Background

Lyme disease is a zoonotic, tick-borne illness transmitted by specific ixodid ticks to humans. With approximately 300,000 cases per annum, Lyme disease is the most common reportable vector-borne disease in the United States . The most common presenting clinical feature is a skin lesion called erythema migrans . In the United States, Lyme disease is caused only by the spirochete B . burgdorferi , whereas in Europe and Asia, B . afzelii and B . garinii are also clinically important . In the United States, it is transmitted by I . scapularis ticks, often referred to as deer ticks, in the northern and Midwestern states and by I . pacificus ticks in the western states. In Europe and Asia, the main vectors are Ixodes ricinus and Ixodes persulcatus , respectively. This is in accordance with the incidence rate of erythema migrans, which peaks during the spring and summer months . Risk factors for Lyme disease include occupational and recreational exposure to fields and woods in endemic areas, as well as outdoor activities such as gardening on residential properties near woodlands . Ixodid ticks are also known to be vectors for other diseases that may produce co-infection with B . burgdorferi , which can show clinical manifestations from asymptomatic to severe and life threatening .

Although more cases are diagnosed during the summer months, infections can occur throughout the year. Individuals of all ages are susceptible to Lyme disease; however, the disease has a bimodal distribution: it is most common amongst children between the ages of 5 and 9, and adults between the ages of 55 and 59. More than half of the cases occur in men (53.1%) . Only 30,000 cases are reported to the Centers for Disease Control (CDC) each year; however, according to the CDC, cases are underreported with approximately 300,000 individuals infected in the United States each year . The incidence rate continues to increase, may be due to better surveillance and increased awareness or to a higher infection rate from more frequent travel to endemic areas.

Clinical disease presentation

There are three distinct infection phases of Lyme disease: early localised, early disseminated and late disseminated. All phases have overlapping features . The early localised phase begins with an often painless rash called erythema migrans, appearing around 3–30 days after the tick bite ( Table 1 ). The rash is located around the tick-bite site, and it is traditionally described as an erythematous oval surrounded by a zone of clearing and another ring of erythema. Erythema migrans rash occurs in >80% of individuals with Lyme disease; however, only approximately 20% show the classic “bull eye” lesion . During the early localised phase, individuals may also show flu-like symptoms including fatigue, headache, myalgia, arthralgia, anorexia, neck stiffness, lymphadenopathy and fever, but they may lack respiratory or gastrointestinal symptoms .

The second early dissemination phase of Lyme disease occurs within days to months after the appearance of the initial erythema migrans . Symptoms are most common in the joints as transient monoarticular or oligoarticular symptoms of arthritis, in the nervous system with radiculopathy, lymphocytic meningitis or predominately unilateral cranial neuropathies and in the cardiovascular system most commonly presenting as atrioventricular nodal block or as myopericarditis . The symptoms of the second stage may be accompanied by fever, fatigue, myalgia and arthralgia.

The last stage of Lyme disease is characterised by either intermittent or chronic symptoms of arthritis, peripheral neuropathy or encephalomyelitis, which occur from months to years after the initial tick bite. This stage lacks systemic symptoms as opposed to the earlier stages. It is also different to post-treatment Lyme disease syndrome, which is referred to as non-specific symptoms that persist after the completion of antibiotic treatment, and from chronic Lyme disease, which is a controversial entity of chronic symptoms in patients who may have or have not ever had true Lyme disease .

Arthritis is the most common extracutaneous manifestation in patients with Lyme disease in the United States if untreated after B . burgdorferi skin infection. Approximately 60% of untreated patients show intermittent bouts of arthritis, including severe joint pain and swelling. Large joints, particularly the knees, are most often affected. Joint pains can be mistaken for other types of arthritis, such as rheumatoid arthritis (RA). The diagnosis of Lyme arthritis can usually be made by serologic testing of antibodies against Borrelia or through polymerase chain reaction (PCR) of the synovial fluid and skin biopsy; however, current recommendations state that upon the presentation of erythema migrans, treatment should commence prior to laboratory conformation ( Table 1 ). Clinical features also help to distinguish Lyme disease from RA. Unlike RA, the involvement of small joints of the hands and feet is uncommon in patients with Lyme arthritis. Furthermore, most patients with Lyme arthritis report a history of erythema migrans or other early disease manifestations, and they have been in endemic regions where tick exposure is likely . Lyme arthritis usually improves with the administration of medication against inflammation, for example, non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs) and intra-articular steroids. Antibiotic therapy does not resolve arthritis per se, but it usually prevents the development of Lyme arthritis .

