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Asthma

There is no consensus on definition of asthma. It can be stated that asthma represents an umbrella term for several diseases with similar clinical manifestations but different underlying pathophysiological mechanisms often referred to as asthma endotypes.

GINA ( Global initiative for asthma ) in 2015 described asthma as a heterogeneous disease , usually characterized by chronic airway inflammation . It is defined by the h/o resp symptoms such as wheeze , shortness of breath , chest tightness and cough that vary over time and in intensity , together with variable expiratory airflow limitation.

 

Terminology – Severe asthma -is defined as asthma which requires treatment with high dose of inhaled corticosteroid ( ICS ) plus a second controller ( and or systemic corticosteroids ) to prevent it from being uncontrolled or which remains uncontrolled despite this therapy Problematic severe asthma ( PSA ) is described by Bush et al as asthma in children who require specialist referral because of the apparent poor reponse to maximum asthma treatment. This is further broadly divided into
(1 ) Difficult to treat ( or difficult ) asthma ( DA )
( 2) Asthma with co-morbidities ( Asthma plus )
(3 ) Severe therapy resistant asthma Thunderstorm asthma – epidemics that occur during or shortly after a thunderstorm where the affected individuals would experience asthma related symptoms as breathlessness , wheezing and cough Work-related asthma ( WRA ) due to exposure to asthmagens or inciting sensitizing agents. Two distincy subtypes are recognised
( 1) Work aggrevated / exacerbated asthma ( WEA )– which affects individuals with pre-existing ashma
( 2 ) Occupational asthma -which affects individuals with no prior asthma diagnosis. OA is further sub classified as Immunoglobulin ( Ig)-E mediated or sensitizer induced OA ( majority of cases ) and irritant induced OA

 

How common -From Greek word asthmaino ( panting or gasping ) Major global non-communicable disease which affects both children and adults 
( significantly more common in children ) A heterogeneous disorder and its heterogeneity changes according to age Asthma is a common disease which affects about 300 million people worldwide across all age ranges In 2004 it was estimated that 5.4 million people in the UK were being treated for asthma and among them 1.2 million were children Global epidemic is still continuing particularly in low to middle income countries – it has subsided in some developed countries Global prevalence ranges from 1 to 21 % in adults , with up to 20 % children aged 6-7 yrs experiencing severe wheezing episodes within a year ,the reason for the wide prevalence is because of gene-by-gene environmental interactions Childhood asthma is more common in boys while adult asthma is more common in women ( changeover after puberty indicating role of hormones ) Globally asthma ranks 16th among the leading causes of years lived with disability and 28th among the leading causes of burden of disease as measured by disability-adjusted life years In Northern hemisphere a predictable epidemic happens when children return to school every September – important factors which contribute to this include seasonal rhinovirus infection , reduction in use of inhalers during summer months , exposure to seasonal allergens and possibly the stress of returning to school

 

What happens -Heterogeneous disease with complex pathophysiology and phenotypes possibly multifactorial disorder and its etiology is increasingly being attributed to interactions between genetic susceptibility , host factors and environmental exposure underlying mechanisms may involve airway inflammation , control of airway tone and reactivity ( only 30 % of asthma is due to allergies – rest happen due to multiple mechanisms that have complex interactions ) the pathophysiology can be variable and includes eosinophilic , neutrophilic , mixed granulocytic and paucigranulocytic pathways treatment pathways have been classically based on the understanding that asthma is a TH-2 type inflammatory disorder frequently associated with atopy and allergic comorbidities it should also be noted that there are many phenotypes ( phenotypes can be different as early versus late onset , presence of atopy and significant allergic symptoms , severity of lung function reduction and response to treatment ) and endotypes of asthma ( endotypes describe the distinct pathophysiological mechanisms at a cellular and molecular level ) – this implies that the patient may have similar symptoms but may respond differently to a similar therapeutic intervention airway inflammation that happens often following an environmental exposure is fully reversible

 

Environmental exposure -widely incriminated allergic and non allergic airborne triggers include house dust mite , animal hair and dander , pollen , mold ( fungal ) spores , food allergens , tobacco smoke , grass pollen and other pollutant exposures. It is also known that childhood and adult onset asthma share many of the same causes and triggers outdoor environment can impact respiratory health directly as well as by infiltration. Air pollutants as nitrogen oxide
 ( NO ) , sulphur dioxide ( SO2 ) , ozone and carbon monoxide as well as VOCs , SVOCs and aeroallergens can impact indoor environment – role of indoor pollutants has been studied extensively , although the role in the etiology of asthma is not clear

 

Pre-natal and personal smoking – possibly multi factorial prenatal risk factors prenatal maternal smoking has been shown to be consistently associated with early childhood wheezing- a dose-response relationship between exposure and decreased airway caliber in early life has been reported it has also been reported that grandmaternal smoking while the mother is in utero and paternal smoking during his adolescence can independently increase the risk of subsequent offspring childhood asthma smokers are likely to have suboptimal asthma control and develop asthma- copd overlap syndrome ( ACOS ) in later life. It has also been observed that

 

