Respiratory – Pulmonary – Asthma

 Asthma
  

• Introduction:
    
  Asthma is a serious chronic disease that causes a substantial morbidity and mortality in more than 17 million people in the United States. It is a leading chronic illness in children and forms the fourth leading cause of disability in them. Since 1980, the prevalence of asthma has increased by 61% and the mortality rate due to asthma has jumped from 0.9 per every hundred thousand, 20 years back to 1.5 per every hundred thousand uptil 1995. Coming to an alarming 67% increase, the annual healthcare costs resulting from asthma estimated to be 12.6 billion dollars and asthma leads to 10 million lost school days and 3 million lost work days.
    
  Development of Asthma
      
  RT Stein, CJ Holberg, D Sherrill, et al (Pontificia Universidade Catolica RS, Porto Alegre, Brazil; Univ of Arizna Tucson; Natl Jewish Med and Research Ctr, Denver)
  Influence of Parental Smoking on Respiratory Symptoms during the First Decade of Life: The Tucson Children’s Respiratory Study
  Am J Epidemiol 149: 1030-1037, 1999
      
  The exact effect of parental smoking on childhood respiratory illness has been difficult to point out. However, Sten and colleagues in the largest Tucson Children’s Respiratory Study, evaluated the link between prenatal and postnatal maternal smoking based upon a careful longitudinal study. They have found that maternal prenatal smoking is associated to wheezing below 3 years of age and interestingly this effect was found to be more pronounced in girls rather than in boys. It is likely that this prenatal smoking results in smaller airways due to the reduced lung development, resulting into wheezing. Postnatal smoking, however, is likely to be related to recurrent upper respiratory tract infections. Hence our aim to prevent smoking induced lung disease should be aimed at the potential mother.
      

• M Yung, M South (Royal Children’s Hosp, Melbourne, Victoria, Australia).
  Randomized Controlled Trial of Aminophylline for Severe Acute Asthma.
  Arch Dis Child 79:405-410, 1998.
     
  Aminophylline still has a role to play in the treatment of children with severe, acute asthma in whom initial treatment has been unsuccessful. However, agents with a lower risk of adverse effects, such as frequent ipratropium, should be used before aminophylline.
        

• Pulmonary Tuberculosis
  Chaulk CP, for the Public Health Tuberculosis Guidelines Panel [ Annie E. Casey Found, Baltimore, MD]
  Directly Observed Therapy for Treatment Completion of Pulmonary Tuberculosis : Consensus Statement of the Public Health Tuberculosis Guidelines Panel
  JAMA 279: 943-948, 1998
     
  Being an infectious disease its treatment needs to be strictly followed. The number of patients stopping therapy on their own is high. Supervised therapy and its enforcement are advised in this article. The directly observed therapy [DOT] is an important way of achieving this goal.
      

• Johannes.H. Wildhaber, Grant W Waterer, et al, (Department of Respiratory Medicine, Univ. Children’s Hospital, Switzerland and Royal Perth Hospital, Western Australia)
  Reducing electrostatic charge on spacer devices and bronchodilator response.
  Br.J.Cl. Pharmacol; Sept.2000: 50(3), 277-280.
      
  Summary: Plastic spacers are widely used with pressurised metered dose inhalers (pMDI). Reducing electrostatic charge by washing spacers with detergent has been shown to greatly improve drug delivery. The authors have assessed whether this finding is associated with an improved bronchodilator response in adult asthmatics. They have shown an improvement in bronchodilator response, in adult asthmatics, after reducing the electrostatic charge in a spacer device by washing it with ordinary household detergent
     

• J Tamaoki, M Kondo, et al (First Department of Medicine, Tokyo Women’s Medical University School of Medicine, Tokyo)
  Effect of Suplatast Tosilate, a Th2 Cytokine Inhibitor, on Steroid-dependent Asthma: A Double blind Randomised Study.
  Lancet, vol. 356, July 22, 2000, p. 273-278.
     
