Asthma exacerbations are frequently induced by respiratory tract infections (RTIs). Bacterial lysates have been described to possess immune‐modulatory effects and reduce RTIs as well as asthma symptoms in children. However, whether bacterial lysates have similar effects in adult asthma patients is unknown.To reduce asthma exacerbations by add‐on bacterial lysate therapy in adults with severe asthma and to characterize the clinical and immune‐modulatory effects of this treatment.Asthma patients (GINA 4) with ≥2 annual exacerbations in the previous year were included. The intervention regimen consisted of OM‐85/placebo for 10 consecutive days per month for 6 months during two winter seasons. Primary end‐point was the number of severe asthma exacerbations within 18 months. The study was approved by the national and local ethical review board and registered in the Dutch Trial Registry (NL5752). All participants provided written informed consent.p = 0.77). With the use of OM‐85, FEV1% increased by 3.81% (p = 0.04) compared with placebo. Nasopharyngeal swabs taken during RTIs detected a virus less frequently in patients using OM‐85 compared to placebo .Seventy‐five participants were included . Exacerbation frequencies were not different between the groups after 18 months . Immune‐modulatory effects included an increase in several plasma cytokines in the OM‐85 group, especially IL‐10 and interferons. Peripheral blood T‐ and B cell subtyping, including regulatory T cells, did not show differences between the groups.In subjects with type 2 inflammation adherent to the protocol , a non‐statistically significant decrease in exacerbations in the OM‐85 group was observed . While intention to treat (ITT) analysis revealed no difference in exacerbation frequencies between the groups after 18 months, per protocol analysis in patients with type 2 inflammation (PPT2) showed a non‐significant decrease. Nasopharyngeal swabs detected a virus less frequently in the OM‐85 group during respiratory tract infections. Immune‐modulatory effects were seen in several plasma cytokines. To conclude, OM‐85 might be an effective add‐on therapy in severe asthma patients with type 2 inflammation. OM‐85 did not reduce exacerbation frequency in the studied group of heterogeneous adult severe asthma patients;OM‐85 may be an effective add‐on therapy to reduce exacerbations in asthma patients with type 2 inflammation;Immune‐modulatory effects were observed with the use of OM‐85.1Asthma patients with recurrent exacerbations suffer the highest disease burden and account for over half of the asthma‐associated healthcare expenditure, with 80% of the total direct costs of asthma attributed to the treatment of exacerbations.Several recent reports and meta‐analyses concluded bacterial lysate therapy has a favourable safety profile and reduced RTIs, COPD exacerbations and preschool wheezing episodes.22.1We conducted a 1:1 double‐blind, randomized, placebo‐controlled study in two large teaching hospitals in Rotterdam, the Netherlands, between September 2016 and April 2019. The study was approved by the national and local ethical review board and registered in the Dutch Trial Registry (NL5752). All participants provided written informed consent.2.22‐agonists). Exclusion criteria were as follows: other relevant respiratory conditions; systemic immunological diseases and/or immunosuppressive medication ; untreated comorbidities; known non‐compliance; current or planned pregnancy; non‐comprehension of Dutch language; and current or past smoking with >10 pack years. Type 2 inflammation (T2+) was defined according to the GINA 2020 guidelines  ≥20 ppb and/or presence of a clinical relevant allergy).Asthma patients between 16 and 60 years of age with ≥2 physician‐diagnosed asthma exacerbations  in the previous year were invited to participate in this study. Asthma diagnosis was based on the GINA 2016 criteria.2.3Haemophilus influenzae; (2) Streptococcus pneumoniae, sanguinis and pyogenes; (3) Klebsiella pneumoniae and ‐ozaenae; (4) Staphylococcus aureus and (5) Moraxella catarrhalis.Patients received 7 mg capsules of either OM‐85 or matching placebo  in addition to their asthma treatment regimen. OM‐85 consisted of an extract of lyophilized lysates from 21 strains from the following pathogenic bacteria: (1) 2.4T = 0) and thereafter at 3, 6, 9, 12, 15 and 18 months (study end) and exacerbation visits  and antibiotics if necessary, according to the treating physician. Secondary study outcomes were as follows: time to first and second asthma exacerbation, number of viral RTIs, prescriptions of oral corticosteroids and/or antibiotics, ACQ and asthma‐related quality of life (AQLQ), pulmonary function, FeNO and immunological measurements. Also, adverse events were registered.2.6Literature on the use of OM‐85 for exacerbation prevention in adults with asthma was unavailable. Power analysis was targeted at a 20% reduction in asthma exacerbations, based on previous literature describing a 20%–40% reduction of RTIs in children and adults.2.7Block randomization of all patients was stratified for atopy status . Randomization was performed by allocating the first consecutive number in the strata to the participant. Patients, investigators, treating physicians and the hospital pharmacists were blinded to the allocation during the study. The unblinding key was released after all active participants finished their 18‐month visit and after the exacerbations of every participant had been filed in the study database were verified by a second investigator, and the database was locked. The investigational active and matching placebo medicinal products were packed‐ and labelled by OM Pharma and shipped directly to the hospital trial pharmacy. Medication was handed over to patients in packages with 3 strips of 10 capsules.2.8Forced expiratory volume in 1 s as percentage of predicted (FEV1%) was performed with the Vmax Sensor Medics Viasys, type 6200 EncoreMycoplasma pneumoniae by multiplex PCRNasopharyngeal swab liquid was stored at −80°C and analysed batch‐wise for the presence of respiratory viruses and Blood leukocyte differentiation, serum IgE, IgA, IgM and IgG were measured with Beckman Coulter equipment  for baseline, 6‐, 12‐ and 18‐month samples.Plasma cytokines IL‐6, IL‐8, IL‐9, IL‐10, IL‐13, IL‐17E, IL‐17F, TNFα, IFNγ and IFNλ were quantified with ELISA  for baseline, 6 and 12‐month samples. Plasma cytokines measured below the lower detection limit (D) were set to √D.+ participants being adherent to the study protocol (PPT2). Supplementary Methods show the flow cytometric protocol; Table + and CD8+T cells and intracellular cytokines, regulatory T cells and B cells.Peripheral blood mononuclear cells (PBMC) phenotyping by flow cytometry was performed for baseline, 6‐, 12‐ and 18‐month samples of T22.9Pre‐specified statistical analysis was performed for all included patients. Study data were analysed according to the intention to treat (ITT) principle. A negative binomial regression model with number of exacerbations as dependent variable and allocated intervention (OM‐85/placebo) as independent variable, adjusted for age and atopy was used to estimate the primary outcome, number of exacerbations within 18 months; missing data were excluded from analysis. Adjusted outcomes are presented as incidence rate ratio (IRR) with 95% confidence intervals (95%CI) of the binomial regression.p‐value. Also, median values and interquartile ranges of the data are shown. For cytokine data, to prevent under‐ or overestimation, outlier analysis was performed by clipping the upper and lower 10% of data points within groups. Skewed variables were log‐transformed before repeated measurements were performed. Fold‐changes were used to compare differences in time between groups for plasma cytokines (baseline vs. 12 months), with the Mann‐Whitney U test, as data were non‐parametric. A p < 0.05 (two‐sided) was regarded statistically significant. To correct for multiple‐testing Bonferroni correction was applied for fold‐change data resulting in p < 0.005 for statistical significance. All analyses were performed using SPSS 26.0 (IBM) and GraphPad 8.4.3. Interim analysis was not performed.Analysis of secondary end‐points was only adjusted for atopy (stratification variable), as age in both groups was comparable. Time to first and second exacerbation was evaluated using Kaplan‐Meier curves with logrank test and Cox regression. Repeated measurements of continuous variables were used to compare differences within patients over time (trends over time) and differences between patients over time (treatment effect) by linear mixed modelling  and the covariate atopy status), resulting in estimated marginal differences of continuous secondary end‐points. The estimated difference (ED) between both groups is reported with the corresponding 95%CI and 2.10N = 42). Rationale of this PPT2 analysis is that bacterial lysate therapy decreases childhood asthma exacerbations, in asthma that often is allergic in origin.Post hoc subgroup analyses, with identical outcomes and statistical plan as described above, were performed for patients being adherent to the study protocol (PP) and PPT2 (3n = 38 OM‐85 vs. n = 37 placebo)   in the OM‐85 group and 67 (mean number per patient: 1.81 ± 1.91) in the placebo group (IRR) 1.07, 95%CI [0.68–1.69], ) Figure . Mean nu) Figure . A separ3.2p = 0.610 and p = 0.560 respectively). Cox‐regression analysis showed a hazard ratio of 1.09 for OM‐85   (Table Time to first exacerbation or between first and second exacerbation was comparable for both groups (logrank ) Figure a, b. Medp = 0.04)  Figure ; Table 33.3p = 0.02).We next compared relevant microbiological and immunological parameters between the two treatment groups. At baseline, 3 and 6 months, the proportion of samples in which viruses could be detected did not differ Figure . In totaN = 63) were visiting the research facility for evaluation. A respiratory virus was detected in 54% of these swabs, with no differences between treatment groups . No significant differences between the groups were observed within the other plasma cytokines at baseline. Linear mixed model analyses revealed that plasma cytokine levels of IL‐6 (p = 0.03), IL‐10 (p = 0.01), IL‐13 (p = 0.02) and IL‐17E (IL‐25) (p = 0.02) showed significantly higher levels in the OM‐85 group compared with placebo over time, which was not present in the placebo group  in the OM‐85 group as compared to placebo group  showed a slight but not statistically significant decrease in exacerbations (OM‐85 41 (1.52 ± 1.37) vs. placebo 61 (1.97 ± 1.89), IRR 0.77 (0.47–1.17), p = 0.23). We performed a parallel analysis on the PPT2 group . Within 18 months, a reduction was seen in exacerbation frequency (30 OM‐85 vs. 48 placebo group) that did not reach statistical significance   Figure . Time be) Figure c,d. Betwp = 0.02), IL‐10 (p = 0.001) and IL‐13 (p = 0.03) in time with the use of OM‐85 compared to placebo  and IFNγ (p = 0.0005) in the OM‐85 group compared to placebo group , which is in accordance with previous literature. However, self‐reported RTIs are prone to subjective self‐reporting and could include episodes of allergic rhinitis. Nevertheless, we did not observe a difference in the numbers of viral RTI‐associated asthma exacerbations between patients using OM‐85 and placebo. Possibly, when having acquired a viral infection, immunomodulation by bacterial lysates in severe asthma patients does not prevent further progression to an asthma exacerbation.Several studies and meta‐analyses describe a reduction of recurrent RTIs with the use of OM‐85 in adults.