Year : 2019 | Volume
: 33 | Issue : 1 | Page : 8--13
Allergy asthma practice in India: Beyond the guidelines “Shivpuri Oration 2017”
Department of Pulmonary Medicine, JSS Medical College, JSS AHER, Mysore, Karnataka, India
Dr. P A Mahesh
Department of Pulmonary Medicine, JSS Medical College, JSS AHER, Mysore, Karnataka
This article summarizes two decades of allergy and asthma research in Mysore, South India, encompassing epidemiologic, mechanistic and biomarker studies as well as diagnostic and prognostic studies. The deficiencies of some of the current guidelines in the diagnosis and treatment of allergic diseases. Two of the most important considerations for future guidelines are to adopt the concept of progression of allergic disease and discuss plans to prevent or mitigate them to reduce the burden of morbidity as well as the enormous costs that go along with disease progression. The other is to consider serial spirometry for the diagnosis of asthma and COPD in difficult to diagnose subjects. The future directions for research in the field are discussed.
|How to cite this article:|
Mahesh P A. Allergy asthma practice in India: Beyond the guidelines “Shivpuri Oration 2017”.Indian J Allergy Asthma Immunol 2019;33:8-13
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Mahesh P A. Allergy asthma practice in India: Beyond the guidelines “Shivpuri Oration 2017”. Indian J Allergy Asthma Immunol [serial online] 2019 [cited 2019 Aug 23 ];33:8-13
Available from: http://www.ijaai.in/text.asp?2019/33/1/8/260173
This article will discuss some important studies conducted in Mysore, South India, over the last two decades and the lessons learned therein. The studies that will be discussed encompasses the entire clinical spectrum of asthma including the prevalence studies and pathogenesis; diagnosis of asthma including the role of spirometry, skin prick tests, and serum-specific immunoglobulin E (IgE); and management including disease progression, treatment responsiveness, newer pollens causing sensitization and which of the participants with rhinitis are likely to progress into asthma.
A temporal trend of prevalence of asthma and allergic rhinitis was evaluated in around 1800 children aged 6–14 years every 5 years since 1998 in Mysore and the last was in 2013. The study used the core questions from the ISAAC study. An increasing trend of about 50% every 5 years was observed during the first three surveys, and a much steeper increase was observed in 2013. The key causes for this needs to be evaluated further, but some important factors could be lack of physical activity, hygiene hypothesis, increase in consumption of fats and sugars, and increased awareness among both the parents and the pediatricians. Although pollution is sometimes hypothesized as one of the factors that could be related to the increasing prevalence of asthma and allergic rhinitis, the study in Mysore did not find a link between gaseous and particulate matter temporal trends over a decade and the increasing prevalence of allergic diseases. After the legislation that mandated decrease in vehicular and industrial pollutants in 2003, there was a significant drop in the levels of air pollutants in Mysore, but there was no associated drop in the prevalence of allergic diseases. Thus, it can be concluded that although undoubtedly, pollution aggravates existing allergic diseases, it may not be responsible for increase in allergic diseases. The Western nations have a much higher prevalence of asthma and allergic rhinitis as compared to Asian and African nations, and future research should not only concentrate on the risk factors but also on the protective factors that should be retained in the low prevalence countries to avoid this significant health burden to their community.
A more detailed pollution studies have now been performed in Mysore. The whole city has been divided into a 300 m × 300 m grid, and 150 sites have been randomly selected and monitored for nitric oxide (NO) levels in urban Mysore city as part of a PhD work in association with Yale University (Investigator: Amruta A Nori-Sarma). NO has been measured four times in a year including the premonsoon, monsoon, winter, and summer seasons. NO correlates very well with other pollutants, which can be inferred based on measured NO levels. Data from satellite imaging will be added to further strengthen the observations. This data will be correlated with the lung functions performed in the randomly selected general population above the age of 40 years as part of the burden of obstructive lung disease (BOLD) study (BOLD I) as well as the follow-up study in the same population, the BOLD II study. Mysore was observed to have very low levels of atmospheric pollution, especially in the residential areas.