  Th2 cytokines play an important part in pathogenesis of asthma. Authors have studied the effect of suplatast tosilate, a selective Th2 cytokine inhibitor, on asthma control and asthma exacerbations during reduction of inhaled corticosteroid dose in patients with steroid dependent asthma. In an uncontrolled trial, 6 week treatment with suplatast tosilate, reduced airway hyper responsiveness and eosinophilic airway inflammation in mild asthma.
      
  This study has looked at the possible steroid -sparing effect of suplatast tosilate in treatment of patients with moderate to severe persistent asthma who required high-dose inhaled beclomethasone dipropionate to control their symptoms in a double-blind, randomised, parallel group, multicentric trial.
      
  Treatment with this Th2 cytokine inhibitor in steroid-dependent asthma improves pulmonary function and symptom control and allows a decrease in dose of inhaled corticosteroid without significant side-effects.
        

• Donahue JG, Weiss ST, Livingston JM, et al [ Brigham and Women’s Hosp, Boston; Harvard Med School, Boston]
  Inhaled Steroids and the Risk of Hospitalization for Asthma
  JAMA 277: 887-891, 1997
     
  A common cause of hospitalizing children and adults is asthma. Out of 16,941 asthmatic patients 742 needed hospital admission.
     
  This article points out that inhalation of steroids reduced the incidence of hospitalization by 50%. A greater reduction is noticed in patients using bronchodilators.
      

• Sporik R, Hill DJ, Thompson PJ, et al [ Royal children’s Hosp, Melbourne, Australia; QEII Med Ctr, Nedlands, Australia; Univ of West Australia, Melbourne; et al
  The Melbourne House Dust Mite Study: Long-Term Efficacy of House Dust Mite Reduction Strategies
  J Allergy Clin Immunol 101: 451-456, 1998
     
  A well conducted control maintained study in 85 homes shows mite control in carpets is achieved by encasement with semipermeable material. The alternative is removal of carpets, Anti-mite shampoos were not effective in this study.
      
  This study is important because mite sensitive individuals are known to express it as asthma and eczema.
  

• Bowton DL, Fasano MB, Bass DA [ Wake Forest Univ, Winston-Salem, NC]
  Skin Sensitivity to Allergen Does not Accurately Predict Airway Response to Allergen
  Ann Allergy Asthma Immunol 80: 207-211, 1998
     
  Titrated skin testing of 22 asthmatic individuals was compared with the inhaled test. Prick tests were used in this study. The tests were comparable in some subjects with atopy and asthma but not in others.
      
  The question raised in this important study is very pertinent and refers to the relevance of skin testing in asthma.
  

• C Bodner, for the Aberdeen WHEASE Group (Univ of Aberdeen, Scotland)
  Family size, childhood infection and Atopic disease 
  Thorax, 53: 28-32, 1998.
      
  The prevalence of asthma and other allergic disease among children in the developed countries has increased in the past 3 decades. 
     
  Bodner and Aberdeen have in this group reported on cross-sectional survey of 2111 subjects analysed for the determinants of asthma and atopy. They found that hay-fever and eczema were inversely related to family size but asthma less so. They also found a small increased risk for asthma with increasing number of childhood infection. Measles, however, demonstrated a small protective effect for asthma. The effect of childhood infections on this immunologic perturbation is unknown but is likely specific to the class or type of infection.
      

• M Kraft, RJ Martin, S Wilson, et al (Univ of Colorado, Denver; Univ of Southampton, England)
  Lymphocyte and Eosinophilia influx into Aleovular Tissue in Nocturnal Asthma
  Am. J Resp.Crit Care Med 159: 228-234,1999.
       
  Inflammatory cytokines which are produced by T lymphocytes help the promotion of eosinophil migration from blood through the vascular endothelium and the key source for these cytokines probably is the CD4+ lymphocytes, which may also produce chemokines involved in eosinophil chemotaxis, survival, maturation as well as their activation.
      
  The study has been performed into two separate groups. The patients were subjected to bronchoscopies followed by endobronchial and transbronchial biopsy specimens. Amongst patients suffering from nocturnal asthma and those without suffering from nocturnal asthma i.e. nonnocturnal asthma group. Bronchoscopies were performed in a random order, a week apart at 1 at 4 pm and the other at 4 am. The numbers of CD3+, CD4+, CD8+ cells and EG2+ eosinophils were measured in the epithelium, lamina propria and the alveolar tissues.
      
