Abstract

This paper outlines the life cycle, clinical presentation and the challenges in the diagnosis and management of spirocercosis - an emerging worldwide epidemic, with a prevalence of up to 80% in some locations. The diagnosis of typical cases is routinely achieved through faecal flotation, thoracic radiology and endoscopy. Neoplastic transformation and atypical spirocercosis is diagnosed with increasing accuracy owing to enhanced familiarity with the wide-ranging clinical presentation of these cases and advances in diagnostic modalities such as computed tomography. Treatment with doramectin at 400 µg/kg q 14 days is effective in the vast majority of non-malignant cases.

Introduction

Spirocerca lupi (S. lupi) is a nematode of worldwide, tropical and subtropical distribution.¹ Dogs are the definitive hosts and become infected by ingesting coprophagous beetles or various paratenic hosts, including birds, lizards and rodents.^1,2 S. lupi larvae-infected coprophagous beetles feed within the faeces, hence dogs probably become infected through coprophagia rather than by catching the beetle.³ After ingestion, the larvae are liberated in the gastric lumen, from where they migrate through the gastric mucosa via the gastric arteries, and reach the caudal thoracic aorta within 10 days. Later they migrate through the thoracic aortic wall to the caudal esophagus within 3–4 months. The S. lupi larvae settle within the oesophageal wall, mature to adults and promote nodule formation.^1,2 These nodules are usually incorrectly referred to as granulomas.¹ The early nodule is actually composed of fibrocytes that transform into actively dividing fibroblasts, immediately adjacent to the worms and their migratory tracts.^2,4 The associated inflammatory reaction within the nodule is characterized by pockets of neutrophils, associated with the necrotic content of the worms' migratory tracts⁴ and lymphoplasmacytic foci in the periphery. Spirocercosis induces some pathognomonic lesions, aortic scarring, dystrophic calcification and aneurysm formation, caudal thoracic vertebral spondylitis and a characteristic caudal oesophageal nodule. The common clinical signs associated with spirocercosis are related to the presence of oesophageal nodules and include regurgitation, vomiting and weight loss, with other nonspecific signs such as pyrexia, dys- and odynophagia, swollen mandibular salivary glands, haemothorax and paralysis.^5,6

Positive faecal flotation shows numerous, characteristic, small (35 × 15 μm), thick-shelled, larvated eggs. The sensitivity of faecal flotation is limited, because eggs are shed intermittently by the female worms and misdiagnoses in atypical cases, where the worm is often no longer present. It is also technically complicated, because the eggs are relatively heavy and require special techniques and solutions with specific gravity above 1.34, such as supersaturated sodium nitrate, 33% zinc sulfate and sugar solution. Recently a PCR assay was developed to detect faecal S. lupi.⁷ Such a test can maximize the sensitivity of faecal analysis but also depends on presence of egg-shedding female worms in a patent oesophageal nodule.

The clinical diagnosis of spirocercosis largely depends on thoracic radiography, demonstrating a caudodorsal mediastinal mass, caudal thoracic vertebral spondylitis and aortic undulation due to aneurysm formation (with or without aortic mineralization).⁵ A caudodorsal mediastinal mass on its own is highly suspicious for spirocercosis in endemic areas, but if accompanied by spondylitis and/or aortic aneurysms, the radiological changes are pathognomonic for spirocercosis. Yet, the clinical diagnosis of spirocercosis remains challenging due to several factors; nodules may be small or atypically located and thus invisible on radiographs. Cases may present in early disease stages, prior to the formation of oesophageal nodules. Differentiating between a S. lupi-induced benign nodule and a neoplastic tumour is sometimes difficult. Atypical cases due to disease-related complications or aberrant migration are also diagnostically challenging.

Diagnosis of Small or Atypically Located Oesophageal Nodules

Positive radiological diagnosis is very reliable. However, the sensitivity of survey radiology is only about 84%, because small and atypically located oesophageal nodules may not be detected by survey thoracic radiographs.^5,8 Dorsoventral and right lateral recumbent radiographs are recommended to optimize the masses and aortic aneurysms visibility.⁸ Small or atypical nodules may, however, readily be detected in contrast radiographic studies, especially pneumoesophagograms.⁵ In the latter, the air-filled oesophagus provides contrast to enhance the visibility of masses. The mural attachment location can usually also be seen allowing for better surgical planning. Additionally, the extramural extent of the mass is also highlighted. Endoscopy is the most sensitive tool to detect and evaluate Spirocerca-induced intra-oesophageal nodules.^5,6 It is the only tool that allows direct visualization of the nodule, whose typical appearance (smooth, round with or without a protruding worm) contributes to the diagnostic sensitivity and specificity. Furthermore, it is an ideal modality to monitor response to treatment. Endoscopy also has its shortcomings, since it provides no information on any other thoracic complications. Additionally, the equipment is specialized and expensive and the procedure requires a full general anaesthetic. Computed tomography (CT) is emerging as a very effective tool for detecting small intraluminal, mural and extraluminal, as well as atypically located nodules in addition to dystrophic aortic mineralization.⁵ In the case of CT, the cross-sectional images avoid superimposition of structures, thereby enhancing mass detection as opposed to radiography. The greater sensitivity of CT to detect mineralization is also a great advantage; for example, aortic mineralization is seen in up to 50% of CT cases, whereas mineralization is rarely seen on radiographs.

