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Abstract

Practical relevance:

Granulocytic anaplasmosis is a disease in humans and animals caused by the Gram-negative bacterium Anaplasma phagocytophilum within the family Anaplasmataceae. The pathogen is transmitted by ticks of the Ixodes species. Infections with A phagocytophilum have often been described in dogs but reports on natural infections in cats are rare. An infection with A phagocytophilum should be considered as a differential diagnosis in cats if the history reveals tick infestation and/or outdoor access in combination with the relevant clinical signs.

Global importance:

A phagocytophilum is also important in human medicine because of its zoonotic potential. Due to the risk of vector-borne infections for both feline and public health, cats should be protected with ectoparasiticides, especially in endemic areas.

Aim:

The aim of this review is to give an overview of the published data and summarise the epidemiology, pathogenesis, diagnosis, clinical signs and therapy of feline granulocytic anaplasmosis. As clinical signs are vague and non-specific, this review aims to raise awareness of A phagocytophilum infection, both among clinicians, so that they consider testing potentially exposed cats, and scientists, in order to prompt further research.

Evidence base:

Sixteen publications describing 55 cats have been reviewed. Thirty-four cats were well diagnosed based on guidelines of the European Advisory Board on Cat Diseases and blood analyses were performed to varying extents for these cats. Because of the limited number of studies and a lack of knowledge in cats, clinical signs and blood analyses are compared with available data in dogs.

Keywords

vector-borne anaplasmosis granulocytic anaplasmosis zoonosis

Introduction

Anaplasma phagocytophilum is a Gram-negative, obligate intracellular bacterium within the family Anaplasmataceae.¹ The pathogen was formerly variously known as Ehrlichia equi, Ehrlichia phagocytophila and human granulocytic ehrlichiosis (HGE) agent, thus making literature reviews challenging.² A phagocytophilum causes granulocytic anaplasmosis in humans and animals³ and is transmitted by ticks of the Ixodes species within 24–48 h of tick attachment.⁴ Rodents and wild ruminants are the most common reservoirs.³

While infections with A phagocytophilum occur commonly in dogs, the literature only rarely describes natural infections in cats. Case reports of A phagocytophilum infection in cats, based on detection by PCR, have been published in Germany,^5–8 Austria,⁹ Poland,^10,11 Switzerland,¹² Italy,¹³ the UK,¹⁴ Finland,¹⁵ Sweden¹⁶ and the USA.^17,18

Epidemiology

Infections with A phagocytophilum have been described in humans and a number of animal species including cats. The first case report of an infected cat was published in Sweden in 1999.¹⁶ Prior to this, the pathogen had already been described via microscopic detection of morulae in sheep in Scotland in 1932 (cited by Woldehiwet and Scott¹⁹ and Foggie²⁰), in cattle in the UK in 1950,²¹ as well as in other domestic ruminants such as goats²² and deer,²³ in horses in the USA in 1968,²⁴ in dogs in the USA in 1982²⁵ and in humans in the USA via PCR in 1994.²⁶

A phagocytophilum is transmitted by ticks, with the species of tick varying based on geography. In the USA, Ixodes pacificus (West) and Ixodes scapularis (Midwest and Northeast) have been described as vectors.^27,28 In Europe, Ixodes ricinus is the most important vector,³ followed by Ixodes trianguliceps, Ixodes hexagonus and Ixodes ventalloi.^29–31 In Asia and Russia, Ixodes persulcatus and Dermacentor silvarum are the most common vectors.^27,28,32

In humans, rare infections without vector contact have been diagnosed; for example, nosocomial infections in China,³³ infections transmitted via blood transfusion³⁴ and transplacental infections.³⁵ Transplacental infections have also been described in cows³⁶ but not in cats. The natural and experimental transmission of A phagocytophilum via blood/blood transfusion has been described in dogs,^37,38 as well as in cats (MR Lappin, unpublished data). In a study performed in Berlin, Germany, 5/42 clinically healthy blood donor cats were serologically positive for A phagocytophilum; direct pathogen detection via PCR was negative in all cats.⁶ Consensus guidelines from the American College of Veterinary Internal Medicine (ACVIM),³⁹ as well as the European Advisory Board on Cat Diseases (ABCD),^40,41 recommend methods of detection for A phagocytophilum in blood donor cats (see later).

