Bronchial disability, medical expense, and preventable death.

Bronchialasthma is one of the oldest known diseases, but it has only been recognized asa major public health problem since the mid-1970s.

Since then the  prevalence of asthma has been increasing  dramatically, and asthma is now recognized asa major cause of disability, medical expense, and preventable death.Theearliest feature  of asthma described wasthe labored, rapid breathing typical of asthmatic attacks. The word “asthma” isderived from the ancient Greek word for “panting.” Initially all breathingdifficulty were considered as asthma only and as knowledge about asthma has grown, the features described ascharacteristic of asthma have expanded and also breathlessness wasredistributed among cardiac and respiratory diseases.Asthmawas first defined in 1959 as “a disease characterized by wide variation overshort periods of time in resistance to flow in the airways of the lung.”1  National Heart, Lung, and Blood Institute’s (NHLBI’s) 2007Update on Asthma Pathophysiology andTreatment Guidelines definesasthma   as: “Asthma is a chronic inflammatory disorderof the airways in which many cells andcellular elements play a role, including mast cells, eosinophils, Tlymphocytes, macrophages, neutrophils, and epithelial cells. In susceptibleindividuals, inflammation causes recurrent episodes of wheezing,breathlessness, chest tightness, and coughing, particularly at night or in theearly morning. These episodes are usually associated with widespreadbut variable airflow obstruction that is often reversibleeither spontaneously or with treatment.

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The inflammation also causes anassociated increase in bronchial hyperresponsiveness to a variety ofstimuli.”2Although many definitions for asthma are there thewell accepted one is GINA definition .BronchialAsthma is a heterogeneous disease usually characterized by chronic airwayinflammation. It is defined by history of respiratory symptoms such as wheeze,shortness of breath, chest tightness that vary over time and in intensitytogether with variable expiratory air flow limitation.3 It is characterizedby bronchial hyper-responsiveness and variable airflow obstruction, that isoften reversible either spontaneously or with treatment.Thisdefinition involves several components, which are difficult to establish inroutine clinical practice, especially in a resource-limited country like India.Therefore, Joint ICS/NCCP recommendations regarding guidelines for diagnosisand management of asthma defines asthma as “Asthma is defined as a chronic inflammatory disorder of the airwayswhich manifests itself as recurrent episodes of wheezing, breathlessness, chesttightness and cough. It is characterized by bronchial hyper-responsiveness andvariable airflow obstruction, that is often reversible either spontaneously orwith treatment.

4Theglobal prevalence of asthma, using a definition of clinical asthma or treatedasthma, is estimated to be about 4.5% 5 There has been an increase inprevalence of asthma over time, similar to other allergic disorders. It isexpected to have additional 100 million asthmatics world wide by 20256In arecently conducted World Health Survey, the prevalence of wheezing, clinicalasthma and doctor-diagnosed asthma was 9.63%, 3.3% and 3.16%, respectively inIndian adults.7 The Indian Study on Epidemiology of Asthma, RespiratorySymptoms and Chronic Bronchitis (INSEARCH) in adults, which involved 16 centersacross the country in two phases is the largest, prospective multicenter studyon the prevalence of asthma in Indian adults.

8 The prevalence of asthma inadults reported in this study, using a validated International Union againstTuberculosis and Lung Diseases questionnaire, was 2.05%, with an estimatedburden of 17.23 million.8 Currently, it is reasonable to accept a prevalenceof asthma in India of at least 2% .Asthmacauses significant Morbidity also .It is the 25th leading cause ofdisability adjusted life years (DALYs) lost per year accounting for anestimated 15 million DALYs lost (about 1% of all lost DALYs).

6 This issimilar to other diseases like diabetes mellitus and schizophrenia. Asthmaaccounts for 1 in 250 deaths,but most of the asthma deaths are preventable byadequate treatment.InEurope, the estimated direct costs of asthma treatment are about 17.

7 billionEuros every year while the indirect cost due to loss of productivity is about9.8 billion Euros annually. In India, the estimated cost of asthma treatmentper year for the year 2015 has been calculated at about 139.

45 billion Indianrupees (approximately 2.3 billion US dollars). Interestingly, it has beendeduced that this cost is likely to come down to about 48.5 billion Indianrupees if all asthmatics receive treatment according to evidence-basedguidelines.9 Generally,most asthma starts from childhood in relation to sensitization to commoninhaled allergens. Many basic and clinical studies suggested that airwayinflammation was a central key to the disease pathophysiology.

