosis and prognosis of PF-ILD. These findings may be useful in the management of patients with interstitial pneumonia.

Diagnostic significance of secondary bacteremia in patients with COVID-19.

OBJECTIVES: We investigated the occurrence of non-respiratory bacterial and fungal secondary infections, causative organisms, impact on clinical outcomes, and association between the secondary pathogens and mortality in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: This was a retrospective cohort study that included data from inpatients with COVID-19 from multiple centers participating in the Japan COVID-19 Taskforce (April 2020 to May 2021). We obtained demographic, epidemiological, and microbiological data throughout the course of hospitalization and analyzed the cases of COVID-19 complicated by non-respiratory bacterial infections. RESULTS: Of the 1914 patients included, non-respiratory bacterial infections with COVID-19 were diagnosed in 81 patients (4.2%). Of these, 59 (3.1%) were secondary infections. Bacteremia was the most frequent bacterial infection, occurring in 33 cases (55.9%), followed by urinary tract infections in 16 cases (27.1%). Staphylococcus epidermidis was the most common causative organism of bacteremia. Patients with COVID-19 with non-respiratory secondary bacterial infections had significantly higher mortality, and a multivariate logistic regression analysis demonstrated that those with bacteremia (aOdds Ratio = 15.3 [5.97-39.1]) were at higher risk of death. Multivariate logistic regression analysis showed that age, male sex, use of steroids to treat COVID-19, and intensive care unit admission increased the risk for nosocomial bacteremia. CONCLUSIONS: Secondary bacteremia is an important complication that may lead to poor prognosis in cases with COVID-19. An appropriate medical management strategy must be established, especially for patients with concomitant predisposing factors.

Risk factors for poor adherence to inhaled corticosteroid therapy in patients with moderate to severe asthma.

BACKGROUND: Poor adherence to inhaled corticosteroid (ICS) therapy is a common reason for worsened asthma control. OBJECTIVE: We investigated the characteristics of patients with moderate to severe asthma who showed poor adherence to therapy, to identify the barriers for optimal ICS therapy in a real-world observational cohort. METHODS: We enrolled patients aged ≥20 years presenting with moderate to severe asthma who were enrolled at 18 hospitals in Japan. According to the Global Initiative for Asthma 2018 steps 3-5, the patients were considered as moderate to severe asthmatic. At inclusion, clinical information was obtained using a self-completed questionnaire. Poor adherence was defined as skipping the ICS therapy for more than once a week or inability to recognize the necessity of daily ICS therapy. Adherence Starts with Knowledge 20 (ASK-20) questionnaire was used to evaluate the cause of therapy incompliance. RESULTS: Of the total 85 participants, 19 (22%) showed poor adherence. The median age at diagnosis in the poor adherence group was 10.0 years (interquartile range [IQR], 3.0-50.0), and that in the good adherence group was 41.0 years (18.5-51.5; P = 0.050). The scores for the ASK-20 items related to the "resistance to taking too much medicine" and "compliance with the number of dosing" demonstrated statistically significant differences between patients diagnosed with asthma during their childhood and others. CONCLUSIONS: Age at diagnosis is an independent risk factor to predict poor ICS adherence among adults with moderate to severe asthma.

Successful treatment of a patient with adult food allergy and severe asthma using omalizumab.

Food allergy is a typical immediate-onset allergic disease in which symptoms are provoked by exposure to the sensitized antigens. Although previous reports have shown that omalizumab has helped children with egg or milk allergy achieve oral immunotherapy safely, there is still no established method for induction of remission in adult food allergy. A 51-year-old woman with oral steroid-dependent severe asthma was treated with omalizumab for 6 years. She had shellfish and wheat food allergy and oral allergy syndrome induced by kiwi and other foods associated with latex-fruit syndrome. Since omalizumab treatment, her food allergy symptoms had disappeared. After 7 years of this treatment, disseminated erythema suddenly appeared; omalizumab was discontinued because of suspected drug-induced eruption. After omalizumab interruption, she felt an itching sensation in her throat with worsened asthma control immediately after wheat ingestion. Readministration of omalizumab improved these symptoms. Thus, we raised the possibility that omalizumab not only improved asthma control but also induced pharmacological remission of the patient's food allergy. Omalizumab may be considered as a treatment option for adult patients with food allergies and severe asthma.

TLR7 Agonist Suppresses Group 2 Innate Lymphoid Cell-mediated Inflammation via IL-27-Producing Interstitial Macrophages.

