Interleukin-33 increases type 2 innate lymphoid cell count and their activation in eosinophilic asthma.

BACKGROUND: Interleukin-33 (IL-33) exacerbates asthma probably through type 2 innate lymphoid cells (ILC2s). Nevertheless, the association between eosinophilic asthma (EA) and ILC2s remains obscure, and the mechanisms by which IL-33 affects ILC2s are yet to be clarified. METHODS: ILC2s were evaluated in peripheral blood mononuclear cells, induced sputum, and bronchoalveolar lavage fluid obtained from patients with EA. Confocal microscopy was performed to locate ILC2s in lung tissue and the mRNA expression of ILC2-related genes was also evaluated in the EA model. The proliferation of ILC2s isolated from humans and mice was assessed following IL-33 or anti-IL-33 stimulation. RESULTS: The counts, activation, and mRNA expression of relevant genes in ILC2s were higher in PBMCs and airways of patients with EA. In addition, ILC2 cell counts correlated with Asthma control test, blood eosinophil count, Fractional exhaled nitric oxide level, and predicted eosinophilic airway inflammation. IL-33 induced stronger proliferation of ILC2s and increased their density around blood vessels in the lungs of mice with EA. Moreover, IL-33 treatment increased the counts and activation of ILC2s and lung inflammatory scores, whereas anti-IL-33 antibody significantly reversed these effects in EA mice. Finally, IL-33 enhanced PI3K and AKT protein expression in ILC2s, whereas inhibition of the PI3K/AKT pathway decreased IL-5 and IL-13 production by ILC2s in EA. CONCLUSIONS: ILC2s, especially activated ILC2s, might be critical markers of EA. IL-33 can induce and activate ILC2s in the lungs via the PI3K/AKT pathway in EA. Thus, using anti-IL-33 antibody could be a part of an effective treatment strategy for EA.

Quantitative CT Metrics for the Prediction of Therapeutic Effect in Asthma.

Background: Few studies have explored the correlation between asthma medication and features on HRCT images. We aim to analyse the differences and temporal changes of lung function and airway resistance in asthma with diverse HRCT phenotypes in a short period after inhalation of budesonide/formoterol. Method: This observational study recruited 55 adult patients with varying severities of asthma. We performed detailed airway metrics measurements of chest CT scans, such as airway wall thickness (WT), wall area percentage (WA%), wall thickness percentage (T/OR), and airways with an inner perimeter of 10 mm (Pi10). The effect of lung structural features on asthma medication response was explored according to the WA% and T/OR twelve hours post-drug administration. Using multivariable regression models, we then assessed the influence of WA% on lung function. Results: WA% (p < 0.001) and T/OR (p < 0.001) significantly increased in asthma than in healthy control subjects. Compared to mild asthma, airway walls were further thickened (WA%, p = 0.023; T/OR: p = 0.029) and associated with lumen narrowing (Pi10, p = 0.055) in moderate to severe asthma. WA% and T/OR correlated well with lung function (FEV1, FVC, MMEF, and PEF) and airway resistance (R5, R20, Rp, and Fres). Regression analysis showed that MEF25 decreased with increasing age and WA% (R2 = 0.58, p < 0.001). Patients with thickened airway walls experienced a maximal increase in FVC, FEV1, and PEF at 2 h (p < 0.001) and a maximal decrease of R5, Z5, and Rp at 2 h (p < 0.001) in those with a thickened airway pattern. Conclusions: Asthma patients with different bronchial wall thicknesses exhibited variable lung function changes. Specifically, patients with thick airway wall patterns were more sensitive to inhaled budesonide in the short term.

Tropheryma whipplei detection by metagenomic next-generation sequencing in bronchoalveolar lavage fluid: A cross-sectional study.

Tropheryma whipplei is the bacterium associated with Whipple's disease (WD), a chronic systemic infectious disease primarily involving the gastrointestinal tract. T. whipplei can also be detected in different body site of healthy individuals, including saliva and feces. Traditionally, Tropheryma whipplei has a higher prevalence in bronchoalveolar lavage fluid (BALF) of immunocompromised individuals. Few studies have explored the significance of the detection of T. whipplei in BALF. Herein, we retrospectively reviewed 1725 BALF samples which detected for metagenomic next-generation sequencing (mNGS) from March 2019 to April 2022 in Zhuhai, China. Seventy BALs (70/1725, 4.0%) from 70 patients were positive for T. whipplei. Forty-four patients were male with an average age of 50 years. The main symptoms included cough (23/70), expectoration (13/70), weight loss (9/70), and/or dyspnea (8/70), but gastrointestinal symptoms were rare. Chronic liver diseases were the most common comorbidity (n=15, 21.4%), followed by diabetes mellitus (n=13, 18.6%). Only nine patients (12.9%) were immunocompromised. Twenty-four patients (34.3%) were finally diagnosed with reactivation tuberculosis and 15 patients (21.4%) were diagnosed with lung tumors, including 13 primary lung adenocarcinoma and two lung metastases. Fifteen patients (21.4%) had pneumonia. Among the 20 samples, T. whipplei was the sole agent, and Mycobacterium tuberculosis complex was the most common detected other pathogens. Among the non-tuberculosis patients, 31 (31/46, 67.4%) had ground glass nodules or solid nodules on chest CT. Our study indicates that T. whipplei should be considered as a potential contributing factor in some lung diseases. For non-immunocompromised patients, the detection of T. whipplei also needs attention. The mNGS technology improves the detection and attention of rare pathogens. In the future, the infection, colonization, and prognosis of T. whipplei in lung still need to be studied.