Diagnosis of Early Infection Without Oesophageal Nodules

The detection of early cases of spirocercosis remains challenging. Computed tomography may detect early spondylitis and aortic mineralization as well as aberrant migration. Other diagnostic modalities such as endoscopy and faecal examination depend on the presence of an oesophageal nodule or a viable egg-laying worm, respectively. Serology might prove to be a promising modality to detect early infection. Preliminary results of an immunofluorescent antibody test (using the midbody region of the male worm as an antigen source) showed 100% sensitivity and 80% specificity for S. lupi at a titre of 1:640.⁹ However, as yet nothing more has been published on this topic.

Differentiating Benign and Neoplastic Infection-Induced Nodules

With time, oesophageal nodules may undergo malignant transformation to sarcoma.⁴ Antemortem differentiation between nonmalignant and malignant cases is challenging, yet clinically, therapeutically, and prognostically very important. Hypertrophic osteopathy (HO) occurs in 40% of patients with S. lupi-induced oesophageal sarcoma and is an indicator of neoplastic transformation. Spondylitis is more common and severe in malignant cases, but the prevalence of spondylitis in benign cases is 38%, indicating that spondylitis is progressive and initiated early in the disease process.¹⁰ Anemia, leukocytosis, and thrombocytosis occur more commonly in malignancy, likely due to continuous oesophageal irritation, inflammation and blood loss or as a paraneoplastic syndrome.¹⁰ The length of oesophageal masses on radiography is similar in both benign and malignant cases. This unexpected finding is a result of the confluence of smaller nodules along the caudal length of the oesophagus. The height and width of oesophageal masses are significantly higher in neoplastic compared to benign masses and bronchial displacement is more common in the malignant group, probably secondary to the larger mass size.¹⁰ Gross endoscopic appearance of neoplastic masses is very characteristic including cauliflower-like proliferation, ulceration and necrosis. Positive endoscopy-guided biopsy is very reliable, yet has very low sensitivity,^5,6,11 because biopsies frequently include only the necrotic superficial layers of the tumour, rendering a definite diagnosis of these cases impossible. Thoracotomy and surgical resection of the mass with histology of the entire mass has the highest sensitivity and specificity, but is invasive with increased risk of complications, can be cost-prohibitive and should be reserved for cases that show endoscopic evidence of neoplasia, HO, or mineralization on imaging. Computed tomography may aid in the decision and planning of the surgical procedure.⁸ Where there is uncertainty about the diagnosis of neoplastic transformation, response to medical therapy followed by repeated endoscopy might aid in the diagnosis, demonstrating nodule regression in nonneoplastic cases and further proliferation in neoplastic nodules. Benign oesophageal nodules regress with doramectin (Dectomax, Pfizer, France) treatment, 400 µg/kg SC at 2-week intervals,¹² but its use is extra-labelled in dogs. Pharmacokinetic studies of doramectin in dogs showed good absorption results for oral administration, suggesting that it could be an effective route of administration. The pharmacokinetics of doramectin and ivermectin in dogs are quite similar, rendering the latter a therapeutic option too. In avermectin-susceptible breeds such as collies, milbemycin-oxime may be used.

Disease-Associated Complications and Aberrant S. lupi Migration

Atypical clinical signs of spirocercosis result from larval or adult worm migration, their presence in different organs and resultant secondary inflammation. Respiratory signs are very common, occurring in 25%–50% of cases² and are due to airway tract compression by oesophageal masses, aspiration pneumonia secondary to regurgitation, mediastinitis, pleuritis, haemothorax, pyothorax and pulmonary metastasis.^5,6 Pyothorax occurs quite commonly due to oesophageal perforation or aberrant migration. Although aortic lesions are extremely common in spirocercosis, aortic rupture with consequent haemothorax is rare and is almost always fatal. Lameness is not uncommon and results from HO or secondary septic or immune-mediated arthritis.⁵ Paraparesis and back pain occur occasionally and may be attributed to the presence of spondylitis in the midthoracic vertebrae.⁶ Hind-quarter paralysis has been described in spirocercosis-associated aortic thromboembolism and aberrant spinal migration. Severe intractable dysphagia with firm mandibular salivary gland enlargement has been documented in up to 8.5% of patients presenting with spirocercosis with fox terriers and Jack Russell terriers overrepresented. These dogs were all treated symptomatically and with doramectin and phenobarbitone (2 mg/kg q 12 h) and showed marked improvement within 48 hours from initiating phenobarbitone treatment. This response to phenobarbitone suggests an underlying central nervous system involvement, most likely continuous vagal stimulation known as visceral epilepsy.¹³

Future Research and Therapeutics

Spirocercosis is a natural animal model of inflammation-induced neoplastic transformation. A very recent study has shown significantly higher serum IL-8 concentrations in S. lupi-infected dogs than in controls.¹⁴ The increased IL-8 in spirocercosis is consistent with the neutrophilic infiltrate in spirocercosis lesions and similar to those of other inflammatory-induced neoplasias such as Barret's oesophagus and Helicobacter gastritis. In contrast, IL-18 concentrations were significantly lower in neoplastic cases,¹⁴ demonstrating a negative regulatory effect and potentially allowing the worm to evade the host response and to induce neoplastic transformation. Such findings may herald an era of investigation into the pathomechanism of neoplastic transformation, potentially spawning new immunotherapies.

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