Abstract
A 14-year-old neutered male Persian cat was evaluated because of an acute exacerbation of a chronic cough of 2–3 years of duration. Physical examination was normal except for the auscultation of accentuated breath sounds and wheezes cranially on both sides of the chest. Complete blood count, biochemical parameters and urinalysis were normal. Thoracic radiographs showed a generalised nodular pattern with multiple mineral opacities. Oral prednisone and doxycycline were prescribed. Two weeks later, the frequency of the cough was significantly reduced. Terbutaline was recommended for relief of acute exacerbations. Three years later the cat was evaluated again due to a non-related disease that led to the euthanasia of the cat. Concerning its respiratory disease, the cat had experienced nearly asymptomatic periods of 3–6 weeks of duration punctuated by acute exacerbation periods of 7–10 days, during which terbutaline was useful to relieve the cough. Thoracic radiographs showed a mild increase in the size and extent of the pulmonary mineralisation. Histopathologically, mild bronchitis and bronchiectasis were evident, accompanied by calcified bronchial plugs and marked hyperplasia and hypertrophy of the seromucinous glands. Based on clinical and pathoanatomical findings, a final diagnosis of miliary broncholithiasis and bronchiectasis was made. Broncholithiasis should be considered in differential diagnosis of pulmonary mineralisation in cats. When no concomitant diseases are present, this rare disease appears to have a slowly progressive evolution that does not appear to carry a bad prognosis and may be satisfactorily managed with combinations of bronchodilators and corticosteroids.
A 14-year-old neutered male Persian cat (5.0 kg) was presented to the Cardiorespiratory Service of the Veterinary Teaching Hospital of the University of Murcia with an exacerbation of a 2–3-year history of a chronic cough. Symptomatology consisted of non-productive daily coughing (1–2 times/day) with episodic exacerbations 2–3 times/year. The cat was kept exclusively indoors, in a flat in an urban environment. Annual polyvalent vaccination (Fel-O-Vax Lv-K IV, Fort Dodge Animal Health) and internal deparasitation status were current. Before presentation, the respiratory problem had not received any clinical investigation or specific treatment. Except during the most serious coughing paroxysms, the owner had not observed respiratory distress or exercise intolerance.
On physical examination, the cat showed good nutritional condition (body condition score, 3/5) and appeared alert and playful. The mucous membranes were normal and the capillary refill time was less than 2 s. Respiratory pattern was normal, with a respiratory rate of 45 breaths/min. Gentle laryngeal and tracheal palpation were well tolerated without signs of discomfort. After strong tracheal palpation/compression, a series of 4–6 profound non-productive coughs were elicited. Thoracic auscultation revealed accentuated breath sounds in all lung fields and inspiratory and expiratory wheezes in the cranial regions of both hemithorax. Cardiac auscultation was normal, with a heart rate of 160 beats/min.
Results of complete blood count, biochemical parameters and urinalysis were within normal limits (Table 1). Thoracic radiographs showed a generalised nodular pattern characterised by the presence of multiple (1–10 mm) mineral opacities (Fig 1). Moreover, bronchial wall thickening was also evident. At this point, differential diagnosis included broncholithiasis, pulmonary alveolar microlithiasis, chronic pneumonia, chronic bronchitis/asthma and bronchopulmonary neoplasia with calcification. Bronchoscopy, bronchoalveolar lavage, pulmonary biopsy and high resolution computed tomography were suggested as useful ancillary tests, but the owner declined these investigations. A treatment trial consisting of oral prednisone (1 mg/kg/bid for 2 weeks) and doxycycline (5 mg/kg q24 h for 2 weeks) was proposed. Two weeks later, the frequency of the cough was significantly reduced. Doxycycline was withdrawn and the dose of prednisone was slow tapered (1 mg/kg/48 h) and withdrawn 2 weeks later. Intermittent administration of terbutaline (0.625 mgbid) was recommended for acute relief of acute exacerbations of the cough.
Complete blood count and serum biochemical parameters in a 14-year-old (5 kg) neutered male Persian cat at first presentation (day 0) and 3 years later
Lateral (A) and dorsoventral (B) thoracic radiographic views of a 14-year-old (5 kg) neutered male Persian cat with broncholithiasis, showing the presence of multiple mineral opacities distributed diffusely throughout all lung fields.