Clinical Course and Factors Associated with Viral RNA Shedding and Radiologic Resolution in Patients with COVID-19: a Retrospective Study.

BACKGROUND: The outbreak of SARS-CoV-2 lead to a worldwide pandemic which poses substantial challenges to public health. METHODS: We enrolled 102 consecutive recovered patients with laboratory-confirmed SARS-CoV-2 infection. Epidemiological and demographic characteristics, temporal dynamic profiles of laboratory tests and findings on chest CT radiography, and clinical outcomes were collected and analyzed. RESULTS: Independent risk factors for prolonged fever, viral RNA shedding or radiologic recovery included age of more than 44 years, female gender, having symptoms of cough and fever, a delay from the symptom onset to hospitalization of more than 3 days, a lower CD4 count of less than 500/µL on admission, and severe or critical illness in hospitalization. The estimated median time from symptom onset was 6.4 (5.5 - 7.4) days to peak viral load, 9.1 (7.9 - 10.4) days to afebrile, 8 (6.7 - 9.4) days to worst radiologic finding, 12.7 (11.2 - 14.3) days to viral RNA negativity, and 26.7 (23.8 - 29.9) days to radiologic resolution. This study included the entire cross-section of patients seen in our clinical practice and reflected the real-world situation. CONCLUSIONS: These findings provide the rationale for strategies of active symptom monitoring, timing of quarantine and antiviral interventions, and duration of radiologic follow-up in patients with COVID-19.

The Role of Impulse Oscillometry in Evaluating Disease Severity and Predicting the Airway Reversibility in Patients With Bronchiectasis.

Background: Impulse oscillometry (IOS) can be used to evaluate airway impedance in patients with obstructive airway diseases. Previous studies have demonstrated that IOS parameters differ between patients with bronchiectasis and healthy controls. This study aims to explore the usefulness of IOS in assessing disease severity and airway reversibility in patients with bronchiectasis. Method: Seventy-four patients with non-cystic fibrosis bronchiectasis who visited our Respiratory Medicine outpatient clinic were consecutively recruited. Spirometry, plethysmography and IOS tests were performed. Patients were stratified into mild, moderate and severe disease according to Reiff, Bhalla, BSI, FACED, and BRICS scores. Airway reversibility was measured by bronchodilation test (BDT) and the result was classified as positive or negative. ROC curves of IOS parameters were used to assess the usefulness of IOS parameters in predicting airway reversibility. Correlations between the IOS, spirometric lung function and bronchiectasis severity parameters were analyzed. Results: Many IOS parameters, such as airway resistance at 5 Hz (R5), small airways resistance (R5-R20), total airway reactance (X5), resonance frequency (Fres), total airway impedance at 5 Hz (Z5), and peripheral resistance (Rp) increased in patients with bronchiectasis who presented a moderate to severe severity as categorized by the FACED, BSI and Reiff scores. Large airway resistance (R20) and central resistance (Rc) were not significantly different among groups with different bronchiectasis severity. The difference between R5 and R20 (R5-R20) showed 81.0% sensitivity, and 69.8%specificity in predicting the airway reversibility in bronchiectasis with AUC of 0.794 (95%CI, 0.672-0.915). Conclusion: IOS measurements are useful indicators of bronchiectasis severity and may be useful for predicting the airway reversibility.

Hypersensitivity in the lungs is responsible for acute respiratory failure in COVID-19 patients: Case series of patients who received high-dose/short-term methylprednisolone.

BACKGROUND: COVID-19 is a highly contagious respiratory disease caused by the SARS-CoV-2 virus. Patients with severe disease have a high fatality rate and face a huge medical burden due to the need for invasive mechanical ventilation. Hypoxic respiratory failure is the major cause of death in these patients. There are currently no specific anti-SARS-CoV-2 drugs, and the effect of corticosteroids is still controversial. METHODS: The clinical data of 102 COVID-19 patients, including 27 patients with severe disease, were analyzed. The serum levels of total IgE and anti-SARS-CoV-2 specific IgE were compared in healthy controls and COVID-19 patients, changes in the level of anti-SARS-CoV-2 specific IgE and clinical response to methylprednisolone (MP) treatment were analyzed, and the effect of high-dose/short-term MP therapy for patients with critical illness and respiratory failure was determined. RESULTS: COVID-19 patients had elevated serum levels of anti-SARS-CoV-2 specific IgE, and patients with severe disease, especially critical illness, had even higher levels. Application of short-term/high-dose MP significantly reduced the level of these IgE antibodies and also blocked the progression of hypoxic respiratory failure. Hypoxic respiratory failure in patients with COVID-19 is related to pulmonary hypersensitivity. CONCLUSIONS: Hypersensitivity in the lungs is responsible for acute respiratory failure in COVID-19 patients. Application of high-dose/short-term MP appears to be an effective life-saving method for COVID-19 patients who have hypoxic respiratory failure.

