Phosphorylated p38 MAP kinase expression by leucocytes is increased in allergic humans and associated with IgE responses.

Mitogen-activated protein kinases (MAPK) activate cascades that regulate cell proliferation, differentiation and death. Phosphorylated (phos-)p38 MAPK is a cell-signalling pathway associated with Th2 cytokine responses, which is required for immunoglobulin (Ig)E production. It is unknown whether MAPK are associated with IgE production. We examine the evidence linking p38 MAPK to inflammatory responses. Phos-p38, extracellular signal-related kinase (ERK) and c-JUN-n terminal (JNK) MAPK expression by blood leucocyte subsets and levels of serum Igs were measured in blood from adults with asthma and/or rhinoconjunctivitis (N = 28) and non-asthma (N = 10) (flow cytometry, microfluorenzymeimmunoassay). Peripheral blood mononuclear cells (PBMC) from allergic subjects were cultured for 10 days ± anti-CD40/recombinant IL-4 ± inhibitor of phos-P38. Culture supernatants were assayed for IgE (ELISA). Phos-p38 MAPK expression by all leucocyte subsets of allergic subjects was associated with serum IgE levels (p ≤ 0.01), after adjusting for cell counts, age, sex, race and smoking status (p ≤ 0.04). Leucocyte expression of phos-ERK and JNK did not correlate with IgE (p = 0.09-0.99). Instead, phos-ERK expression was associated with serum IgG. When PBMC from atopic subjects were cultured for 10 days with anti-CD40/rhIL-4, IgE levels were 26.2 ± 18 ng/mL. Inclusion of SB202190 (5-20 µg/mL), a specific inhibitor of phos-p38 MAPK, in culture suppressed IgE production in dose-dependent manner, with peak suppression obtained with SB202190 at 20 µg/mL (82.1% ± 11.8) (p = 0.0001), with virtually no cytotoxicity (<5%). Different MAPK pathways may be associated with IgE (p38) and IgG (ERK) responses. Phos-p38 MAPK can be a potential anti-allergy drug target.

The Relationship Between Allergic Rhinitis, Asthma, and Cardiovascular Disease in the National Health Interview Surveys (NHIS), 1999-2018.

BACKGROUND: Atopic disease has been associated with immune dysregulation and chronic inflammation, but current practice guideline recommendations do not include the evaluation of inflammatory outcomes among patients with asthma and allergic rhinitis (AR). OBJECTIVE: This study investigates the relationship between asthma, AR, and cardiovascular disease (CVD) using data from the U.S. National Health Interview Survey (NHIS) between 1999 and 2018. METHODS: We used data from adults in the NHIS (n = 603,140, representing a population of 225,483,286). Exposures were physician-diagnosed asthma (lifetime/past-year) and AR (past-year). Outcomes were physician-diagnosed heart disease: coronary heart disease (CHD), angina, heart attack, and nonspecific "heart-condition" (all lifetime). We used survey-weighted descriptive analysis and logistic regression adjusting for demographic and socioeconomic factors. RESULTS: A total of 11.44% reported at least 1 heart condition, with CHD the most prevalent (4.27%) across 20 years of pooled data. Asthma and AR were associated with higher CVD in all bivariate analyses. Specifically, lifetime asthma was associated with increased odds of CHD, (odds ratio [OR] 1.36; 95% confidence interval [95% CI] 1.29-1.42), with stronger effects observed for a past-year asthma attack (OR 1.66; 95% CI 1.55-1.80). The strongest effect of all was observed in those with a past-year asthma attack having increased odds of angina (OR 2.42; 95% CI 2.24-2.63). Allergic rhinitis was independently associated with increased odds of CHD (OR 1.25; 95% CI 1.18-1.28). CONCLUSIONS: Asthma and AR are risk factors for all types of CVD in this nationally representative study covering a 2-decade period in the United States. Clinicians should consider screening patients with severe and/or uncontrolled asthma and AR early for CVD, particularly angina and CHD. Future studies are warranted to explore the immunological milieu in these patients and identify therapeutic targets.