Pathogenesis of disease

B . burgdorferi lacks virulence factors and toxins; thus, the clinical symptoms related to Lyme disease result from the immune response to infection . Histopathologic analyses in humans reveal a mononuclear-type inflammation with macrophages, dendritic cells and plasma cells characteristically seen in all tissues except for the synovial fluid, where polymorphonuclear leukocytes, such as neutrophils and B- and T-cells, predominate . Initiation of inflammation begins with dendritic cells and macrophages responding to B . burgdorferi through pattern-recognition receptors. The interaction of B . burgdorferi components with Toll-like receptors (TLR) constitutes the main recognition pathway . TLR stimulation activates mitogen-activated protein (MAP) kinases and nuclear factor-κB (NF-κB), which induces the production of pro-inflammatory cytokines such as interleukin (IL)-1-β, tumour necrosis factor (TNF), IL-6 and type I interferons (IFN) . B . burgdorferi also induces the anti-inflammatory cytokine IL-10, which may be a survival strategy as it has been found that blocking IL-10 production significantly enhances bacterial clearance in mice .

Unexplained clinical features in the pathogenesis of Lyme arthritis include the delayed onset after infection and the spontaneous remission of inflammation in one joint with recurrence in the same or different joint . B . burgdorferi generally reaches the joint via hematogenous dissemination during the early stage of infection. The joint is presumably infected long before the onset of swelling. It has been postulated that B . burgdorferi resides in structures in close proximity to the joint space such as the synovial membrane, joint capsule, tendons and/or tendon sheaths, ligaments, cartilages or menisci . In chronically infected mice, B . burgdorferi has been visualised in small number in the highly vascular synovia as well as in avascular tendons, without showing associated inflammation . Identification of spirochetes in clinical samples from inflamed synovia is rare during the pre-arthritis stage. Spirochetes may reside in protective niches, and they initiate inflammation after seeding the synovia, where they are bound by specific antibodies or are recognised by the innate immune cells. Spirochetes may induce host responses in sites such as blood vessel walls or tendons with an effect on these tissues. Observed features of Lyme arthritis are obliterative vasculopathy, enthesopathic changes and cartilage calcification . Magnetic resonance imaging (MRI) studies in humans usually show inflammation primarily affecting the synovia and occasionally the adjacent muscles .

Background

Lyme disease is a zoonotic, tick-borne illness transmitted by specific ixodid ticks to humans. With approximately 300,000 cases per annum, Lyme disease is the most common reportable vector-borne disease in the United States . The most common presenting clinical feature is a skin lesion called erythema migrans . In the United States, Lyme disease is caused only by the spirochete B . burgdorferi , whereas in Europe and Asia, B . afzelii and B . garinii are also clinically important . In the United States, it is transmitted by I . scapularis ticks, often referred to as deer ticks, in the northern and Midwestern states and by I . pacificus ticks in the western states. In Europe and Asia, the main vectors are Ixodes ricinus and Ixodes persulcatus , respectively. This is in accordance with the incidence rate of erythema migrans, which peaks during the spring and summer months . Risk factors for Lyme disease include occupational and recreational exposure to fields and woods in endemic areas, as well as outdoor activities such as gardening on residential properties near woodlands . Ixodid ticks are also known to be vectors for other diseases that may produce co-infection with B . burgdorferi , which can show clinical manifestations from asymptomatic to severe and life threatening .

Although more cases are diagnosed during the summer months, infections can occur throughout the year. Individuals of all ages are susceptible to Lyme disease; however, the disease has a bimodal distribution: it is most common amongst children between the ages of 5 and 9, and adults between the ages of 55 and 59. More than half of the cases occur in men (53.1%) . Only 30,000 cases are reported to the Centers for Disease Control (CDC) each year; however, according to the CDC, cases are underreported with approximately 300,000 individuals infected in the United States each year . The incidence rate continues to increase, may be due to better surveillance and increased awareness or to a higher infection rate from more frequent travel to endemic areas.

Clinical disease presentation

There are three distinct infection phases of Lyme disease: early localised, early disseminated and late disseminated. All phases have overlapping features . The early localised phase begins with an often painless rash called erythema migrans, appearing around 3–30 days after the tick bite ( Table 1 ). The rash is located around the tick-bite site, and it is traditionally described as an erythematous oval surrounded by a zone of clearing and another ring of erythema. Erythema migrans rash occurs in >80% of individuals with Lyme disease; however, only approximately 20% show the classic “bull eye” lesion . During the early localised phase, individuals may also show flu-like symptoms including fatigue, headache, myalgia, arthralgia, anorexia, neck stiffness, lymphadenopathy and fever, but they may lack respiratory or gastrointestinal symptoms .

The second early dissemination phase of Lyme disease occurs within days to months after the appearance of the initial erythema migrans . Symptoms are most common in the joints as transient monoarticular or oligoarticular symptoms of arthritis, in the nervous system with radiculopathy, lymphocytic meningitis or predominately unilateral cranial neuropathies and in the cardiovascular system most commonly presenting as atrioventricular nodal block or as myopericarditis . The symptoms of the second stage may be accompanied by fever, fatigue, myalgia and arthralgia.