Group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma via the robust production of type 2 cytokines. Recent studies have demonstrated that TLR7 (Toll-like receptor 7) signaling skews toward a type 1 inflammatory response in asthma, which may lead to the development of novel treatment strategies. However, the effect of TLR7 signaling on ILC2-dependent nonallergic eosinophilic inflammation remains unclear. In this study, we investigated the effects of R848, a TLR7 agonist, in a mouse model of IL-33-induced eosinophilic airway inflammation. Intranasal administration of R848 decreased infiltration of airway eosinophils and ILC2s, mucus production in epithelial cells, and type 2 cytokine production. Flow cytometric analysis identified an increased number of interstitial macrophages (IMs) expressing a high level of TLR7 in the lung upon IL-33 stimulation. IL-33-induced IMs also expressed high levels of alternatively activated (M2)-type genes and chemokines (CCL17 and CCL24). However, R848 stimulation modified these gene expressions and elicited the production of IL-27. Coculture experiments revealed that IL-33-induced IMs directly suppressed ILC2 activation in response to R848. In addition, the inhibitory effects of R848 on ILC2-induced type 2 inflammation were defective in WSX-1-deficient mice lacking the IL-27 receptor. Taken together, these findings indicate that R848 stimulates IL-33-induced IMs to suppress ILC2-mediated type 2 airway inflammation via IL-27. These findings highlight the therapeutic potential of TLR7 agonists and/or IL-27 cascades in nonallergic asthma.

Clinical characteristics of patients with not well-controlled severe asthma in Japan: Analysis of the Keio Severe Asthma Research Program in Japanese population (KEIO-SARP) registry.

BACKGROUND: Multiple phenotypes exist within the classification of severe asthma. However, characteristics of patients with not well-controlled severe asthma have not been well identified. METHODS: Japanese patients with asthma (age ≥ 20 years) were enrolled at the Keio University Hospital and its affiliated hospitals in this observational study (Keio Severe Asthma Research Program). Among them, patients with severe asthma (those undergoing Global Initiative for Asthma [GINA] 2018 step 4 or 5 treatment) were included in this analysis and investigated clinical characteristics based on asthma control status. RESULTS: Of the 154 patients (men, 46.8%; age, 60.1 ± 14.9 years), 87 (56.5%) had not well-controlled (partly controlled and uncontrolled) asthma (GINA step 4, 42 patients; step 5, 45 patients). Overall, there were no significant differences in clinical characteristics between patients with well-controlled and not well-controlled asthma. However, cluster analysis revealed that distinct 5 clusters (cluster 1, well-controlled; cluster 2, eosinophilic; cluster 3, non-type 2 inflammation; cluster 4, high periostin; and cluster 5, late-onset type 2 inflammation), and clusters 2-5 were not well-controlled. Among them, cluster 3 was characterized by low eosinophil counts, low periostin levels, and less frequent olfactory disturbance, and this cluster had the worst asthma control. CONCLUSIONS: Japanese patients with severe asthma were divided into well-controlled and not-well controlled asthma, and we confirmed heterogeneity of not well-controlled severe asthma. These patients, especially non-type 2 phenotype, require a further therapeutic approach. (University Hospital Medical Information Network Clinical Trials Registry, UMIN000002980).

Characteristics of severe asthma with fungal sensitization.

BACKGROUND: Some patients with severe asthma also have fungal sensitization and are considered to have severe asthma with fungal sensitization. However, there is limited information on the clinical features of SAFS. OBJECTIVE: To investigate the clinical characteristics of severe asthma with fungal sensitization. METHODS: The present study enrolled 124 patients with severe asthma. We evaluated clinical aspects, such as various serum cytokines, fractional exhaled nitric oxide, pulmonary function, and serum immunoglobulin E (IgE). Fungal sensitization was assessed by determining serum levels of IgE specific to fungal allergens (Aspergillus, Alternaria, Candida, Cladosporium, Penicillium, and Trichophyton species and Schizophyllum commune). The protocol was registered at a clinical trial registry (www.umin.ac.jp/ctr/index-j.htm; UMIN 000002980). RESULTS: Thirty-six patients (29%) showed sensitization to at least 1 fungal allergen. The most common species were Candida (16%), Aspergillus (11%), and Trichophyton (11%). The rate of early-onset asthma (<16 years of age) was higher in patients with fungal sensitization than in those without fungal sensitization (45% vs 25%; P = .02). Interleukin-33 levels were higher in patients with fungal sensitization than in those without fungal sensitization. Of patients with atopic asthma, Asthma Control Test scores were worse in patients with multiple fungal sensitizations than in patients with a single fungal sensitization or those without fungal sensitization. CONCLUSION: Severe asthma with fungal sensitization is characterized by early onset of disease and high serum levels of interleukin-33. Multiple fungal sensitizations are associated with poor asthma control. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR; www.umin.ac.jp/ctr/index-j.htm): UMIN 000002980.

