Introduction

Allergic diseases are developing as one of the major health issues in India (Singh and Kumar 2002, 2003). Approximately 25% of the Indian population is sensitized with diverse forms of allergen sources such as pollen grains, fungal spores, foods, insects and house dust mites (HDMs) (Singh and Shahi 2008; Dey et al. 2014, 2016, 2018a; Bhattacharya et al. 2018). HDMs are globally ubiquitous in human habitats and act as one of the most important source of indoor allergens (Sporik and Platts-Mills 1992; Wong et al. 2011; Dutta et al. 2017). Contact to HDM allergens may be increasing due to spending more time in the indoor environment of air conditioned home that led to reduced ventilation. Foam mattresses and carpets provide ideal habitat for the dust mites (Squillace et al. 1997; Ring 1997; Downs et al. 2001). Mite allergens can provoke symptoms by direct external contact (conjunctivitis, eczema), inhalation (rhinitis, asthma, eczema) and ingestion (urticaria, anaphylaxis) in a sensitized person (Mondal et al. 2018; Ghosh et al. 2018). Among the HDMs, members of the family Pyroglyphidae are established as the potential source of allergens that play a significant role in various allergic disorders including bronchial asthma (Podder et al. 2010). Dermatophagoides pteronyssinus (Dp) and Dermatophagoides farinae (Df) are the two pyrogliphid HDM species mostly linked to allergic diseases. Like other aeroallergens, the rate of sensitization toward HDMs varies significantly between countries, regions and even individual test centres (Calderón et al. 2015). According to a study by The Global Asthma and Allergy European Network (GA2 LEN) Dp and Df sensitisation rates were 31.3 and 28.9%, respectively, across 14 European countries (Heinzerling et al. 2009). Sensitization rates to HDM were the highest in Nordic and Mediterranean countries; specifically, sensitization to both Dp (Der p) and Df (Der f) was most prominent in Portugal (Der p: 68.8%; Der f: 68.0%) and Denmark (Der p: 51.5%; Der f: 51.8%) (Heinzerling et al. 2009). Allergy skin tests administered in the second and third National Health and Nutrition Examination Surveys (NHANES II and III) conducted in USA revealed 27.5% sensitization rate for dust mite (Arbes et al. 2005). In Latin American countries, sensitization to Dp varied from 60.7% in Cartagena (Colombia) to 91.2% in Sao Paulo (Brazil); to Df from 53.3% in Córdoba (Argentina) to 97.2% in Caracas (Venezuela); to Blomia tropicalis (Bt) from 46.5% in Mexico City (Mexico) to 93.7% in Sao Paulo (Fernández-Caldas et al. 1993). From Africa, 48 and < 60% HDM sensitivity are reported for Nigeria and Ghana, respectively, and Dp is the major reported allergen (Tham et al. 2016; Addo-Yobo et al. 2001). HDM sensitisation in childhood has also been reported from Australia and New Zealand (Sears et al. 1993; Peat et al. 1996). The overall burden of dust mite sensitization in Asia is much higher than that seen in USA and Europe, even in areas of similar climate and/or urbanization, which raises the question as to whether other factors such as genetics may play a role (Tham et al. 2016). From the Asian countries, dominance of Dp from Hong Kong (Leung et al. 2002), Malaysia (Yadav and Naidu 2015); Dp and Df from Korea (Kim et al. 2010) and Japan (Shirai et al. 2012) are mentioned to show significant sensitization rates. Dp, Df and Bt sensitization are reported from China (Zhang et al. 2012), Singapore (Kidon et al. 2005; Andiappan et al. 2014), Philippines (Albano and Ramos 2011), Taiwan (Wan et al. 2010), Vietnam (Lam et al. 2014), Pakistan (Shafique et al. 2018) and India (Tandon et al. 1988; Saha et al. 1989; Podder et al. 2006, 2010; Mondal et al. 2018).

Dust mites are cosmopolitan in distribution throughout India and HDMs are reported to be the dominant allergens to cause nasobronchial allergies (Podder et al. 2009; Ghosh et al. 2018). Ample report on the present situation of HDM allergy is not yet abundant in the Indian context. A complete scenario from the impact of HDM allergy in the Indian population to the diagnosis and therapy of the patients would be beneficial for the future of allergy treatment. This review discusses the prevalence, risk factors, possible therapeutic aspects and perspectives for therapy in India through an extensive survey of HDM allergy-related published literature. The schematic workflow followed for this review is presented through Fig. 1.