  These studies from Kraft and her colleagues at National Jewish have enlightened us with a role of alveolar tissue inflammation in asthma. The study demonstrates that there are an increased number of CD4+ lymphocytes in alveoli in patients with nocturnal asthma and with those correlated inversely with nighttime lung function. Whether this was causally related is unknown. More information is needed regarding the circulation of CD4 lymphocytes in the lungs and their release of potential mediators of asthma symptoms. These cells may be either innocent bystanders or be the result in the alveoli from the spilling over from the increased numbers in the airways. Further studies of optimal timing of anti-inflammatory mediators in patients with nocturnal asthma are needed.
       

• BH Rowe, GW Bota, et al (Univ of Alberta, Edmonton, Canada; Sudbury Regional Hosp, Ont, Canada; univ of British Columbia, Vancouver Canada, et al)
  Inhaled Budesonide in Addition to Oral corticosteroids to prevent asthma relapse following discharge from the Emergency Dept. – A Randomized Control Trial.
  Jama 281: 2119-2126, 1999
       
  Systemic corticosteroid treatment can decrease acute asthma relapses after discharge from the emergency department. This study undertook to decide whether inhaled corticosteroids provide any additional benefit. 
    
  The study is double-blind placebo-controlled randomized clinical trial which was conducted over a period of 2 yrs on patients between ages from 16 to 60. 188 patients were included in this study and on discharge they were given non-tapering course of oral prednisolone which is 50mg/day for 7 days along with 1600 mg inhaled budesonide or a placebo. These patients were followed up for a period of 21 days. 
     
  This well performed study demonstrates a beneficial effect from the addition of inhaled corticosteroids at the time of discharge of an asthma patient from the emergency dept. For a variety of reasons, the emergency room physicians often do not add inhaled corticosteroids for asthma patients at discharge. Few of them being cost, lack of long term of follow up with the patient, interference with primary care physician’s role inadequate time to provide a metered dose inhaler technique information. 
     
  However, this study argues whether we should be changing our emergency department practice to include inhaled corticosteroids for a minimum of 3 week period probably even longer and to prove our point we need further studies to determine the optimal dosages and the length of treatment required.
     

• SF Lanes, JE Garrett, et al (Epidemiology Resources Inc, Newton Lower Falls, Mass; Green Lane Hosp, Auckland, New Zealand, Vancouver Gen Hosp, BC, Canada; et al)
  The effect of adding atropine bromide and salbutamol in the treatment of acute asthma. This is a pooled analysis of 3 trials.
  Chest 114: 365-373,1998.
     
  For patients with acute asthma, it is not clear whether an addition of ipratropium bromide would result in bronchodilatation rather than just b2-agonist therapy. Three major randomized trials which have been performed were pulled into the study. An American study found no difference, whereas study from New Zealand showed significant advantage with the combination therapy and a Canadian study found a non-significant benefit. Results of these 3 trials have been pooled to estimate the effects of ipratropium bromide + salbutamol in patients with acute asthma. 
          
  Several studies have demonstrated that ipratropium bromide should be added to acute treatment for patients with asthma both in adult as well as in children. Zorc et al found a significant reduction in length of stay in emergency department and use of additional doses of albuterol. A reduction of length of stay is found in any busy urban emergency department. It is important to keep in mind that the effectiveness of ipratropium is primarily in acute treatment in the emergency dept. and it should not be continued in hospital setting for more than 36 hours. Thus it can be probably concluded that the additional use of ipratropium is not useful and will diminish any potential cost savings from the acute use of ipratropium.
     
  It is best to say the use of ipratropium bromide should be restricted to emergency dept. for a maximum period of upto 36 hours in case of acute asthmatic attack.
    