Childhood respiratory infections -about 50 % of preschool children have wheezing but only about 10-15 % have a diagnosis of true asthma by the time they reach school several phenotypes have been developed for e.g never wheezers , early transient wheezers , persistent wheezers , late onset wheezers ( Tuscan classification ) persistent ( starts before age 3 and persists beyond 6 yrs ) and late onset ( onset of wheezing between 3 -6 yrs of age ) may represent 2 asthma predictive phenotypes who are more likely to experience asthma – like symptoms that persist into later childhood , adolescence and adult life it remains difficult to differentiate these phenotypes as the expression of symptoms and risk factors can change over time it is also known that different factors , including genetic , environmental and host factors can impact a child’s condition and contribute to the development of wheezing and the progression of symptoms

 

Antibiotic use- Role of antibiotics both prenatal and use to treat frequent URTIS has been studied. No clear message can be drawn from the studies if this predisposes to increased risk of asthma

 

Lifestyle factors – Role of different aspects have been looked into as obesogenic diet infant breastfeeding infant delivery mode diet and nutrition stress family structure and socioeconomic status

 

Occupational exposure -over 250 agents can cause sensitization and possibly occupational asthma it is estimated that about 10-20 % of all adult onset asthma may be related to occupational exposure to respiratory sensitizers and or / irritants

 

Diagnosis – Diagnosis is based on a good clinical history and evidence of variable airflow limitation The symptoms have been classically explained on the basis of 
- bronchial hypersensitivity leading to airway inflammation and increased mucus production which causes an increase in airway resistance which is most pronounced during expiration
- airway obstruction happens due to inflammatory cell infiltration , mucus hypersecretion with mucus plug formation and smooth muscle contraction
- bronchospasms , edema , excessive mucus , epithelial and muscle damage can cause bronchoconstriction and bronchospasm this can manifest as episodes of coughing , shortness of breath and wheezing recent advances have demonstrated basement membrane thickening in association with non-reversible airflow obstruction

 

History- NICE recommends taking a structured clinical history asking particularyl for 
- wheeze , cough or breathlessness and any daily or seasonal variation in these symptoms
- any triggers that make symptoms worse
- a personal or family h/o atopic disorders

NICE advices that a normal examination does not r/o asthma
 It is important to take into account that signs and symptoms of asthma can vary from patient to patient and may change within the same patient at different circumstances ( Sarver and Murphy 2009 )

 

Spirometry – most guidelines suggest spirometry testing in patients suspected of having asthma spirometry measures lung volumes and airflow Children over age 5 should be offered spirometry asthma should be suspected if FEV1/forced vital capacity ratio of < 0.7 or less than the LLN and airflow reversibility after SABA – FEV1 improvement of atleast 12 % and 200 mls a normal spirometry does not exclude asthma

 

Peak Expiratory Flow Rate Measurement-cheap and readily available- effort dependent most children over 7 should be able to perform this diurnal variation over 2 weeks and response to inhaled beta 2 agonists or after a trial of oral steroids BTS/ SIGN guideline quotes the difference between maximum and minimum expressed as a percentage of the mean peak flow with more than 20 % being considered abnormal can aid in help in early identification of children with airway obstruction

 

Fractional excretion of Nitric Oxide – recommended by NICE draft for diagnosis is an indirect marker of airway inflammation FeNO is more sensitive to eosinophilic airway inflammation and is not as as useful in the diagnosis of non-eosinophilic asthma

 

Bronchoprovocating agents – for patients with normal spirometry- agents as methacholine or mannitol can be used methacholine causes bronchoconstriction and airflow obstruction- asthma patients will have a heightened response to methacholine mannitol is an indirect stimulator of bronchoconstriction

 

Exercise testing -similar principles as cardiac treadmill test consider for those patients in whom exercise induced bronchoconstriction is suspected.

 

There is no current therapeutic regimen known to cure asthma Rates of death due to asthma have reduced in the last 25 yrs No current primary prevention strategy has shown robust evidence to be implemented in clinical practice Goal of treatment is 
- reduce impairment ie to prevent chronic symptoms , require infrequent use of SABA and maintain near normal lung functions and normal activity levels
- reduce risk ie to prevent exacerbation , minimize need for emergency care , hospitalization , prevent loss of lung function and minimize adverse effects of therapy Important to ensure ( evidence base of effectiveness )
- patient education
- written asthma action plan
- ensuring proper technique
- addressing patient adherence and concerns
- stepwise approach to identify appropriate treatment options

 

Beta agonists – bind to beta -2 adrenergic receptors on the bronchial smooth muscle cells leading to smooth muscle relaxation and bronchodilatation inhaled therapy produces more vasodilatation than systemic oral therapy- has a faster onset of action ( SABA – onset 1-5 minutes with peak effects at 2 hrs and median duration of action of 3 hrs ) with less dose compared to systemic therapy LABA- first LABAs exhibited prolonged bronchodilatation allowing 12h dosing , newer ultra long acting agents allow 24 hr dosing LABAs generally have a greater specificity for the beta receptors compared to short acting agents all beta agonists can cause tachycardia and palpitations

