Which is more severe?What is the predominant pattern ofasthma, eosinophilic or neutrophilic in Indian children.RESEARCH QUESTION- GAPS IN KNOWLEDGE- Enrico Hefler published a study in jul2017, where 76 Severe asthma adult patient defined by ERS and ATS,attending allergy and asthma outpatientclinic during an 8-month period (since May 1 and until October 31, 2016) andwithout any exacerbation or respiratory infection for at least 1 month wereenrolled in the study.
A significant correlation between blood Eosinophilcounts assessed by HemoCue WBC DIFF and standard CBC analyzer was found (R2=0.854, P < .001). Similar significant correlations were found also for WBCcount (R2 ¼ 0.
798, P < .001), Neutrophils (R2 = 0.793, P < .001), andlymphocytes (R2 ¼ 0.
688, P < .001). Point of care blood Eosinophil count ina severe asthma clinic setting is helpful for the respiratory physician, theallergist, and any other physician directly caring for patients with severeasthma to better phenotype and treat them.(13) Blood Eosinophil Count measurement is as an additional Biologic markerwhich assist in the identification of adultpatients with persistent asthma and with higher risk for future exacerbationsand excessive short acting beta2 agonist use found in a large managed careorganization in administrative data based study.
(11,12)High blood Eosinophil counts areassociated with an increased risk of both moderate and severe asthma exacerbations,while high blood Neutrophil counts are associated with an increased risk ofmoderate, but not severe exacerbations. In the Copenhagen General Populationstudy(24) of 81 351 participants, 4838 with self-reported asthma wereincluded. baseline blood Eosinophil andNeutrophil counts, and asthma exacerbations during follow-up in 2003–2011 wererecorded, exacerbation defined as moderate where (short-course treatment ofprednisolone given) or severe (hospitalization needed).The multivariable-adjusted incidence rateratios (IRRs) were 1.28 (95% CI, 1.06 –1.
55) for moderate exacerbations and1.55 (1.20 –2.00) for severe exacerbations for individuals with bloodeosinophil counts 290/cumm (highest tertile) vs individuals with bloodeosinophil counts 180/cumm (lowest tertile). For blood neutrophils, themultivariable-adjusted IRRs were 2.
14 (1.74 –2.63) for moderate exacerbationsand 1.18 (0.
89 –1.55) for severe exacerbations for individuals with bloodneutrophil counts 4851/cumm (highest tertile) vs individuals with bloodneutrophil counts 3771/cumm (lowest tertile). Blood eosinophil and neutrophilcounts interacted on moderate exacerbations (P = 0.0003), but not on severeexacerbations.
It was also found that high blood Neutrophil counts were howeverassociated with an increased risk of moderate exacerbations and may identify aphenotype with a higher symptomatic score leading to Prednisolone treatedexacerbations not requiring hospital admission.Recent important study published in AmericanAssociation for Clinical Chemistry Feb2017. It is hypothesized that: . Recently in oct 2016, in Expert Rev Respiratory Medicine BloodEosinophilis & FeNO have the highest diagnostic accuracy; in particular if used in combination torule in or rule out Eosinophilic Asthma.(6) But Hanneke coumau in Apr 2015, in a systemic review & metaanalysis it was found that FeNO, Blood Eosinophils, and IgE have moderatediagnostic accuracy. Their use as a single surrogate marker for airwayeosinophilia in patient with asthma lead to a substantial number of falsepositives or false negatives.
(4) Wagnear AH in Feb 2015, for External validation of Blood Eosinophils,FeNO and serum Periostin as surrogates for sputum Eosinophils in asthma. It wasfound that In patient with mild to moderate asthma, as well as patient withmore severe asthma, Blood Eosinophils had the highest accuracy in theidentification of sputum Eosinophils in Asthma. so, the use of bloodEosinophils can facilitate individualized treatment and management of asthma.(5) Recently in 2017 review on AsthmaBiomarker in the age of Biologics published in Allergy, Asthma clinicimmunology by Assessing Biomarkers in a Real-world Severe Asthma (ARIETTA)study. where the relationship between asthma biomarkers and disease-relatedhealth outcomes in approximately 1200 patients with severe asthma within morethan 20 countries. The different phenotypes of Asthma to be identified on thebasis of biomarkers. Among which blood Eosinophil countis very important.