In European cats, antibody prevalences for A phagocytophilum have been described, ranging from 0% to 33.3%, and in the USA prevalences from 4.3% to 37.6% have been reported (Table 1). Direct pathogen detection via PCR or within a blood smear was positive in 0–23.1% of cats in Europe, and in 0–6.9% of cats in the USA (Table 1). Direct methods of detection of A phagocytophilum in European dogs showed a prevalence of 0–21.7% in different countries;^72–74 via indirect detection methods, 2.7–56.5% of dogs tested positive.^72,74 In the USA, prevalences in dogs ranged from 3% to 37% using direct detection methods and 0% to 55.4% via antibody testing.^72,74

Table 1

Prevalence of feline Anaplasma phagocytophilum infections in selected studies

	Country	Region	n	Study population	Detection method	Prevalence	Period	Reference
Europe	Germany	North East Germany (Berlin/Brandenburg)	265	150/265 indoor, 99/265 outdoor access, 16/265 stray cats 49/265 clinically healthy, 216/265 with clinical signs (96/265 with ectoparasitic treatment), 72/265 with tick infestation	IFAT PCR	24/265 (9.1%) 1/265 (0.4%)	11/2007–11/2008	6
		Bavaria, Lower Saxony	326 306	238/326 domestic cats, 58/326 animal shelter cats, 20/326 laboratory cats, 10/326 suspected A phagocytophilum infection 24 domestic cats, 6 animal shelter cats and 2 cats with suspected infection tested positive 238/306 domestic cats, 58/306 stray cats (clinically healthy), 10/306 suspected A phagocytophilum infection; 1 cat, with a history of travel to Denmark 6 months earlier, tested positive	IFAT PCR	53/326 (16.3%) 1/306 (0.3%)	05/2006–08/2008 05/2006–08/2008	7
		Southern Germany	479	Domestic cats	PCR	2/479 (0.4%)	–	5
	UK	England	60	Domestic cats with clinical signs indicative of suspected vector-borne infections	PCR	1/60 (1.7%)	08/2001–10/2001	14
	Ireland	Dublin and surrounding area	116	75/116 stray cats, 41/116 domestic cats	PCR	0/116	01/2008–05/2008	42
	Sweden	Central Sweden	90	Domestic cats presented to a veterinary clinic*	IFAT	19/90 (21.1%)	2010–2011	43
	Greece	Crete, Mykonos, Skopelos, Athens	148	Cats with outdoor access	PCR	0/148	Summer 2015	44
	Greece	Northern and central Greece	100	Domestic cats: 40/100 indoor, 60/100 with outdoor access 50/100 clinically healthy, 50/100 with clinical signs	IFAT PCR	0/100 0/100	–	45
	ITALY	Northern and central Italy	250	Cats with outdoor access	Morulae	15/250 (6%)	1997–2000	46
		Central Italy	Central Italy	Clinically healthy cats: 176/560 animal shelter cats, 384/560 domestic cats 7/176 animal shelter cats and 18/384 domestic cats tested positive (21 cats with tick attachment in the previous 3–6 months)	IFAT	25/560 (4.5%)	01/2005–12/2011	47
		Northern Italy (Milan)	260	Stray cats	PCR	60/260 (23.1%)	01/2008–01/2010	48
		Southern Italy	42	Domestic cats with outdoor access and ectoparasites; 20/42 clinically healthy, 22/42 with clinical signs	IFAT PCR	14/42 (33.3%) 0/42	03/2012–01/2013	49
		Southern Italy	197	134/197 cats with outdoor access (29.1% serologically positive), 63/197 indoor cats with ectoparasitic treatment (22.1% serologically positive); 10/197 clinically healthy, 187/197 with clinical signs	IFAT PCR	53/197 (26.9%) 0/197	03/2012–03/2013	50
	Portugal	Lisbon and Évora	37	22/37 domestic cats, 13/37 animal shelter cats, 2/37 stray cats (3 animal shelter cats and 2 domestic cats tested serologically positive)	IFAT PCR	5/37 (13.5%) 0/37	08/2007–04/2008	51
		Northern and central Portugal	320	Domestic cats: 192/320 outdoor access, 124/320 indoor, 4/320 unknown 2/192 cats with outdoor access clinically healthy and tested positive	PCR†	2/320 (0.6%)	–	52
		Southern Portugal	649	329/649 stray cats, 320/649 domestic cats 35/649 tested positive (26/35 stray cats, 9/35 domestic cats; 8/35 clinically healthy, 3/35 with suspected infection)	PCR†	35/649 (5.4%)	01/2012–08/2013	53
	Spain	Northeastern regions	168	Domestic cats: 70/168 clinically healthy, 60/168 with clinical signs 47/168 additionally examined via PCR (27/47 clinically healthy, 20/47 with clinical signs)	IFAT PCR	3/168 (1.8%) 0/47	–	54
		Barcelona and surrounding area	100	48/100 clinically healthy, 52/100 with clinical signs (1/52 tested positive)	PCR†	1/100 (1%)	01/2006–12/2006	55
		Madrid and surrounding area	52	Domestic cats; 28/52 clinically healthy, 24/52 with clinical signs 1/4 cats serologically positive with clinical signs	IFAT PCR + culture	4/52 (7.7%) 0/52	10/2005–06/2007	56
		Madrid and surrounding area	680	539/680 domestic cats, 141/680 stray cats 247/501 with outdoor access, 34/440 with tick infestation, 117/420 with ectoparasitic treatment	IFAT PCR	57/680 (8.4%) 0/680	09/2005–08/2008	57
		Catalonia	116	Animal shelter cats with outdoor access	IFAT PCR	0/116 0/116	09/2012–11/2012	58
USA	USA	Florida	484	Clinically healthy stray cats	PCR	0/484	06/1999–02/2000	59
		Northeastern regions	93	Domestic cats with outdoor access (84/93 clinically healthy, 9/93 with clinical signs)	IFAT ELISA	28/93 (30.1%) 35/93 (37.6 %)	1985–1989	60
		Arizona	112	57/112 animal shelter cats, 50/112 stray cats, 5/112 cats living in a veterinary clinic	PCR‡	0/112	03/2004–07/2004	61
		USA	146	Clinically healthy cats presented for blood donation	PCR	0/146	^–	62
		Alabama, Maryland, Texas	92	54/92 humane shelter cats, 38/92 domestic cats	PCR‡	0/92	–	63
		Florida, California, Michigan	460	373/460 stray cats, 65/460 animal shelter cats, 22/460 domestic cats Examination via PCR in 158/460 cats with IFAT >1:50	IFAT PCR	20/460 (4.3%) 0/158	–	64
		Colorado	133	Cats with anaemia of unknown origin	PCR	0/133	01/2001–11/2004	65
		Maine	159	42/159 cats with clinical signs, 117/159 clinically healthy	SNAP§	10/159 (6.3%)	^–	66
		California, Illinois, Massachusetts	5416	Domestic cats	Specific peptide immunoassay	9.7%	09/2014–02/2015	67
		Northeastern regions	4334	4334 blood samples of cats sent to a commercial laboratory	PCR∞	40/4334 (0.92%)	05/2009–05/2011	¹⁸
		Maryland	25	70 clinically healthy domestic cats (SNAP results from 25/70 cats)	SNAP§	1/25 (4%)	04/2011–04/2014	68
		Massachusetts	175	175 clinically healthy stray cats (in 2/175 cats no examination via PCR possible)	SNAP§ PCR	17/175 (9.7%) 12/173 (6.9%)	06/2015–12/2015	69
Other countries	USA, Canada, Caribbean	USA, Canada, Caribbean	858	827/858 cats from the USA, 28/858 cats from Canada, 3/858 cats from the Caribbean Examination via SNAP test in 715/858 cats, via PCR in 406/858 cats	SNAP# PCR^†	13/715 (1.8%) 13/406 (3.2%)	2008–2013	70
Other countries	Korea	Seoul	222	Animal shelter cats	PCR	2/222 (0.9%)	–	71