Fig. 1
figure 1

Schematic workflow followed in this review article. HDM house dust mite, Dp Dermatophagoides pteronyssinus, Df Dermatophagoides farinae, Bt Blomia tropicalis, IgE immunoglobulin E, SPT skin prick test

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Reports on the diversity of the domestic mites in India

Mite concentration and diversity present in the dust samples of patients’ houses are found to vary in different indoor environments (Sharma et al. 2011; Gill and Kaur 2014; Chaudhury et al. 2005). The possible reason for this could be the difference in the structure and materials of the buildings, socioeconomic status of the individuals, type of mattresses used, hygiene standard, and difference in the microclimatic conditions that contributes to the higher accumulation of mites in the house dust (Modak et al. 1991, 2004). In a survey of homes with dust mites, 60% of the dust mite population is reported from the bed, mattresses and pillows, 30% in upholstery and 10% in carpet (Sharma et al. 2011).

Previous studies suggested that the number of allergenic mites in the bed and floor dust of the patients is well correlated with intensity of the skin test reactions (Spieksma and Spieksma-Boezeman 1967). Allergen load of mites in the dust samples were found directly proportional to the severity of allergic attack in some of the typical cases. From India, Dp and Df were found to dominate in the house dust collected from patient homes (Mondal et al. 2018) and these two mites possess significant skin test reactions in the sensitized persons (Mondal et al. 2018).

India tops the list of the highest recorded HDM diversity with 12 species (Colloff 2009). Shivpuri and co-workers were the first Indian acarologists to conduct extensive and intensive studies on mites and recorded that mites could grow well in house dust at 25 °C temperature and 80% relative humidity (Shivpuri 1962, 1977; Shivpuri and Dua 1974). Since then several authors from different parts of the country reported the dominance of Dp over Df (Dixit and Mehta 1973; Nayar et al. 1974; Krishna Rao et al. 1981; Maurya et al. 1983). In contrast, Sharma et al. (2011) and Maurya and Jamil (1980) reported the predominance of Df from other parts of the country. Other domestic mites namely Bt, Acarus siro (AS), Lepidoglyphus destructor (LD), and Tyrophagus putrescentiae (TP) have been reported from different parts of India (Mondal et al. 2018). Table 1 portrays the distribution of the domestic mites from India having skin sensitization potential.

Table 1 Distribution of domestic mites in Indian cities based on published reports until 2019 [Adopted from Colloff 2009, with minor modifications and a few extensions]
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Prevalence of HDM sensitisation in India through skin prick test (SPT)

Skin prick testing is the standard for diagnosing immunoglobulin E (IgE)-mediated allergies. However, different allergen extracts and different testing procedures have been applied by different allergy centres. Thus, it has been difficult to compare results from different centres or studies across the country. It was, therefore, crucial to standardize and harmonize procedures in allergy diagnosis and treatment within India.

A multifaceted pattern of HDM sensitization was seen in various parts of India. Figure 2 represents the states and major cities of India where positive HDM sensitization is reported and details of the publications are depicted in Table 2.

Fig. 2
figure 2

Map of India indicating the regions of reported house dust mite sensitization

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Table 2 Significant publications related to house dust mite (HDM) allergy from various cities of India
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HDM prevalence study was done in Delhi and Allahabad during 2008–2011. SPT was performed on a total of 918 patients [548 (59.7%) males and 370 (40.3%) females] for 58 types of aeroallergens. HDM sensitivity was found in 12.4% of patients (Kumar et al. 2012). Another 8 year retrospective study (2008–2016) was carried out among 4835 patients from Delhi (Kumar et al. 2017). SPT was performed on 4263 patients consisting of 2361 (55.4%) males and 1902 (44.6%) females and this revealed 12.0% to be affected with HDM. Another aeroallergen sensitization study of childhood asthmatics was done in Allahabad city (Raj et al. 2013). 180 children above 5 years of age exhibited 7.8% sensitivity to HDM allergens. A group of 60 patients with united airway disease (UAD) from Allahabad was tested with 60 different allergens with SPT during August 2010 to July 2011 (Mishra et al. 2016); 60% was found to be SPT positive with Df extracts.

In 2011, a HDM sensitization study depicted 52.5 and 46.0% SPT reactivity for Dp and Df, respectively. This study was performed on 139 BA patients in the Bangalore region. Another Bangalore-based study (2014) involving 486 AR patients revealed HDM as the most common allergen, with positive results in 44.7% of cases (Gowda et al. 2014). From Andhra Pradesh, 73.7% HDM sensitivity was reported among 331 nasobronchial allergic patients (Lal et al. 2011). In 2012–2013, a hospital-based study was done in Central Kerala consisting of 139 patients from five districts, namely Alappuzha, Idukki, Ernakulam, Kottayam and Thrissur (Kunoor et al. 2017); 23% HDM sensitivity was reported among asthma and AR patients. In the city of Mumbai, a SPT-based investigation was performed to identify HDM sensitivity in children with allergic rhinitis, allergic wheezing and eczema. In total 92 children underwent an SPT; 49 (53.2%) showed significant positivity to one or more dust mite (Doshi and Tripathi 2016). This study revealed Dp, Df and Bt to be the most sensitised aeroallergen eliciting 65.3, 46.9 and 12.2% SPT in children, respectively.

