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11 NOVEMBER/DECEMBER 2017 ■ TVPJOURNAL.COM HEARTWORM HOTLINE Wolbachia possess surface proteins (WSPs) 8 that are responsible in part for the pathogenesis of heartworm disease. When adult heartworms die naturally or as a result of melarsomine administration, the bacteria and their components, including WSPs, are released. The WSPs recruit neutrophils and other immune cells; as these cells are recruited on the microscopic level in the blood vessels, partial blockage of vessels can result, which can impede blood flow. Furthermore, inflammation of the dog's lungs can manifest in clinical signs, such as coughing and dyspnea. 2,9 Although we do not understand the complete role of Wolbachia in the pathogenesis of heartworm disease, experimental and clinical trials have shown that elimination of the bacteria using doxycycline decreases both macroscopic and microscopic pathology, as well as clinical signs. 2,7,10 WHY IS DOXYCYCLINE IMPORTANT IN HEARTWORM TREATMENT? The American Heartworm Society (AHS) recommends that doxycycline be incorporated into an adulticidal treatment regimen 11 to eliminate Wolbachia. Elimination of Wolbachia has 2 clinical benefits: (1) reducing the WSPs released into the bloodstream, thus decreasing inflammation in the canine host; and (2) reducing worm mass, thereby decreasing the severity of pulmonary thromboembolisms (PTEs) associated with adulticidal treatments. 2 The AHS recommendation is based on findings from important clinical studies: • McCall et al 7 demonstrated that in animals administered prophylactic doses of ivermectin and doxycycline before melarsomine treatment, there were fewer inflammatory infiltrates in the lungs and a lower possibility of development of PTEs ( Figure 1 ). The dose used in this study was 10 mg/kg q24h for an extended period (weeks 1 to 6, 10 to 11, 16 to 17, 22 to 25, and 28 to 33) before melarsomine treatment. • Kramer et al 12 administered doxycycline to dogs at 20 mg/kg q24h for 30 days, with or without a prophylactic dose of ivermectin. Two months after the end of the doxycycline regimen, animals were administered melarsomine using the standard 3-dose protocol. In this study, the groups receiving doxycycline had almost no thrombi in their lungs when compared with melarsomine-only controls. This study further supports the use of doxycycline for reducing the pathology associated with Wolbachia released from dying heartworms. Doxycycline not only has effects on adult worms but also decreases numbers of microfilariae and prevents development of heartworm in subsequently infected dogs. • Decrease in microfilariae • In microfilaremic heartworm-infected dogs administered doxycycline for 30 days at a dose of 10 mg/kg q12h, microfilariae levels slowly declined by 12 to 13 months after administration of doxycycline. In McCall et al, 7 elimination of microfilariae was noted in 9 weeks with an increased amount of doxycycline (10 mg/kg q24 h for weeks 1 to 6 and then weeks 10 to 11, 16 to 17, 22 to 25, and 28 to 33). • Prevention of adult heartworm development in subsequently infected dogs 13 • Microfilaremic heartworm-positive dogs were administered doxycycline for 30 days at a dose of 10 mg/kg q12h. At different time points, including 161 days after doxycycline administration, microfilaremic blood was fed to laboratory-reared mosquitoes. • Sixteen days after feeding, infective L3s were harvested from the mosquitoes and dogs were experimentally infected. • When the dogs were necropsied at least 7 months after infection, no adults were found in the experimental animals. FIGURE 1. Pulmonary pathologic features associated with the death of heartworms in experimentally infected heartworm-positive dogs pretreated with ivermectin and doxycycline before receiving melarsomine injections. The top two panels are pictures of representative lungs obtained during necropsy. The bottom panels are photomicrographs of hematoxylin-eosin–stained lung sections. Photographs courtesy of John McCall, PhD, and Laura Kramer, DVM, PhD.