The last stage of Lyme disease is characterised by either intermittent or chronic symptoms of arthritis, peripheral neuropathy or encephalomyelitis, which occur from months to years after the initial tick bite. This stage lacks systemic symptoms as opposed to the earlier stages. It is also different to post-treatment Lyme disease syndrome, which is referred to as non-specific symptoms that persist after the completion of antibiotic treatment, and from chronic Lyme disease, which is a controversial entity of chronic symptoms in patients who may have or have not ever had true Lyme disease .

Arthritis is the most common extracutaneous manifestation in patients with Lyme disease in the United States if untreated after B . burgdorferi skin infection. Approximately 60% of untreated patients show intermittent bouts of arthritis, including severe joint pain and swelling. Large joints, particularly the knees, are most often affected. Joint pains can be mistaken for other types of arthritis, such as rheumatoid arthritis (RA). The diagnosis of Lyme arthritis can usually be made by serologic testing of antibodies against Borrelia or through polymerase chain reaction (PCR) of the synovial fluid and skin biopsy; however, current recommendations state that upon the presentation of erythema migrans, treatment should commence prior to laboratory conformation ( Table 1 ). Clinical features also help to distinguish Lyme disease from RA. Unlike RA, the involvement of small joints of the hands and feet is uncommon in patients with Lyme arthritis. Furthermore, most patients with Lyme arthritis report a history of erythema migrans or other early disease manifestations, and they have been in endemic regions where tick exposure is likely . Lyme arthritis usually improves with the administration of medication against inflammation, for example, non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs) and intra-articular steroids. Antibiotic therapy does not resolve arthritis per se, but it usually prevents the development of Lyme arthritis .

Pathogenesis of disease

B . burgdorferi lacks virulence factors and toxins; thus, the clinical symptoms related to Lyme disease result from the immune response to infection . Histopathologic analyses in humans reveal a mononuclear-type inflammation with macrophages, dendritic cells and plasma cells characteristically seen in all tissues except for the synovial fluid, where polymorphonuclear leukocytes, such as neutrophils and B- and T-cells, predominate . Initiation of inflammation begins with dendritic cells and macrophages responding to B . burgdorferi through pattern-recognition receptors. The interaction of B . burgdorferi components with Toll-like receptors (TLR) constitutes the main recognition pathway . TLR stimulation activates mitogen-activated protein (MAP) kinases and nuclear factor-κB (NF-κB), which induces the production of pro-inflammatory cytokines such as interleukin (IL)-1-β, tumour necrosis factor (TNF), IL-6 and type I interferons (IFN) . B . burgdorferi also induces the anti-inflammatory cytokine IL-10, which may be a survival strategy as it has been found that blocking IL-10 production significantly enhances bacterial clearance in mice .

Unexplained clinical features in the pathogenesis of Lyme arthritis include the delayed onset after infection and the spontaneous remission of inflammation in one joint with recurrence in the same or different joint . B . burgdorferi generally reaches the joint via hematogenous dissemination during the early stage of infection. The joint is presumably infected long before the onset of swelling. It has been postulated that B . burgdorferi resides in structures in close proximity to the joint space such as the synovial membrane, joint capsule, tendons and/or tendon sheaths, ligaments, cartilages or menisci . In chronically infected mice, B . burgdorferi has been visualised in small number in the highly vascular synovia as well as in avascular tendons, without showing associated inflammation . Identification of spirochetes in clinical samples from inflamed synovia is rare during the pre-arthritis stage. Spirochetes may reside in protective niches, and they initiate inflammation after seeding the synovia, where they are bound by specific antibodies or are recognised by the innate immune cells. Spirochetes may induce host responses in sites such as blood vessel walls or tendons with an effect on these tissues. Observed features of Lyme arthritis are obliterative vasculopathy, enthesopathic changes and cartilage calcification . Magnetic resonance imaging (MRI) studies in humans usually show inflammation primarily affecting the synovia and occasionally the adjacent muscles .

Background

CHIKV is the aetiological agent of the debilitating arthropod-borne disease chikungunya fever (CF), an acute illness characterised by incapacitating joint pain in humans. A member of the Togaviridae family and the ‘Semliki Forest antigenic group’, CHIKV is a positive sense, single-stranded RNA virus. CHIKV is maintained in an enzootic transmission cycle between mosquitoes, principally of the genus Aedes ( Ae ), and non-human primates. This cycling of CHIKV can lead to human transmission when infectious vectors bite individuals. Subsequent urban transmission (human–mosquito–human) can spread CHIKV rapidly within human populations causing outbreaks of CF. The two major vectors associated with outbreaks are Ae aegypti and Ae albopictus .