 

Corticosteroids – effective as a major proportion of patients have inflammatory phenotype they decrease airway hyper-responsiveness and inflammatory response to allergens by exerting multi antiinflammatory actions including inhibition of inflammatory cytokine release and reduced activity of inflammatory immune cells they also interact with specific receptors in tissue to regulate expression of corticosteroid- responsive genes known to reduce exacerbations and improve lung function systemic use predisposes to significant SEs which can include endocrine suppression , increased risk of infections , osteoporosis , osteonecrosis , cataract formation , fluid and electrolyte imbalance and development in children

 

Antimuscarinics – have been used for several hundred years disrupts the vagally mediated muscarinic receptor activation leading to bronchodiltation

 

Theophylline -orally administered xanthine derivative leads to increased levels of cyclic AMP and cyclic GMP-resulting in bronchodilation and a decreased release of inflammatory mediators from mast cells antagonizes adenosine receptors in the airways- possibly preventing contraction of smooth muscles and release of inflammatory markers

 

Leulotrine receptor antagonists -leukotrienes are lipid mediators which are involved with smooth muscle constriction , immune cell infiltration and vascular changes which lead to edema by inhibiting leukotrine synthesis these medications downregulate airway inflammation and have been demonstrated to improve lung function and serve as add on therapy

 

References

  1. Asthma diagnosis and management Jennifer Y So , Albert J Mamary , Kartik Shenoy EMJ. 2018;3[4]:111-121
  2. Dharmage, Shyamali C et al. “Epidemiology of Asthma in Children and Adults.”Frontiers in pediatricsvol. 7 246. 18 Jun. 2019, doi:10.3389/fped.2019.00246.
  3. A summary of the new GINA strategy: a roadmap to asthma control Helen K.Reddel,Eric D.Bateman,AllanBecker,Louis-PhilippeBoulet,Alvaro A.Cruz,Jeffrey M.Drazen,TariHaahtela,Suzanne S.Hurd,HiromasaInoue,Johan C.de Jongste,Robert F.Lemanske,Mark L.Levy,Paul M.O’Byrne,PierluigiPaggiaro,Soren E.Pedersen,EmilioPizzichini,ManuelSoto-Quiroz,Stanley J.Szefler,Gary W.K.Wong,J. MarkFitzGerald European Respiratory JournalSep 2015,46(3)622-639;DOI:10.1183/13993003.00853-2015
  4. Kuruvilla, Merin E et al. “Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease.”Clinical reviews in allergy & immunology vol. 56,2 (2019): 219-233. doi:10.1007/s12016-018-8712-1
  5. Subbarao, Padmaja et al. “Asthma: epidemiology, etiology and risk factors.”CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadiennevol. 181,9 (2009): E181-90. doi:10.1503/cmaj.080612
  6. The Lancet summary https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(15)00156-7.pdf
  7. Al-Shamrani, Abdullah et al. “Wheezing in children: Approaches to diagnosis and management.”International journal of pediatrics & adolescent medicinevol. 6,2 (2019): 68-73. doi:10.1016/j.ijpam.2019.02.003
  8. Clinical Pharmacology of Bronchodilator Medications Dennis M Williams PharmD BCPS AE-C and Bruce K Rubin MEngr MD MBA FAARC RESPIRATORY CARE JUNE 2018 VOL 63 N Hashmi MF, Tariq M, Cataletto ME. Asthma. [Updated 2020 Aug 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-.Available from: https://www.ncbi.nlm.nih.gov/books/NBK430901/
  9. NATIONAL INSTITUTE FOR HEALTH AND CARE 2 EXCELLENCE 3 Guideline 4 Asthma: diagnosis, monitoring and chronic 5 asthma management 6 Draft for consultation, October 2019
  10. Levy, Mark L. “Is spirometry essential in diagnosing asthma? No.”The British journal of general practice : the journal of the Royal College of General Practitionersvol. 66,650 (2016): 485. doi:10.3399/bjgp16X686965
  11. Pharmacotherapy of Asthma Martin M. Zdanowicz, PhD American Journal of Pharmaceutical Education 2007; 71 (5) Article 98.
  12. Primary Care Respiratory UPDATE Introduction Peak flow monitoring and microspirometry as aids to respiratory diagnosis in primary care Dr Duncan Keeley Executive Committee Member, PCRS-UK
  13. Understanding asthma pathophysiology, diagnosis, and management By Shari J. Lynn, MSN, RN, and Kathryn Kushto-Reese, MS, RN July 2015 American Nurse Today 49
  14. Childhood Asthma-Predictive Phenotype Theresa W. Guilbert, MDa , David T. Mauger, PhDb , and Robert F. Lemanske, Jr, MDc Cincinnati, Ohio; Hershey, Pa; and Madison, Wis J ALLERGY CLIN IMMUNOL PRACT VOLUME 2, NUMBER 6
  15. Asthma: epidemiology, etiology and risk factors Padmaja Subbarao MD MSc, Piush J. Mandhane MD PhD, Malcolm R. Sears MB ChB CMAJ • OCTOBER 27, 2009 • 181(9)

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