IFAT = immunofluorescence antibody test; morulae = detection of inclusion bodies in blood smears

No history/anamnesis available

†

Anaplasma species/Ehrlichia species PCR without species differentiation

‡

Multiplex PCR with species differentiation (Ehrlichia species, Anaplasma phagocytophilum, Neorickettsia risticii, Mycoplasma haemofelis, ‘Candidatus Mycoplasma haemominutum’)

SNAP 4Dx Plus Assay (IDEXX)

Coinfection with Borrelia burgdorferi

∞

Multiplex PCR with species differentiation (Anaplasma phagocytophilum, Bartonella henselae, Bartonella clarridgeiae, Bartonella quintana, Ehrlichia species, Mycoplasma haemofelis, ‘Candidatus Mycoplasma haemominutum’, ‘Candidatus Mycoplasma turicensis’, Rickettsia rickettsii and Rickettsia felis)

SNAP Multi-Analyte Test (detection of antibodies against Anaplasma species, Borrelia species, Ehrlichia species); in the case of enough sample material, specific IFAT and SNAP 4Dx Plus Assay (IDEXX)

These wide ranges in prevalence of A phagocytophilum infection in dogs and cats could be explained by the large geographical areas studied, with their varying climates and environments, tick populations and reservoir host populations. The different study populations also have an impact on the prevalence rates (Table 1). Stray cats and dogs will have received little or no veterinary care and prophylactic measures against vector-borne infections will not have been implemented. Living outdoors all the time, they also have an increased risk of vector contact and infection. Some studies have been performed in areas not endemic for Ixodes species and, as expected, these studies showed a dramatically lower prevalence compared with areas in which Ixodes species are endemic. Cats with and without outdoor access have also been studied (Table 1). Compared with cats with outdoor access (and also with dogs), cats living only indoors are less likely to have vector contact. Moreover, the intensive grooming behavior of cats might lead to the removal of ticks before the transmission of pathogens.⁴ Furthermore, cats may show lower numbers of A phagocytophilum in circulating neutrophilic granulocytes in comparison with dogs, potentially leading to false-negative PCR results.^5,17

