Vector-borne diseases of dogs and cats transmitted by arthropods, e.g. fleas, ticks, sandflies and mosquitoes, are caused by infectious agents, including viruses, bacteria, protozoa and helminths. These agents may cause subclinical to potentially fatal clinical pictures and some have a zoonotic potential. Despite vector-borne diseases being of primary relevance in small animal medicine, some of them are still overlooked and underestimated. This is the case for canine and feline hepatozoonosis, which is an emerging vector-borne disease caused by different protozoa species of the genus Hepatozoon (Baneth, 2011; Amoli et al, 2012). Species within this genus are not strictly species-specific, as Hepatozoon americanum infects dogs, Hepatozoon felis and Hepatozoon silvestris infect cats, while Hepatozoon canis (the most widely known species) infects both animals (Baneth, 2011; Giannelli et al, 2017; Hodžić et al, 2017; Guo et al, 2020; Pacifico et al, 2020; Morelli et al, 2021).
The life cycle of H. canis is indirect, and dogs (the intermediate hosts) become infected through ingestion of an infected tick (the definitive host) harbouring mature oocysts. After ingestion the sporozoites penetrate the gut wall and reach different organs (including the liver, spleen, lymph nodes, muscles and bone marrow) where they develop into meronts which release micromerozoites (Baneth et al, 2007; Baneth, 2011). The parasites invade monocytes and neutrophils and become gamonts, which are taken in by ticks when they feed on an infected animal (Baneth et al, 2007; Baneth, 2011). The life cycle of H. americanum is similar to that of H. canis, although this species develops in skeletal and cardiac muscles, forming cysts that release mature merozoites and elicit an intense inflammatory response. The merozoites develop into gamonts within leucocytes and the life cycle continues as described above (Baneth, 2011). The biological cycle of H. felis and H. silvestris has not been clarified. It is likely that feline species of Hepatozoon have a biology similar to that of H. canis, although H. felis may invade the heart and the skeletal muscles.
Transplacental transmission and carnivorism (e.g. ingestion of rodents or lagomorphs) have been reported as alternative transmission pathways of Hepatozoon spp. (Murata et al, 1993; Baneth, 2011; Baneth et al, 2013). While H. canis is spread among canine populations in several countries, to date H. americanum has been reported only in the Americas (Baneth, 2011; Amoli et al, 2012; Guo et al, 2020; Pacifico et al, 2020). In cats, H. felis has been reported in the Mediterranean basin and central Europe (Beaufils et al, 1998; Vilhena et al, 2013; Attipa et al, 2017; Díaz-Regañón et al, 2017; Basso et al, 2019; Morelli et al, 2021), H. silvestris in Switzerland (Kegler et al, 2018) and H. canis in France and Spain (Criado-Fornelio et al, 2009; Díaz-Regañón et al, 2017). As for other vector-borne diseases, hepatozoonosis can be imported into areas free of infection or with negligible presence of ticks and transmitted pathogens. As a key example, three cases of hepatozoonosis caused by H. canis have been described in the UK (Attipa et al, 2018).
In Europe, H. canis is transmitted by the brown dog tick Rhipicephalus sanguineus, in which transstadial transmission may also occur (Giannelli et al, 2013; Aktas et al, 2017; Pacifico et al, 2020). The vectors of H. felis and H. silvestris are unidentified, although their DNA has been detected in R. sanguineus and Ixodes ricinus respectively (Maia et al, 2014; Duplan et al, 2018).
The clinical presentations of canine and feline hepatozoonosis range from subclinical to a severe and potentially life-threatening disease, which is often challenging and hard to diagnose in clinical settings. Therefore, increasing awareness of these diseases is needed to allow efficient clinical, diagnostic and control approaches.
Dogs
Hepatozoonosis caused by H. canis is often subclinical or characterized by non-specific clinical signs, i.e. fever, lymphadenopathy, weight loss, anorexia, lethargy and haematobiochemical alterations, i.e. polyclonal hyperglobulinaemia and hypoalbuminaemia, increased creatine kinase and alkaline phosphatase levels, leukocytosis, anaemia and thrombocytopenia (Voyvoda et al, 2004; Baneth, 2011). Moreover, gastrointestinal distress, respiratory signs, skeletal pain, oral, skin and ocular lesions, pneumonia, hepatitis and glomerulonephritis may occur (Baker et al, 1988; Marchetti et al, 2009; Acevedo et al, 2010; Baneth, 2011; Little and Baneth, 2011; De Bonis et al, 2021). Life-threatening conditions have been described in puppies, in immunocompromised animals or in dogs co-infected with other vector borne pathogens (e.g. Ehrlichia spp., Anaplasma spp., Leishmania infantum, Babesia canis) (Sasanelli et al, 2009; Baneth, 2011; Kruzeniski et al, 2013; Kwon et al, 2017).