The normalrange of blood eosinophil count is 30–350 cells/µL, (26) however, there iscontroversy with respect to the cut of level associated with increased risk ofasthma complications. Mepolizumab trials employed blood eosinophil cut offsof ? 150 to ? 300 cells/µL (27, 28). This was in line withthe findings of the Epidemiological study on the Genetics and Environment ofAsthma group, who concluded that a blood eosinophil level ? 250cells/µL correlated with more active asthma (i.e.
, lower FEV1) (29). However,several studies determined that poor asthma control was associated with ahigher eosinophil cut off. A large scale (N = 130,248) UK cohortstudy used negative binomial regression to identify that poorer asthma controland more severe exacerbations were experienced by patients with blood eosinophilcounts > 400 cells/µL (30). Zieger et al. likewise concludedthat a blood eosinophil count > 400 cells/µL was an independentrisk factor for asthma exacerbations and asthma-related emergency department visitsor hospitalizations (31). So, Optimization of Biomarker testing methods bycombining greatest sensitivity and specificity with non invasiveness,availability and affordability is critical to the continued advancement ofasthma control.
So, Blood counts may be a useful aid inthe monitoring of uncontrolled asthma.Zhang XY, Simpson JL in sep 2014,conducted a study where Full blood count parameters were analyzed for detectionof asthma inflammatory phenotypes.(1) The optimum cut-point for blood Eosinophilpercentage was 2.7%, and this yielded a sensitivity of 92.
2% and a specificityof 75.8%. The absolute blood Eosinophil count was also highly predictive withan AUC of 0.898 (P < 0.
0001) at a blood Eosinophil cut-off of 269/cumm. Theblood Eosinophil/lymphocyte ratio (ELR) and Eosinophil/neutrophil ratio (ENR)were also increased in Eosinophilic asthma specially in patient with persistentuncontrolled asthma despite treatment, and the Neutrophil/lymphocyte ratio(NLR) was increased in Neutrophilic asthma. Neutrophilic asthma could also bedetected by blood Neutrophil percentages and NLR, but with poor surrogates.
Neutrophilmorphological parameters more precisely can be used as a biomarker for asthmaphenotypes compared to absolute Neutrophil counts. Neutrophils of asthmapatients had fewer granules than those of healthy volunteers.(2) Schleich FN, Manise et al, in feb 2013, a largeretrospective study conducted in 508 asthmatic patients in University Asthmaclinic of Liege.(12) FENO was first measured, followed by spirometrywith bronchodilation, sputum induction and blood sampling. All tests wereperformed on the same day in adult mean age 52 years. out of the 508subjects who underwent a successful sputum induction, 211 (42%) hadeosinophilic inflammation (?3% eosinophils), 80 (16%) neutrophilic inflammation(?76% neutrophils), 14 (3%) mixed granulocytic and 203 (40%) paucigranulocytic(sputum eosinophils count < 3% and Neutrophils <76%).
There was asignificant positive relationship between Blood Eosinophil count, eitherexpressed as percentage(>3%) or absolute value (>220/cumm), andpercentage of sputum eosinophil count (r = 0.6, p < 0.0001; r = 0.6, p < 0.0001;respectively). Whereas the sputumneutrophilic phenotype has a weakcorrelation between sputum and blood neutrophil count taken in percentage(>66%)(r = 0.19, p = 0.0015) but not in absolute value(cut off of 4960/cumm) (r =0.
19,p=0.11). Eosinophilic and pauci-granulocytic are the most frequent asthmaphenotypes in a large unselected asthmatic population. Like FENO, bloodeosinophil counts may provide a practical alternative to predict sputumeosinophilia ?3%. In contrast, sputum neutrophilia is only poorly related toblood neutrophil count it is better predicted independently by advanced age andhigh FRC. Traditionally, Airwaybiopsies or Bronchoalveolar lavage are considered as the gold standard for assessingairway inflammation but this method is too invasive for routine clinical use.Therefore, there has been great interest in methods to assess airwayinflammation non-invasively and in a convenient and inexpensive way.