Pathogenesis

Based on studies in humans and dogs, A phagocytophilum is known to be spread by Ixodes species ticks via transstadial transmission. For the pathogen to be transmitted, it is assumed that the vector has to be in direct contact with the host for 24–48 h.^4,75 The pathogen then spreads via blood and lymphatic circulation,⁷⁶ and the incubation time ranges from 1 to 2 weeks.³⁷ Neutrophilic granulocytes are infected via endocytosis following P-selectin-mediated adhesion.^77–80 After the pathogen has penetrated the cell membrane of the phagosomes, it proliferates by forming morulae.^81,82 The pathogen inhibits some of the vital functions of the neutrophilic granulocytes, such as neutrophilic motility, phagocytosis, release of reactive oxygen radicals (oxidative burst) and interaction of neutrophilic granulocytes with endothelial cells, in order to survive and ensure its own proliferation.^80,83–85 The breakdown of the phagosomes and the host's cell membrane releases the pathogen and leads to infection of further cells and organs.⁷⁶ The bacterium is able to prevent its recognition by the immune system by activating certain pathogenic mechanisms⁸⁶ and delaying apoptosis.⁸⁷

There is little information on the specific pathogenesis of A phagocytophilum infection in cats. In an experimental study with six cats, mild clinical signs (transient fever) were triggered by intraperitoneal administration of infected blood. Blood tests showed a slight decrease in leukocytes (neutrophilic granulocytes and lymphocytes), significant reduction of mean cell volume and elevated liver enzymes (alanine aminotransferase and aspartate transaminase).⁸⁸ Mild to severe thrombocytopenia is a common – and the most diagnostically relevant – laboratory finding in A phagocytophilum infections in both cats and dogs (Table 2).^90,91 Mechanisms of induced thrombocytopenia could include reduced production of platelets, increased consumption due to disseminated intravascular coagulopathy, shortened platelet lifespan due to immunemediated destruction or sequestration of platelets in an enlarged spleen.⁹⁰ In humans and dogs, antiplatelet antibodies have been detected, indicating that immunemediated factors may also play an important role.^90,92 Antinuclear antibodies, as well as an elevated release of interferon gamma-messenger ribonucleic acid, has been noted in cats,⁸⁸ which could indicate an immunological pathogenesis, eventually leading to the development of clinical signs.³

Table 2

Case reports of feline Anaplasma phagocytophilum infections (n = 55, 1989–2019)