+/CD8+ T cells, indicating that the observed increase in plasma cytokine levels might not be mediated by T cells. Previous observations in humans have also revealed higher levels of plasma IL‐10, after OM‐85 administration compared with placebo or control group.+ regulatory CD4+ T cells. IL‐10 might therefore be used as a biomarker for bacterial lysate‐induced immune‐modulatory responses. Future research in adults with asthma should address this possibility. Other cytokines increased in our study have a generally more pro‐inflammatory function, including cytokines associated with type 1 (IFNγ) and type 2 inflammation . While the strongest effects were seen for IL‐10 and IFNγ, our study lacks evidence for suppression of type 2 inflammation as measured by levels of cytokines in the circulation.Despite the absence of effects on exacerbation frequency in the complete study group, we did find evidence for immune‐modulatory effects induced by bacterial lysate therapy. These effects were mainly related to peripheral blood cytokine levels and lasted at least 6 months until after OM‐85 treatment (12‐month sampling time‐point). These effects seemed more pronounced in the PPT2 group as compared to the ITT group, with the former showing higher levels of several cytokines and especially IL‐10, a cytokine with immune‐modulatory functions and interferons. Some of these cytokines have been described as immune‐modulatory and anti‐inflammatory and can be produced by various immune cells including T cells. Flow cytometry analysis did not reveal significant changes in cytokine‐producing CD4+ airway dendritic cells combined with an increase in Tregs and an up‐regulation of IL‐10 secreting cells in the trachea upon OM‐85 treatment. These up‐regulations result in a decrease in airway hyperresponsiveness and improved protection against airway inflammation in OM‐85 treated animals.Our study did not show a significant effect of OM‐85 on function and numbers of naïve and activated Treg cells. In literature, animal models suggest an up‐regulation of CD86Although carefully designed, our study has limitations. First, due to the unknown effect of OM‐85 in adults with asthma, we powered our cohort based on paediatric studies. Next, the number of asthma exacerbations during the study was lower than anticipated in the complete study group . Reasons for this could be a trial participation effect, as a result of the more frequent hospital visits or possibly increased therapy compliance and regression to the mean. This was observed in several other asthma studies and referred to as the Hawthorne effect. Nevertheless, our results suggest a potential clinically relevant beneficial effect for patients with type 2 inflammation, and therefore, this might be a good selection indicator as a starting point for future studies into the effect of bacterial lysate therapy. A different treatment regimen of OM‐85, which is currently being studied in the PrecISE network study (NCT04129931), might be more effective in adults.In conclusion, our study did not demonstrate a benefit of bacterial lysate therapy on the incidence of asthma exacerbations in a heterogeneous group of adult patients with severe asthma and recurrent exacerbations. However, we did find an increase in FEV1% and non‐specific immune‐modulatory effects. Interestingly, post hoc subgroup analysis did show a trend towards a positive effect on exacerbation frequency in asthma with type 2 inflammation.GT reports speaker fees and investigator‐initiated grant support from OM Pharma and Astra Zeneca, not paid in person but directly to a research foundation. GJB has received grant/research support for consultations and/or speaking at conferences from Novartis, GSK, AstraZeneca, ALK, Teva, Sanofi and Chiesi. GMB, EKP, CMZ, AB, GE, MN, JWB, GV, EB, BMBK, RS and RWH have no conflicts of interest.GT had the original idea for this study and designed the study protocol. GMB carried out the clinical part of the study under supervision of GT, GJB, GE and GV. GJB, GT, CMZ and AB assisted GMB with clinical follow‐up visits and sample collection. EKP, JWB and MvN assisted GMB with immunological analysis, EKP performed flow cytometric experiments under supervision of RWH and RS. GMB and GT performed statistical analysis under supervision of BBK and EB. GMB and GT wrote the manuscript, with special assistance on clinical topics from GJB and on immunological topics from RWH and RS. All authors reviewed the final manuscript and approved it before submission.The study was approved by the national and local ethical review board and registered in the Dutch Trial Registry (NL5752). All participants provided written informed consent.Supplementary MaterialClick here for additional data file.Figure S1Click here for additional data file.


To evaluate capillaries perfusion and retinal nerve fiber layer (RNFL) thickness diurnal changes of macular/optic disc regions among participants with or without obstructive sleep apnea-hypopnea (OSA) using spectral-domain optical coherence tomography angiography (OCTA).In this study, we enrolled a cohort of 35 participants including 14 patients with mild-to-moderate OSA, 12 patients with severe OSA, and 9 healthy individuals. All participants had Berlin questionnaire filled. At 20:00 and 6:30, right before and after the polysomnography examination, a comprehensive ocular examination was conducted. The systemic and ocular clinical characteristics were collected, and OCTA scans were performed repeatedly. Blood flow and RNFL thickness parameters were then exported using built-in software and analyzed accordingly.After sleep, the overall vessel density (VD) variables, especially macular and choriocapillaris VDs, were relatively comparative and stable. One exception was the RPC vessel density at the inside-disc region with a decreasing trend in the mild-to-moderate group (p=0.023). RNFL changes before and after sleep in the nasal-inferior and peripapillary region were statistically significant  among three groups. And multiple testing correction verified the significant difference in diurnal changes between the mild-to-moderate group and the control group in pairwise comparisons .The changes of imperceptible blood flow and RNFL thickness overnight around optic disc areas could be observed in OSA patients. Despite physiological fluctuations, aberrant diurnal changes might be useful for identifying a decrease in micro-environmental stability associated with the development of various ocular diseases such as glaucoma. Other VD variables, especially macular and choriocapillaris VDs, are relatively stable in eyes of patients having OSA with different severity. Obstructive sleep apnea–hypopnea (OSA) is a highly prevalent systemic disorder characterized by episodes of obstruction or collapse of the upper airway and subsequent partial (hypopnea) or complete (apnea) cessation of airflow for more than 10 s despite the remaining respiratory effort. It is frequently related to aberrant blood-gas changes and is always associated with anomalous sleep patterns and cortical arousal , 3. AbnoOSA has already been verified to be highly associated with neurological disorders such as stroke, depression, headache, elevated cranial pressure, and peripheral neuropathy . The higin vivo.Up to now, the pathogenesis between OSA and ocular optic nerve-related diseases or pachychoroid diseases is still unclear , probablQuantitative assessment of microvascular circulation changes in patients with OSA is scarce. The first study of quantitative OCTA measurements in patients with OSA was performed by Yu et al. in 2017, who concluded that vascular density (VD) in the macular and retinal regions differed significantly among groups classified by OSA severity. The severe group with an apnea–hypopnea index (AHI) of more than 30 breaths/hour had significantly lower VD in the peripapillary area. In addition, vessel densities in the parafoveal and peripapillary regions were significantly negatively correlated with AHI  reportedTherefore, in this study, we investigated the diurnal variation of nerve fiber layer thickness near the optic disc and the microvascular VD in the optic disc and macular regions in OSA patients.This prospective observational study consisted of 26 consecutive participants newly diagnosed with OSA and nine age-matched controls, all recruited from the Sleep Laboratory of the People’s Hospital of Peking University. The study was performed between January 2018 and September 2020 and was approved by the ethics committee at mentioned university. The protocols adhered to the aims of the Declaration of Helsinki. All subjects participated voluntarily, and their written informed consent was obtained.The general experimental method has been elaborated in the previous study . ParticiAfter filling out the Berlin questionnaire, ocular data were collected at around 20:00. Baseline demographic data including, sex, age, current cigarette smoking status, neck circumference, body mass index (BMI), and blood pressure were also documented. The examiner and the participants were unaware of the polysomnography (PSG) results at the time of receiving the ocular and body examination. The next morning after PSG, the same set of OCTA scans was repeated as soon as the PSG test was completed (at around 6:30 a.m.). The morning blood pressure and intraocular pressure (IOP) were also collected.All participants received comprehensive ocular examinations, including BCVA (transformed into LogMAR score), IOP measured using a non-contact tonometer , anterior segment examination, fundus examination, axial length and central corneal thickness (CCT) measured using the optical method , and OCTA scans . All images and data were evaluated by the same expert examiner (YC). To ensure consistency