The progression of heartworm associated respiratory disease (HARD) in SPF cats 18 months after Dirofilaria immitis infection

Abstract

BackgroundHeartworm-associated respiratory disease (HARD) in cats is induced by the arrival and death of immature adult Dirofilaria immitis in the pulmonary system and is indistinguishable from mature adult heartworm infection.MethodsA controlled, blind research study investigated the long-term (18 months post infection, PI) consequences of the inflammatory response associated with the death of immature adult heartworms in cats.Three groups of cats, 10 per group, were infected with 100 third-stage (L3) larvae by subcutaneous injection. Group A cats were treated with selamectin (Revolution®; Zoetis) per label directions at 28 days PI and once monthly for 17 months. Group B cats were treated orally with ivermectin (Ivomec®; Merial) at 150 μg/kg) at 70 days PI, then every 2 weeks for 15 months. Group C cats were untreated PI. At baseline (Day 0) and on Days 70, 110, 168, 240, 309, 380, and 505 PI, peripheral blood, serum, bronchial lavage, and thoracic radiographic images were collected.ResultsThe selamectin-treated cats (Group A) and ivermectin-treated cats (Group B) were free of heartworms or heartworm fragments at necropsy. All cats became heartworm antibody positive at some time point in the study except for one cat in Group A. Only cats in Group C (all with adult heartworms) were heartworm antigen positive. The heartworm antibody titer for Group B was highest on Days 110 to 168 and then decreased over time and 50% were serologically antibody negative on Day 240. Eosinophilic bronchoalveolar lavage (BAL) cytology and peripheral eosinophilia were most pronounced on Day 110 in all cats. Randomly distributed myofibrocytes in the lungs of some Group A cats suggest that precardiac larval stages were affecting the lungs. Radiographs in Group B cats demonstrated partial resolution of the initial HARD reaction but chronic myofibrocyte proliferation was histologically evident 18 months after infection.ConclusionHARD was induced by immature adult worm infection with progressive improvement starting 6 to 8 months after infection but histologic lesions were evident in some cats 18 months after infection. The serologic antibody assay was negative in 50% of cats at 8 months and 100% of cats at 18 months post infection. Abnormal radiographic lung patterns continued in a subset of Group B cats for months after heartworm antibody serology and BAL cytology returned to normal.

Heartworm prevalence in dogs versus cats: Multiple diagnostic modalities provide new insights

“…Antibody testing is the only means of identifying immature infections in cats, and cats with clinical signs are more likely to test antibody-positive than asymptomatic cats ( Lee and Atkins, 2010 ). Experimental infections have demonstrated that antibodies can persist for months after infection even if infections were abbreviated with a macrocyclic lactone 28 days after infection ( Dillon et al, 2017 ). In one study that followed a small cohort of naturally infected cats identified by positive antibody tests, cats became antibody negative up to one to three years after initial detection ( Venco et al, 2011 ).…”

Dirofilarioses in cats: European guidelines from the ABCD on prevention and management

“…24,25,27 In experimental studies, the inflammatory response due to the death of immature adult heartworms is associated with chronic myofibrocyte proliferation, which is histologically evident in the lungs up to 18 months after infection. 28 Pulmonary arterial disease, associated with exposure to D immitis, is considered more severe in cats compared with dogs due to the increased activity of pulmonary intravascular macrophages in cats. 29,30 In one case, pathological changes in the arterial wall caused fatal dissection of the pulmonary artery ( Figures 3 and 4).…”

Feline asthma and heartworm disease: Clinical features, diagnostics and therapeutics

“…Death of immature worms incites an intense inflammatory response leading to airway, interstitial and vascular changes in the pulmonary parenchyma. 5,6 Importantly, assuming no reinfection, these lesions of HARD show progressive improvement, starting 6–8 months post-infection; over time there appears to be substantial reversibility of lesions. 6 One study determined that by 18 months post-infection, there was no significant difference in the histologic grading of airways, interstitium or arteries/arterioles between cats treated with selamectin 28 days post-infection (in which ‘pre-cardiac’ third- and fourth-stage larvae were present but immature adults were killed before reaching the pulmonary arteries, thus no HARD) and cats with HARD.…”

“…5,6 Importantly, assuming no reinfection, these lesions of HARD show progressive improvement, starting 6–8 months post-infection; over time there appears to be substantial reversibility of lesions. 6 One study determined that by 18 months post-infection, there was no significant difference in the histologic grading of airways, interstitium or arteries/arterioles between cats treated with selamectin 28 days post-infection (in which ‘pre-cardiac’ third- and fourth-stage larvae were present but immature adults were killed before reaching the pulmonary arteries, thus no HARD) and cats with HARD. 6 However, there was tremendous variation between cats and within lung lobes of individual cats, with some cats having lesions present, just more interspersed rather than uniform.…”

“…6 One study determined that by 18 months post-infection, there was no significant difference in the histologic grading of airways, interstitium or arteries/arterioles between cats treated with selamectin 28 days post-infection (in which ‘pre-cardiac’ third- and fourth-stage larvae were present but immature adults were killed before reaching the pulmonary arteries, thus no HARD) and cats with HARD. 6 However, there was tremendous variation between cats and within lung lobes of individual cats, with some cats having lesions present, just more interspersed rather than uniform. 6 The clinical implications of these chronic lesions is unknown but suspected to be minimal.…”