	Country	n	Signalment	History	Clinical signs	Laboratory results	Diagnostic methods	Therapy	Outcome	Reference
Europe	Sweden	1	ESH, 1 year, MN	Lethargy, anorexia, tachypnoea	Depression, fever (41.3°C), dehydration, tick infestation	Neutrophilia, lymphopenia	Morulae*, PCR positive	Doxycycline	Very good	16
	UK	1	Unknown	Acute pyrexia, weakness, lethargy	Fever	Unknown	PCR positive	Unknown	Unknown	14
	Italy	15	Unknown	Anorexia/poor appetite (13/15); weight loss (5/15); vomiting (4/15); incoordination (3/15); tick infestation, haematuria, polydipsia, dyspnoea, hiding (2/15 each)	Pain (8/15); lethargy, lymphadenomegaly, poor coat condition (6/15 each); gingivitis, periodontitis, conjunctivitis (5/15 each); fever (3/15); pharyngitis, dehydration, pale mucous membranes (2/15 each)	Thrombocytopenia in most cats^†, monoclonal gammopathy (2/15)	Morulae*	Doxycycline	Very good	46 ‡
	Austria	2	ESH, 3 years, FN	Tick infestation, lethargy, poor appetite, incoordination	Dehydration, conjunctivitis, fever (40.4°C)	Thrombocytopenia^†, elevated lactate dehydrogenase, lymphocytosis	Morulae*, PCR positive, IFAT positive	Doxycycline	Very good	9
	Austria		ELH, 4 years, MN	Tick attachment, anorexia, lethargy, pain	Fever (40.3°C), dehydration, conjunctivitis, serous nasal secretion, tachypnoea	Anaemia, thrombocytopenia^†, eosinophilia	No morulae*, PCR negative, IFAT positive	Doxycycline	Very good
	Italy	1	Unknown	Unknown	Clinical signs indicative of vector-borne infections⁵	Unknown	PCR positive, IFAT positive	Unknown	Unknown	13 ^‡
	Switzerland	1	ESH, 14 years, MN	Lethargy, anorexia	Fever (40.1°C), minor dehydration, gingivitis	Thrombocytopenia, leukocytosis, hypoalbuminaemia, hypokalaemia, low iron	Morulae*, PCR positive, IFAT positive	Doxycycline	Very good	12
	Finland	1	Maine Coon, 3.5 years, FN	Tick infestation, reduced appetite, hiding, lethargy, ocular discharge	Fever (39.5°C), tachypnoea, painful cranial abdomen, bilateral increased lung sounds	Lymphopenia, hyperglycaemia	Morulae*, PCR positive, IFAT positive	Doxycycline	Very good	¹⁵
	Poland	3	ESH, 2.5 years, M	Loss of appetite and thirst, lethargy	Pale mucous membranes, fever (39.8°C), pain	Anaemia, thrombocytopenia^†, leukopenia	Morulae*, PCR positive	Doxycycline	Very good	10
			ESH, 3 years, M	Tick infestation, pain, reduced appetite	Lethargy, pale mucous membranes	Anaemia, thrombocytopenia^†, leukopenia	Morulae*, PCR positive	Doxycycline	Very good
			ESH, 6 years, F	Tick infestation, lethargy, reduced thirst and appetite	Fever (39.6°C)	Anaemia, thrombocytopenia^†, leukopenia	No morulae*, PCR positive	Doxycycline	Very good
	Poland	1	ESH, 2.5 years, M	Loss of appetite, lethargy, tick attachment	Pale yellow mucous membranes, pain	Anaemia, thrombocytopenia^†, elevated liver enzymes	PCR positive, IFAT positive	Doxycycline	Very good	11
	Germany	2	ESH, FN	Fever, loss of appetite, weight loss, polyuria, polydipsia, ocular lesions	Dehydration, hypothermia (37.4°C)	Anaemia, neutrophilia with left shift, monocytosis, lymphocytosis renal azotaemia, electrolyte shift	PCR positive	Unknown	Unknown	5 ^‡
	Germany		ESH, M	Unknown	No clinical signs	Thrombocytopenia^†, leukocytosis, monocytosis, lymphocytosis, neutrophilia	PCR positive (coinfection with haemotrophic mycoplasma)	Unknown	Unknown
	Germany	1	Persian, 7 years, MN	Tick attachment, ocular discharge	Pain, gingivitis	Thrombocytopenia^†, leukocytosis, eosinophilia, hyperproteinaemia	PCR positive	Unknown	Unknown	7 ^‡
	Germany	1	Unknown	Unknown	Obstructive feline lower tract disease	Azotaemia	PCR positive	Unknown	Unknown	6 ^‡
	Germany	1	LaPerm longhair, 7 years, MN	Tick attachment, loss of appetite, lethargy	Fever (40.8°C)	Leukopenia, thrombocytopenia^¶, hyperproteinaemia, hyperglobulinaemia, hyperglycaemia, lymphopenia	Morulae*, PCR positive, IFAT positive	Doxycycline	Very good	8
USA	USA	5	DSH; 9 months to 3 years; 3 MN, 2 FN	Lethargy (5/5), tick attachment (3/5)	Fever (5/5, 39.7–40.9°C)	Thrombocytopenia^† (3/5, 1/5 thrombocytic aggregation), hyperglycaemia 1/5	PCR positive, IFAT positive (1/5 positive for Bartonella henselae, 3/5 positive for Toxoplasma gondii IgG)	Doxycycline	Very good	17
USA	USA	16	Median 2 years old (4 months to 13 years); 9 MN, 1 M, 6 FN	Lethargy (16/16), loss of appetite (14/16), ocular signs (7/16), ataxia (1/16)	Fever (15/16, 39.6–41.5°C), pain (4/16), tachycardia (3/16), proteinuria (2/16), hepatosplenomegaly (1/16)	Thrombocytopenia^† (7/16, thrombocyte aggregation); lymphopenia (6/16); hyperglycaemia, anaemia, neutropenia (2/16 each); leukopenia (1/16)	PCR positive (1/16 positive for Mycoplasma haemominutum and Bartonella clarridgeiae), morulae* (3/16)	Doxycycline	Very good	18 ^‡
Africa	Kenya	3	10 years, M	Loss of appetite, weight loss, dyspnoea	Tick infestation, fever (40.1°C), splenomegaly	Normocytic, normochromic anaemia, hyperproteinaemia, hyperglobulinaemia	Morulae*	Tetracycline hydrochloride	Very good	89
			4 years, M	Loss of appetite, weight loss	Tick infestation, fever (39.7°C), splenomegaly	Normocytic, normochromic anaemia	Morulae*	Imidocarb-dipropionate	Very good
			2 years, F	Loss of appetite, weight loss, dyspnoea	Tick attachment, fever (40°C), splenomegaly, lymphadenomegaly	Normocytic, normochromic anaemia, leukopenia, neutropenia	Morulae*	Imidocarb-dipropionate	Very good

ESH = European shorthair; ELH = European longhair; DSH = domestic shorthair; M = male; MN = male neutered; F = female; FN = female neutered; IFAT = immunofluorescence antibody test

Microscopic detection in blood smears

†

No manual count of platelets with a haemocytometer

‡

Prevalence study with additional case report content, providing further description of infected cats

No further definition of clinical signs

Confirmed by manual count of platelets with haemocytometer

In a study from Colorado, USA, wild-caught I scapularis ticks were transferred onto four cats, resulting in a subclinical coinfection with A phagocytophilum (detection via PCR and antibody ELISA) and Borrelia burgdorferi (detection via antibody ELISA).⁹³ The ticks were collected in a region in which previous examinations had detected A phagocytophilum DNA in 15% and B burgdorferi DNA in 50% of ticks. The cats showed transient lymphopenia postinfection. In the following 13 weeks, no changes in general condition, appetite, body weight or blood cell count, besides lymphopenia, were detected. The failure of the cats to develop clinical anaplasmosis may have been related to the immune status of the cats, the dose of the organism or the strain of A phagocytophilum.⁹³