Serum Immunoglobulin Levels as Potential Biomarkers of COVID-19 Pneumonia.

OBJECTIVE: Severe Acute Respiratory Coronavirus-2 (SARS-CoV-2) has been known to cause immune dysregulation. However, the association between specific immunoglobulins and clinical characteristics in COVID-19 remains poorly understood. This study investigated the relationship between immunoglobulins and clinical outcomes in adults hospitalized with COVID-19 pneumonia. METHODS: A retrospective chart analysis was performed (N=569, December 2020-April 2021). Information on demographics, clinical factors, and total serum immunoglobulin (IgG, IgA, IgM, and IgE) levels were collected (N=60). Clinical outcomes of interest included: symptom duration, comorbidities (Charlson 10-year-estimated-survival (C10YES) and comorbidity index (CCI), vital derangements upon presentation (NEWS-2-score), length of stay (LOS), and mortality. Spearman correlation, chi-square tests and linear regression were conducted. RESULTS: Serum IgM levels were positive predictors of C10YES (ß=0.104, p=0.023) and negative predictors of CCI (ß=-0.007, p=0.047). There was an association between higher serum IgG levels and longer LoS (ß=7.455, p=0.047). We found no significant associations between immunoglobulins and preadmission symptom duration, medication use, or mortality. CONCLUSIONS: Total IgM was associated with increased survival and decreased comorbidity, and total IgG was associated with length of hospitalization. IgM may predict the body's initial ability to produce humoral immune responses, and IgG may function as a possible signature of chronic antigenic responses and inflammation, associated with comorbidities that increase COVID-19 hospitalization. Evaluating total IgM and IgG as prognostic biomarkers in COVID-19 pneumonia patients may contribute to improved management and clinical outcomes.

Chlamydia pneumoniae-immunoglobulin E antibody responses in serum from children with asthma.

Chlamydia pneumoniae is an obligate intracellular bacterium that causes respiratory infections in humans. An association between persistent C. pneumoniae infection and asthma pathogenesis has been described. It is unknown whether specific immunoglobulin E (IgE) is a marker of persistent immune activation responses. Therefore, the association between C. pneumoniae-specific-IgE antibodies (Abs) and interferon (IFN)-gamma produced by C. pneumoniae-stimulated peripheral blood mononuclear cells (PBMC) was examined. Blood was collected and serum separated. PBMC from 63 children with or without stable asthma (N = 45 and 18, respectively) were infected or not infected with C. pneumoniae AR-39 and cultured for up to 7 days. Supernatants were collected, and IFN-gamma levels measured (ELISA). Serum C. pneumoniae-IgE Abs were detected by immunoblotting. C. pneumoniae-IgE Abs were detected in asthmatics (27%), compared with non-asthmatics (11%) (P = NS). IFN-gamma responses were more prevalent among asthmatics who had positive C. pneumoniae-IgE Abs (60%) compared with asthmatics without C. pneumoniae-IgE Abs (20%) (P = 0.1432). IFN-gamma responses in C. pneumoniae-stimulated PBMC from children with asthma were more frequent in children who had specific anti-C. pneumoniae-IgE Abs compared to those who did not. This immune response may reflect persistent infection, which may contribute to ongoing asthma symptoms.

Comparison of Mycoplasma pneumoniae IgM and IgE Antibody Levels in Asthmatic and Non-Asthmatic Adults.