• D Vervloet, T Ekstrom, et al (Hopital Sainte Marguerite, Marseilles, France; Univ Hosp, Sweden, Ospedale Civile, Osimo, Italy; et al)
  A 6-Month Comparison Between Formeterol and Salmerterol in Patients with Reversible Obstructive Airways Disease
  Respir Med 92: 836-842, 1998.
     
  The newer long acting B2-agonists including formoterol and salmeterol, can be prescribed for regular use by patients with asthma. The long-term treatment with these agents has important benefits including reduced symptomatology and improved lung function. Formeterol as well as salmeterol have not been directly compared for safety and efficacy. The efficacy and safety of 6 months of treatment have been compared in multi-randomised open trials. In-vitro studies have shown that mast cells following treatment with formeterol have significantly decreased in numbers a finding, which is not supported by studies with salmeterol. However, studies by Vervloet et al argues that in-vivo or in real life these differences may not be important. Further larger double-blind randomized controlled trial studies with formeterol when compared its efficacy with salmeterol are required to make this decision.
        
  The study by Palmquist et al argues that formeterol is more protective against methacholine induced bronchoconstriction than salmeterol. However the doses to achieve this protection which they have implemented are much higher than the currently recommended one for the use of either drug in clinical practice. The effect of Formeterol on the bronchodilating ability of short acting B-agonist such as albuterol over a period of time needs to be inves
     

• F Pierart, JH Wildhaber, I Vrancken, et al (Princess Margaret Hosp for Children, Perth, Western Australia)
  Washing plastic spacers in household detergent reduces electrostatic charge and greatly improves delivery
  Eur.Res Jr. 1999.
      
  Plastic spacers have been widely used along with pressurized metered dose inhalers. However the electrostatic charge that accumulates on this devices has been shown to have significant impact on drug delivery. In-vitro studies suggested that the spacers coated with ionic detergent have reduced static and improved drug delivery and hence a study was undertaken to study the effects of these household detergents on the electrostatic charge on plastic spacers. 
       
  In the vitro studies all detergents increased the mean small particles Salbutamol output by almost by 50%. This increase in output was noted even for spacers coated with very dilute detergent in constitution as low as 1 : 10,000. Spacers developed an electrostatic charge within one week after coating. The charged remained low for at least 4 weeks. This is surprising finding that the use of household detergent to clean and keep dry on a spacer can improve drug delivery 3-fold. This simple technique is not well-known and nor it is found in current asthma management guideline.
      
  The study by Pierart et al demonstrates that any household detergent when diluted will decrease the electrostatic charge in spacers for up to almost 4 weeks. This interesting findings require further studies to be performed along with other medications and other chlorofluorocarbon-free propellants to confirm the results. It is also important that we start educating our patients on the proper care of spacers so as to optimize drug delivery.
         

• RA Pauwels,for the Formoterol and Corticosteroids Establishing Therapy (FACET)International study group (Univ Hosp. Ghent, Belgium)
  Effect of Inhaled Formoterol and Budesonide on Exacerbations of Asthma
  N Engl J Med 337: 1405-1411, 1997.
      
  The first-line treatment for patients with moderate to severe persistent asthma is inhaled glucocorticoids, but many patients continue to have symptoms and need additional treatments. This broad-based, double-blind, randomised, parallel group study has included 4 treatment groups. Their suggestion that long acting, inhaled b2- agonist to inhaled glucocorticoid would produce symptomatic improvement without long-term negative effects is aptly supported by the results. It is advisable to give a trial of maximal dose of inhaled glucocorticoids prior to the addition of inhaled long acting b2-agonists. Such studies form a good platform for laying down guidelines. However, individualisation remains a commonly used option in initial treatment.
        

• ML Lara-Marquez, A Deykin, S Krinzman, et al (Brigham and Women’s Hosp, Boston; Harvard Med School, Boston; Harvard School of Public Health, Boston)
  Analysis of T-Cell Activation After Bronchial Allergen Challenge in Patients with Atopic Asthma.
  J Allergy Clin Immunol 101:699-708, 1998.
       
  There is increasing evidence of T cell involvement in the airway inflammation in asthma patients and an important functional role may also be played by CD4+ T helper (TH) cells in regulating the immunoglobulin E synthesis.
     