Infections with A phagocytophilum most often produce an acute disease (Table 2). To date, there are only a few reports in the literature supporting persistent infections in dogs, sheep and horses.^94–97 In cats, there are two cases reported where persistent infection was documented, with one cat still PCR positive on day 120 after the initiation of treatment and the other cat being PCR positive until day 37 and negative on day 139 after the initiation of treatment.¹⁷ There are reports of asymptomatic infections with A phagocytophilum in cats.^93,98 Subclinical and self-limiting infections have been described after natural exposure in dogs,^99,100 and have also been experimentally confirmed in studies with sheep and horses.^101,102 PCR-positive dogs may also be clinically healthy.⁹⁹ There is widespread serological detection of the pathogen in naturally infected dogs without the development of clinical signs, especially in endemic areas.^{99,100,103–105}

Clinical and laboratory findings

Thirty of 34 cats previously reported in the literature to have A phagocytophilum infection (see box below) had outdoor access. Twelve of the 34 cats (35%) were infested with ticks; of those cats, outdoor access was available in nine and unknown in three. Clinical signs were described in 33/34 cats; the remaining cat (3%) was clinically asymptomatic. Cats mostly showed non-specific clinical signs such as lethargy (31/33 cats, 94%), increased rectal temperature ranging from 39.1°C to 41.5°C (29/33 cats, 88%), anorexia or reduced appetite (25/33, 76%), conjunctivitis (12/33, 36%) and dehydration (5/33, 15%). Ten of 33 cats (30%) had a painful abdomen or painful limbs. Further clinical signs included pale mucous membranes (3/33, 9%), respiratory signs (3/33, 9%) and tachycardia (3/33, 9%). Neurological signs (2/33, 6%), weight loss (2/66, 6%) and dental calculus (2/33, 6%), with or without gingivitis, were also described in a few cats. Rare clinical signs included recurrent epistaxis, polyuria and polydipsia, and hypothermia, as well as abnormal lung sounds on auscultation.

Clinical signs often occur shortly after tick contact and rapidly improve with antimicrobial therapy.⁴⁰ For example, in the study by Adaszek et al, the owners of three cats reported the development of clinical signs 3–7 days after vector contact.¹⁰

In a recent study by Chirek et al of 63 dogs in Germany with granulocytic anaplasmosis, lethargy was listed as the most common clinical sign, with 83% of dogs affected, followed by fever (67%) and inappetence (63%);⁹¹ these rates are comparable to those in cats (Table 2). Haemorrhage was reported in 13% of dogs, but has been rarely described in cats.

In all of the 34 cats with A phagocytophilum infections from the literature that are analysed here (see box on page 432), haematological examination was performed (Table 2). Thrombocytopenia was diagnosed in 20/34 cats (59%); however, low platelet counts in cats must be interpreted with caution (see box), and in six of these 20 cats platelet aggregation was present. Nine out of 34 cats (26%) were anaemic. Five out of 34 cats (15%) were leukopenic and 3/34 cats (9%) had leukocytosis. Similarly to cats, in the 63 dogs with granulocytic anaplasmosis investigated by Chirek et al, thrombocytopenia was the most common laboratory abnormality (86%), followed by anaemia (70%) and leukocytosis (27%), as well as leukopenia (14%).⁹¹ Leukopenia occurred more often in cats than leukocytosis. A differential blood count was available in 25/34 cats (74%). Nine of 25 (36%) cats were lymphopenic and 3/25 (12%) had a lymphocytosis or a neutrophilia (2/3 with a left shift). Further abnormalities included neutropenia (2/25, 8%), eosinophilia (2/25, 8%) and monocytosis (2/25, 8%). Again, in Chirek et al’s study of 63 dogs, similar laboratory abnormalities such as lymphopenia (44%), monocytosis (43%), neutrophilia (35%), eosinophilia (10%), lymphocytosis (8%) and neutropenia (2%) were described.⁹¹

Blood chemistry was performed to varying extents in 27 of the 34 cats (79%) (Table 2). The most common finding was hyperglycaemia, which was found in 6/27 cats (22%). Two out of 27 cats (7%) showed azotaemia, one of them due to an underlying disease (chronic renal insufficiency with a suspected acute component) and one during the course of disease while under intensive care. Electrolyte imbalances and increased liver enzymes were detected in 2/27 cats (7%). Further abnormalities included an increase in lactate dehydrogenase (1/27, 4%) and an abnormal albumin concentration (1/27, 4%), as well as a reduction in serum iron levels (1/27, 4%). Hyperproteinaemia with corresponding hyperglobulinaemia was detected in 1/27 cats (4%), and hyperproteinaemia without hyperglobulinaemia in another cat. In Chirek et al’s 63 dogs with granulocytic anaplasmosis, the proportion of animals with increased liver enzymes and hyperbilirubinaemia was considerably higher, at 75%.⁹¹ Hyperproteinaemia was detected in 43% of dogs and hypoproteinaemia in 2%. Hypoalbuminaemia was reported more commonly in the dogs (62%). Electrolyte imbalances such as hypernatraemia (10%), hyperkalaemia (2%), hyponatraemia (24%) and hypokalaemia (19%) were additionally recorded. Azotaemia was only documented in a small number of dogs in the study (3%).⁹¹