Aeroallergen sensitivity was studied in 1050 AR patients from Udaipur during 2002–2016, and 44.2% was reported to be Df-sensitive through intradermal allergy testing (Matta et al. 2017). West Bengal, especially the city of Kolkata, is one of the most explored areas of India with respect to aeroallergen sensitization. Saha et al. (1989) probably started the evaluation of HDM sensitization in Kolkata population using SPT. Among 188 asthmatic patients, 82% reacted to Dermatophagoides mites, 80% to Df, 46% to Dp, and 43% to both species of mites. Another RAST (radioallergosorbent test)-based study reported 73 and 90% sensitivity toward Dp and Df, respectively, among urban and rural asthmatics of West Bengal (Saha 1993). In 2010, a Kolkata-based study reported Dp (75.1%), Df (63.7%) and Bt (72%) sensitivity, and Bt was reported first time from Kolkata (Podder et al. 2010).

A recent retrospective study from June 2016 to May 2018 revealed 80.3 and 84.9% sensitivity for Dp and Df, respectively, from West Bengal (Dey et al. 2018b). Three new storage mites, namely Acarus siro (AS), Lepidoglyphus destructor (LD), and Tyrophagus putrescentiae (TP), were described for the first time in Kolkata (Mondal et al. 2018). These three mites caused 33.0, 25.2 and 18.8% sensitization in Kolkata population, respectively. The same population were also sensitised for Dp, Df and Bt with sensitization rate of 81.2, 87.9 and 74.2%, respectively. A Bhopal-based study reported 74.2% sensitization for Df among 89 patients with UAD investigated during April 2013 to March 2014, with 120 different allergen extracts (Dave and Srivastava 2014). Nagpur revealed 56.6% Dp sensitization among 143 patients of AR and BA (Arbat et al. 2016). Apart from Dp and Df (49%), Blomia sp. (50.4%) showed significant SPT among the patients. Although most of the patients are from Nagpur and adjacent districts of Maharashtra, 46% were from Madhya Pradesh. Another multicentre study was undertaken to evaluate the allergen patterns in patients with severe persistent allergic rhinitis from Central India. The study group comprised 810 persons (male and female) of the age group between 6 to 63 years. Df showed 18% sensitivity (Jain and Gupta 2018).

Human genetic predisposition of HDM sensitization—recent advances in India

The impact of genetic predisposition in the allergic diseases has become an inevitable question since the same level of exposure to different individuals led to different grades of hypersensitivity or no hypersensitivity at all. Thus the susceptibility to allergies, including dust mite, substantially varies from individual to individual and genome analysis is required to answer the causes to some extent. Next generation sequencing (NGS) has taken our understanding of human genetics to the next level. Single nucleotide polymorphisms (SNPs) analyses have facilitated the selection of novel and interesting candidate genes. Extensive analysis in this regard has suggested genetic heterogeneity triggering allergic phenotypes. Genes opposing and favouring the risk of developing allergies are inherited according to the Mendelian inheritance pattern and environmental triggers interplay a pivotal role in the gene expression (Patel and Meher 2016). Genes coding for cytokines, major histocompatibility complex (MHC) IgE, stem cell factors and insulin growth factors are reported for allergic manifestations. Gene polymorphisms of the beta-adrenergic receptor, 5-lipoxygenase has also been associated to allergy risks (Borish 1999).

Apart from the identification of offending allergens, early detection of genetically predisposed individuals is also crucial for better management of the disease. Some candidate genes have been identified through genome-wide searches for candidate loci regulating atopic responses. Among these, CD14 is the most important gene reported regarding the HDM allergic responses (Vercelli et al. 2001). Tan et al. (2006) also reported the association of genetic polymorphism of CD14 gene with disease development and severity in a HDM-sensitive Chinese paediatric population. Similar study on CD14 in an Indian population revealed a significant difference in the distribution of alleles and genotypes for CD14 polymorphism with an increase in disease severity (Ghosh et al. 2018).