  In this article, a number of immunologic markers have been measured from the peripheral blood in 9 adult individuals undergoing either cold air challenge or entire bronchoprovocation challenge with allergen. What is found is that peripheral blood at 2 and 24 hours after allergen challenge has a significant increase in CD45RO+, IL-2 receptor positive CD4+ TH cells compared with baseline, increasing from about 12% to about 18% at both 2 and 24 hours. The major histocompatibility complex class II expression and IL-2 receptor expression were also increased but not as significantly, and coexpression of the IL-2 receptor and major histocompatibility complex class II was only found on a small population of CD45RO+ TH cells suggesting that a significant percentage of cells stimulated by bronchoprovocation and cold air co-express the same receptor leading to an up-regulation of the other immune markers on these cells may represent the effects of immune cells passing through the lung. The significance of these findings is that we need to work toward the potential identification of markers that can be viewed as somewhat reliable in identifying noninvasive markers of airway inflammation in asthma. This would get us closer towards better assessments of therapy and disease severity.
     

• A-L Ponsonby, D Couper, T Dwyer, et al (Univ of Tasmania, Australia)
  Cross Sectional Study of the Relation Between Sibling Number and Asthma, Hay Fever, and Eczema.
  Arch Dis Child 79: 328-333, 1998.
    
  The prevalence of pediatric asthma has been increasing worldwide especially in the Western countries and the reasons for this increase are not known. However, an inverse relationship between the prevalence of allergic rhinitis and sibling number has been noted. 
     
  The study is a cross-sectional survey of pediatric atopy conducted in the year 1995 in Tasmania.
      
  The prevalence of asthma, hay fever and eczema was found to be 27%, 19% and 22% respectively, in this population under the study. The prevalence of asthma and hay fever, but not of eczema, was inversely related to sibling number, with a dose-response trend for up to 3 siblings.
     
  This study confirmed a protective effect of larger sibling number or household size with respect to pediatric asthma and hay fever. An understanding of the mechanism may provide insights into the pathogenesis of pediatric asthma.
      
  The protective effect of high sibling number could not be separated from household size, but at the earlier edges it appears to be of significant effect in reducing prevalence of atopic diseases in high-sibship families.
     

• TD Weir, N Malleck, AJ Sandford, et al (Univ of British Columbia, Vancouver; Univ of Saskatchewan, Saskatoon; Sir Charles Gairdner Hosp, Nedlands, Australia; et al).
  B2-Adrenergic Receptor Haplotypes in Mild, Moderate and Fatal/Near Fatal Asthma.
  Am J Respir Crit Care Med 158: 787-791, 1998.
      
  Fatal and nonfatal asthma have been associated with excessive use of inhaled b-agonists. Genetically dysfunctional B2 adrenergic receptors (B2ARs) may have an important role in fatal asthma. Several polymorphisms of the B2AR gene have been reported.
     
  Polymerase chain reaction methods were used to genotype the B2AR variants to determine their prevalence in fatal and near-fatal asthma and to compare B2AR allele frequencies among persons of varying ethnic backgrounds in the study quoted.
    
  Genotyping was performed in persons with fatal asthma, near-fatal asthma, nonfatal asthma, and normal controls. 
     
  Studies resulted into inconclusive evidence that the presence of any of the haplotypes is linked with severity of fatal or non-fatal asthma in the white population as well as in among Asians and African Americans. However, a larger cohort study involving larger population of each of these races would probably help to give us a greater and in-depth insight into the correlation between the B2AR genes and fatality of asthma.
     

• OM Kon, BS Sihra, CH Compton, et al (London Chest Hosp; Natl Heart and Lung Inst, Londong; Smithkline Beecham Pharmaceuticals, Harlow, Essex, England; et al)
  Randomized, Dose-ranging, Placebo-controlled Study of Chimeric antibody to CD4 (Keliximab) in Chronic Severe Asthma.
  Lancet 352: 1109-1113, 1998
      
  CD4 lymphocytes play a significant role in the pathogenesis of chronic asthma. In the study quoted the efficacy and safety of a single IV infusion of a chimeric monoclonal antibody to CD4, were studied in patients with severe corticosteroid-dependent asthma.
     