Diagnosis

Several direct and indirect methods have been described for diagnosing infections with A phagocytophilum.^40,107 The detection of morulae in neutrophilic granulocytes in a blood or buffy-coat smear is one such method and is highly indicative of an infection with A phagocytophilum. However, these morulae cannot be differentiated from those of Ehrlichia ewingii; hence, further tests are necessary for confirmation of an infection with A phagocytophilum. In addition, there is always the possibility of falsely interpreting stain residues, nuclei or basophil precipitates in the blood smear as morulae.¹⁰⁸ In experimentally infected cats, morulae were detectable 7–9 days post-infection⁸⁸ or within the first 10 weeks after tick infestation.⁹³ In experimentally infected dogs, morulae were detectable 4 days postinfection and persisted for 4–8 days.³⁷

Table 3

Antiparasitic agents against Ixodes species ticks licensed for use in cats

Application type	Active ingredient	Registered trademark	Repellent effect (ticks)	Antiparasitic effect	Precautions for use
Collar	Imidacloprid, flumethrin	Seresto (Bayer)	Insecticide, acaricide (killing effect) and repellent effect (antifeeding effect)	Ixodes hexagonus, Amblyomma americanum: 8 months. Dogs: I hexagonus, A americanum Ixodes scapularis, Dermacentor variabilis, Ixodes holocyclus. Indirect protection in dogs against transmission of pathogens vectored by Dermacentor reticulatus and Ixodes Ricinus	Treatment in kittens over 10 weeks
	Selamectin, sarolaner	Stronghold Plus (Zoetis)	Insecticide, acaricide (killing effect), but tick has to be attached and has to take up the active ingredient	I ricinus, I hexagonus: 5 weeks D reticulatus, Rhipicephalus sanguineus: 4 weeks	Treatment in kittens over 8 weeks with body weight over 1.25 kg
Spot-on	Fluralaner	Bravecto Spot-on Solution (MSD Animal Health)	Insecticide, acaricide (killing effect), but tick has to be attached and has to take up the active ingredient	I scapularis, I ricinus: 12 weeks D variabilis: 8 weeks	Not effective for 12 weeks’ duration in kittens less than 6 months of age Treatment with body weight over 2.6 kg
	Fluralaner, moxidectin	Bravecto Plus (MSD Animal Health)	Insecticide, acaricide (killing effect), but tick has to be attached and has to take up the active ingredient	I ricinus: 12 weeks	Treatment in kittens over 9 weeks with body weight over 1.2 kg
	Fipronil, (s)- methoprene	Frontline Combo (Boehringer Ingelheim)	Insecticide, acaricide (killing effect), but tick has to be attached and has to take up the active ingredient	I ricinus, D variabilis, R sanguineus: up to 2 weeks	Treatment in kittens over 8 weeks and body weight over 1 kg
	Fipronil	Frontline (Boehringer Ingelheim)	Insecticide, acaricide (killing effect), but tick has to be attached and has to take up the active ingredient	I ricinus, D variabilis, R sanguineus: up to 2 weeks	Treatment in kittens over 12 weeks
Spray	Fipronil	Frontline Spray (Boehringer Ingelheim)	Insecticide, acaricide (killing effect) but tick has to be attached and has to take up the active ingredient	I ricinus, D variabilis, R sanguineus: 4 weeks	Treatment in kittens over 12 weeks

PCR examination detects the pathogen’s DNA in peripheral blood, buffy coat, bone marrow or splenic tissue. Some protocols also include the detection of DNA from other pathogens such as A platys or Pseudomonas species, meaning that further sequencing is necessary for the confirmation of A phagocytophilum infection. In dogs, the detection of Pseudomonas sequences has been reported to cause false-positive results, which will not be apparent until further sequencing has been implemented.¹⁰⁹ To the authors’ knowledge, there are no similar experiences in cats. Another study in cats described direct antigen detection via PCR, which has a high sensitivity and specificity in acute cases but can be falsely negative in chronic infections due to the absence of the pathogen in blood.⁹³

The detection of antibodies via immuno-fluorescence antibody test (IFAT) or ELISA also indicates exposure to A phagocytophilum. However, an acute infection is only confirmed if the antibody titre increases or decreases four-fold within 4 weeks.⁴⁰ In general, IFAT and ELISA have a high sensitivity and specificity, but it is important to give consideration to the limitations of these tests, which include, for example, possible cross reactions with Ehrlichia species and A platys (see box on page 436).^111,112