Classically, the major regions of circulating virus, east/central Africa, Asia and west Africa, experience cyclical epidemics and sporadic cases of CF. However, since the re-emergence of CHIKV in 2005/2006, during a series of large-scale outbreaks that began in Kenya and spread throughout India and the islands of the Indian Ocean, CHIKV has continued to spread rapidly . Outbreaks have subsequently been reported throughout South East Asia, and recently CHIKV has expanded into the Americas. As of 21 November 2014, local transmission had been identified in 40 countries or territories in the Caribbean, Central America, South America or North America with a total of 914,960 suspected cases of CF . Autochthonous transmission of CHIKV has also been found in Europe: in Italy, following an outbreak initiated by a traveller returning from India, and more recently in France, likely from a laboratory-confirmed imported case returning from Asia . The global spread of the virus has been aided, in part, by international travel, with imported cases of CHIKV confirmed in travellers returning to areas including Australia and North America . In addition, the scale of recent epidemics has also been associated with the adaptation of CHIKV strains to the widely distributed vector Ae albopictus . An A226V mutation in the CHIKV E1 glycoprotein was shown to enhance infectivity in Ae albopictus , a vector that is regularly active and has a relatively long natural life . The E1 A226V mutation has since been detected in CHIKV isolates following numerous outbreaks, particularly where Ae albopictus was the predominant vector of urban transmission. It is likely that the increased viral fitness in this vector species together with the invasive nature of Ae albopictus will continue to contribute to the global spread of CHIKV.

The outbreak in 2005/2006 in India and in the islands of the Indian Ocean also drew global attention owing to the atypical and severe clinical symptoms of infected patients. Usually a nonfatal self-limiting disease, CF during the Indian Ocean outbreak was associated with neurological complications, haemorrhage and an increased mortality rate. In Reunion Island, a case-fatality ratio of about 1 in 1000 was reported . The increased mortality rate and the majority of severe disease complications observed in patients during this outbreak were often associated with underlying medical conditions. Another factor linked to serious forms of CF was age, with the elderly, neonates and infants found to be more at risk of developing severe manifestations . Currently, no licensed vaccine or antiviral drug against CHIKV is commercially available. The lack of a specific therapeutic against CHIKV means that the treatment of CF is largely symptomatic. The majority of standard cases rely on paracetamol and NSAIDs to reduce fever and provide pain relief from rheumatic symptoms. Thus, the re-emergence of CHIKV and the scale and severity of outbreaks over the last 10 years has forced research efforts to concentrate on understanding the pathogenesis of this neglected virus.

Clinical disease presentation

Once infected with CHIKV, the virus has an average incubation period of 2–4 days . After incubation, acute CF is characterised by a high fever (up to 40 °C) followed shortly by a severe arthritis/arthralgia as that resembling in patients with RA . Disabling migratory polyarthralgia is the most common feature of CF, experienced by practically all patients . Arthralgia is often symmetrical, and it regularly affects the distal joints, such as the fingers, wrists, toes and ankle joints, although there are reports of proximal and large-joint involvement (e.g., shoulders and spine) . Signs of soft tissue swelling can be seen in the affected joints, and patients can experience difficulty performing even basic tasks such as standing straight and walking. Other commonly described features of acute CF include myalgias, headache, tenosynovitis and a maculopapular erythematous rash typically found on the trunk ( Table 1 ). Digestive symptoms such as diarrhoea and vomiting have also been described during outbreaks or in cohorts of travellers . These acute signs usually resolve within 1–2 weeks; however, in a considerable number of patients, the arthralgia can persist for months or years having a significant impact on their quality of life . Studies suggest that over half of patients previously infected with CHIKV report persistent or episodes of recurrent arthralgia over 2 years post infection, and that a proportion of these patients fulfil the criteria set by the American College of Rheumatology for RA . The risk of developing persistent/chronic arthralgia is very much linked to age, with older patients more likely to experience persistent joint pain. In addition, the underlying co-morbidities and the severity of arthralgia during the acute phase of CF have been linked with chronic disease .