OBJECTIVE: Mycoplasma pneumoniae (M. pneumoniae), an extracellular pathogen lacking a cell wall, causes respiratory infection in adults and children and has been implicated in asthma exacerbation; immunoglobulin (Ig) E may be involved in these exacerbations. Specific IgM and IgG immune response to M. pneumoniae has been reported, but less is known about IgE M. pneumoniae antibody (Ab) responses in asthma. Previous studies in our laboratory demonstrated that asthmatic children have increased IgM M. pneumoniae levels, but not IgE. Thus, we sought to investigate whether past M. pneumoniae infection triggers production of M. pneumoniae-specific IgE Abs in adult subjects with/without asthma. METHODS: M. pneumoniae- IgE and -IgM Ab responses were studied in adult asthmatic (N=22) and non-asthmatic (N=22) subjects (ELISA). Data are reported as antibody index. Threshold detection levels: IgE, IgM: 0.2, 0.9, respectively. RESULTS: M. pneumoniae-IgE Ab levels were low and below the threshold of detection in both asthmatic and non-asthmatics (0.002±0.008 vs. 0.02±0.03; P=0.021). However, specific-IgM levels were slightly higher in non-asthmatics compared with asthmatics (0.96±0.37 vs. 0.79±0.31; P=0.054). M. pneumoniae-IgM Ab positivity was similar in both groups (P=1.0). CONCLUSION: IgM M. pneumoniae Abs may play an important role in non-asthma and persist for months after acute infection. IgE M. pneumoniae Abs may play a less important role in both groups.

Azithromycin decreases Chlamydia pneumoniae-mediated Interleukin-4 responses but not Immunoglobulin E responses.

BACKGROUND: Chlamydia pneumoniae is an obligate intracellular bacterium that causes respiratory infection. There may exist an association between C. pneumoniae, asthma, and production of immunoglobulin (Ig) E responses in vitro. Interleukin (IL-4) is required for IgE production. OBJECTIVE: We previously demonstrated that doxycycline suppresses C. pneumoniae-induced production of IgE and IL-4 responses in peripheral blood mononuclear cells (PBMC) from asthmatic subjects. Whereas macrolides have anti-chlamydial activity, their effect on in vitro anti-inflammatory (IgE) and IL-4 responses to C. pneumoniae have not been studied. METHODS: PBMC from IgE- adult atopic subjects (N = 5) were infected +/- C. pneumoniae BAL69, +/- azithromycin (0.1, 1.0 ug/mL) for 10 days. IL-4 and IgE levels were determined in supernatants by ELISA. IL-4 and IgE were detected in supernatants of PBMC (day 10). RESULTS: When azithromycin (0.1, 1.0 ug/ml) was added, IL-4 levels decreased. At low dose, IgE levels increased and at high dose, IgE levels decreased. When PBMC were infected with C. pneumoniae, both IL-4 and IgE levels decreased. Addition of azithromycin (0.1, 1.0 ug/mL) decreased IL-4 levels and had no effect on IgE levels. CONCLUSIONS: These findings indicate that azithromycin decreases IL-4 responses but has a bimodal effect on IgE responses in PBMC from atopic patients in vitro.

Chlamydia pneumoniae immunoglobulin E antibody levels in patients with asthma compared with non-asthma.

Chlamydia pneumoniae is an obligate intracellular bacterium that causes respiratory infection in adults and children. There is evidence for an association between atypical bacterial pathogens and asthma pathogenesis. We sought to determine whether past C. pneumoniae infection triggers C. pneumoniae- IgE antibodies (Abs) in asthmatics and non-asthmatics, who had detectable IgG titers. C. pneumoniae IgE Abs were quantified using enzyme immunoassay (EIA). C. pneumoniae IgE Ab levels were higher in asthmatics compared with non-asthmatics. There was no correlation found between total serum IgE levels and specific C. pneumoniae IgE Ab levels. C. pneumoniae infection may trigger IgE-specific responses in asthmatics.

Chlamydia pneumoniae-induced tumour necrosis factor alpha responses are lower in children with asthma compared with non-asthma.