Recently, the Global Asthma Network has completed the survey of asthma and allergic rhinitis in children aged 6–7 years and 13–14 years in a large number of countries around the world. Mysore was one of the centers in India, and 3000 children each in both the age groups were surveyed with a self-administered questionnaire (parental) along with a separate questionnaire for the parents. Around 6000 children and 12,000 adults have been surveyed, and the data are being analyzed. It would be interesting to observe the prevalence data on allergic diseases among children and adults and compare them with the air pollution data of the Mysore city from the previous study.
In one of our early studies comparing asthma, allergic rhinitis, and atopy among children residing in urban and rural areas in Mysore district, we observed a significant difference in the prevalence of atopy and allergic diseases, which were higher in urban children. Urban children had higher sensitization to all the five allergens studied (house dust mite, cockroach, cat, dog, and cattle). The prevalence of dust mite sensitivity was nearly three times higher in urban children. Although one in five of the rural houses had kept cattle within their homes and more than half in the immediate surroundings, sensitization to cattle was 50% higher among urban children (9% urban and 6% rural). Among rural households, 79% had pets (dogs and cats) compared to 3% of the urban households. Even with such a high and close exposure to these pets, the sensitization to pets was lower among rural children than urban children. “Asthma ever” in the urban children was four-fold higher and “allergic rhinitis ever” was more than twice the prevalence as compared to their rural counterparts. House dust was collected methodically using a different broom for each house, and dust was collected in an endotoxin-free sterile bag and the levels of endotoxin were estimated using the amoebocyte limulus assay. Most of the rural households used cow dung to clean their house floors everyday. Endotoxin levels in house dust from rural households were nearly twice that of the urban house dust. This study added some evidence to the hygiene hypothesis although other important contributors such as fungal glycans and muramic acids were not evaluated in this study.
In a study on food allergy that evaluated sensitization to common 24 food allergens from the EuroPrevall study, one of the protective factors identified that decreased sensitization was being “vegetarian,” who had much lower sensitization to both inhalants and food allergens., A possible mechanism to explain this has been published in the work by Maslowski and Mackay. The vegetarian diet is rich in dietary fibers. Although the human gut does not have the enzymes necessary to digest these dietary fibers, the bacteria in the human gut does. This releases short-chain fatty acids (SCFAs) such as propionate and butyrates as well as peptidoglycans and polysaccharide A, important immunoregulators. The SCFA is the most important of the lot and binds to G protein-coupled receptor 43 (GPR43), present in most immune cells, and helps to maintain homeostasis. Lack or deficiency of these molecules in the gut could be an important mechanism for dysbiosis of the immune system.
During the initial studies, we studied one or two cytokines that were already well established to be associated with asthma.,,, We studied both the association with asthma and the association with asthma severity. We studied important polymorphisms of these cytokines and correlated them to the measured levels of these cytokines in the serum., Some of the cytokines showed significant association with asthma as well as asthma severity. However, many, which were already well established, to be associated with asthma did not show any difference between asthmatics and controls. For example, interleukin-13 and gamma interferon are important cytokines involved in the asthma pathways, which did not show any significant difference between asthmatics and controls and no difference between participants with mild, moderate, and severe asthma. Some possible reasons for this could be that the cytokines act in unison than in isolation. Therefore, it is necessary to study a battery of cytokines and the interaction between them that is most likely to explain the clinical onset of disease and its behavior. We have now adopted the string analysis to understand the interaction between these various cytokines. Furthermore, a system biology approach is better than studying the cytokines in isolation.
For a beginner, the differential diagnosis between asthma and chronic obstructive pulmonary disease (COPD) can be difficult in some cases. Although the guidelines for Global Initiative for Asthma (GINA) and COPD Global Initiative for Obstructive Lung Disease define how these are diagnosed by spirometry, these guidelines do not always stand true in a proportion of cases. For example, GINA recommends that the diagnosis of asthma be defined by a bronchodilator reversibility of 12% and 200 ml. Although most of the asthmatics would satisfy these criteria, some asthmatics do not satisfy and some COPD patients would satisfy these criteria. The reversibility in asthma includes both bronchospasm and mucosal edema. Bronchodilators used for diagnosis of asthma reverse only smooth muscle spasm but not mucosal edema that needs steroids for its reversal. Therefore, it is not unusual for a clinician to observe that a patient who fails to show reversibility on the day of presentation may show significant reversibility after a month of asthma treatment that includes steroids. On the other hand, a COPD patient who has a forced expiratory volume 1 (FEV1) of 0.5 L, which improves to 0.7 ml after bronchodilators, would satisfy the diagnostic criteria for asthma. However, even after 3 months of adequate treatment, his FEV1 would remain at 0.7 L and is likely to behave as COPD. India has a significant number of nonsmoking COPD that may add to the confusion in the diagnosis. I would recommend that in these situations, the final diagnosis is reserved for a couple of months when the response to treatment will give a better indicator whether we are dealing with a case of asthma or COPD.