Three years later, the cat was presented again because of a large mass on its back. Concerning respiratory disease, the owner indicated that the cat had alternated between nearly asymptomatic periods of 3–6 weeks with exacerbation periods of 7–10 days with increasing frequency and intensity of the cough. During exacerbations, the owner believed terbutaline was useful at relieving the cough. On physical examination, the cat appeared lethargic and depressed. Cardiovascular and respiratory parameters were within normal limits. A solid, round mass (11 cm diameter) was present on the back caudally to the interscapular area. Cytological examination obtained by fine needle aspiration was consistent with neoplasia. Blood count, biochemical parameters and urinalysis were unremarkable (Table 1). In thoracic radiographs, the mass appeared between T8 and L4 vertebral bodies without signs of bone involvement (Fig 2). Lung fields appeared unchanged compared to 3 years ago, but with more extensive pulmonary mineralisation (Fig 2). Surgical excision of the mass was recommended. The cat was, however, euthanased a week later, at the owner's request.
Lateral (A) and dorsoventral (B) thoracic radiographic views 3 years after initial presentation. A round mass extending between T8 and L4 vertebral bodies can be seen. Lung fields' appearance is similar to 3 years ago, with a mild intensification and mild increased extension of pulmonary mineralisation.
On post-mortem examination, the mass appeared white, hard and well delineated, extending to subcutaneous tissue. In the lungs, multiple, yellowish, hard nodules (1–10 mm) were distributed throughout the lung parenchyma. No lesions were seen in any of the other organs examined. Samples of the mass and lungs were obtained, fixed in 10% buffered formalin and embedded in paraffin wax at 56°C. Haematoxylin–eosin staining was used for initial histopathological analysis. Later, Gram and Grocott stains were carried out to investigate the presence of bacteria or fungi, respectively, in the bronchial secretions and broncholiths. In order to test bacterial colonisation in the lesions, a broad range polymerase chain reaction (PCR) technique was carried out on the paraffin embedding samples. Primer design was based on the highly conserved regions of the eubacterial 16S rRNA gene that has been used previously in veterinary medicine (Pille et al 2007). The technique was performed following the method described by (Ortega et al 2007). A previously diagnosed salmonella abortion in an ewe served as positive control. Characterisation of the lymphoid infiltration in the lung was carried out using polyclonal antibodies against CD3 (T cells) and CD79 (B cells) antigens (Dako Corp, California, USA). An avidin–biotin-peroxidase complex (ABC) method was used and positive reaction was demonstrated by the precipitation of diaminobenzidine tetrahydrochloride.
Histopathological study of the mass led to a diagnosis of a grade I fibrosarcoma. With regard to the lung samples, both bronchi and bronchioli displayed marked dilation (bronchiectasis), coexisting with intraluminal plugs of eosinophilic material containing cell debris and multiple aggregations of calcified concretions forming broncholiths (Fig 3). Gram and Grocott stains failed to identify the presence of bacteria or fungi in the broncholiths. The negative results of the PCR analysis with universal bacterial primers dismissed the presence of bacteria in the bronchial lesions at the time of the death. The epithelium of ectatic bronchi displayed areas of atrophy, small areas of necrosis, and marked hyperplasia of globet cells (Fig 4). Hyperplasia and hypertrophy of the bronchial glands were consistent findings, with expanded lumen containing an eosinophilic material that was secreted and accumulated to the ectatic airways (Fig 5). Mild to moderate lymphoid infiltration was observed in the lamina propria of the ectatic bronchi, mainly composed of T cells and a scarce number of B cells among them. Occasionally, small aggregates of neutrophils were observed in the wall of the airways. Findings of atelectasia in the alveoli surrounding ectatic airways alternating with areas of emphysema were also present (Fig 3). Based on clinical and pathoanatomical findings, a final diagnosis of miliary broncholithiasis and bronchiectasis was made.
Panoramic view of an ectatic airway with a large bronchiolith (BL) within the lumen. The bronchial wall (BW) shows a marked hyperplasia of the glands. Surrounding areas of lung parenchyma show atelectasis (AT) and compensatory emphysema (EN). Haematoxylin and eosin ×5. Bar=500 μm.