SNAP tests, for example the SNAP Multi-Analyte Test and the SNAP 4Dx Plus Assay (IDEXX), are used as rapid in-house ELISAs in veterinary medicine. Both tests have been developed as canine assays, but have also successfully detected antibodies against A phagocytophilum in domestic cats.^70,93,113 A comparison between the two SNAP tests and a commercial IFAT for the detection of A phagocytophilum in cats showed discrepancies between the different assays.⁷⁰ Reasons for this could include the lack of specificity of peptides chosen in the design of the assays, the lack of sensitivity of commercial ELISA and/or IFAT and/or an enhanced analytic sensitivity of p16 analytes for testing cat sera. In this study, the IFAT was slightly more sensitive than the ELISA.⁷⁰

Treatment and management

A phagocytophilum is resistant to several antimicrobial agents.^{110,114–116} Doxycycline is the antibiotic of choice for treating rickettsial infections in cats, although currently there are only retrospective case reports supporting this recommendation. It is administered at 10 mg/kg PO q24h for 28 days.⁴⁰ It is recommended that the tablets be dissolved in water or administered with food in order to prevent oesophagitis.¹¹⁷ The ABCD guidelines describe rapid clinical improvement in patients within the first 24–48 h after initiation of antimicrobial treatment with doxycycline.⁴⁰ One cat tested negative as soon as 1 day after the initiation of treatment with doxycycline.⁹ In contrast, however, some studies have described that the pathogen was no longer detectable in blood via PCR after treatment with doxycycline on day 15,¹⁶ after 3 weeks,¹¹ on days 25, 27 and 30,¹⁷ after 6 weeks¹² and on day 139.¹⁷ A further case report documented that the pathogen was detectable via PCR 8 days after starting treatment with doxycycline;⁸ in another cat it was detectable even 120 days after the initial treatment period of 28–30 days.¹⁷ A further cat tested positive after 37 days and negative on day 139.¹⁷ In dogs there are several studies providing varying information. A study in Germany described complete pathogen elimination in all 18 infected dogs 2–8 weeks after the initiation of doxycycline treatment;⁹⁰ however, another study described recurrence of clinical signs after antimicrobial therapy or poor response to treatment.¹¹⁸

All of this confirms that the required duration of treatment in cats is unknown. In comparison, in dogs infected with A phagocytophilum, treatment recommendations are doxycycline 5 mg/kg q12h for 14 days.⁷²

Prevention and public health considerations

Humans are also susceptible to infections with A phagocytophilum, making this pathogen relevant for both human and veterinary medicine.¹¹⁹ Prevention in animals therefore plays an essential role, especially in order to avoid the development of reservoirs.

It is important to raise awareness of tick prevention in endemic areas. Also, clinicians should consider testing potentially exposed animals, as clinical signs are vague and nonspecific. Feline vector-borne infections should be on the list of differential diagnoses in cases with a history of vector contact and clinical signs suspicious of an infection.

If cats are housed indoors and arthropod control (see box on page 437) is maintained, the risk to people should be minimal.³ In addition to antiparasitic treatment, regular examinations for ticks should be carried out by owners and veterinarians.³

The ACVIM guidelines recommend direct and indirect methods of detection for A phagocytophilum in blood donor cats. Only sero-negative and PCR negative cats should donate blood. If no other blood donors are available in endemic regions, seropositive and PCR negative cats may also be used as blood donors.³⁹

Future research needs and concusions

Feline vector-borne infections are gaining in importance. Further research to investigate the pathogenesis of A phagocytophilum infections in cats is required. The spread of potential vectors and pathogens to currently non-endemic regions due to growing tourism, increasing numbers of imported animals, goods traffic and climatic changes makes prophylaxis for companion animals and biological limitation of the tick population even more relevant. As with other vector-borne infections, A phagocytophilum is of great importance for public health in human and veterinary medicine due to its zoonotic potential.

Key Points

Feline vector-borne infections, such as infections with A phagocytophilum, should be on the list of differential diagnoses in cases with a history of vector contact and clinical signs suspicious of an infection.

Clinical signs are often vague and non-specific, which is why diagnosis can be challenging for veterinarians. A thorough history should include information on vector contact and stays abroad.

Avoidance of vector contact plays an important role both in preventing the development of pathogenic reservoirs and infections with vector-borne pathogens in animals, w^^^^^F and in public health in human and veterinary medicine.

Footnotes

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

This work did not involve the use of animals and therefore ethical approval was not necessarily required.

Informed consent

This work did not involve the use of animals and therefore informed consent was not required. No animals or humans are identifiable within this publication, and therefore additional informed consent for publication was not required.

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Anaplasma phagocytophilum infection in cats: A literature review to raise clinical awareness

Abstract

Practical relevance:

Global importance:

Aim:

Evidence base:

Keywords

Introduction

Epidemiology

Pathogenesis

Clinical and laboratory findings

Diagnosis

Treatment and management

Prevention and public health considerations

Future research needs and concusions

Key Points

Footnotes

Conflict of interest

Funding

Ethical approval

Informed consent

References