Better knowledge of the intricatecellular mechanism i.e. Pathobiologic networks underlying the onset andprogression of Eosinophilic andNeutrophilic airway inflammation in asthma will provide the way for substantialimprovements in the treatment of disease. (11) Wenzel SE, In year 2012 defined the asthmaphenotypes in 3 groups specially in children as: A) Transient Early wheezingseen upto 3 years age. B) Non Atopic wheezing in toddler and preschool childrenwhich is having early RSV=LRI in 1st 3 year of life. C)atopic/allergic asthma persistent wheezing associated with Atopy in early life.(10) 2.
Non Allergic Asthma: These are seen morecommon in adult. sputum of these patients may be Neutophilic, Eosinophilic orPaucigranulocytic. These pattern can also be seen during severe exacerbation in children and oftenrespond less well to inhaled corticosteroid treatment.1. Allergic Asthma (Eosinophilic): mosteasily recognized asthma phenotype, which often commences in childhood andassociated with past history of allergic disorder.
Induced sputum of thesepatients often reveals eosinophilic airway and usually respond well to inhaledcorticosteroid treatment.Bel EH, in year 2004 defined different phenotypeof Asthma.(9) Some of the most common include Mucosal mast cells, Eosinophils, Tlymphocytes, Dendritic cells, Macrophages, Neutrophils are the inflammatorycells. Over 100 different mediators are now recognized which mediates thecomplex inflammatory process of airway.
Asthma is chronic inflammatory disordersof airway. Multiple inflammatory cells and its mediators are involved in thepathogenesis of asthma. Till date, no strong relationship has been found .
Between specific pathological features and particularclinical patterns or treatment responses specially in children.Asthma is the most common chronic pulmonarydisease in children. Interactions of Susceptible Host (Genetic, obesity, sex) with certainenvironmental conditions (allergens,occupations, infections etc) leads to manifestation of asthma. Early diagnosisand treatment of asthma is very important as it can alter the course of disease.Reviewof Literature: Thus, there is need of a robustnoninvasive, simple, routine investigation. So, absolute Eosinophil count or Neutrophiliacould add predictive value to GINA controlled based risk assessment forexacerbation of asthma and response to treatment.Blood eosinophil count is a marker ofeosinophilic airway inflammation which is more common in children and diseaseseverity in asthma.
However, blood neutrophil count might also be associatedwith disease severity. we want to test the hypothesis that, high eosinophil andneutrophil counts are both associated with the risk of asthma exacerbationsamong individual with asthma specially in children 6 to 12 years of age amongthis which is more common during exacerbation, its severity and response totreatment.An ideal biomarker should be reliable,minimally invasive, easy to collect and measure, inexpensive and can be used toidentify either a clinical phenotype or a treatment response phenotype,measures changes in disease activity, or confirm a diagnosis. Asthma is a heterogeneous disease with differentunderlying disease processes. Many clinical phenotypes are identified. Inchildren, three asthma phenotypes are now well defined: transient infantwheezing, nonatopic wheezing of the toddler, and IgE mediated wheezing/asthma.Recently, a fourth phenotype, late onset childhood asthma.
(5) some of the mostcommon include: a) Allergic (Eosinophilic) asthma b) Non allergic(Neutrophilic, eosinophilic or paucigranulocytic) asthma.Goal of asthma management is asthma control. Responseto treatment is reviewed by clinical status i.e. symptoms improved, oxygensaturation and lung function after one hour of treatment FEV1 or PEF 60 to 80%of predicted shows good response to treatment.Exacerbations represent a change in clinicalfeatures and lung function from the patient’s usual status.(6) the decrease inpeak expiratory flow (PEF) or forced expiratory volume in 1 second ( FEV1), (7)are more reliable indicators of severity of the exacerbation than symptoms. Thefrequency of symptoms may, however, be a more sensitive measures of the onset ofan exacerbation than PEF.
(8)Symptoms and airflow limitation mightsometimes resolve spontaneously or otherwise in response to treatment, and maybe sometimes absent for up to months. However, patients may experience episodicflare-ups (exacerbations) of asthma characterized by a progressive increase insymptoms of shortness of breath, cough, wheezing or chest tightness, signs ofexacerbation severity, including vitalsigns (e.g level of consciousness, temperature, pulse rate, respiratory rate,blood pressure, ability to complete sentences, use of accessory muscles) andprogressive decrease in lung function that can be life threatening and carry asignificant burden to patients and the community.(6) Exacerbations may occur inpatients with a diagnosed Asthma or, occasionally, as the first presentation ofasthma.