The rate of asymptomatic infection with CHIKV is lower than most other arboviral infections, with approximately 15% of infected individuals being asymptomatic. Interestingly, the proportion of patients infected with CHIKV requiring medical attention is higher than with other arboviral infections. More atypical clinical manifestations of CHIKV disease have also been reported. The neurological disorders associated with approximately 25% of severe cases of CHIKV infection during the Reunion outbreak included encephalitis, malaise, meningoencephalitis, syndrome of meningeal irritation, acute flaccid paralysis, Guillain–Barré syndrome and cerebellar syndrome . The vast majority of these patients suffered from previous disorders such as epilepsy, hypertension, ischaemic heart disease, alcohol abuse and stroke. Despite this, neurological disorders including encephalitis and meningoencephalitis occurred in previously healthy cases upon infection. Similarly, arrhythmias, myocarditis, pericarditis and myocardial infarction were reported in patients infected with CHIKV and with no history of cardiovascular disease. Encephalitis and cardiac complications were principally responsible for mortality in children with severe CHIKV disease during the Reunion outbreak . Additional uncommon cutaneous complications associated with CHIKV infection have been described, including aphthous-like ulcers, exfoliative dermatitis, hypermelanosis, vesiculobullous lesions with desquamation and vasculitic lesions . Haemorrhagic manifestations, although rare (1–7% of patients), are an important distinction from dengue fever for clinicians ( Table 1 ). Retrospective studies have also revealed sensitive diagnosis of CF by observing fever together with polyarthralgia, or arthralgia with rash . Further studies propose clinical and clinicobiological scores that examine arthralgia on the hands and wrists, with the presence of lymphopaenia to diagnose CF . Despite this, laboratory confirmation is crucial in diagnosing CF due to the similar clinical manifestations and epidemiology associated with diseases such as dengue fever, malaria and other infectious arthritogenic diseases.

Pathogenesis of disease

CHIKV pathogenesis is currently an area of intense research owing to the dramatic scale and severity of recent outbreaks. Clinical studies have provided vital insight into the virus–host interactions that mediate CHIKV disease, and since the late 2000s, much effort has been made to develop suitable animal models that replicate the self-limiting arthritis, tenosynovitis and myositis seen in patients infected with CHIKV. The now-established non-human primate and mouse models of CHIKV disease are able to reproduce the viral, clinical and immunopathological features observed in human disease. Subsequent data from in vivo studies strengthen observations made in the clinic.

When transmitted by mosquito bite, CHIKV is delivered intradermally where local replication occurs in resident endothelial cells, macrophages and fibroblast cells. From here, CHIKV rapidly enters the circulatory system, likely gaining access via dissemination to the lymphoid organs, triggering an early type I IFN response . Viraemia is detectable within the first 5–7 days post infection. From the blood, CHIKV is able to disseminate to target organs and tissues. In vivo studies have identified IFN-α/β as key innate immune mediators responsible for limiting the spread of CHIKV during the early stages of infection. Aberrant type I IFN signalling in infected mice led to severe disease signs and death . Similarly, in clinical studies, high levels of IFN-α were consistently found in patients with acute CHIKV disease suggesting a strong innate immune response .

A variety of other cell and tissue types have also been shown to be susceptible to CHIKV infection, including dendritic cells, muscles and osteoblast cells . Infection of these tissues, and the accompanying inflammatory response, likely results in the acute disease symptoms associated with chikungunya. The exact mechanisms that underlie the debilitating arthralgia that is typical of acute CHIKV infection remain unknown; however, a growing number of clinical and in vivo studies suggest that the host-immune response plays a major role in CHIKV-induced pathologies. Clinical studies revealed high levels of IL-1-β, IL-6, monocyte chemotactic protein-1 (MCP-1) and monokine induced by gamma interferon (MIG) in the serum of infected patients . Moreover, plasma levels of IL-6 and MCP-1 were found to be reliable biomarkers of high viral loads in patients with acute CHIKV infection . In line with this, CHIKV infection in animal models was associated with the production of inflammatory factors MCP-1, TNF-α, IL-6, IFN-α/β and IFN-γ, suggesting that the increased expression of pro-inflammatory cytokines and chemokines is associated with CHIKV disease . CHIKV has been found to replicate to high titres in the joints and skeletal muscles of mice and non-human primates, and it was associated with extensive inflammatory cell recruitment to those tissues, features observed in human disease . Pathological analysis of infected tissues revealed infiltration by numerous inflammatory cells, largely mononuclear cells including macrophages. Further infiltration of inflammatory cells, including natural killer (NK) cells and neutrophils, was observed in the synovial membranes, connective tissues and the tendon capsule. Macrophages are particularly important during CHIKV-induced rheumatic disease demonstrating a dual role in mediating CHIKV inflammatory disease and in regulating viral clearance and resolution of inflammation . Furthermore, a number of studies have reported active infection of human monocytes and persistence of CHIKV within macrophages in lymphoid, muscle and joint tissues . Collectively, these data suggest that macrophages are a primary cellular target during CHIKV infection, which may assist in virus dissemination.

Recent studies have demonstrated that CHIKV infection of bone cells stimulates osteoclastogenesis. By disrupting the receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) ratio, an observation consistent with serum data from infected patients, CHIKV infection creates a pro-osteoclastic microenvironment . The expression of MCP-1, MCP-2 and MCP-3, which modulate the chemotaxis of osteoblasts and osteoclasts, was also elevated in the joints of CHIKV-infected mice, accompanied by increased cellularity within the bone marrows and ankle joints. Osteoclastogenesis promotes bone resorption, and CHIKV-induced bone loss was evident in the proximal tibial epiphysis of infected mice. Interestingly, bone loss and inflammation were significantly reduced in CHIKV-infected mice receiving the MCP inhibitor, bindarit, further characterising the importance of MCPs and monocytic cells in the pathogenesis of CHIKV.