of the longitudinal assessment, topical mydriatic eye drop was not applied and all OCT scans were performed inside a silent room with a few minutes of dark adaptation.2 centered on the foveola (We preferred the right eye as the study eye unless there were obvious motion artifacts difficult to eliminate despite repeating. High-definition (HD) imaging was conducted using the RTVue XR Avanti Spectral Domain OCT System , which had been described in detail in our previous study . The mac foveola . Each OCAll subjects were monitored using a standard polysomnography system  with standard nocturnal polysomnography continuous electroencephalography recorded from 10 p.m. to 6 a.m. . All subjects underwent nocturnal polysomnography (PSG) for at least 6 h in a quiet, individual room. The definition of apnea events obeys the sleep guidelines. The AHI (times/h) was assessed for each patient based on Academy of Sleep Medicine standards and used as the indicator of the severity of OSA . Participost-hoc tests were used for pairwise comparison. Circadian valuable change was analyzed using paired t-test or paired-sample Wilcoxon signed-rank test. For two continuous measurements of the same scan item, the intraclass correlation coefficient (ICC) was calculated to determine the consistency of the corresponding continuous variables. Correlation coefficients between sectional RNFL diurnal difference and other parameters were analyzed and adjusted in the multiple regression analysis. p-values <0.05 were considered statistically significant.Statistical analyses were performed using R (version 4.0.3). Continuous data were expressed as mean ± SD . The Shapiro–Wilk test was used to verify normality for continuous data. One-way analysis of variance (ANOVA) was used to perform a cross-sectional comparison between three groups for normal distribution data; otherwise, Kruskal–Wallis was used as an alternative, and Tukey A total of 14 subjects diagnosed with mild-to-moderate OSA, 12 subjects with severe OSA, and nine control subjects without a diagnosis of OSA were included in the final analysis. The systemic and ocular parameters regarding age, blood pressure, BMI, AL, CCT, and intraocular pressure that may affect the analysis of quantitative OCTA data were all comparable. The characteristics of the subjects’ systemic and ocular parameters are shown in Considering the prevalence of nerve fiber layer defect in OSA patients in the previous studies as mentioned above, we first investigated the retinal nerve fiber layer thickness changes in different peripapillary subdivisions corresponding to the Garway-Heath mapping of the VF in the range of 2–4-mm dual-ring area centered on the optic disc among different groups. The results suggested that the mean total peripapillary RNFL thickness in the baseline examination before PSG showed a decreasing trend in the OSA group compared to the control group, although without any statistical significance. In contrast, in certain Garway-Heath subdivisions, there were significant differences in the mean RNFL thickness at baseline, including the inferior hemisection (p = 0.048) and IT section (p = 0.009), respectively. In the longitudinal observation of circadian nerve fiber layer thickness changes using paired t-test analysis, the severe group was found to have significant differences between nocturnal and morning RNFL thickness in both the peripapillary, GH-S-Hemi, and GH-IN sections , with the thickness being significantly higher in the morning than measured at night. In contrast, there were no significant diurnal differences of other sections in other groups . ICC of RPC VD at the inside-disc area revealed 0.80 . Comparative and statistical analysis results are demonstrated in post-hoc tests verified a significant difference in diurnal changes between the mild-to-moderate group and the control group , which is demonstrated in Comparisons of diurnal difference in OCTA vessel density and RNFL parameters between the three groups revealed that RNFL changes in the GH-NI and peripapillary regions were significantly different  among the three groups, and Correlation analysis of the diurnal difference changes in RNFL thickness in the above two regions showed that nocturnal IOP and AL were significantly correlated with RNFL changes in the GH-NI region , but none of them was significant after being adjusted in the multiple linear regression  was significantly lower in OSA patients than that of the first measurement and in controls during the 1-year follow-up of OSA patients and proposed that AHI was significantly correlated with retinal nerve fiber layer thickness . Besidessections . In contNo research on the VD diurnal change in OSA was ever analyzed. In the present study, we did not find any significant diurnal variable in macular regions at the level of either SCP or DCP. VDs in macular regions were all comparable in three groups, regardless of the time collected. This was consistent with the previous research regarding the macular regions in normal participants , 35. We Regarding VD in the optic disc areas, we found that the RPC vessel density at the inside-disc region decreased significantly in the mild-to-moderate group in the morning, although the decline was slight, while other groups remained relatively stable during the day and night. In our previous cross-sectional study, we had noticed that VD decreased significantly in the moderate-mild group compared to the control group in the peripapillary region on the radial peripapillary capillary (RPC) network . The samIn the analysis of blood flow changes at the level of choriocapillaris in the macular area, no significance was noticed between the three groups, and VD differences between day and night were also comparable. As mentioned above, the choroid tissue is richly innervated by autonomic vasoactive innervation and thus vulnerable to blood flow change in larger vessels and activation of the sympathetic nervous system, however, it can also regulate blood flow quickly at the same time. In one meta-study analysis of CSCR and OSA, findings suggested that patients with CSCR were more likely to have OSA, while patients with moderate/severe OSA had decreased subfoveal choroidal measurements on EDI-OCT scans . BesidesThis study has several limitations. First, the subjects included in the study were relatively young and the population was small. Given the large number of examinations performed on every subject, to control the total time of the ophthalmic examination for better cooperation, and to meet the independence condition in statistical analysis, we performed OCTA measurements in only one eye, which further affects the sample size, although there was no evidence of differences in choosing different eyes. Second, considering that this is an exploratory study, we did not correct for multiple testing for various macula and optic disc subregions, which may lead to an inevitable increase in false discovery rate. Third, given the sitting position required to perform OCTA, the OCTA examination could not be performed in the sleeping or supine position. During episodes of apnea and hypopnea events, dynamic vascular changes cannot be captured. Also, changes in body position, light stimulation during transfer, etc., may have some impact on OCTA quantification. Future studies with larger populations and more accurate and reproducible OCTA algorithms are needed to further investigate the effects of OSA on retinal and optic disc microcirculation.In conclusion, microcirculation blood flow and overnight RNFL thickness change around the optic disc areas might emerge in OSA patients. Although there may be physiological fluctuations, aberrant diurnal changes may signal a decrease in microenvironmental stability that may be associated with the development of various ocular diseases such as glaucoma. Other vessel density (VD) variables, especially macular VDs and FAZ parameters, are relatively stable in the eyes of patients with OSA of different severity.drxuanshi@163.com).The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. The data supporting this study are available upon request from Prof. XS , and National Key R&D Program of China, No. 2020YFC2008200.The authors are grateful to all the subjects who participated in this study.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Introduction: Ramadan can alter the course of diseases by changing nutrition patterns, sleep habits, and medication-taking schedules. There are some concerns that patients with asthma may be affected by these alterations during Ramadan and experience deterioration of their symptoms. This study aimed to investigate the effect of fasting in Ramadan on the severity of the disease and spirometric parameters in patients with asthma.Methods: An overall 120 patients with moderate to severe asthma were investigated during Ramadan and categorized into two groups of fasting (60 cases) and non-fasting (60 cases) groups. Patients underwent spirometry before and after Ramadan and asthma control status was also assessed. The parameters measured in spirometry were compared in each group before and after Ramadan and also between the two groups.Results: Spirometric measurements including forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF), and FEV1/FVC were not significantly different before and after Ramadan in both groups of fasting and non-fasting patients. Furthermore, there was no significant difference between the two groups in terms of these spirometric parameters changes from baseline. Nevertheless, FEV1 change in the fasting group was significantly higher than that in the non-fasting group .Conclusion: The results of this study demonstrated that fasting has no significant effect on the severity of asthma and spirometric findings in patients with moderate to severe asthma. Therefore, fasting during Ramadan can be considered safe for patients with asthma. A variety of strategies have been identified for the prevention of asthma attacks and reducing its symptoms and complications; however, the best strategy which is indicated by all established guidelines and treatment protocols is the regular use of medications along with a close follow-up, education of patients, and diminishing known risk factors.6 Asthma is a long-term condition affecting children and adults that is characterized by hyperresponsiveness, reversible airflow obstruction, and bronchial hyperresponsiveness.dawn) to sunset (iftar) should be continued for a month.9 Islamic fasting, like other Circadian rhythms, includes periods of “nutrition - abstinence from nutrition” which are repeated in a certain order, the way of repetition of these periods is such that the interval between the time