Halicephalobus gingivalis in and around equine vasculature

Halicephalobus gingivalis continues to be an antemortem diagnostic challenge often resulting in mortality in equine patients, as demonstrated in the case report by Rodriguez et al. (2013). Although this disease is rarely reported compared to other causes of equine neurological disease, it remains an important differential diagnosis for meningoencephalomyelitis, renal masses, nasal and facial deformities and now haemoabdomen. Previously reported sites of infection of halicephalobosis have been widespread and include meningoencephalomyelitis (Brojer et al. 2000; Bryant et al. 2006; Akagami et al. 2007), nephritis (Shibahara et al. 2002; Akagami et al. 2007), mandibular and maxillary osteomyelitis (Teifke et al. 1998; Ferguson et al. 2008), gingivitis (Teifke et al. 1998), posthitis (Dunn et al. 1993; Muller et al. 2008), orchitis (Kinde et al. 2000), papillitis (Kinde et al. 2000), retinitis (Kinde et al. 2000), pulmonary nodules (Spalding et al. 1990) and disseminated disease (Ruggles et al. 1993). While the case described by Rodriguez et al. documents a unique presentation of periaortic granuloma and haemoabdomen, the organism has previously been reported to cause granulomatous inflammation in the walls of vessels (Reiser et al. 2011). Halicephalobus has been documented in the walls of the pulmonary artery (Aleksandersen et al. 2000), carotid artery (Deniau et al. 2012) and in the caudal vena cava after apparent extension from adjacent lymph nodes (Wollanke et al. 2000). Additionally, H. gingivalis is always closely associated with the vasculature of affected organs. Larvae have been seen free in pulmonary capillaries (Ondrejka et al. 2010), within the lumina of blood vessels of the brain (Yoshihara et al. 1985) and within meningeal vessels (Trostle et al. 1993). Parasite tracks run close to vessels and parasites are typically located adjacent to vessels (Vasconcelos et al. 2007). Further, H. gingivalis is generally thought to circulate from sites of infection to organs such as the brain and kidneys. The dense capillary beds associated with these organs make them a natural target for infection. In cases of halicephalobosis, it is likely that it is the larval stage (as opposed to adults or eggs) that gains access to circulation and is transported to distant capillary beds. Capillary diameter is about 8 mm. Adult H. gingivalis have been measured in tissues of horses and man. The range of published diameters is 15–25 mm (mean 17.9 mm) (Johnson and Johnson 1966; Stone et al. 1970; Ferris et al. 1972; Rubin and Woodard 1974; Keg et al. 1984; Yoshihara et al. 1985; Blunden et al. 1987; Simpson et al. 1988; Spalding et al. 1990; Dunn et al. 1993; Ruggles et al. 1993; Rames et al. 1995; Kinde et al. 2000; Johnson et al. 2001; Mandrioli et al. 2002; Shibahara et al. 2002; Schmitz and Chaffin 2004; Akagami et al. 2007; Ferguson et al. 2008; Muller et al. 2008; Ondrejka et al. 2010; Sponseller et al. 2011). Because 15 mm rigid microspheres are removed by passage through pulmonary and systemic capillary beds (Lamm et al. 2005), it seems unlikely that adult H. gingivalis are responsible for haematogenous infection of distant organs. Likewise, because H. gingivalis eggs have minimum dimensions of 10–17 mm (mean 14.9 mm), they are unlikely to traverse capillary beds. The dimensions of H. gingivalis can be compared to those of nematode microfilariae, which have evolved to live and move intravascularly and, although of comparable length to H. gingivalis, are slender enough to pass through capillaries. For example, Dirofilaria striata microfilariae are 4–5 mm wide and D. immitis are 5–6.5 mm (Nayar 2008). In contrast to H. gingivalis adults and eggs, larvae have been seen histologically within pulmonary capillaries (Ondrejka et al. 2010) and the range of diameters published for larval stages, 8–15 mm (mean 11.6 mm), suggests that at least some larvae may pass through the pulmonary circulation and to distant organs. One intriguing idea is that H. gingivalis may colonise large vessel walls via entry into the vasa vasorum, the small vessel network feeding the walls of large blood vessels. This route has been suggested for embryos of Echinococcus granulosus which formed intramural hydatid cysts in pulmonary arteries (Alper et al. 1995) and less convincingly for larvae of Strongylus vulgaris in the cranial mesenteric arteries of horses (Maxie and Robinson 2007). Unfortunately, anthelmintic treatment of H. gingivalis has been unsuccessful in neurological presentations and in most other presentations. In the authors’ experience, horses with neurological signs typically demonstrate a fairly rapid and severe progression regardless of treatment, an observation also supported by the published literature (Darien et al. 1988; Spalding et al. 1990; Brojer et al. 2000; Bryant et al. 2006; Akagami et al. 2007). Published therapies have included larvicidal doses of fenbendazole (Trostle et al. 1993; Vasconcelos et al. 2007), regular and high doses of ivermectin (Keg et al. 1984; Kinde et al. 2000; Ferguson et al. 2008) and moxidectin systemically and topically (Muller et al. 2008). Successful treatment has been recorded with ivermectin and diethylcarbamazine citrate for granulomas of the prepuce (doses not stated) (Dunn et al. 1993), nephrectomy and ivermectin for a horse with unilateral renal involvement (Schmitz and Chaffin 2004) and debulking plus high dose ivermectin (1.2 mg/kg bwt 3 times at 2 week intervals) for a lesion adjacent to an eye (Pearce et al. 2001). Anthelmintic failures may be attributable to tolerance or resistance of the organism to anthelmintics. Various isolates of H. gingivalis have demonstrated tolerance to high doses of ivermectin and thiabendazole compared to other free living panagromailid nematodes (Fonderie et al. 2012). Interestingly, in the paper by Fonderie et al., an isolate from tissues of an bs_bs_banner