. Theinflammation is induced by the release of potent chemical mediators frominflammatory cells and  resulted inairway remodeling, characterized by thickening of all compartments of theairway wall .Air way remodelling has profound consequences on the mechanics of airway narrowing in asthma andcontribute to the chronicity and progression of the disease.

 Asthmais a complex inflammatory disease that involves many inflammatorycells.Multiple inflammatory effects, including bronchoconstriction, plasmaexudation, mucus hypersecretion and sensory nerve activation has been recognisedin pathogenesis of asthma .Multipleinflammatory mediators are involved in asthma, including lipid and peptidemediators, chemokines, cytokines and growth factors.

Thischronic inflammation may lead to structural changes in the airways, includingsubepithelial fibrosis, airway smooth muscle hypertrophy/hyperplasia,angiogenesis and mucus hyperplasia.    VitaminD is a fat soluble vitamin and a secosteroid hormone which is widely recognizedas a modulator of calcium absorption and bone health and further regulatesneuromuscular function cellular differentiation, insulin secretion and bloodpressure10We nowknow that vitamin D receptors (VDRs) are expressed in many cell types  including various immune cells, suggestingthe role of vitamin D on immune system These recent findings have increased interest in vitamin D status andits link to several nonskeletal diseases Wjstand Dold were the first scientists to hypothesize a link between vitamin D andallergic diseases11. The authors suggest that the geographic trend of higherdisease prevalence in more developed countries runs in parallel with vitamin Dexposure. The authors found that higher risk for atopy, allergic rhinitis, andasthma was associated with increase in vitamin D supplementation for newbornsin order to prevent infantile rickets . A second hypothesis developed latersuggested that vitamin D deficiency may contribute to the recent increase inallergies in Western countries12Thereis a combination of different factors which determine 25(OH)D serum levels andvitamin D deficiency like skin pigmentation, low sun exposure, more time spentindoors, obesity, higher latitudes, and winter season .

Other secondary causesthat could affect vitamin D serum levels are diseases including rheumatoidarthritis, cystic fibrosis, ulcerative colitis, Crohn’s disease, celiacdisease, rickets, and medications 13Of thedifferent allergic disorders, perhaps asthma has been the most closely examinedin the context of vitamin D. Although the underlying mechanisms of how vitaminD modulates the pathogenesis of asthma have not been completely understood, theavailable data suggest an association between vitamin D deficiency and asthma.On the other hand, there is insufficient and weak evidence for an associationbetween vitamin D status and atopic disease other than asthmaAirway epithelial cells canhydroxylate 25(OH)D to its active form  leading to increased differentiation and recruitment of macrophages  enhanced production of cathelicidin and CD14,and potentiation of host defences against Mycobacterium tuberculosis,  and other bacteria, fungi, and viruses 14Inaddition to promoting appropriate antigen tolerance, vitamin D also modulatesother aspects of allergen-stimulated immune responses. Vitamin D can suppressproduction of IgE by human B lymphocytes  in vitro and increase IL-10 production,promoting a regulatory B-lymphocyte phenotype15 Additionally, vitamin D hasbeen shown to have the capacity to suppress mast cell activation, reducinghistamine and tumor necrosis factor-alfa release Vitamin D can also promotemast cell production of anti-inflammatory IL-10 .

 In thepathogenesis of non allergic asthma epithelial damage is now understood toprompt release of cytokines known as alarmins, forexample, IL-25, IL-33, and thymic stromal lymphopoietin, that directlystimulate multiple cell types, including type2 innate lymphoid cells (ILC2s) and mast cells. These stimulated ILC2s thenproduce Th2-type cytokines, including IL-5,which in turn promotes eosinophilic inflammation. Vitamin D has been shown tomodulate the epithelial response to stimulation, with a potentiallyanti-inflammatory role for this action.16.

Studiesshow that vitamin D plays an important role in airway remodelling also.Airwaysmooth muscle cells are involved in airway narrowing as well as in productionof inflammatory mediators involved in asthma. Vitamin D inhibit smooth musclecell proliferation as well as inhibit production of inflammatory mediatorsthere by plays a role in the pathogenesis of asthma.Vitamin D alters human airway smooth muscleexpression of chemokines and inhibit the expression of a steroid resistant gene.

Vitamin D deficiency has been associated with increased airway hyperresponsiveness ,lower pulmonary function ,worse asthma control and steroidresistance.17 Overthe past few years, several RCTs of vitamin D therapies to improve asthmacontrol have been completed and their findings published.many of these showspositive correlation  of poor asthmacontrol and asthma severity with lower vitamin D levels.

 

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