of the sunset Adhan to the sunrise Adhan, which is the dark phase, is called the feeding phase, and the interval between the sunrise Adhan and the sunset Adhan, which is the phase of light, is called the phase of abstinence or abstinence from having food. In better words, Islamic fasting takes place in the form of rhythms and harmonic process.10 Fasting is of paramount importance among many major religions worldwide, particularly Islam, and is a religious practice in which the faithful abstinence from eating and drinking from before sunrise  are the two main challenges that occur in Islamic fasting. In the current study, we aimed to evaluate the fasting effect in the holy month of Ramadan on spirometric parameters and respiratory symptoms in asthmatic patients. As far as we investigated, few studies have evaluated the influence of fasting on the exacerbation of asthma and variations in spirometric findings associated with conflicting outcomes. The current study was conducted as a cohort study between May and June 2019 on 120 volunteer patients with moderate to severe asthma according to GINA guidelines referred to the lung sub-specialty clinics at Imam Reza Hospital in Tabriz. The sampling method was simple sampling and patients were included consecutively. The Sample size was calculated using G - Power software version 3.1.9.2 by considering an alpha error of 0.05 and study power of 0.8. Moreover, with an effect size equal to 0.5, an overall of 51 cases for each group resulted by calculation, which by considering the probability of loss to follow up, a final 60 individuals was considered adequate for each group . The inclusion criteria were as follows; Muslim patients aged in the range of 18-50, with a previous diagnosis of asthma by a physician, FEV1 less than 80%, presence of two or more asthma symptoms such as recurrent wheezing, cough, or chest tightness at rest, night, or early morning wheezing, activity-based cough or wheezing. The exclusion criteria were as follows; the presence of cardiovascular disease, hypertension, hypo/hyperthyroidism, pregnancy, lactating women, recent respiratory disease, abnormal chest graphic, chronic cardiovascular or known neuromuscular disease, malignancy, chest deformations, and abdominal or thoracic surgery. The included patients were categorized into two groups: 60 patients were fasting and 60 patients were non-fasting depending on whether they fast during the holy month of Ramadan. The study was performed according to the Declaration of Helsinki. Written informed consent was obtained from the participants. The demographic characteristics including age, gender, occupation, education, as well as the number of fasting days, symptoms, illness duration, and spirometric findings were also recorded in a pre-prepared checklist. The status of asthma control was assessed before and after Ramadan according to the Asthma Control Assessment Questionnaire. This questionnaire consisted of 5 items including asthma symptoms , the use of rescue medications, the effect of asthma on daily functioning, and the patient’s perception of asthma control over the previous 4 weeks with a score ranging from 1 to 5 for each item. Subsequently, responses for each of the 5 items were summed to yield a score ranging from 5 to 25. The scores above 20 were assumed as well-controlled, the score between 15-20 as poorly-controlled, and the score less than 15 as very poorly-controlled. Spirometry was conducted on all patients the day before and the day after Ramadan to assess pulmonary function. Before each spirometry, an explanation of the procedure was given to patients. In each patient, spirometry was performed three times to choose the most acceptable one.P values below 0.05 were considered statistically significant. The statistical software of SPSS 24 was used to analyze the data. Paired t-test was implied to compare the quantitative data in each group, a chi-square statistical test was also utilized to compare qualitative data between the two groups, and an independent t-test was performed on the quantitative variables. P = 0.040). The average age of patients was 35.79 ± 9.08 years old. The average fasting duration was 26.13 ± 3.13 days in the fasting group. The minimum and maximum fasting durations were 20 and 30 days. The demographic and baseline data of the fasting and non-fasting groups are summarized in P = 0.151). The results of the asthma control questionnaire before and after Ramadan between the fasting and non-fasting group are depicted in 17 One of the oldest acts of worship in Islam is fasting during the holy month of Ramadan, which is common among the ethnicities and nations of the world and is a divine duty for all Muslims.17 During the period from Sahar to Iftar, Muslims are forbidden from eating and drinking during this month. Besides in this month, the sleep-wake cycle is disrupted and hence it may have some effects on the body systems.18 On the other side, other studies have reported fasting may worsen or improve symptoms in asthmatic patients. In this study, we evaluated the effect of fasting within the holy month of Ramadan in asthmatic patients using spirometry and the Asthma Control Assessment Questionnaire. Spirometric results did not indicate a statistically significant difference among fasting and non-fasting groups before and after Ramadan. Nevertheless, FEV1 had more change from baseline (before Ramadan) and larger improvement in fasting patients compared to the non-fasting ones, and this may show a potential positive effect of fasting in asthma improvements, although further randomized clinical trials are warranted to support this idea. The observed positive effect of fasting on FEV1 can be a result of weight loss during Ramadan as the higher level of cytokines and inflammatory mediators such as Interleukin-6, TNF-alpha, eotaxin, leptin in obese contribute to the development or increased clinical expression of asthma in promoting airway inflammation. Therefore, weight loss during Ramadan may improve FEV1 in asthmatic patients. Weight changes during Ramadan have been identified as one of the reasons for changes in respiratory markers during this month 19. In a study by Hakala et al on 15 overweight asthmatic patients, a low-calorie diet led to weight loss resulting in a decrease in the amount of airway constriction.20 Furthermore, due to the lower level of energy in fasting patients, they are inclined to stay more in indoor environments and rest until iftar. Therefore, they will have less contact with allergens during Ramadan. Consequently, a lower inflammatory response due to lower contact with allergens can be considered as another mechanism for improved FEV1 during Ramadan. Moreover, some other mechanisms that are recognized in some studies to be able to modify lung function and alleviate disease severity during the holy month of Ramadan can be considered for justifying this positive effect, including the reduction of food allergens, reduction of physical activity, low stomach volume which impose less pressure on the diaphragm, smoking cessation, and reduction of gastroesophageal reflux disease. Additionally starvation causes physical stress which leads to further release of catecholamines and consequently the expansion of airways.16 Previous researches have reported the positive and negative influences of fasting on some diseases such as diabetes and other endocrine diseases.21 with the increase in the FEV1 after Ramadan. Nevertheless, Mousavi et al showed an increase in the lung capacity of healthy people during Ramadan which is a result of reduced lung recoil, increased outward recoil of the chest wall, and increased strength of contraction of the inspiratory muscles.22 On the other hand, Norozi et al have demonstrated that among the lung function tests, peak expiratory flow (PEF) improved within 29 patients with controlled asthma after Ramadan (PEF decreased from 13% to 10% after 4 weeks of fasting).15 In a study on 1590 asthmatic patients for 4 years, Bener et al did not observe any significant change in all pulmonary function tests during Ramadan compared to the previous or subsequent months.23 No difference between the results of pulmonary tests and the severity of asthma was observed in the study of Adeli et al before and after Ramadan among asthma patients.16 Amini et al reported similar results in a study on the asthmatic patients, except for peak expiratory flow rate (PEFR), which increased during the fasting period.15 Askari et al also found that fasting had positive effects during Ramadan on asthma.6 Several hypotheses have been indicated to justify the variations in the findings of studies, including cultural and economic differences among the countries, hormonal variations between men and women, season changes in the month of Ramadan, different diets, and general health status among the evaluated patients in these studies.25 Similar results have been reported by Subhan et al 26 Erkekol et al indicated that asthma is not a barrier for asthmatic patients against fasting during Ramadan, and these patients, by continuing their medications and treatments habits can safely fast during the holy month of Ramadan.27 Altogether, considering that asthma control status remained relatively unchanged during Ramadan, our observations support the idea that fasting can be considered safe for asthmatic patients. Some studies have also reported no significant changes in asthmatic patients’ symptoms such as dyspnea, wheezing, cough, and chest tightness by fasting.28 Some other studies have examined the fasting effect on healthy non-asthmatic individuals and reported no significant effect by fasting in these participants. Siddiqui et al observed no changes in the respiratory test data of 46 healthy men during Ramadan. Nevertheless, due to BMI increase and weight regain in patients after a short period after Ramadan (by returning to a regular diet) FVC had decreased in these patients.29 It has been similarly expressed in other lung diseases that fasting does not have any impact on spirometry findings. Zouraei et al in their study on male COPD patients indicated that fasting during Ramadan does not have any impact on spirometry parameters. The results of this study demonstrated that fasting has no significant effect on the severity of asthma and spirometric findings in patients with moderate to severe asthma. Therefore, fasting during Ramadan can be considered safe for patients with asthma. None. The protocol of this study was approved by the ethics committee of the Tabriz University of Medical Sciences with the ethics code IR.TBZMED.REC.1398.485. This study was supported by a fund from the Tabriz University of Medical Sciences.