Potential therapeutic strategies proposed in India for HDM sensitised patients

Allergen immunotherapy (AIT) refers to an immunomodulatory method for the treatment of IgE-mediated allergic diseases. Sequentially increasing dose of antigen(s) is implied to induce a shift of the immunological response from TH2 to TH1 that is expected to decrease the sensitivity toward the offending allergens (Moingeon and Mascarell 2012). Guidelines for AIT are already available in Western countries, but a separate guideline for India is also necessitated due to a multitude of factors. AIT is believed to be a better replacement to pharmacotherapy as AIT assures long-term effect by halting the progression of allergen-induced pathology (Patel and Meher 2016). In India, immunotherapy (IT) guidelines were published by Gaur et al. (2009). These guidelines were prepared following the expert suggestions from the Indian College of Allergy, Asthma and Applied Immunology (ICAAI) along with an extensive literature study. Most of the clinical trials displayed significant improvement in allergic asthma and rhinitis or rhino-conjunctivitis patients post IT (1–5 years) compared to the baseline or placebo. However, it was strongly suggested that IT should be practiced by professional clinicians. The purpose of implementing these guidelines was to sustain a consistency in the methods of diagnosis and management, i.e., immunotherapy throughout the country. These guidelines are based on available guidelines with few alterations keeping in mind the multitude of factors in India. In 2017 update by the ICAAI prepared another revised guideline to review the recent data, updating the guidelines published in 2009 (Gaur et al. 2017). This recent guideline has recommended HDM-sensitised atopic dermatitis (AD) patients to be appropriate candidates for AIT.

Successful immunotherapy in India for HDM sensitised patients

A retrospective analysis of a prospective symptom review in patients receiving AIT has been conducted in India to determine the type, number, concentration, and combination of allergens on the efficacy of AIT. AIT involving a mixture of 5–8 allergens and HDM were administered separately to the patients. Only 42% of the patients showed improvement whereas 58% had no improvement or worsening of their symptoms. It was further analysed that the 58% of patients who did not benefit from AIT, received allergens in incorrect combination. The compatibility of allergens was determined by the protease activity of the individual allergens. High protease-containing enzymes included dust mites, fungal, and insect allergens. These results clearly highlight the impact of the nature of allergens and their combination to be used in IT (Susmita et al. 2007).

Another study proved the efficacy of HDM immunotherapy over a 15-year period in a group of 31 patients (with perennial BA, >+2 SPT and for Df extract) from the Bombay (presently Mumbai) region of India. A patient group was administered immunotherapy for continuous 5 years and then followed-up for a further 10 years. Significant improvement was noted when the global symptom scores and FEV1 values were compared with another group of 38 patients that refused immunotherapy. This improvement was sustained for at least 10 years after termination of immunotherapy (Shaikh 2005).

Possible perspectives of therapy

Recent advances in the field of molecular allergology have contributed tremendous advancement in the field of allergen biology. Considering the steady inclination in the rate of asthma and other allergic diseases, India should now focus on designing tools and strategies for the improvement of the evaluation and management of allergy. For example, Bt sensitization rate in Mumbai city was found to be 15% when measured with the use of Blo t 5 (Lim et al. 2002).

Recent progress regarding allergy treatment strongly suggests the practice of personalised immunotherapies where ‘precision medicine’ will be used according to the disease phenotype of the individual patient (Passalacqua and Canonica 2016; Ferrando et al. 2017). Thus, personalized therapy is a novel approach that launches a customized model for individual patient. The evolution of therapy from the previously used ‘mass targeted treatment’ to the ‘personalised therapy’ in the future is represented through Fig. 3.

Fig. 3
figure 3

Evolution of therapy: past and expected future (Adopted from Ferrando et al. (2017), with minor modifications)

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Conclusions

The causative agents of allergy in tropical countries like India significantly differ from the complex etiology noticed in temperate countries. Although the prevalence of allergic airway diseases is substantially higher, their mono-specific cause also offers a unique opportunity to study, treat, and manage the allergic phenotypes by specifically targeting HDM allergens (Andiappan et al. 2014).

In India, HDM play a major role in the pathogenesis of allergic rhinitis and asthma. With its stable year-round tropical climate, India typically does not experience wide fluctuations in environmental or indoor allergens, so that dust mites and thus allergic disease phenotypes tend to be perennial rather than seasonal. The prevention of HDM needs to be done in order to lessen the socioeconomic and healthcare burden of allergic diseases. Immunotherapy is the only option to combat HDM allergic consequences. Accurate characterization of novel allergens is an important aspect regarding this. It refers to a multistep discovery approach consisting of identification, purification, and molecular characterization of individual allergen molecules from a particular source. As compared to the tremendous development in the field of molecular allergology worldwide, there have been only a few reports on the molecular characterization of allergens prevalent on the Indian subcontinent (Bhattacharya et al. 2018). Dp and Df being the major culprits for HDM sensitization worldwide have been extensively studied at the molecular level for the identification of allergens (Radauer et al. 2014). Numerous HDM allergens are reported from various parts of the world. However, there has not been any report on the molecular and structural nature of dust mite allergens from India. As a consequence, allergologists in India are still relying upon the less characterized and less standardized allergen extracts. Molecular studies with reference to the cross-reactivity of HDM allergens are to be performed in India for the proper diagnosis and treatment of allergies toward HDM.