Asthma is aserious global health problem affecting all age groups. Its prevalence isincreasing in many countries, especially among children. Asthma is a heterogeneous disease, usuallycharacterized by chronic airway inflammation. It is defined by the history ofrespiratory symptoms such as wheeze, shortness of breath, chest tightness andcough that vary over time and in intensity, together with variable expiratoryairflow limitations.(1) Asthmaimposes immense burden with more than 300 million individuals currentlysuffering from asthma worldwide. About atenth lives in India.(2) Its prevalence has been estimated to range 3-38% in childrenand 2-12% in adults (3), thus making it the commonest chronic disorder amongchildren.
One recent Indian Study on Epidemiology of Asthma, (INSEARCH)estimated national burden to be 18 millions.(4) The World Health Organization Global Burden ofDisease Study estimates that 13.8 million disability adjusted life years(DALYs) are lost annually due to asthma.(5)Introduction: Research question What is the predominant pattern of asthma, (Eosinophilic or Neutrophilic) in Indian children. Which is more severe? Which has better response to treatment? Aim: To compare the incidence of Eosinophilic and Neutrophilic Asthma during acute exacerbation and to observe the correlatations, if any, with severity and response to treatment. Objectives: Primary Objective The present study is to throw light on: 1.
The incidence of Eosinophilic and Neutrophilic Asthma during acute exacerbation of asthma in children (6 to 12 years of age). Secondary Objective 1.To study the correlation of Severity of disease in Asthma prototype (Eosinophilic versus Neutrophilic). 2. To study the Response of standard treatment for (Eosinophilic versus Neutrophilic) asthma. Setting: This study will be conducted in Pediatric OPD, Casualty and Inpatient department of Swami Dayanand Hospital, Delhi. Study Design: This study will be observational, cross-sectional, analytical.
Time Frame: February 2018 – October 2018 (10 months) Participants: Asthmatic children aged 6-12 completed years Inclusion Criteria: 1.Physician diagnosed Asthma with acute exacerbation as per GINA guidelines. 2.Children ( 6 to 12 years of age). 3.Parents giving consent for the study. Exclusion criteria: 1.
All Asthamatic children with coexisting other pulmonary diseases i.e-Bronchiestasis, cystic fibrosis, Allergic bronchopulmonary aspergillosis, interstitial lung disease. 2. All Asthamatic children with high fever (>/39*C i.e 103*F) and evidence of severe bacterial infection.
3. All Asthmatic children with co-existing cardiac disease. 4.
All Asthamatic children who received oral systemic corticosteroid in last 2 weeks. 5. All Asthmatic children with muscular disease or chest deformity. Sample Size : The minimum required sample size is 96 patients.
Methods: This cross-sectional study is going to be conducted in Department of Pediatrics Swami Dayanand Hospital after obtaining the approval of institutional research committee & institutional ethics committee. All eligible children will be enrolled in study after obtaining informed consent from the patient. For every child enrolled in study, CBC (complete blood count) and peripheral smear examination will be done. Severity of exacerbation of Asthma as mild, moderate and severe as per PRAM (Paediatric Respiratory Assesment Meausres) at 0 hrs i.e during Triage and standard recommended treatment according to severity of illness as per GINA-2017 guidelines will be started and response to treatment will be assessed by PRAM score at 1 hr and 3 hrs after start of treatment and duration of hospital stay. Outcome measures 1.
Blood smear incidence of Eosinophilia and Neutrophilia. 2. Severity of Asthma exacerbation according to PRAM score. 3.
PRAM scoring at 1 and 3 hrs and Duration of Hospital stay. Statistical analysis: statistical testing will be conducted with the statistical package for the social science system version SPSS 17.0. continuous variables will be presented as mean +_ SD or median ( IQR) for non normally distributed data. Categorical variables will be expressed as frequencies and percentage. Nominal categorical data between the groups will be compared using Chi-squared test or Fisher’s exact test as appropriate.
For all statistical tests, a p value less than 0.05 will be taken to indicate a significant difference.