The American Academy of Pediatrics recommends blood pressure screening at every health care encounter in children younger than 3 years if they have a history of prematurity or other neonatal complications requiring intensive care because these children have an increased risk for hypertension.A multidisciplinary team conducted a quality improvement initiative to improve blood pressure screening at a single-center outpatient neonatal follow-up clinic. We developed a focused intervention program including a standardized blood pressure measurement protocol, staff training and education, and streamlined documentation. We conducted two Plan-Do-Study-Act cycles from November 2019 to January 2021. The outcome measure was the percentage of patients with a blood pressure measurement. Process measures included the percentage of medical assistants educated on the new protocol, percentage of patients 3 years, and younger old with the first blood pressure measurement taken from the right arm, and the percentage of patients 1 year and younger with 3 documented blood pressures. The balancing measure was staff satisfaction with time to obtain vital signs. We used statistical process control charts and Wilcoxon rank-sum test.At baseline, only 15.3% of patients had documented blood pressure. During the 10-month intervention period, there were 954 patient visits. Overall, blood pressure measurement increased to 54.7% with study interventions. The balancing measure was not negatively impacted.After implementing a program of focused interventions, we substantially improved the frequency of blood pressure measurements and increased adherence to American Academy of Pediatrics screening guidelines. Improved blood pressure screening allows us to identify and evaluate at-risk infants after hospital discharge. One study has assessed adherence to AAP clinical practice guidelines within a large pediatric healthcare system.8 Among children younger than 3 years of age with risk factors for hypertension, only 38% had at least 1 blood pressure documented. Only 4% of primary care encounters had blood pressure documented.Given the vital importance of early detection of hypertension, the American Academy of Pediatrics (AAP) recommends measuring blood pressure at routine well-child visits.10 Here, we describe the development of interventions to improve the low rate of blood pressure screening in the CHOP neonatal follow-up clinic using the Model for Improvement framework. The objective of this project was to increase the percentage of patients in the CHOP neonatal follow-up clinic who have a blood pressure measurement taken from 15% to 35% over 6 months.There was no standard approach to blood pressure screening in the neonatal follow-up clinic at the Children’s Hospital of Philadelphia (CHOP). However, studies in adults suggest multi-pronged interventions including staff education, clinical training, automated devices, and support systems for change may successfully improve blood pressure measurement in primary care clinics.The neonatal follow-up clinic at the Buerger Center for Advanced Pediatric Care provides comprehensive medical and developmental care for premature and medically complex infants after they leave the hospital. The majority of patients seen after discharge are from the Hospital of the University of Pennsylvania Intensive Care Nursery and the Children’s Hospital of Philadelphia (CHOP) neonatal/infant intensive care unit. The University of Pennsylvania Intensive Care Nursery is a 38-bed, level III unit with approximately 700 annual admissions. The CHOP neonatal/infant intensive care unit is a quaternary, 98-bed unit with over 1,200 annual admissions. All infants born younger than 32 weeks gestation or weighing <1500 g at birth are referred to the neonatal follow-up clinic and any infant with neurologic, cardiorespiratory, or other significant medical concerns. More than 1,300 patient visits are completed in the follow-up clinic each year. The first visit occurs within 2 to 3 months after discharge, with the number and frequency of subsequent appointments depending on the patient’s individual medical and developmental needs.The multidisciplinary project team included neonatologists, a pediatrician, a nephrologist, nurse practitioners, certified medical assistants, and a clinical quality improvement (QI) coordinator. The team created a protocol and program to improve the frequency of blood pressure screening in the neonatal follow-up clinic.The team developed a key driver diagram Fig.  using thDeveloping a standardized clinic blood pressure protocolTraining and education for clinic staff on the new protocolStreamlined medical record documentationWe implemented and evaluated interventions using sequential Plan-Do-Study-Act (PDSA) cycles.http://links.lww.com/PQ9/A374) for the follow-up clinic and created a flowchart to detail the sequence of steps , who would then attempt to obtain a blood pressure measurement using an automated blood pressure measurement device .Per the protocol, a certified medical assistant took a set of vitals after a patient checked in to the clinic. The appropriate size cuff was determined based on age using the color-coded guide and placed on the patient. The protocol emphasized placing the cuff directly on the right upper arm on the skin. The patient’s position was documented in the EHR. Ideally, 3 blood pressure measurements were obtained for any patient 1 year and younger corrected gestational age or if the patient was older than 1 year corrected gestational age with an elevated initial blood pressure measurement (≥90th percentile based on cutoffs from the fourth report) to get an average of the readings.Before protocol implementation, a project team member trained the clinic medical assistants on the process and best blood pressure measurement practices during group presentations and individual educational sessions to ensure understanding of the new workflow. Medical providers were educated with a presentation on the new protocol during a monthly clinic meeting before the first PDSA cycle. In addition, we posted educational infographics in provider workspaces. The infographics detailed the number of blood pressure measurements needed and the proper technique.Vitals are documented and stored using an electronic health record . We adjusted the EHR workflow based on staff feedback and recommendations. Previously, the medical assistant or provider would need to create a “new reading” to document each additional set of vitals, which entailed additional clicks and data entry. In addition, we added a blood pressure tab to the navigator to streamline blood pressure documentation. This modification allowed providers to enter 2 additional blood pressures without creating new readings and allowed easier extraction of blood pressure data from the EHR.We referred the patient to pediatric nephrology if the systolic blood pressure was ≥99th percentile in 2 out of 3 measurements. If the systolic blood pressure was ≥90th percentile but <99th percentile, the medical provider would communicate to the pediatrician through the EHR recommending repeat measurements in subsequent primary care or specialty care visits. During the neonatal follow-up visit, all recommendations were also discussed with the patients’ families.Baseline data were collected from the EHR for 11 months before the PDSA cycles (January 2019 to November 2019). We collected intervention data for 10 months (November 2019 to January 2021), not including the months the clinic was closed due to the coronavirus disease 2019 (COVID-19) pandemic. The team lead, clinical QI coordinator, and data engineer created an EHR-based data report dashboard. The dashboard automatically extracted age and blood pressure measurement data, including blood pressure values, cuff location, and patient position from all patients seen in the follow-up clinic. The first PDSA cycle began in November 2019 with the new standardized clinic blood pressure protocol roll out after training the clinic staff and EHR updates. The second PDSA cycle began in June 2020 once the clinic reopened after being closed due to the COVID-19 pandemic from March 2020 to June 2020. We distributed a survey to measure provider satisfaction in October 2019 for a baseline and after 6 months of project implementation. All members of the clinic staff received the surveys via electronic communication.We obtained data for all measures through EHR chart abstraction. The primary outcome measure was the percentage of patients with a blood pressure measurement taken in the follow-up clinic. This measure was defined as the number of patients who had a blood pressure measurement taken divided by the number of patients seen in the clinic on a 2-week basis. The process measures were the percentage of medical assistants educated on the new blood pressure protocol, the percentage of patients 3 years and younger old with the first blood pressure measurement taken from the right arm, and the percentage of patients 1 year and younger corrected gestational age with 3 documented blood pressures. The percentage of patients 3 years and younger old with the first blood pressure measurement taken from the right arm was defined as the number of patients 3 years and younger old who had a blood pressure measurement taken in the right arm divided by the number of patients 3 years and younger old seen in clinic on a 2-week basis. The percentage of patients 1 year and younger corrected gestational age with 3 documented blood pressures was defined as the number of patients 1 year and younger corrected gestational age with 3 documented blood pressures divided by the number of patients 1 year and younger corrected gestational age seen in clinic on a 2-week basis. The balancing measure was staff satisfaction with time to obtain vital signs, as measured by a survey including the question “obtaining vital signs takes too little time, the right amount of time, or too much time?” On a sliding scale, staff was asked to what extent they felt obtaining vital signs took too little time (0), the right amount of time (50), or too much time (100).11 The balancing measure was compared by a Wilcoxon rank-sum test performed in Stata 16  with P < 0.05 as the level for statistical significance.We interpreted the primary outcome measure and 1 process measure with a p-chart for statistical process control, created using QIMacros software . Control limits were adjusted using traditional health care special cause variation rules. Eight consecutive data points above or below the mean centerline determined special cause variation.This study was determined to be a QI initiative by the Children’s Hospital of Philadelphia Institutional Review Board and was exempt from further review.During the 11-month baseline period, there were 1,102 patient visits, and 15.3% of patients had a blood pressure measurement documented in the EHR. During the 10-month intervention period, there were 954 patient visits. The percentage of patients who had blood pressure taken increased to 64.2% during the first PDSA cycle and then 54.7% once the clinic reopened after being closed due to the COVID-19 pandemic. Overall, a control chart of the primary outcome data demonstrated a centerline shift from a baseline of 15.3% to 54.7% . In addition, the balancing measure of staff satisfaction with time to obtain vital signs were not negatively impacted by study interventions with a median score of 75 (interquartile range 66−80) preintervention versus a median score of 75 postintervention (interquartile range 75−88) and This QI initiative demonstrated a significant improvement in blood pressure measurement in an outpatient neonatal follow-up clinic. The percentage of patients in the neonatal follow-up clinic who had a blood pressure measurement increased from 15.3% to 54.6% without a decrease in clinic staff satisfaction with the time required to obtain the vital