Contribution to the understanding of the pathogenesis and the therapeutic management of canine idiopathic eosinophilic bronchopneumopathy

Idiopathic eosinophilic bronchopneumopathy (EBP) is a chronic disease characterized by eosinophilic infiltration of the lung and bronchial mucosa in young adult dogs of medium-large breeds such as Siberian Huskies (Corcoran et al. 1991, Clercx et al. 2000, Clercx & Peeters 2007). Definitive diagnosis of idiopathic EBP requires combination of compatible clinical signs, radiographical features, bronchoscopy findings, cytologic evidence of bronchial or bronchoalveolar eosinophilic infiltration, and exclusion of potential other causes of eosinophilic airway inflammation such as cardio-pulmonary parasites. The aetiology of this chronic inflammatory condition is still unclear. An underlying type I hypersensitivity reaction is highly suspected while the inciting antigens remain mostly unidentified (Clercx et al. 2002, Peeters et al. 2005). The treatment usually consists in oral steroid therapy (Clercx & Peeters 2007). Because of potential side effects or contraindicative comorbidities, the use of inhaled steroid therapy (IST) is common in practice (Clercx & Peeters 2007, Casamian-Sorrosal et al. 2020).
As idiopathic EBP is a diagnosis by exclusion, specific investigation of cardio-pulmonary parasites is needed once eosinophilic airway inflammation is demonstrated. Angiostrongylus vasorum is one of the major parasites that are able to cause an eosinophilic airway inflammation. It is important to discriminate between EBP and angiostrongylosis, especially since long-term management and prognosis differ. Over the last 10 years, several studies high-lightened the presence of A. vasorum in all countries of western Europe including neighbouring countries of Belgium (Bourque et al. 2008, Yamakawa et al. 2009, Taubert et al. 2009, Barutzki & Schaper 2009, Van Doorn et al. 2009, Helm et al. 2010, Gredal et al. 2011, Conboy 2011, Gallagher et al. 2012, Traversa et al. 2013). The aims of Study 1 and Study 2 were to investigate a posteriori the possibility of previously undiagnosed angiostrongylosis among a series of coughing and healthy dogs using qPCR on collected and stored broncho-alveolar lavage specimens and to compare the usefulness of qPCR on lavage with non-invasive tests for the diagnosis of angiostrongylosis. Based on results of Study 1, pulmonary angiostrongylosis was negligible in Belgium until 2013 and previous misdiagnosis of idiopathic EBP is unlikely. Study 2 confirmed that qPCR on BALF is the most sensitive technique to definitely rule out angiostrongylosis in dogs with eosinophilic inflammation on BALF, as non-invasive diagnostic tools (faecal analysis and rapid serological device) have imperfect sensitivities.
Precedent clinical studies unsuccessfully investigated some potential infectious triggers of the development of EBP, including non specific bacteria or fungi (Clercx et al. 2000, Clercx et al. 2002, Johnson et al. 2019a). Although human asthma and canine EBP differ because of the lack of bronchial hyper-responsiveness in dogs with EBP, the role of bacterial genera, that are known to be implicated in induction or exacerbation in humans, has never been investigated in dogs with EBP. In human medicine, infections with specific bacteria such as Mycoplasma pneumoniae and Bordetella pertussis have been associated with asthma for decades (Hansbro et al. 2004, Harju et al. 2006, Blanchard & Raherison 2010, Atkinson 2013). Although Mycoplasma cynos was recently identified as an emerging and possibly lethal pathogen in dogs with canine infectious respiratory disease (CIRD) (Rycroft et al. 2007, Zeugswetter et al. 2007, Priesnall et al. 2014), the role of M. canis and M. cynos as primary respiratory pathogens still remains unclear (Chandler & Lappin 2002, Chalker et al. 2004, Chan et al. 2013). On the other hand, Bordetella bronchiseptica (Bb) is recognized as one of the primary causative pathogen agents of CIRD. It can also cause chronic cough without any systemic signs or alveolar foci on radiographs; therefore, chronic infection might remain undiagnosed without the use of sensitive methods such as qPCR on BALF. The diagnostic utility of qPCR was firstly assessed in a clinical series of young dogs with typical Bb infection, in comparison with cytological examination and conventional culture of BALF (Study 3). Based on results of Study 3, qPCR was demonstrated as being the most sensitive method for Bb confirmation as compared to conventional bacterial culture, especially in dogs previously-treated with antibiotics. Secondly, the presence and the bacterial load of M. canis, M. cynos and Bb were evaluated in dogs newly-diagnosed with EBP in comparison with dogs having chronic bronchitis and healthy dogs, using specific qPCR on bronchoalveolar lavage samples (Study 4). Results failed to support a potential role of M. canis and M. cynos in the pathogenesis of EBP. Nevertheless, in EBP dogs, Bb was detected more frequently in dogs with more severe clinical signs and moderate or high loads were only observed in dogs with EBP.
Considering other potential infectious triggers, the investigation of Aspergillus spp. in idiopathic EBP has been limited to fungal culture (Clercx et al. 2002, Johnson et al. 2019a). In humans, sensitization to Aspergillus fumigatus can occur in asthmatics experiencing life-threatening dyspneic episodes (Shah & Panjabi 2016, Page et al. 2015) and the investigation can combine dosage of specific serum immunoglobulins G and E, fungal culture and PCR. Results of qPCR on BALF and specific serum immunoglobulins E were not different between dogs with EBP, dogs with chronic bronchitis and healthy dogs but higher concentrations of serum immunoglobulins G for A. fumigatus at several dilutions were found in dogs with EBP compared to dogs with chronic bronchitis and healthy dogs (Study 5).
Lastly, the well-described treatment of canine EBP consists in long-term oral administration of steroids such as prednisolone (Clercx et al. 2000) and/or IST (Bexfield et al. 2006). Despite a rapid positive clinical response, discontinuation of the oral treatment is frequently followed by clinical recurrence (Corcoran et al. 1991, Clercx et al. 2000, Casamian-Sorrosal et al. 2020). Chronic oral steroid therapy may however lead to iatrogenic hyperadrenocorticism and its use may also be contraindicated wih some comorbidities. So far, despite its regular use in practice in dogs, publications related to long- term clinical response and potential side effects of IST as single therapy in dogs with idiopathic EBP were scarce (Bexfield et al. 2006). Study 6 demonstrated that long-term fluticasone monotherapy fails to control cough in part of dogs with EBP, in which oral treatment is ultimately required. Furthermore, inhibition of the pituitary-adrenal-axis was also confirmed in two dogs treated with IST for 48 months and one of them developed progressive clinical signs of iatrogenic hyperadrenocorticism.