Non-infectious illness after tick bite

Tick bites are common and may have non-infectious complications. Reactions range from local reactions to systemic syndromes, tick paralysis, mammalian meat allergy and tick anaphylaxis. Management revolves around prevention with vector avoidance and immediate removal of the tick if bitten. Treatment of bite reactions is usually symptomatic only with anti-histamines or corticosteroids. Adrenaline may be indicated for severe cases.

Ticks are ubiquitous arthropods which incidentally bite humans during outside activities (i.e. exposure to burrows and caves in regards to Argasid (soft) ticks, and exposure to vegetation for Ixodid (hard) ticks)¹. Seventy species of ticks have been recorded in Australia². Common Argasid ticks that bite humans include Argas and Ornithodoros species, whereas Ixodid ticks include Amblyomma, Dermacentor, Haemaphysalis, Hyalomma and Ixodes species¹. Human-biting ticks in Australia include A. triguttatum³ and Ixodes genus ticks (predominantly I. holocyclus and I. cornuatus but include I. fecialis, I. tasmani, I. australiensis)². Two biting seasons have been described in south-eastern Australia, the predominant one peaking in October/November with a secondary peak in April⁴.

Accurate data about the prevalence of post tick-bite illness are hard to find, but as many as 10% of tick-bite victims may experience illness overseas⁵. This includes local reactions (57.6% of total reactions in Polish patients)⁶, systemic syndromes, tick paralysis and anaphylaxis.

Tick saliva is injected during a bite and contains a complex mix of chemicals. These neutralise host protective mechanisms such as pain, haemostasis, inflammation (which can reduce transmitted infections) and immune reactions⁷. Transcriptome analysis has characterised the sialotranscriptome of specific ticks⁸, which changes depending on life stage and feeding status.

Of the human biting ticks, Ixodes spp. saliva contains proteins encoded by a metalloproteinase family of genes that inhibit wound healing and facilitate prolonged feeding via anti-haemostatic agents⁷.

Boophilus (previously Rhipicephalus) bites differentially induce acute phase proteins in infested cows (increased haptoglobin in sensitive and serum amyloid A in resistant strains)⁹. Cows have varying genetic susceptibilities to Boophilus tick bite that may be mediated by induction of inflammation (via leukocyte adhesion modulated by ICAM-1, VCAM-1 and P-selectin)¹⁰. Downregulation of host immunity via regulatory dendritic cells in murine bone marrow¹¹ and bovine leucocyte recruitment (eosinophils, basophils) have been reported¹². Cows resistant to tick bite express more E-selectin¹² and downregulate genes encoding production of volatile compounds that attract tick larvae¹³.

These can have an erythaematous, nodular, pustular or plaque-like appearance¹⁴. Local reactions are minimised by immediate removal of the tick¹⁴ with symptomatic treatment (i.e. anti-histamines or corticosteroids).

Gauci divided allergic reactions to I. holocyclus into six classes using skin-prick tests and radioimmunoassay (RIA). All systemic hypersensitivity (class 3) and atypical reactions (class 4) were IgE-mediated. 73% of the large local reactions (class 2) and only 12.5% of the small local reactions (class 1) were associated with IgE specific for tick allergens. Heavy exposure to tick-bite was associated with positive RIA values. There was an association between atopic status and tick allergy¹⁵.

Biopsies of tick bites in humans demonstrate deep perivascular and interstitial infiltrates of lymphocytes, neutrophils and eosinophils. Late biopsies show vascular eosinophilic hyaline thrombi which can mimic Type 1 cryoglobulinaemia¹⁶. Retention of tick mouth parts may drive this inflammatory reaction¹⁷. Other local reactions include foreign body granuloma, tick bite alopecia (may be scarring or non-scarring¹⁴), intermediate cell histiocytosis and cutaneous lymphoid hyperplasia¹⁸. Chronic papular urticaria due to A. reflexus has been reported¹⁹.

The local immune response to early tick bite lesions in humans (predominance of macrophages and dendritic cells with elevated mRNA for macrophage and neutrophil chemoattractants as well as IL-1β and IL-5) differs from those with longer tick attachment times (increased lymphocytes and decreased macrophages and neutrophils)²⁰. Antibodies directed against components of tick saliva can be detected in humans and used to determine the epidemiology of specific tick activity in certain regions²¹.

These include headache (10.8%), fever (5.4%), lymphadenitis (5.9%) and arthralgia (4.3%)⁶. No in-vivo physiological studies in humans with systemic symptoms induced by tick bite exist, but systemic toxicosis was demonstrated in an animal model²². After Ornithodoros ticks fed on rats, hyperaemia of oral mucosa and ocular mucosa, pilo-erection, tachypnoea, ocular and nasal discharge was observed in association with local haemorrhagic lesions. Increased bleeding times, eosinophilia and basophilia, raised creatinine kinase (total and MB) and LDH were noted. Myocardial myocyte degeneration and necrosis was also documented.

In-vitro studies of blood collected from humans previously bitten by ticks, when stimulated with Ixodes antigens, was shown to induce basophilia²³.

Symptomatic treatment with anti-histamines or corticosteroids are usually sufficient for this syndrome.