Edoxaban treatment for pulmonary arterial thromboembolism associated with azygous vein aneurysm.

A 76-year-old woman, diagnosed 5 years previously with an asymptomatic mediastinal bronchogenic cyst, was referred to our department as the mass had grown slightly larger. Contrast-enhanced computed tomography and magnetic resonance imaging scans revealed an azygous vein aneurysm with a pulmonary arterial thromboembolism. The patient was treated with heparin for 5 days, and anticoagulation therapy with edoxaban was continued for 12 months. The thrombus resolved, and the aneurysm remained unchanged. An azygous vein aneurysm is a very rare condition that causes pulmonary arterial thromboembolism. Although surgical resection is indicated for patients with azygous vein aneurysms with a risk of rupture and pulmonary embolism, we chose anticoagulation therapy because of the patient's advanced age. This case suggests that the azygous vein aneurysm is one of the differential diagnoses for a mediastinal mass and that anticoagulation therapy can be the treatment of choice for pulmonary arterial thromboembolism with an azygous vein aneurysm.

Hemoperitoneum Secondary to Rupture of a Hepatic Metastasis from Small Cell Lung Cancer during Chemotherapy: A Case with a Literature Review.

A 65-year-old man was diagnosed with small cell lung cancer with multiple liver metastases. Three days after initiating chemotherapy, he experienced abdominal discomfort with hypotension. Computed tomography revealed a ruptured liver metastasis and the presence of hemorrhagic ascites. Transcatheter arterial embolization to the appropriate hepatic artery in concomitant with supportive therapies successfully stabilized his condition. Unlike with hepatocellular carcinoma, the rupture of a liver metastasis and associated hemoperitoneum is very rare in patients with lung cancer. We comprehensively reviewed the literature and found 10 similar cases with this serious condition. Physicians should therefore be aware of the risk of hemoperitoneum caused by ruptured liver metastases in patients with lung cancer.

A Case of Disseminated Cryptococcal Infection and Concurrent Lung Tuberculosis in a Patient under Steroid Therapy for Interstitial Pneumonia.

Both disseminated cryptococcal infection and tuberculosis occur in hosts with impaired cell-mediated immunity, but there have been few reports about the concurrent infections in patients without human immunodeficiency virus infection. A 64-year-old man, who had been taking corticosteroids for interstitial pneumonia, was diagnosed with disseminated cryptococcal infection. While the patient was receiving anticryptococcal therapy, pulmonary tuberculosis also emerged. The patient developed acute exacerbation of interstitial pneumonia and passed away. Based on the patient's clinical course, serial computed tomography images, and autopsy results, we believe that the preceding several months of corticosteroid treatment might have contributed to these coinfections in the lungs already vulnerable due to underlying fibrosis.

Phenotype of asthma related with high serum periostin levels.

BACKGROUND: Asthma is a heterogeneous disease composed of various phenotypes. Periostin, a molecule inducible with interleukin (IL)-4 or IL-13 in bronchial epithelial cells, is a biomarker of "TH2-high" asthma. The objective of this study is to examine whether the serum periostin concentrations are correlated with the severity, specific phenotype(s), or comorbidity of asthma. METHODS: Serum concentrations of periostin were measured in 190 Japanese asthmatic patients and 11 healthy controls. The protocol was registered under UMIN 000002980 in the clinical trial registry. RESULTS: The serum concentrations of periostin were significantly higher (P = 0.014) in asthmatics [70.0 (54.0-93.5) ng/ml] than in healthy subjects [57.0 (39.0-63.0) ng/ml], though we found no correlation between serum periostin concentrations and treatment steps required to control asthma. To characterize "high-periostin" phenotype(s), the patients with asthma were divided among tertiles based on the serum concentrations of periostin. The high-periostin group was older at onset of asthma (P = 0.04), had a higher prevalence of aspirin intolerance (P = 0.04) or concomitant nasal disorders (P = 0.03-0.001), higher peripheral eosinophil counts (P < 0.001), and lower pulmonary function (P = 0.02-0.07). The serum concentrations of periostin were particularly high in asthmatic patients complicated by chronic rhinosinusitis with nasal polyps and olfactory dysfunction. In contrast, neither atopic status, control status of asthma, nor quality of life were related with the "high-periostin" phenotype. CONCLUSION: Elevated periostin concentrations in serum were correlated with a specific phenotype of eosinophilic asthma, late-onset and often complicated by obstructive pulmonary dysfunction and nasal disorders.