Background

RRV is an alphavirus that, like CHIKV, belongs to the Semliki Forest antigenic group. RRV is responsible for Ross River virus disease (RRVD) in humans, which often presents as fever, rash, lethargy and painful polyarthritis in acutely infected patients. RRV is endemic to Australia and Papua New Guinea, where it is responsible for frequent outbreaks of polyarthritis. On average, 4000–5000 cases of RRVD are reported annually in Australia. This makes RRVD the most common arboviral disease in Australia, and RRV the most widespread mosquito-borne virus in Australia.

RRV has since been found in multiple mosquito vector genera including Ae , Anopheles , Coquillettidia ( Cq ) and Culex ( Cx ) . Only a small number of species are considered principal vectors, and these generally occupy an environmental niche within Australian habitats. Seasonal changes and floodwater can also influence vector abundance and RRV transmission, and they can aid predictions of RRVD epidemics, thus improving the effectiveness of public health responses.

The primary vertebrate hosts of RRV are thought to be macropods, such as kangaroos and wallabies. In addition, flying foxes, horses, possums and humans have been implicated as amplifying hosts with possible roles in urban transmission of RRV . Human–mosquito–human transmission is thought to occur during outbreaks of RRVD, with high viraemia recorded in febrile patients, and the spread of the virus to non-endemic areas is likely a result of viraemic travellers .

It has been suggested that RRV could emerge as one of the most common infections of Oceania’s poorest people within the next decade . Although much effort has been made to understand the epidemiology, distribution and vector competence of RRV in Australia, the prevalence of RRV in Papua New Guinea remains unclear due to inadequate research efforts. With the broad range of mosquito vectors able to transmit RRV, there is also a need for greater surveillance to monitor the potential spread of the virus.

Clinical disease presentation

RRV is thought to have an average incubation period of 7–9 days. In general, patients present with arthritis, malaise, fever, headache and a non-itchy maculopapular erythematous rash, commonly affecting the limbs and trunks. The best estimates of the number of asymptomatic RRV infections give an asymptomatic–symptomatic ratio of 3:1. The disease sign most commonly associated with symptomatic infection is symmetrical joint pain, usually in the peripheral joints such as the wrists and small joints of the hands and feet. The severity of the arthralgia experienced by patients with RRVD has been likened to that of osteoarthritis, RA or the arthritis of Lyme disease . In general, the acute symptoms of RRV infection resolve within weeks. However, the duration of arthritic symptoms and especially chronic fatigue attributed to RRV infection remains a contentious topic. Although protracted arthralgia has been described in patients previously infected with RRV, studies suggest that chronic arthralgia in these patients may be the result of additional co-morbidities. Clearer diagnostic guidelines and a greater understanding of protracted arthritic disease following RRV infection are therefore required to enable better follow-up care of RRVD patients . In almost all patients, RRV-induced arthralgia is thought to resolve within 3–6 months. Other, less common, clinical manifestations reported include lymphadenopathy, nausea and sore eyes or photophobia. The suggestion of RRV infection causing encephalitis, glomerulonephritis, splenomegaly and meningitis is limited to very few case reports ( Table 1 ).

With no curative therapy currently available, recommendations for the treatment of RRVD are limited to symptom relief and maintaining joint mobility. NSAIDs are effective in reducing the severity of joint pain. Physical interventions, such as swimming, hydrotherapy, physiotherapy or massage, have been found to be beneficial, as has rest. Diagnosis of RRVD is usually made using serological testing. The non-specific symptoms of RRVD make it almost impossible to diagnose RRVD on clinical grounds alone, particularly given the shared geographical range of RRV with other arthritogenic viruses such as BFV. Furthermore, the isolation of infectious RRV from patient samples is rare, likely due to the short viraemia of infected patients and to viral clearance. PCR-based RRV detection methods, although available, are not widely used to confirm the presence of RRV in clinical samples. Therefore, laboratory tests, based on enzyme-linked immunosorbent assays (ELISAs), are available to serodiagnose RRV infections. RRV-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) can be detected early after the onset of symptoms, with patients remaining IgG+ for years post infection. Thus, firm diagnosis of a recent RRV infection requires two serum samples to be taken at least 10 days apart and a fourfold or a greater increase or decrease in antibody titre observed between the samples .