Tick paralysis is caused by several neurotoxins that vary according to tick species and (therefore) region of the world²⁴. The best characterised is a 5 kDa protein contained in the saliva of gravid females that interferes with acetyl choline release²⁵. Bancroft described the first human case of tick toxicosis in Australia in 1888¹⁴. TP can be induced by 69 tick species worldwide but Ixodes ticks (I. holocyclus or I. cornuatus) are usually implicated in Australia²⁶ and Dermacentor (D. andersoni and D. variabilis) in North America²⁴. Widespread reports of TP have subsequently come from Spain, Turkey, Egypt, Ethiopia, Thailand, and Argentina²⁴. Cases acquired in Australia but presenting elsewhere have been reported²⁴, and may delay the diagnosis. Aside from humans, dogs and cats are the most commonly affected animals but sheep, cattle, goats, pigs and horses may also be involved.

Tick attachment sites are predominantly on the head in the US but vary in different regions. Ectopic sites (such as intra-aural²⁶) are often associated with delayed diagnosis. Most US cases occur in young girls (possibly due to long hair obscuring the attached tick) but adults are also affected. A flu-like prodrome followed by development of weakness, ascending symmetrical paralysis, ataxia, dilated pupils, slurred speech and depressed deep tendon reflexes is described. Laboured breathing, bradycardia and asystole may develop requiring supportive care. Myocarditis, diplopia and facial palsy may also occur. The duration of illness is very short in American cases after tick removal but is often longer in Australian cases²⁶. The differential diagnosis includes Guillain–Barre syndrome, spinal cord lesions, myaesthaenia gravis, botulism, poliomyelitis, organophosphate or heavy metal poisoning and diphtheria. Rapid recognition enables prompt tick removal and avoids inappropriate therapy such as plasmaphoresis²⁶.

Treatment requires immediate removal of the tick, which may be associated with temporary worsening of the paralysis. In order to not facilitate envenomation, the tick must be killed before removal, which is most readily achieved by freezing with ether-containing agents (i.e. Wart-Off, Tick-Off)¹⁵. The tick may be removed with narrow forceps applied as close to the skin as possible (which is the most common method used in the USA)²⁶.

This may due to a direct IgE–mediated reaction against components of tick saliva, or an indirect IgE reaction against galactose-α-1,3-galactose (α-gal, a saccharide found in all non-primate mammalian cells, but not in humans¹⁵) injected by the tick. It was first reported in Australia in 1940²⁷ and has since been recognised overseas after Ixodes¹⁵ Rhipicephalus²⁸ and A. reflexus (in 8%)²⁹ tick bites.

Management includes prevention with vector avoidance (i.e. application of diethyltoluamide (DEET) to skin, permethrin impregnation of clothes, tucking trousers into socks and daily tick checks), immediate removal of the tick, anti-histamines and corticosteroids and adrenaline for severe cases.

Red meat allergy triggered by tick bite was first recognised in Sydney in 2007¹⁵ when 25 cases related to I. holocyclus bites were reported. Subsequent cases were recognised in eastern Australia and Costa Rica, South-east USA, France, Spain, Germany, Switzerland, Sweden, Italy, Korea, Japan, and China²⁰. Aside from I. holocyclus and I. cornuatus, ticks triggering these events have included A. americanum, I. ricinus and H. longicornis. The author’s laboratory recently diagnosed a case of MMA that was acquired in the Kimberley region, demonstrating that this condition is also found west of the Nullabor Plain. Another subsequent case in WA, possibly related to I. australiensis has confirmed this observation¹⁵.

In 2009, delayed anaphylaxis triggered by consumption of mammalian meat was found to be associated with the presence of α-gal-specific IgE antibodies¹⁵ and it was noted that >80% of these patients had a history of tick bite. Subsequently α-gal IgE antibodies were prospectively shown to develop in response to tick bite. α-gal has now been definitively identified in the gastrointestinal tract of I. ricinus¹⁵ completing the pathogenetic puzzle. These reactions have been described after eating beef, lamb and pork¹⁵. Anaphylaxis has also occurred after eating kangaroo meat, but the patient’s tick bite status was not known³⁰. As well as meat, cetuximab (a mouse-human chimeric antibody)¹⁵, gelatine¹⁵ or milk products can also trigger MMA.

Clinical manifestations, including a delay of 3–6 hours after oral exposure, can range from gastrointestinal upset to angioedema and frank anaphylaxis¹⁵. Skin prick testing (SPT) typically gives weak reactions (<5 mm) to commercial preparations of mammalian meats but stronger reactions with fresh meat extracts. Patients always have elevated specific IgE levels (>1.0 IU/mL) to the relevant meat, cow’s milk, cat and dog reagents as well as to α -gal. SPT and specific IgE levels are always negative to poultry or fish reagents. Management of MMA revolves around avoidance of meat and tick exposures with ready availability of adrenaline (i.e. Epi-Pen) for severe reactions¹⁵.

Recently a number of Australians have become convinced that a protean illness, which may or may not be associated with tick bite, is a manifestation of locally acquired Lyme Disease (cited in Boyle et al.³¹). Enquiries by the Chief Health Officer (cited in Boyle et al.³¹) and both houses of Parliament (cited in Boyle et al.³¹) were unable to identify convincing proof of this concept. I have proposed that a non-controversial name for the syndrome, ‘Australian Multisystem Disorder’, should be adopted³². The Australian Senate has counter-proposed with the title ‘Debilitating Symptom Complexes Attributed to Ticks’³³.

Appropriate management of this syndrome relies on development of adequate research funding to identify the aetiology and efficacious protocols.

Non-infective complications of tick bites are common and may have potentially fatal consequences. Prevention of tick bites is crucial and prompt removal of ticks will limit their adverse effects.

The author declares no conflicts of interest.