Skin prick testing
Skin prick testing is a common tool used by the allergist to diagnose atopy and identify allergens causing sensitization in the individual. Although skin prick testing procedure is easy to master, the most important aspect of the testing is the interpretation of the results. The key to do this well is to repeat the history after the test results are available. For each positive test result, the following steps and questions need to be carefully considered and answered by the clinician. Is the subject exposed to the allergen? What is the peak season in the year for this allergen? Is there a temporal relationship between exposure and onset of clinical symptoms? For most clinically relevant aeroallergens, we are testing for Type I hypersensitivity in patients with allergic rhinitis and asthma. Hence, we would expect symptoms within 2 h after exposure. Most participants who have delayed Type I reaction (after 6 h after exposure) also have an immediate Type I reaction. What is the type of symptoms, the participant has on exposure to the allergen? Is it asthma, allergic rhinitis, conjunctivitis, or all the three? When the participant is sensitized to multiple allergens as is common, then the clinician needs to decide which is the most clinically important allergen. Sometimes, different allergens may be relevant for different organ systems. For example, the participant's wheal diameters are 18 mm for parthenium and 6 mm for house dust mite. On history, it is clear that the house dust mite is the most important for the participant's severe asthma with peak symptoms in the winter season and early morning, but his mild eye symptoms are present only when he spends time in close contact with parthenium in the field during de-weeding in the rainy season. His asthma does not get worse even after spending many hours in the field. Therefore, he is sensitized to parthenium, which is clinically important for his mild allergic conjunctivitis but is not relevant for his asthma. The most clinically relevant allergen in this participant is house dust mite although the wheal size of parthenium is three times more than that of house dust mite. The wheal size does not always correlate with the clinical relevance.
Serum-specific immunoglobulin E
Another less commonly used test to diagnose atopy is the serum-specific IgE. Skin prick testing is always better than serum-specific IgE since it not only detects the presence of specific IgE but it also confirms that these are located on the mast cells and basophils in the correct configuration. The serum-specific IgE only measures free-specific IgE in the blood. The EuroPrevall study was a very large study in the general population done in Mysore and Bengaluru and is one of the very few studies in India in the general population. The study screened 32,000 adults and children with a one-page screening questionnaire and followed by a detailed questionnaire, skin prick testing, and serum-specific IgE. The key observations in the study were that Indians were high IgE producers and the mean total IgE was 522 IU/ml in the control general population who did not have any symptoms related to allergic disease “ever.” Many laboratories use values around 100 or 120 IU/ml as the upper limits of normal and have to be revised in light of this study. Indians are high IgE producers, similar to other Asians and Africans as IgE is involved in many normal protective responses such as detoxifying insect bites or xenobiotics along with protection against parasites. Among adults, it was observed that more than 25% were sensitized to foods and more than 30% were sensitized to any one of the six aeroallergens tested according to specific IgE measured by the ImmunoCAP.
Need to be very careful when interpreting serum-specific IgE in the Indian populationMore than 26% of the normal population are sensitive to one of the common foods, who do not have food allergyMore than 32% of the normal population are sensitive to one of the common aeroallergens, who do not have any clinical symptomsThe actual prevalence of probable food allergy in India is very low both in adults and children in spite of very high sensitization ratesWhat are the protecting factors?Need for the study into these factors.