INTRODUCTION: Chlamydia pneumoniae respiratory tract infection has been implicated in the pathogenesis of reactive airway disease and asthma. Innate cytokine responses that are protective of infection with intracellular pathogens may be impaired in patients with asthma. Tumour necrosis factor alpha (TNF-α) is a cytokine related to functions of monocytes and may inhibit C. pneumoniae infection. We investigated TNF-α responses in C. pneumoniae-infected peripheral blood mononuclear cells (PBMCs) in patients with asthma and non-asthma, and whether ciprofloxacin, azithromycin or doxycycline affects TNF-α responses. METHODS: PBMC (1.5×106) from paediatric patients with asthma (n=19) and non-asthmatic controls (n=6) were infected or mock infected for 1 hour with or without C. pneumoniae AR-39 at a multiplicity of infection=0.1, and cultured+ciprofloxacin, azithromycin or doxycycline (0.1 ug/mL) for 48 hours. TNF-α levels were measured in supernatants by ELISA. RESULTS: When PBMC from patients with asthma were infected with C. pneumoniae, levels of TNF-α were significantly lower than in subjects without asthma (48 hours) (5.5±5.6, 38.4±53.7; p=0.0113). However, baseline responses (no infection with C. pneumoniae) were similar in asthma and non-asthma (1.0±1.7, 1.1±1.2; p=0.89). When PBMC frompatiens with asthma were infected with C. pneumoniae+ciprofloxacin, azithromycin or doxycycline, TNF-α levels increased (25%-45%); this affect was not observed in PBMC from patients without asthma. CONCLUSIONS: We identified differences in the quantity of TNF-α produced by C. pneumoniae-infected PBMC in asthma compared with non-asthma.

Doxycycline suppresses Chlamydia pneumoniae induced interferon-gamma responses in peripheral blood mononuclear cells in children with allergic asthma.

Persistent respiratory infections caused by Chlamydia pneumoniae have been implicated in the pathogenesis of chronic diseases (e.g. asthma). Antibiotics are used to treat C. pneumoniae respiratory infections; however, the use of antibiotics as anti-inflammatory agents in treatment of asthma remains controversial. The current study investigated whether ciprofloxacin, azithromycin, or doxycycline can suppress C. pneumoniae-induced production of immunoglobulin (Ig) E or cytokines in peripheral blood mononuclear cells (PBMC) obtained from asthmatic children. Apart from blood, nasopharyngeal swab specimens were also collected to test for the presence of C. pneumoniae and/or M. pneumoniae (qPCR). PBMC (1.5 x 106) from asthmatic pediatric patients (N = 18) were infected or mock infected for 1 h ± C. pneumoniae AR-39 at a multiplicity of infection (MOI) = 0.1, and cultured ± ciprofloxacin, azithromycin, or doxycycline (0.1 or 1.0 µg/mLmL) for either 48 h (cytokines) or 10 days (IgE). Interleukin (IL)-4, interferon (IFN)-γ and IgE levels in supernatants were measured (ELISA). When PBMC were infected with C. pneumoniae, IL-4 and IFNγ production increased (p = 0.06 and 0.03, respectively); IgE levels were low. The now-elevated levels of IL-4 didn't decrease significantly after addition of ciprofloxacin, azithromycin, or doxycycline. However, infected PBMC IFNγ formation decreased significantly when 0.1 µg/mL doxycycline was employed (p = 0.04); no dose of ciprofloxacin or azithromycin had any impact. This inhibitory outcome with doxycycline lends support to the use of tetracyclines as immune modulators and anti-inflammatory medications in treatment of C. pneumoniae-infected asthma patients.

IgE anti-Haemophilus influenzae type b (Hib) antibodies detected in serum of Hib-vaccinated asthmatic and non-asthmatic pediatric patients.