Pathogenesis of disease

Through clinical and in vivo studies using the well-established mouse model of RRVD, much progress has been made in understanding RRV pathogenesis and the contribution of immune-mediated pathology to RRVD. As is the case with other alphaviruses, RRV disseminates through the host following inoculation by mosquito bite, gaining access to the blood via the microvasculature and lymph nodes. The type I IFN response is a major component of the anti-RRV innate immune response mounted early in infection to limit viral spread. Depletion of type I IFN during RRV infection leads to exacerbation of arthritic disease and myositis in mouse models . Interestingly, recent studies suggest that elements of this early IFN response may act in a tissue-specific manner to enhance viral clearance, but that this response may be defective in certain tissues, such as the joints . Although infectious RRV is yet to be recovered from affected joints, RRV RNA has been recovered from the synovial samples of infected patients. Here, infection elicits an inflammatory response governed by various soluble and cellular factors, whose assembly is closely associated with the pathology and disease outcome observed in infected patients.

In muscle tissue, myositis and focal necrosis of muscle fibres during acute infection is found, with significant infiltration of mononuclear cells. The inflammatory infiltrate is largely composed of inflammatory macrophages, with an increase in NK cells, and CD4+ and CD8+ T lymphocytes also observed within the skeletal muscle. Similarly, macrophages, NK cells, and CD4+ and CD8+ T lymphocytes have been detected within synovial exudates and tissue sections from the knees of RRV-infected patients . TNF-α, IFN-γ, reactive nitrogen intermediates (RNIs) and MCP-1 were elevated in the synovial fluid samples of patients with acute RRVD. The role of these and other soluble factors in RRV pathogenesis has been examined in some detail. Serum macrophage migration inhibitory factor (MIF), critical to the up-regulation of MCP-1, levels were significantly elevated in patients infected with RRV . MCP-1 has been shown to be involved in macrophage recruitment during RRV-induced inflammation .

RRV was recently shown to replicate in bone cells, disrupting the RANKL/OPG ratio, as observed in the synovial fluid of RRV patients . An increase in the RANKL/OPG ratio, in an IL-6-dependent manner, skews the balanced process of bone formation and bone resorption in favour of bone resorption, leading to pathological bone loss. Thus, RRV-induced bone loss may contribute to the arthralgia after RRV infection. Studies have demonstrated that the mannose-binding lectin (MBL) pathway of complement activation is also essential for the development of RRV-induced disease. Patients infected with RRV had elevated serum MBL levels compared to healthy controls, and, interestingly, MBL levels in both the serum and the synovial fluid correlated with the severity of disease . Complement component 3 (C3) has also been shown to be an important component of the downstream signalling cascade of complement activation during RRV infection. C3 promotes the expression of pro-inflammatory factors S100A9/S100A8 and IL-6 within inflamed tissues, leading to cytotoxicity and the tissue damage associated with severe RRVD .

Background

SINV is a member of the Western equine encephalomyelitis virus complex of the genus Alphavirus within the family Togaviridae . Like CHIKV and RRV, SINV is an enveloped, positive, single-stranded RNA virus with the potential to rapidly adapt to new vectors and hosts due to high genetic plasticity and mutation rate . SINV is maintained in a vertebrae (bird) host and invertebrate (mosquito) vector transmission cycle, with Culex mosquitoes suspected as the primary vectors and grouse hypothesised as the amplifying hosts . Occasionally, the virus leaves its natural cycle when humans are bitten by an infected mosquito. In Finland, SINV has been identified as the causative agent of Pogosta disease presenting with common clinical signs of arthritis, maculopapular rash and low fever, and symptoms of fatigue, arthralgia and myalgia . In Sweden, epidemic arthritis-exanthema syndrome commonly known as Ockelbo disease has been linked to SINV . In the Russian Karelia, SINV has been isolated from Ae sp mosquitoes, and it has been identified as the causative agent of Karelian fever .

SINV and antibodies to SINV are widespread, and they can be found in wildlife and in humans across Eurasia, Africa and Oceania . However, clinical manifestations of SINV disease have mostly been reported in Northern Europe . Large outbreaks of Pogosta disease have occurred every 7 years in Finland since 1974, with hundreds to thousands of patients . In addition, the number of subclinical infections is suggested to be 17 times higher than reported cases. The age-standardised seroprevalence of SINV antibodies amongst the Finish population is 5.2%, and it varies considerably between different parts of the country . Seroprevalence was significantly higher for men (6%) than for women (4%), and it increased with age, reaching 15.4% among persons of 60–69 years of age. Prevalence and average annual incidence have been the highest in North Karelia in Eastern Finland. The reason for this geographical distribution is unknown; however, studies suggest that certain climatic conditions such as temperature and precipitation as well as the density of hatch-year black grouse are determinants of the occurrence and incidence of human SINV infections in Finland . In Sweden, the seroprevalence of SINV antibodies has been the highest in the central part of the country . As cases in Finland generally occur in the late summer months from late July to October, the virus is most likely transferred by late summer mosquitoes such as Culex and Culiseta , from which SINV has previously been isolated in Sweden.