signs. By developing a standardized protocol, additional staff training and education, and streamlined medical record documentation, the clinic improved adherence to AAP blood pressure screening guidelines.13 A mixed-methods study of a pediatric practice-based research network found that blood pressure was only documented in 14% of health care visits in children younger than 3 years of age with a history of prematurity.13 Reasons for low adherence rates to the AAP blood pressure screening guidelines are postulated to include provider time constraints and lack of a standardized protocol for measuring blood pressure.Our neonatal follow-up clinic had a low baseline rate of blood pressure screening. This rate is similar to the low rates of blood pressure screening in patients less than 3 years of age with risk factors for hypertension documented in prior studies.14 After engaging in online interactive workshops, each center developed specific interventions, including training clinic staff, providing appropriate supplies, and developing provider alerts. Over an active intervention period of 20 weeks, appropriate blood pressure measurement improved from 11% to 78%. In contrast, our project was a single-center study in a neonatal follow-up clinic rather than multiple pediatric kidney transplant centers. Our project emphasized blood pressure screening and included a longer intervention period.This initiative is the first documented in the literature to improve blood pressure screening in an outpatient neonatal follow-up clinic. There have been few reported efforts to improve blood pressure measurement in outpatient pediatric general or subspecialty practices, except pediatric renal transplant clinics. The Improving Renal Outcomes Collaborative used standard QI methodology and training to successfully improve and standardize blood pressure measurement in multiple renal transplant clinics.6 Measuring blood pressure over time using a standard technique allows us to recognize children who may require hypertension treatment and identify children at risk of developing adult cardiovascular disease.15 This QI initiative demonstrates that it is possible to improve practice with focused interventions.By improving blood pressure measurement in children following discharge from the NICU, we aim to improve short- and long-term care of this vulnerable population at increased risk for hypertension. Elevated childhood blood pressure is associated with adult hypertension and metabolic syndrome.16 There was imperfect adherence to protocol elements, as evidenced by the low but improved percentage of patients with the first blood pressure measurement taken from the right arm and poor adherence to obtaining 3 blood pressure measures in children 1 year and younger corrected gestational age.Overall, the clinic achieved a robust implementation of the new protocol. The adherence was robust enough to sustain change even with disruptions and adjustments due to the COVID-19 pandemic. However, there was a drop in both the primary outcome measure and the process measure of right arm blood pressure measurement after the clinic reopened, which may have been due to a lack of reeducation or worry regarding COVID-19 precautions. The slight decline in blood pressure measurements from January to March 2020 may reflect a leveling off after the immediate rapid improvement secondary to the initiation of tailored interventions or a need for more regular reminders. Future strategies to improve protocol compliance might include regular protocol reeducation sessions, an EHR reminder, or an EHR mandatory record field. When compared with adult clinic efforts to improve documentation of blood pressure measurement, our team demonstrated similar improvements. For example, after implementing a mandatory computer field, the proportion of patients who had their blood pressure measured increased from 40.6% to 58.5% in 9 clinics in a preferred provider organization in Tel Aviv.Despite the strengths of this study, there were several limitations. We designed the interventions for use in a large outpatient neonatal follow-up clinic. Therefore, the results may not generalize to other clinics or hospital settings with different staffing models or access to equipment. Additionally, a key component of our intervention involved streamlined EHR documentation, which would not be possible in a clinic without an advanced EHR. Due to the nature of the clinic workflow, we were unable to assess time to obtain blood pressures, which would have been a useful metric. We used staff satisfaction as a proxy for time to obtain vitals instead. Finally, we have not yet studied how often providers make appropriate referrals for elevated blood pressures.This initiative will be expanded to include other neonatal follow-up clinic sites within the CHOP Newborn Care Network. Further work includes evaluating how often appropriate referrals for elevated blood pressures were placed and assessing how frequently referred children were diagnosed with and treated for hypertension to determine whether this program improves patient care and outcomes.This study demonstrated that implementing a program of focused interventions can enhance adherence to blood pressure screening guidelines by improving blood pressure measurement in an outpatient follow-up clinic. Other clinics can apply this framework to improve blood pressure screening in children at risk of hypertension.The authors have no financial interest to declare in relation to the content of this article.The authors would like to acknowledge the team members at the Buerger Center for Advanced Pediatric Care neonatology follow-up clinic, without whom this project would not have been possible.


Hypertension is an urgent public health problem. Consistent summary from natural and quasi-experiments employed to evaluate interventions that aim at preventing or controlling hypertension is lacking in the current literature. This study aims to summarize the evidence from natural and quasi-experiments that evaluated interventions used to prevent or control hypertension.We searched PubMed, Embase and Web of Science for natural and quasi-experiments evaluating interventions used to prevent hypertension, improve blood pressure control or reduce blood pressure levels from January 2008 to November 2018. Descriptions of studies and interventions were systematically summarized, and a meta-analysis was conducted.Thirty studies were identified, and all used quasi-experimental designs including a difference-in-difference, a pre-post with a control group or a propensity score matching design. Education and counseling on lifestyle modifications such as promoting physical activity (PA), promoting a healthy diet and smoking cessation consultations could help prevent hypertension in healthy people. The use of computerized clinical practice guidelines by general practitioners, education and management of hypertension, the screening for cardiovascular disease (CVD) goals and referral could help improve hypertension control in patients with hypertension. The educating and counseling on PA and diet, the monitoring of patients’ metabolic factors and chronic diseases, the combination of education on lifestyles with management of hypertension, the screening for economic risk factors, medical needs, and CVD risk factors and referral all could help reduce blood pressure. In the meta-analysis, the largest reduction in blood pressure was seen for interventions which combined education, counseling and management strategies: weighted mean difference in systolic blood pressure was − 5.34 mmHg  and in diastolic blood pressure was − 3.23 mmHg .Interventions that used education and counseling strategies; those that used management strategies; those that used combined education, counseling and management strategies and those that used screening and referral strategies were beneficial in preventing, controlling hypertension and reducing blood pressure levels. The combination of education, counseling and management strategies appeared to be the most beneficial intervention to reduce blood pressure levels.The online version contains supplementary material available at 10.1186/s40885-022-00198-2. Cardiovascular diseases (CVD) represent the leading cause of death, accounting for one in three deaths in the United States (US) and worldwide –3. One ohigh internal validity [low external validity) [To this effect, several randomized clinical trials (RCT) have been conducted to evaluate interventions used to prevent hypertension or improve its control –8. Howevvalidity , 10, thealidity) . To evalalidity) , we willalidity) . These ealidity) –15.As utilization of natural and quasi-experiments is increasing in public health and in the biomedical field –15, moreWe searched PubMed, Embase and Web of Science from January 2008 to November 2018. This time frame was selected to encompass studies that would have likely benefited from recent development and improvement in natural and quasi- experiments , 20. BriTwo trained members  screened abstracts and full-text articles. Disagreements were decided by a third member (RN). We included studies that used natural and quasi-experiments to evaluate interventions aimed at preventing hypertension, controlling hypertension or reducing blood pressure levels. The outcome measures were prevalence of hypertension and changes in mean blood pressure. Studies were excluded if they were not in English, were not a natural experiment or a quasi-experimental design, did not include a control group  , did notThe following information was extracted: study design, sample size, study duration, data source, geographic location, participants’ socio-demographic characteristics, intervention types, intervention levels , behaviEducation and counseling: This subcategory includes strategies that aim at educating and providing knowledge and counseling to participants on lifestyle modifications , eating better, avoiding or stopping smoking, etc.).Management: This subcategory includes strategies that aim at monitoring patients’ metabolic factors and chronic diseases  as well as patients’ adherence to medication. These strategies are generally done or facilitated by physicians, general practitioners , nurses, other staffs, or patients themselves.Education, counseling and management: This subcategory combines education and counseling strategies with management strategies as described above.Screening and referral for management: This subcategory includes strategies that aim at screening for  economic risk factors, medical needs, and CVD risk factors, followed by the referral of participants who screened positive to professionals who specialize in the management of those needs.The interventions were classified by strategies into four types:We also classified the interventions by settings into (1) community level; (2) health center level , (3) organization level and (4) nationwide. In addition, we have classified the intervention by duration of the study into short-term  and long-term .We implemented the Cochrane Risk of Bias Tool for risk of bias and used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to assess the quality of the evidence for mean blood pressure change outcome , since tn = 27) [To summarize the effectiveness of interventions on mean blood pressure changes, we also conducted a meta-analysis. Due to the high heterogeneity in the studies and interventions, we undertook a random-effects model and only summarized the effectiveness of intervention strategies by subgroup defined by intervention types, settings and duration. We estimated the weighted mean difference (WMD) of blood pressure and 95% confidence intervals (CIs). The studies included in the meta-analysis were only those whose outcomes were mean differences (MDs) in blood pressure n = 27) , 25–49 an = 27) , 39, 43 7 , 25–49I2 .Overall, 788 titles of potentially relevant studies were