BACKGROUND: Haemophilus influenzae type b (Hib) bacterium causes severe illness in infants and children, but has largely been eliminated by introducing a universal Hib conjugate vaccine. While effects of certain vaccinations on atopic disease have been studied, little is known about the relationship between Hib vaccination and diseases of altered immunoglobulin E (IgE) regulation (asthma or atopy). As such, it is necessary to provide more evidence concerning Hib vaccination as a possible risk factor for atopic disease. METHODS: Total serum IgE and IgE-and IgG-anti-Hib antibody responses were studied in Hib vaccinated asthmatic (N.=14) and non-asthmatic children (N=26) (VaccZyme™ Human Anti Hib Enzyme Immunoassay Kit). Data are reported as mean optical density (OD) values. RESULTS: We found that: 1) total serum IgE levels were higher in asthmatic compared with non-asthmatic subjects (389±125 vs. 125±129, P<0.001); 2) IgE and IgG anti-Hib antibody responses were similar in both asthmatic and non-asthmatic subjects (0.722±0.279 and 0.681±0.280, respectively; P=0.65; 0.450±0.505 and 0.573±0.779, respectively; P=0.580). CONCLUSIONS: The universal Hib vaccine antigen did not result in either increased IgE, or IgG anti-Hib antibody responses in asthmatic or non-asthmatics subjects. Thus, in this cohort, no association between Hib vaccination and asthma status was identified.

Negative IgG Varicella Zoster Virus Antibody Status: Immune Responses Pre and Post Re-immunization.

INTRODUCTION: Varicella zoster virus (VZV) causes chicken pox and herpes zoster and is a self-limiting disease in healthy children. Vaccination is recommended for children, adolescents, and adults. This study discusses a healthy pediatric patient with negative immunoglobulin (Ig) G VZV antibody (Ab) status after two doses of varicella vaccine and then subsequently re-immunized. Since measurement of serum IgG titers alone may not reflect vaccine protection, we further evaluated cell-mediated and humoral immune responses before and after re-immunization. METHODS: Blood lymphocyte distributions (CD3+CD4+, CD3+CD8+, CD19+, CD4+CD60+, CD8+CD60+), total serum IgG and IgE levels, and VZV-IgG, IgM, and IgE Ab levels were measured in a healthy girl (14 year-old) pre- and post-VZV re-immunization (weeks 1-8) [flow microfluorimetry, nephelometry, ELISA, enzyme immunoassay (EIA)]. RESULTS: Pre-re-immunization numbers of T cells (CD3+CD4+, CD3+CD8+, CD4+CD60+, CD8+CD60+) and B cells (CD19+) were within normal ranges. After re-immunization, numbers of T cells remained relatively unchanged; however, numbers of CD19+ B cells increased (48%). Total serum IgG was low (757 mg/dl), and total serum IgE was normal (30 IU/ml). Pre-reimmunization, VZV IgG and IgM Ab levels were negative (< 0.90 and < 0.90 antibody index, respectively), and VZV IgE levels were undetectable. After re-immunization, VZV IgG Ab levels were positive (690.70 Ab index), VZV IgM Ab levels were negative (≤ 0.90), and VZV IgE levels remained undetectable. CONCLUSION: Vaccination with the VZV vaccine may boost IgG but not IgE-specific viral responses and concurrently increase the numbers of CD19+ B cells.

An Extubation Protocol for Angioedema.

Angioedema-nonpitting edema of the mucous membranes and skin-most commonly occurs as a complication from the use of angiotensin-converting enzyme inhibitors. At our institution, the otolaryngology department has incorporated the use of the endotracheal tube cuff-leak test and bedside direct laryngoscopy to aid in timing for extubation of angioedema patients. Prospective data collection of patients presenting to the emergency department with angioedema was performed. Of 76 patients with angioedema, 9 required fiberoptic intubation. Intubation was performed at a median of 73 hours (range, 44-118). An endotracheal tube cuff-leak test was performed in 7 patients prior to extubation, and bedside direct laryngoscopy was also performed in 3 of these 7 patients to document resolution of laryngeal edema. The use of the endotracheal tube cuff-leak test and bedside direct laryngoscopy is an easy and inexpensive method to help determine eligibility for extubation in patients intubated for angioedema.

Clinical Toxicology and Its Relevance to Asthma and Atopy.

Although both the prevalence of asthma and the prescription drug use, notably the opiate analgesic class, epidemics are increasing, there is a complex interplay between both disorders, with both protective and exacerbating factors involved in the effect of opiates on asthma pathogenesis and clinical severity. This review examines the airway effects, both immunologic and neurologic, of opiates, which may interact and result in protection or exacerbation of asthma.