Progression in disease
Both ARIA guidelines and GINA guidelines are useful for the beginner to understand the nuances of management of allergic rhinitis and asthma, respectively. However, there are significant lacunae that need to be addressed urgently. It is possible that there are limited or no studies at all to deal with some important aspects of management, and there is a need to develop good clinical evidence in these critical areas. One of these is that clinicians need to assess disease progression. Patients progress through these stages at a different pace. For example, one patient with GINA Stage I asthma is still in Stage II even after 10 years, whereas another moves from GINA I to IV in a few years. The second patient needs more careful consideration and more aggressive management than the first patient. The guidelines still are not clear on how to assess disease progression and have made no attempt even to classify them as having progressive disease. How can a clinician identify a patient with progressive disease? Few simple questions will help. Over a period of time (different for different patients) have they observed an increase in any or all of the following?
Frequency of daytime and nighttime symptomsFrequency of attacksSeverity of daytime and nighttime symptomsMedication requirement (annual or monthly; for example, a participant needing medications 3 months in a year now needs it for 6 months in a year and needs twice the dose of medications in the same month as compared to the previous year)Response to medications (for example, a child whose asthma attack would resolve with one nebulizer and then be free for a few months would now be symptomatic even after 3 days of twice a day nebulizationInvolvement of additional organ systems (for example, onset of asthma in a patient who had only allergic rhinitis).
An increase in any or all of these could be defined as progressive disease, and the rate of the progression varies from person to person and patients with more rapidly progressive disease would need more aggressive management. We observed from our database of more than 14,000 asthmatics that 75% of patients with allergic disease had progressive disease.
The other important aspect of the management of patients with allergic disease is treatment responsiveness. Again most of the guidelines do not deal with or define treatment responsiveness, except the National Asthma Education and Prevention Program. They have defined it as the ease at which control is achieved. It is a good definition although we need to establish standardized and validated measures to assess this “ease to achieve control.” It is common for clinicians to see patients who have mild disease according to the GINA category but do not respond to treatment very well in spite of months of treatment and do not achieve control as defined by GINA (poorly treatment responsive), whereas a patient with a FEV1 of 20% may reach normal levels within a week of treatment and achieve good control (highly treatment responsive). These phenotypes have not been studied in most of the studies on asthma, and it remains to be seen as the guidelines develop whether these can be assessed and applied in regular clinical practice with different set of treatment guidelines for poorly, moderately, and highly treatment-responsive patients. It would be very useful to have a biomarker that could help to differentiate these patients before the start of the treatment. Cluster analysis can help to further define these populations for the future studies.
Evaluating new local pollens
It is common for clinicians to find the tests for sensitization (SPT, serum-specific IgE) to be negative in spite of a strong clinical history suggestive of atopy. One of the reasons other than testing with poor quality extracts, poor technique is the absence of a locally relevant allergen panel. We need to collaborate with the local aerobiologists and botanists to identify the local flora and test whether there are any that are not present in your testing panel. In one of our aerobiology studies, we found Dolichandrone platycalyx pollens in the slide. It is a common tree in most parts of the world and is an entomophilous pollen that is quite large (40–45 μ), a moderate pollen producer (66,000 pollens/flower) and is usually not dispersed easily in the air. Since it is a common tree and pollen fragmentation could cause the dispersion of allergenic fragments, we tested more than 300 participants with allergy and 30 controls. We observed that it was the fourth most common sensitizer and this warrants studies of pollens that were not considered allergenic so far due to their entomophilous nature.
Need for establishing aerobiology centers across the country in different environmentsNeed to have regular pollen calendars with reporting every weekNeed to relook at newer plants/trees that have not been tested so far and when causing sensitization, need to characterize their allergensICAAI should take the lead and establish a credible team and distribute the workload among scientists and the group should jointly apply for funding.