identified and screened. In total, 545 were excluded and 243 full papers were retrieved, then 30 studies were included in the final sample Fig. .Of the 30 studies included in this review , 24–49, , whereas the prevalence of hypertension in the control group did not change  [P = 0.01), compared to that in control group  [Two studies evaluated the education and counseling intervention strategies, and both found that those strategies could help prevent hypertension in healthy people , 25. One = 0.39) . The othP < 0.001) [A study in the US showed that patients whose general practitioners accessed the computerized clinical practice guideline at least twice a day improved their hypertension control compared to the patients whose general practitioners never accessed the computerized clinical practice guideline (< 0.001) .P = 0.03) [A study in the US found that patients who received education about hypertension and did home blood pressure monitoring had a better control of their hypertension compared to the control group ( = 0.03) .A study in the US showed that for White patients, interventions which involved a coordinator who identified and reached out to patients not meeting CVD goals and linked them to management programs could improve the odds of blood pressure control  compared to no intervention .Seven , 34, 35 P = 0.01) compared to outpatient expense not covered [P = 0.01), but it did not compare the MD between treatment and control group [Two , 39 of t covered . The othSix , 42–45 oFour , 46–48 o, Fig. The largest blood pressure reduction  was seen for interventions that combined education, counseling and management intervention strategies  and in health center settings  had large SBP reduction. Participants experienced interventions implemented in organization settings had large DBP reduction   had a large reduction in blood pressure  and participants who were followed for longer than or equal to 12 months  had a moderate reduction in blood pressure   prevent hypertension in the general population, (2) improve hypertension control in patients with hypertension or (3) reduce blood pressure levels in both the general population and patients.In this systematic review, we found that the intervention strategies such as (1) education and counseling, (2) management, (3) education, counseling and management and (4) screening and referral for management were beneficial in preventing, controlling hypertension or reducing blood pressure levels. In particular, we found that education and counseling on lifestyle modifications  could help prevent hypertension in healthy people. The use of computerized clinical practice guidelines by general practitioners, education and management of hypertension, screening for CVD goals and referral to management could help improve hypertension control in patients with hypertension. The education and counseling on lifestyle modifications, the monitoring of patients’ metabolic factors and chronic diseases  as well as patients’ adherence to medication, the combined education and management of hypertension, the screening for economic risk factors, medical needs, and CVD risk factors, followed by the referral to management all could help reduce blood pressure levels. Our study is one of the few systematic reviews that have summarized the evidence from quasi-experiments on hypertension prevention and control. A previous systematic review  which suOur review did not find natural experiments studies according to the definition used in this study. Quasi-experimental designs included DID, propensity score matching and pre-post designs with a control group (PPCG). While PPCG designs generally involve two groups (intervention and control) and two different time points (before and after the intervention), DID designs generally involve two or more intervention and control groups and multiple time points . In thisGiven that there was high heterogeneity in the studies included in this systematic review, we have performed a random effects model and have only presented the subgroup analysis by intervention types, settings and duration of the study. Overall, our study suggested that interventions that combined education, counseling and management strategies appeared to show a relatively large beneficial effect for reducing blood pressure. However, our finding should be interpreted with caution due to the high-risk of bias and lower quality of evidence given the quasi-experimental nature of the designs (as opposed to evidence from randomized experiments). Nevertheless, the findings here can give us some insights on the benefit of interventions such as education, counseling and management, especially given that our findings are in line with previous studies , 52, 55.This review has some limitations. First, the definition of natural and quasi-experiments is not consistent across fields. Second, the main limitation in most if not all the quasi-experimental study designs noted in this review was the potential for unobserved and uncontrolled confounding, which is a threat to internal validity and could lead to biased findings. Third, our findings may not be generalizable to all countries and settings as we only included studies published in the English language in this review. Fourth, as is the case in most other reviews, we could have missed relevant studies despite our best attempt to conduct a thorough search of the literature. Fifth, we found that most studies included in this study had a high risk of bias. It might be because we used the Cochrane Risk of Bias Tool to assess bias which was designed for examining RCTs. Studies in this review only used quasi-experiment designs and did not have randomization, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment. Sixth, studies generally reported the measure of intervention impact differently across studies, making it difficult to combine the findings. In addition, studies were highly heterogeneous in terms of the types of individuals included in the study . We conducted the subgroup meta-analysis to reduce the heterogeneity, but the high heterogeneity still existed. Therefore, the results from meta-analysis need to be interpreted with caution. The individual impact reported for each individual study and the results from systematic review should be given more consideration.In this systematic review, interventions that used education and counseling strategies; those that used management strategies; those that combined education, counseling and management strategies and those that used screening and referral for management strategies were beneficial in preventing, controlling hypertension and reducing blood pressure levels. The combination of education, counseling and management strategies appeared to be the most beneficial intervention to reduce blood pressure levels. The findings in this review, highlight that, a number of interventions that aim at preventing, controlling hypertension or reducing blood pressure levels are being evaluated through the use of quasi-experimental studies. Given that RCTs are not always feasible or appropriate, scientists should develop more rigorous methods to increase the internal validity of such quasi-experimental studies.Additional file 1: Table S1. Search words. Table S2. Summary of the characteristics of the studies included in this review (n = 30). Table S3. Risk of Bias Tool Assessments Across Studies (n = 30). Table S4. GRADE Evidence Profiles Across Studies in Meta-analysis (n = 24). Table S5. Estimates and parameters in studies that reported on the mean difference in blood pressure (n = 27). Table S6. Sensitivity analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in meta-analysis stratified by intervention type. Table S7. Sensitivity analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in meta-analysis stratified by intervention setting. Table S8. Sensitivity analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) in meta-analysis stratified by intervention duration. Fig. S1. Methods to calculate mean differences (MD). Fig. S2. Methods to calculate standard errors (SE). Fig. S3. Forest plot stratified by intervention settings for blood pressure. (A) Forest plot stratified by intervention settings for systolic blood pressure (SBP). (B) Forest plot stratified by intervention settings for diastolic blood pressure (DBP). Fig. S4. Forest plot stratified by intervention duration for blood pressure. (A) Forest plot stratified by intervention duration for systolic blood pressure (SBP). (B) Forest plot stratified by intervention duration for diastolic blood pressure (DBP). Fig. S5. Funnel plot of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention types. Fig. S6. Funnel plot of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention settings. Fig. S7. Funnel plot of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention duration. Fig. S8. Sensitivity analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention types. Fig. S9. Sensitivity analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention settings. Fig. S10. Sensitivity analysis of systolic blood pressure (SBP), diastolic blood pressure (DBP) stratified by intervention duration


Combination biological therapies are being considered increasingly for patients with multiple co-morbidities requiring biologics. There are limited data available on this approach, and concerns remain about the possible risk of adverse events, particularly infection.We present three patients on dual biologics for rheumatic disease and asthma. The biologic combinations used were etanercept and mepolizumab, infliximab and omalizumab, and etanercept and omalizumab. The time on combination biologic therapies ranged from 24 to 36 months. Patients were monitored for any serious adverse events.All three patients were able to tolerate combined biologic therapies, with no serious adverse events. All three patients gained improvement in their rheumatic and asthma disease control, with reduction in disease activity scores and reduction in steroid usage.The decision to start dual biologic therapy should be considered carefully, on a case-by-case basis. The number of patients who are on combination biological therapy is small, and data are sparse. Real-world data are needed to examine the long-term benefits and risks of different forms of combination biologic therapies. Key messagesCombination biological therapies are being considered increasingly for patients who present with multiple co-morbidities.Data presented here suggest that combination biologics can be used safely, without serious adverse events.The decision to start dual biologic therapy should be considered carefully, on a case-by-case basis.Combination biological therapies are being considered increasingly for the treatment of patients who present with multiple co-morbidities requiring biological treatment. There are limited data available regarding this, and concerns remain about the risk of adverse events, particularly infections, in addition to potential drug interactions in patients receiving more than one biological therapy . We presLiterature on dual biologic therapy is limited, owing to the infrequency of this clinical approach. There are significant clinical reservations in taking this approach owing to the potential risk of serious infection from immunosuppression . In addiDevelopment of newer agents targeting different pathways has made it possible to use combination therapy in selected patients. Simultaneous use of more than one biological agent has been used in two main scenarios: patients with severe inflammatory disease unresponsive to a single biological agent, or patients with co-existing severe medical conditions, such as Inflammatory Bowel Disease , asthma We present three cases illustrating the outcome of combination therapy for severe asthma and inflammatory arthritis. Formal ethics approval was not required for this work because only anonymized