The disease caused by H. americanum is most often severe and life-threatening. Infected dogs have fever, muscular atrophy and pain, gait disorders (e.g. stiffness, inability to rise), ocular abnormalities (e.g. mucopurulent ocular discharge, uveitis) and polyuria and polydipsia caused by renal amyloidosis or immunoproliferative glomerulonephritis (Baneth, 2011). Laboratory alterations include marked neutrophilia, increased levels of alkaline phosphatase and hypoalbuminaemia (Potter and Macintire, 2010; Baneth, 2011).
Cats
In cats H. felis causes mild inflammatory responses in myocardial and skeletal muscles, with subclinical or non-specific signs, i.e. hyperthermia, jaundice, anorexia, abdominal tenderness, lethargy, lymphadenomegaly and laboratory findings, i.e. anaemia, lymphopenia, mild neutropenia, thrombocytopenia, increased creatine kinase levels, serum lactate dehydrogenase, creatinine, haptoglobin, serum amyloid A (especially in animals showing clinical signs) and decreased levels of paraoxonase-1 (Baneth et al, 2013; Lloret et al, 2015; Vilhena et al, 2017; Basso et al, 2019; Qurollo, 2019). Severe clinical alterations, e.g. haemolytic anaemia, icterus, renal failure or paraparesis, have been described in animals co-infected with retrovirus or mycoplasms (Baneth et al, 1998). The genetic variability of H. felis leads to the hypothesis that different genotypes have varying pathogenicity and/or biology (Morelli et al, 2021). Further studies are warranted to confirm this hypothesis.
A case of fatal myocarditis with pulmonary oedema caused by H. silvestris in a domestic cat has been reported (Kegler et al, 2018). In another recent case, H. silvestris was found within the intestinal villi of a jejunal endoluminal pedunculated nodule causing intestinal intussusception (Simonato et al, 2022). No other clinical data are available on the infection caused by H. silvestris.
Diagnosis and treatment
Hepatozoonosis should be suspected in any animal with compatible clinical signs and changes in laboratory values detected using complete blood count and biochemistry, outdoor access, and irregular or absent treatment against ectoparasites. Diagnosis can be confirmed by direct observation of the ellipsoidal 11 μm x 5.5 μm Hepatozoon gamonts within neutrophils and monocytes cytoplasm (Figure 1) in blood smears stained with Giemsa, May–Grunwald Giemsa or Romanowsky stains. Given that the microscopic examinations have some limitations because there are frequently low levels of parasitaemia (a small proportion of circulating neutrophils show gamonts) (Baneth, 2011; Maia et al, 2014), the parasite can be molecularly detected and identified from the peripheral blood (Tabar et al, 2008; Díaz-Regañón et al, 2017).
Data on the treatment of hepatozoonosis are limited and effective formulations are off label. In dogs, the use of imidocarb dipropionate is reported at 5–6 mg/kg (subcutaneous or intramuscular) at 2-week intervals until blood smears show that there are no parasites left (Baneth and Weigler, 1997; De Bonis et al, 2021). Oral administration of toltrazuril at 5–10 mg/kg every 24 hours for 10 days or doxycycline at 10 mg/kg every 24 hours for 3 weeks, both off label in the UK, can be given along with imidocarb dipropionate. Complete elimination of the parasite takes a long time and sometimes is not possible (Baneth and Weigler, 1997). In cats, oral doxycycline 10 mg/kg has been used with no therapeutic success. In one clinical case, the use of oxytetracycline and primaquine was described with apparent recovery of the cat (Van Amstel, 1979). Two doses of imidocarb dipropionate 6 mg/kg subcutaneous 14 days apart, in combination with oral doxycycline at 5 mg/kg every 12 hours for 4 weeks, lead to clinical and parasitological recovery of a cat infected by H. felis (Basso et al, 2019).
The only preventative measure available for hepatozoonosis is the use of parasiticides, which are efficacious against ticks and the prompt removal of any tick feeding on a pet.
Conclusions
Canine and feline hepatozoonosis are still overlooked in clinical practice in companion animals, especially because they have non-specific clinical features. Thus, in daily clinical practice it is essential to screen all animals at risk of this infection (e.g. outdoor access, history of null or limited preventative measures vs external parasites) for Hepatozoon spp. when referred with at least one compatible clinical or haematobiochemical alteration. In endemic areas it would be advisable to perform routine microscopic blood smears in all animals regardless of their clinical status, including travelling or imported dogs and cats.
Owner education is pivotal to control vector-borne diseases, including hepatozoonosis. To date, many endectocides are available to protect dogs and cats from multiple infections and parasitoses at the same time. The treatment should be selected on a case-by-case basis based on factors such as mode of action (antifeeding, acaricides), formulation, speed of kill, duration of the activity. The use of these products is highly recommended to limit the spread of these pathogens and to protect the health of cats and dogs.
KEY POINTS
- Canine and feline hepatozoonosis is an emerging vector-borne disease.
- In infected animals Hepatozoon spp. may cause variable clinical pictures, from subclinical to potentially life-threatening signs.
- Increased awareness of hepatozoonosis in clinical practice is vital to improve knowledge about this neglected disease.