Prevention of asthma – Identifying the risk factors
One of the most exciting and rewarding aspects of management of allergies is the possibility of preventing asthma in susceptible participants. One of the most important risk factors for developing asthma is allergic rhinitis. Many previous studies have shown that suffering from allergic rhinitis, is one of the strongest risk factors to develop asthma. Studies have also confirmed that one of the important tools for the prevention of asthma in patients with allergic rhinitis is immunotherapy, which takes time to have its effect. Therefore, we wanted to find how much time elapses before a patient with allergic rhinitis develops asthma and what could be the risk factors. It was disappointing to note that 80% of participants younger than 20 years of age and 62% of participants older than 2 years developed asthma within 2 years after the onset of the first symptoms of allergic rhinitis. It is quite rare in most parts of the world for participants with allergic rhinitis who are initially managed by their family physicians, pediatricians, and ENT specialists most of whom are not aware of the potential of immunotherapy to even refer these participants to the allergy specialist in time to be able to prevent asthma. The key risk factor for participants with allergic rhinitis to develop asthma was sensitization to house dust mites, and using nasal steroids “ever” was found to be protective against the development of asthma possibly by its beneficial effect on reducing allergic inflammation in the nose.
Need for a validated and a more robust risk prediction scores that identify which of the patients with allergic rhinitis will develop asthmaNeed to start applying evidence from meta-analysis on the prevention of asthma into clinical practiceAllergy and asthma specialists in India need to spread awareness among the community as well as medical fraternity.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
|1||Sanjana JM, Mahesh PA, Jayaraj BS, Lokesh KS. Changing trends in the prevalence of asthma and allergic rhinitis in children in Mysore, South India. Eur Respir J 2014;44 Suppl 58:1187.|
|2||Coton S, Vollmer WM, Bateman E, Marks GB, Tan W, Mejza F, et al. Severity of airflow obstruction in chronic obstructive pulmonary disease (COPD): Proposal for a new classification. COPD 2017;14:469-75.|
|3||Vedanthan PK, Mahesh PA, Vedanthan R, Holla AD, Liu AH. Effect of animal contact and microbial exposures on the prevalence of atopy and asthma in urban vs. rural children in India. Ann Allergy Asthma Immunol 2006;96:571-8.|
|4||Wong GW, Mahesh PA, Ogorodova L, Leung TF, Fedorova O, Holla AD, et al. The euroPrevall-INCO surveys on the prevalence of food allergies in children from China, India and Russia: The study methodology. Allergy 2010;65:385-90.|
|5||Mahesh PA, Wong GW, Ogorodova L, Potts J, Leung TF, Fedorova O, et al. Prevalence of food sensitization and probable food allergy among adults in India: The EuroPrevall INCO study. Allergy 2016;71:1010-9.|
|6||Maslowski KM, Mackay CR. Diet, gut microbiota and immune responses. Nat Immunol 2011;12:5-9.|
|7||Naik SP, Mahesh PA, Jayaraj BS, Madhunapantula SV, Jahromi SR, Yadav MK, et al. Evaluation of inflammatory markers interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9) in asthma. J Asthma 2017;54:584-93.|
|8||Raeiszadeh Jahromi S, Mahesh PA, Jayaraj BS, Madhunapantula SR, Holla AD, Vishweswaraiah S, et al. Serum levels of IL-10, IL-17F and IL-33 in patients with asthma: A case-control study. J Asthma 2014;51:1004-13.|
|9||Davoodi P, Mahesh PA, Holla AD, Vijayakumar GS, Jayaraj BS, Chandrashekara S, et al. Serum levels of interleukin-13 and interferon-gamma from adult patients with asthma in Mysore. Cytokine 2012;60:431-7.|
|10||Mahdi B, Mahesh PA, Mysore RS, Kumar P, Jayaraj BS, Ramachandra NB, et al. Inheritance patterns, consanguinity & risk for asthma. Indian J Med Res 2010;132:48-55.|
|11||Vishweswaraiah S, Thimraj TA, George L, Krishnarao CS, Lokesh KS, Siddaiah JB, et al. Putative systemic biomarkers of biomass smoke-induced chronic obstructive pulmonary disease among women in a rural South Indian population. Dis Markers 2018;2018:4949175.|
|12||Mahesh PA, Vedanthan PK, Holla AD, Jayaraj BS, Prabhakar AK. Time interval and the factors associated with the development of asthma in patients with allergic rhinitis. Lung 2009;187:393-400.|
|13||Mridula PA, Mahesh PA, Abraham JN, Amrutha DH, Agashe SN, Sitesh R, et al. Dolichandrone platycalyx: New entomophilous pollen – A report on pollen sensitization in allergic individuals. Am J Rhinol Allergy 2011;25:e34-8.|