Maternal microbiome regulation prevents early allergic airway diseases in mouse offspring.

BACKGROUND: Asthma is a serious global health problem, severely affecting the lives of sufferers and their families. An exceptionally hygienic home and reduced microbial exposure can aggravate the incidence of childhood asthma. METHODS: Specific-pathogen-free BALB/c mice were pre-treated with bacterial lysate (BL; 1 mg/kg) as a high microbial load maternal mouse model, and then, the offspring mice were established as an allergic airway disease (AAD) model. The expression levels of TLR2, TLR4, and HDAC9 in the mother's intestine and the offspring's lungs were detected. Relevant indicators of regulatory T cells (Tregs) were identified in the mother and offspring mice. The changes in the expression of Th1-, Th2-, Th9-, and Th17-related cytokines in the offspring mice were evaluated among different pre-treated groups. RESULTS: After augmenting the mothers' intestinal microbiota through oral BL gavage, the expression of TLR2 and TLR4 in the colon mucosa and colon lymphoid tissues was enhanced and that of HDAC9 in the colon mucosa was decreased, and the proportion of spleen Tregs was increased. The offspring showed similar changes in the AAD model compared with the offspring of the control-group mothers: TLR2 and TLR4 expression in the lungs and the proportion of spleen Tregs increased, HDAC9 expression in the lungs decreased, and AAD-induced airway pathologic characteristics were reversed; additionally, Th1/Th2 and Th9 imbalances were rectified. CONCLUSIONS: This study presents a new framework for the prevention of childhood asthma, elucidating the mechanism of regulating the mother's intestinal microbiome to protect the offspring's early asthma via animal experiments.

Household Transmission of SARS-CoV-2, Zhuhai, China, 2020.

BACKGROUND: To illustrate the extent of transmission, identify affecting risk factors and estimate epidemiological modeling parameters of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in household setting. METHODS: We enrolled 35 confirmed index cases and their 148 household contacts, January 2020-February 2020, in Zhuhai, China. All participants were interviewed and asked to complete questionnaires. Household contacts were then prospectively followed active symptom monitoring through the 21-day period and nasopharyngeal and/or oropharyngeal swabs were collected at 3-7 days intervals. Epidemiological, demographic, and clinical data (when available) were collected. RESULTS: Assuming that all these secondary cases were infected by their index cases, the second infection rate in household context is 32.4% (95% confidence interval [CI]: 22.4%-44.4%), with 10.4% of secondary cases being asymptomatic. Multivariate analysis showed that household contacts with underlying medical conditions, a history of direct exposure to Wuhan and its surrounding areas, and shared vehicle with an index patient were associated with higher susceptibility. Household members without protective measures after illness onset of the index patient seem to increase the risk for SARS-CoV-2 infection. The median incubation period and serial interval within household were estimated to be 4.3 days (95% CI: 3.4-5.3 days) and 5.1 days (95% CI: 4.3-6.2 days), respectively. CONCLUSION: Early isolation of patients with coronavirus disease 2019 and prioritizing rapid contact investigation, followed by active symptom monitoring and periodic laboratory evaluation, should be initiated immediately after confirming patients to address the underlying determinants driving the continuing pandemic.

Establishing a high microbial load maternal-offspring asthma model in adult mice.

BACKGROUND: Although it is widely accepted that the "hygiene hypothesis" explains the increased incidence of asthma, the lack of suitable animal models hinders further in-depth studies of the underlying molecular immune mechanisms. Therefore, we aimed to develop a robust mouse asthma model to investigate the role of bacteria in preventing asthma. METHODS: BALB/c female mice were fed a mixture of eight common bacterial lysates (BL; Broncho-Vaxom®) and a commercial probiotic (Bifidobacterium tetravaccine tablets) at different concentrations before and during pregnancy to simulate different microbial load levels. Faeces from the mother mice were subjected to bacterial 16S rRNA sequencing to quantify the maternal microbial load. TLR2/4 expression and the proportion of regulatory T cells (Tregs) in the intestinal tract of female mice were determined, and the safety of the microbial load was evaluated. An asthma model was established in the offspring mice after weaning, and the extent of pulmonary pathological changes and Treg proportion were evaluated. RESULTS: A BL concentration of 1 mg/kg enriched the intestinal flora, increased the proportion of Tregs, and increased the expression of TLR2/4 in the maternal mice. The proportion of peripheral blood Tregs was increased, whereas the risk of asthma decreased only in the offspring from mothers with a high microbial load relative to control mice. CONCLUSION: This study established a safe and stable high microbial load maternal-offspring mouse asthma model, laying the foundation for a study on the molecular mechanism underlying the protective effects of a high microbial load against asthma.