Detail of the bronchial wall (BW) and a bronchiolith (BL) in the bronchial lumen. Note the marked hyperplasia of the glands in the bronchial wall and the histological structure of the bronchiolith, with the presence of cell debris, an eosinophilic material from glandular secretion (*) and multiple small basophilic crystals of calcium (arrows). There is atrophy of the epithelium in the area of contact between the bronchial wall and the bronchiolith. Haematoxylin and eosin ×20. Bar=50 μm.
Detail of the wall of an ectatic airway showing hyperplasia (*) and dilation (#) of the bronchial glands containing eosinophilic material. Peribronchial fibrosis (PF) and images of atelectasis (AT) are also present. Haematoxylin and eosin ×20. Bar=50 μm. BLU=bronchial lumen.
Broncholithiasis is defined as a pathological condition in which calcified or ossified material is present within the bronchial lumen (Olson et al 1999, Seo et al 2002). In humans, the most common cause of broncholithiasis is erosion by and extrusion of a calcified adjacent lymph node into the bronchial lumen, a finding usually associated with tuberculosis or histoplasmosis (Seo et al 2002). Other causes include aspiration of foreign material, in situ calcification, erosion and extrusion of calcified bronchial cartilage plates and migration of stones via nephrobronchial or tracheobronchial fistula (Olson et al 1999, Craig et al 2002, Seo et al 2002). The most common symptoms of broncholithiasis in humans are non-productive cough frequently associated with haemoptysis and, less commonly, lithoptysis (expectoration of calcified material). The most common radiographic findings include the presence of a calcified nodule and signs of airway obstruction (bronchiectasis, air trapping) (Seo et al 2002). In the author's knowledge, only a single clinical case describing miliary broncholithiasis in a cat has been reported (Allan and Howlett 1973). In that case, broncholithiasis was postulated to be associated with a chronic intrapulmonary infection, although a specific agent was not isolated and signs of terminal congestive heart failure were also found at necropsy. The cat had a 2-year history of progressive fatigue associated with moderate to severe dyspnoea on exertion and the progressive worsening of the condition resulting ultimately in euthanasia. Radiographic findings consisted of multiple miliary opaque masses throughout the entire lung field and evidence of fluid in the ventral third of the thorax. Histological examination of the lungs showed marked bronchiectasis, prominent fibrosis of the bronchial walls, calcified bronchiolar plugs and marked hyperplasia and hypertrophy of the seromucinous glands of the ectatic airways. In the present clinical case, respiratory signs were mild and showed a benign long time evolution. In fact, the cat was euthanased at 17 years of age because of a non-related disease. The respiratory disease was relatively stable over a 6-year period and did not significantly affect the cat's quality of life. No signs of cardiac failure or other cardiopulmonary disease were found. Radiographic findings were consistent with miliary broncholithiasis. Histopathologically, mild inflammation was found. In contrast, the most constant findings were bronchiectasis, the presence of calcified bronchial plugs and marked hyperplasia and hypertrophy of the seromucinous glands.
Pathological soft tissue mineralisation is considered to occur through three basic mechanisms: dystrophic, metastatic and idiopathic (Chan et al 2002, Berry and Tyson 2004). In dystrophic mineralisation, deposition of calcium salts occurs in previously injured, degenerating, or necrotic soft tissues with normal plasma levels of calcium and phosphorus, and in the absence of derangements of calcium metabolism (Berry and Tyson 2004). The most common causes of dystrophic mineralisation in small animals are previous inflammation, degeneration, infection or neoplasia (Berry and Tyson 2004). Pulmonary mineralisation in a cat in the last period of a chronic pneumonia caused by Mycobacterium thermoresistible has been reported (Foster et al 1999). Metastatic mineralisation implies previous abnormalities in plasma calcium and phosphorus concentrations; when plasma calcium and phosphorus product concentrations exceed 70, calcification of normal soft tissue can ensue (Chan et al 2002, Berry and Tyson 2004). Causes of metastatic mineralisation can include primary hyperparathyroidism, vitamin D toxicity, bone tumours (multiple myeloma), and chronic renal failure with hyperphosphataemia (Berry and Tyson 2004). Idiopathic mineralisation designs a type of soft tissue mineralisation in which an underlying pathological cause or abnormalities of serum calcium or phosphorus cannot be determined (Berry and Tyson 2004). Idiopathic mineralisation in the lung occurs in alveolar microlithiasis, a rare disease characterised by intra-alveolar calcium deposits (Brummer et al 1989, Brix et al 1994, Chan et al 2002). Its pathophysiology is not well understood although several theories have been proposed. One of these postulates that an inappropriate immune response leads to the formation of the calculi (Brix et al 1994). Microliths begin as inspissated masses of intrabronchial mucus, which act as nuclei for precipitation, with subsequent accumulation of calcium salts (Brummer et al 1989). Another theory about formation of alveolar microliths suggests that an inborn error of metabolism (enzymatic abnormality) leads to excessive alkalinity and decreased solubility of calcium phosphate within the lumen of alveoli (Brix et al 1994). Pulmonary alveolar microlithiasis has been described in a cat with chronic bronchopneumonia, and microliths' formation was considered secondarily to inspissation and mineralisation of mucinous exudates (Brummer et al 1989).