  The successful treatemnt of asthma with immunosuppressive agents, such as cyclosporin A, and use of monoclonal antibody in the other chronic inflammatory conditions has suggested the use of a monoclonal antibody to CD4 in patients with severe steroid-dependent asthma. This was a preliminary study with a single dose of antibody. However, along with other studies using monoclonal technology, this approach seems to be the sunrise in a new era in the treatment of allergic disorders.
      

• DE Schellhase, DD Fawcett, GE Schutze, et al (Univ of Arkansas, Little Rock)
  Clinical Utility of Flexible Bronchoscopy and Bronchoalveolar Lavage in Young Children with Recurrent Wheezing.
  J Pediatr 132: 312-318, 1998.
       
  The need to evaluate recurrent wheezing in a young child is a common occurrence in primary care and consultant practice. There have been various studies which have reported the use of flexible bronchoscope for this purpose. However they have not addressed the clinical value of bronchoaveolar lavage. The study included thirty otherwise healthy children who were subjected to flexible bronchoscopy for recurrent wheezing.
      
  The evaluation of young children with recurrent wheezing can be extremely challenging as the differential diagnosis is so extensive. In majority of cases the reason is the small airways and reactive airways disease which account for wheezing. However there are multiple other causes which can lead to wheezing in a child.
      
  The study was performed on children with chronic wheezing who have responded poorly to b-agonist therapy. The study had a positive diagnostic finding as a result of bronchoscopy and bronchoalveolar lavage (BAL) in 28 of the 30 children. Airway abnormalities were found in 57% of the patients, with segmental trachomalacia the most common anomaly. Bronchoalveolar fluid analysis revealed abnormal differential cell counts in 41% of the patients. 
     
  This study suggest that bronchoscopy with lavage is a safe procedure which can provide valuable diagnostic information in young children with recurrent wheezing poorly responsive to b-agonist therapy.
     

• SD Aaron, RE Dales, B Pham (Univ of Ottawa, Ont)
  Management of Steroid-dependent Asthma with Methotrexate: A Meta-analysis of Randomized Clinial Trials.
  Respir Med 92: 1059-1065, 1998.
      
  Various alternatives to long-term steroid therapy are needed for the control of severe asthma. The efficacy of methotrexate as a steroid sparing agent was examined in a meta-analysis of randomized clinical trials.
      
  It was concluded from the study that methotrexate use enables modest decreases in oral corticosteroids in patients with severe asthma. However, the benefit is relatively small and the possibility of adverse effects should be always outweighed.
     
  There has been controversy concerning methotrexate’s usefulness as a steroid-sparing modality. Different blinded studies have had diametrically opposed results. This meta-analysis, combining experiences with 250 patients, showed a 6.0% improvement in forced expiratory volume over placebo, and an 18.2% decrease in prednisone dose. 
       
  This is relatively small advantage over the effort which has been applied in the entire study and it remains to be seen whether it is really helpful as the patients were subjected to methotrexate therapy were not without risk as two of them developed pneumonias and 1 had hepatic dysfunction as side effects which was an incidence at 1.2% . For a benefit of 6.0% improvement if there is going to be a risk of 1.2% then probably is not worth the effort.
        

• Josef Riedler, Charlotte Braun-Fahrlander et al 
  Exposure To Farming In Early Life And Development of Asthma And Allergy: A Cross-Sectional Survey
  Lancet, Vol.358, October 6, 2001, Pg. 1129-33
        
  Summary : A farming environment protects against development of asthma, hay fever and atopic sensitisation in children. The authors aimed to establish whether increased exposure to microbial compounds has to occur early in life to affect maturation of the immune system and thereby reduce risk for development of allergic diseases.
       
  Exposure of children younger than 1 year, compared with those aged 1-5 years, to stables and consumption of farm milk was associated with lower frequencies of asthma, hay fever and atopic sensitisation. Continual long-term exposure to stables until age 5 years was associated with the lowest frequencies of asthma.