patient information was included and no change to patients’ standard care was required in order to be included in the case series. All patients gave written informed consent to the use of their data. A summary of the clinical presentations and therapies can be found in Etanercept and infliximab are anti-TNF-α agents licensed for the treatment of moderate or severe RA . OmalizuWe have defined serious adverse events in accordance with the US Food and Drug Administration definition . A serioCase one is a 56-year-old woman with severe eosinophilic asthma diagnosed in the late 1990s and seronegative RA diagnosed in 2019. Her asthma was previously treated with bronchodilator and steroid inhalers, montelukast and daily maintenance prednisolone. Mepolizumab was commenced in 2018, and since then she has reported no exacerbations of her asthma. Mid-2022, she was reviewed by the asthma service and was tolerating mepolizumab well, was no longer on montelukast or the steroid inhaler, and had not had to use her salbutamol inhaler for ∼7 months.For RA, she was initially treated with sulphasalazine (SSZ), but this was not tolerated and was stopped. She commenced methotrexate (MTX) 20 mg s.c. once weekly along with prednisolone in early 2020, but after 6 months remained symptomatic, with evidence of active synovitis on musculoskeletal ultrasound (US), despite being on prednisolone 25 mg daily. At this time, her disease activity score (DAS28) was 6.25.Etanercept was then commenced alongside MTX and prednisolone. Twenty-four months after commencing etanercept, she continues etanercept and has reduced her prednisolone to 11 mg daily. Her DAS is 2.27. It has been difficult to reduce her prednisolone further thus far owing to ongoing joint pain, although there is no synovitis on US. She is being encouraged to reduce the corticosteroids (CS) dose gradually. She has been on dual therapy for 24 months and has not had any recorded serious adverse events.Case two is a 35-year-old man, known to have asthma since childhood, requiring multiple hospital admissions and an intensive care unit admission in 2002. He has previously been on a combination of inhalers, aminophylline and montelukast, but still required frequent courses of oral CSs. He was diagnosed with Crohn’s disease in 2006 and was subsequently diagnosed with Crohn’s-associated arthritis, for which he has been on azathioprine (AZA) and infliximab since 2008. In April 2019 he was started on omalizumab for severe asthma that was difficult to control. On follow-up, he reported significant improvement in asthma symptoms, with no further need for oral CSs, and he no longer requires nebulized therapy. He continues infliximab at the same dose and omalizumab and has achieved good control of his Crohn’s disease and associated arthritis. He has not experienced any serious adverse effects after 36 months of combination therapy.Case three is a 62-year-old woman who was diagnosed with atopic eosinophilic adult-onset asthma in the late 1980s and seropositive RA in 2012. Prior therapy for asthma included a combination of bronchodilator and steroid inhalers. She was referred to the severe asthma service in 2018, and omalizumab was commenced in June 2019. Since starting this, her asthma has been well controlled, supported by clinical examination and ACQ-6 score (asthma control questionnaire). Initially, her RA was treated with MTX and hydroxychloroquine (HCQ). However, despite this combination she had evidence of ongoing joint inflammation, and in 2018 she was started on etanercept. She has continued both biologics for 36 months with good control of asthma and RA, without any serious adverse events, and has not required any steroid therapy. This was confirmed by reviewing the omalizumab record sheet.In these three cases, dual biologic therapy has been used to good effect, with no infection or other serious adverse events. This has also enabled patients to reduce oral CS dependence significantly, with the added benefit of minimizing CS-related adverse effects.The decision to start a patient on dual biologic therapy should be considered carefully, on a case-by-case basis, only when conventional treatment options have failed and in the context of life-threatening or significantly disabling disease. The main concerns regarding the use of dual biologic therapy centre around safety, especially a theoretical risk of serious infections ; no infeThe data underlying this article cannot be shared publicly owing to ethical/privacy reasons.


Polypharmacy in patients with cardiovascular diseases (CVDs) has been linked to several adverse outcomes. This study aimed to investigate the pattern of medication use and prevalence of polypharmacy among CVDs patients in Iran.We used the baseline data of the Pars cohort study (PCS). The participants were asked to bring their medication bags; then, the medications were classified using the Anatomical Therapeutic Chemical classification. Polypharmacy was defined as using five or more medications concurrently. Poisson regression modeling was applied. The adjusted prevalence ratios (PR) and its 95% confidence interval (CI) were estimated.Totally, 9262 participants were enrolled in the PCS, of whom 961 had CVDs. The prevalence of polypharmacy in participants with and without CVDs was 38.9% and 7.1%, respectively. The highest prevalence of polypharmacy (51.5%) was among obese patients. Abnormal waist-hip ratio , high socioeconomic status , tobacco-smoking , patients with more than three co-morbidities , high physical activity , use of opiate ever , and healthy overweight subjects  were associated with polypharmacy. Cardiovascular drugs (76.1%), drugs acting on blood and blood-forming organs (50.4%), and alimentary tract and metabolism drugs (33.9%) were the most frequently used drugs. Agents acting on the renin-angiotensin system were the mostly used cardiovascular system drugs among men and those above 60 years old, while beta-blocking agents were mostly prevalent among cardiovascular system drugs in women with CVDs.Given the high prevalence of polypharmacy among CVDs patients, and subsequent complications, programs to educate both physicians and patients to prevent this issue is crucial. The aging trend of the populations around the world has led to an increasing burden of non-communicable diseases (NCDs) , particuIn various studies on different populations, polypharmacy prevalence among patients varied from over 10 to 90% –12. AlsoDespite the significant burden of CVDs in developing countries, the knowledge regarding polypharmacy in CVDs patients is still limited , 17. In This cross-sectional study was conducted on the baseline data of the Pars Cohort Study (PCS). PCS is an ongoing population-based prospective study that started in 2012 to determine the prevalence of NCDs risk factors in a semi-urban area, Valashahr, in Fars province, South of Iran. Valashahr has over 40,000 inhabitants, of whom nearly 10,000 people are between 40 and 75 years old. Detailed information on the studied population was published elsewhere . All ValThe participants were questioned, “Has your physician told you that you have CVDs and need treatment for that?”. If the answer was “Yes”, they were categorized as having CVDs. They were asked to bring their bags of medications to the PCS center. An educated nurse listed the drugs (used at least over the past three months) and asked the patients which medications were taken at the time of the interview. Although various definitions have been proposed for polypharmacy , in the Aside from complementary medicines, we utilized the first level of the Anatomical Therapeutic Chemical (ATC) classification system  to classWe defined the covariates as follows: age , gender , education , marital status , ethnicity (Fars/ non-Fars), tobacco smoking ever-use , central obesity based on waist to hip ratio  , irritable bowel syndrome (IBS), and functional constipation were defined according to previously described clinical criteria . The parFrequency, mean, and standard deviation (SD) were calculated to describe the variables, where appropriate. Prevalence ratio (PR) and its 95% confidence interval (CI) were assessed using Poisson distribution. Considering the standard world population (WHO 2000–25), the age-standardized prevalence of polypharmacy was estimated. Chi-square and Mann–Whitney U tests were used for univariate analyses. To determine independent correlates of polypharmacy prevalence, Poisson regression modeling was applied; variables with a univariate p value of less than 0.3 were included in the multivariable modeling as potentially independent variables. In the final analysis, the model was proportionated using a backward elimination technique. p values less than 0.05 were considered statistically significant. STATA software  was used to analyze the data.Of 9262 participants, 961 were CVDs patients, including 404 (42.0%) men and 557 (58%) women with the mean age of 58.5 ± 9.8. The prevalence of polypharmacy was 374/961 . The overall age- and gender-standardized prevalence of polypharmacy was 36.0% . The estimated age-standardized prevalence of polypharmacy was 29.6%  for males and 40.6%  for females.Among the participants with CVDs, the highest estimated prevalence of polypharmacy  was among obese patients, and the lowest prevalence belonged to patients without central obesity . In all variables, the prevalence of polypharmacy was significantly higher in patients with CVDs compared to those without CVDs  suffered from a minimum of three comorbidities (p < 0.001). According to Table According to Table Cardiovascular drugs (76.1%), drugs acting on blood and blood-forming organs 50.4%), and alimentary tract and metabolism drugs (33.9%) were the most frequently used drugs among the participants with CVDs. Cardiovascular drugs (83.0%) and drugs acting on blood and blood-forming organs (55.1%) had the highest prevalence of use among the elderly. These two drug classes also had equally high prevalence rates among females and males, about 75.0% for cardiovascular drugs and 50.0% for drugs acting on blood and blood-forming organs , followed by blood and blood-forming organs medications (Class B) and those acting on the alimentary tract and metabolism (Class A). Al-Hashar et al.  in Oman Among cardiovascular system drugs, we showed that agents acting on the renin-angiotensin system and beta blocking agents (BB) were the mostly used drugs by CVDs patients. BBs were the topmost used drug in females with a subtle difference. A study from Ethiopia reported that diuretics and angiotensin-converting-enzyme inhibitors were the most frequently used drugs among CVDs patients . Agents Our study has several strengths. It is a population-based ongoing cohort conducted in Iran among patients with CVDs, assessing polypharmacy. Our sample size allowed for statistical analysis with sufficient statistical power. Additionally, to reduce recall bias, we asked the patients to bring their medications with them, and a trained nurse checked the list of drugs. However, the study is not free of limitations. First, the cross-sectional design of the study prevents us from establishing a cause and effect relationship between the variables. Second, the temporality between time-dependent variables like obesity and polypharmacy could not be addressed. Also, our study did not discuss the effects of CVDs relapse or untreated CVDs on polypharmacy. Moreover, we asked the patients whether they were diagnosed with CVDs; this might lead to recall and confirmation bias.The prevalence of polypharmacy was high in patients with CVDs. Higher SES, physical inactivity, tobacco use, existence of several comorbidities, being unhealthy overweight, and abnormal waist-hip ratio were important predictors of polypharmacy in patients with CVDs. Training at physician and patient levels is crucial to inhibit the increasing trend of polypharmacy and subsequent complications.