Clinical disease presentation

The incubation time after the bite of an SINV-infected mosquito to symptoms in infected patients is estimated to be 4 days (range 2–18) . IgM antibodies can be detected within 8 days of illness, and IgG antibodies are detectable 11 days after disease onset . After incubation, clinical symptoms of Pogosta, Ockelbo and Karelian diseases appear, and they include arthritis/arthralgia, myalgia, itching rash, low fever, fatigue, headaches and nausea . Joint pain mainly involves joints of the extremities such as the knees, ankles, elbows, wrists and fingers ( Table 1 ). Hospital admissions are rare, and in most cases, NSAIDS and antihistamines offer relief from acute symptoms . However, patients suffering from SINV infection may show joint manifestations that last for months or even years. Therefore, persisting symptoms of SINV have a considerable impact on public health in areas with high seroprevalence . In a follow-up study on patients with Ockelbo disease, 28% of patients still complained of chronic arthralgia 3–4 years after initial infection . In a publication on Karelian disease in Russia, arthralgia was found to last several months after infection . More recent studies on Pogosta disease in Finland revealed that after 2.5 years, only 50% of patients were symptomless. Others showed chronic musculoskeletal symptoms and findings that could be due to Pogosta disease . Additionally, in some patients, osteoarthritis pains had worsened after the onset of Pogosta disease . In a case report of a 51-year-old man from eastern Finland without rheumatologic history, persistent symptoms from SINV infection were described . The patient developed a maculopapular skin rash, swelling and pronounced tenderness in both wrists and ankles, fever, lower back pain, headache, dizziness and fatigue. He was earlier exposed to mosquitoes during outdoor activities. The majority of symptoms subsided after 4 weeks; however, symptoms in the wrists continued. After the administration of diclofenac, acetaminophen and codeine, symptoms in the left wrist subsided after 2 months, but they continued in the right wrist. Clinical examination revealed swelling and tenderness of the right metacarpophalangeal joints, prominent during extension and flexion, leading to a considerably weakened handgrip. Furthermore, tenderness was also reported in acromioclavicular joint and myalgia in the right supraspinatus insertion region. Despite the described symptoms, the rheumatological status was normal, and blood parameters were within range, except for a marginal elevation in leukocytes, neutrophils and C4 complement. SINV–IgM antibodies were consistently found over the time of patient observation, which suggests active virus replication in parts of the body (likely the joints) .

Pathogenesis of disease

In mouse models used to mimic human SINV infection, studies have shown that SINV replicates in the skeletal muscle, skin and connective tissue adjacent to articular joints and bones , particularly the periosteum, tendons and the endosteum . Generally, macrophages play a crucial role in the development of arthritis, and they have been recognised as potential targets for SINV-induced arthritis. A recent study has shown that macrophages are susceptible for SINV infection . Infection causes macrophage activation and the release of MIF, which induces the expression and secretion of TNF, IL-1-β and IL-6. The production of these cytokines is followed by the expression of matrix metalloproteinase-1 and metalloproteinase-3, which could be the trigger of SINV-associated articular damage. In antibody and knockout studies, MIF was suggested to be the autocrine and paracrine upstream triggers of the macrophage-activation cascade. In a muscle biopsy from a patient with SINV-induced disease 6 months after infection, regeneration of the muscle in previously necrotic tissue lesions was observed . Although necrosis may have been caused by SINV infection, the virus could not be detected. This could be due to either the significant time post infection or the damage may have been caused by a secondary immune-mediated response triggered by the virus infection. In vitro studies on human myotubes and myoblasts showed susceptibility to SINV infection, yielding infectious virus and cytopathic effects. These in vitro findings support the speculations that earlier SINV infection could have triggered necrosis and regeneration of the muscle. In studies on the systemic inflammatory response to SINV in neonatal mice, highly up-regulated levels of interferon-α/β, interferon-γ, TNF and IL-6 were observed . Increased mortality and decreased survival time correlated with increased induction of these pro-inflammatory cytokines. However, in studies with adult mice, IFN-α/β protects SINV-infected mice by restricting virus replication and spread . IFN-α/β knockout mice had higher viraemia, followed by the systemic induction of the pro-inflammatory cytokines IL-12, IFN-γ, TNF and IL-6. In addition, serological studies of confirmed SINV patients were examined for 3 years following acute infection, and they were screened for human leukocyte antigen (HLA) genes, which are known to be associated with rheumatic and infectious disease and autoantibodies. Symptomatic SINV infection was found to be associated with the DRB1*01 allele, which was particularly frequent in patients who experienced joint manifestations at 3 years post infection. In addition, autoantibody titres, particularly antinuclear and antimitochondrial, were elevated in patients 3 years post infection, suggesting a link between SINV-induced arthritis and autoimmune disease .