In the only reported case of feline broncholithiasis, the formation of the broncholiths was attributed to dystrophic mineralisation secondarily to chronic bronchopneumonia and the consequent accumulation of bronchial secretions (Allan and Howlett 1973). However, with the exception of pulmonary alveolar microlithiasis, both dystrophic and metastatic forms of pulmonary mineralisation usually occur in well-perfused tissue (such as pulmonary interstitial or peribronchial tissues). In the present clinical case, mineralisation was only located in bronchial intraluminal plugs. Thus, serum calcium and phosphate levels were within normal range and no features of diseases predisposing to metastatic mineralisation were found.
Bronchiectasis is uncommon in cats, and has been reported mainly in older males secondary to disorders such as neoplasia, chronic bronchitis and asthma (Norris and Samii 2000). In the present clinical case, although the presence of T cells could point to a relationship with chronic bronchitis and asthma (Padrid 2000, Bay and Johnson 2004), other typical findings of asthma, such as eosinophilic infiltrate, airway smooth muscle thickening or contracted bronchioli, were absent. In contrast, the hyperplasia of the bronchial seromucinous glands was a consistent finding, but glandular hyperplasia is an unspecific mucosal strategy in response to external injury. In the present clinical case, the origin of the mucosal plug could be related with an abnormal exacerbated glandular response to a previous bacterial, viral or fungal infection that triggered the process and then becomes self-perpetuating. In that case, bronchiectasis could have been secondary to the chronic presence of broncholiths in the airways.
In human medicine, patients with symptomatic broncholithiasis must be specifically treated to avoid complications such as massive haemoptysis, bronchial fistula, bronchiectasis, and recurrent infections (Olson et al 1999). Therapeutic options include observation, bronchoscopic broncholithectomy, and surgery (Olson et al, 1999, Seo et al 2002). In the only previously reported case of feline broncholithiasis, no therapeutic intervention was detailed by the authors. In the present clinical case, bronchoscopic broncholithectomy or surgery was not considered as a suitable option because of the miliary distribution of the broncholiths. Based on in vivo clinical data available to us, a trial with corticosteroids and doxycycline was considered appropriate in order to treat an underlying inflammation and possible bacterial infections. Considering that airway hyperreactivity and bronchoconstriction could be implicated in the clinical exacerbations, terbutaline was also prescribed. Acute response to corticoids and doxycycline trial was satisfactory. Also, the owner's impression was that terbutaline was useful during exacerbations to reduce the duration, intensity and frequency of the cough.
In conclusion, broncholithiasis should be considered in differential diagnosis of pulmonary mineralisation in cats. When no concomitant diseases are present, this rare disease looks to have a slowly progressive evolution that does not appear to carry a bad prognosis and may be satisfactorily managed with combinations of bronchodilators and corticosteroids. The exact pathogenesis and the meaning of feline broncholithiasis remain to be established and further studies of a possible inciting infectious aetiology are justified.
Footnotes
Acknowledgements
The authors would like to thank Nieves Ortega and Maria C. Gallego from the Department of Animal Health, University of Murcia for perfoming PCR analysis on paraffin-embedded samples.