Rheumatism Mimic – Getting to know Chronic Chikungunya

Topics dealing with tropical medicine are difficult to tackle, as I am never quite sure where to begin. Do I talk about their epidemiology or the clinical presentation? I’ll never recognize one and even if I did, I could offer no therapy outside of “supportive management.” Chikungunya is one of these diseases. This is a single-stranded RNA alpha-virus that circulates in the forested regions of sub-Saharan Africa (1). The virus most likely originated in East and central Africa, and typically follows a sylvatic cycle between mosquitoes and non-human primates (2). The sylvatic and rural cycles interact and leads to an urban cycle which can lead to pandemics:

Sudden onset fevers, arthralgias, headache, and rash is the rule in acute infections, with only 15% of those infected achieving asymptomatic seroconversion (2). The onset of fever coincides with viremia, with the intensity of acute infection correlating with the level of viremia:

Another review noted that  95% of infected people develop symptoms (3). Indeed, the symptoms are similar to other viral hemorrhagic fevers, however persistent arthralgia is the hallmark of the disease. 

Infection is divided into an acute phase (<3 months) and a chronic phase (>3 months). Further, the acute phase is divided into the viremic (5-10 days) and the acute post-viremic (6-21 days, 4). I’ll talk about the chronic phase in a bit, since that is the interesting part of the post but I’ll highlight some of the data on the acute phase of the illness. A prospective study from Bangladesh described the clinical characteristics of acute febrile illness. 90% had a fever with a maximum temperature of 103.6F, with median duration being 4.88 days (5). Rash occurred prior to fever in more confirmed cases:

Arthralgia was also prominent, with it being oligoarticular in 40% and polyarticular in 56% of cases:

A retrospective report of 296 patients from South India found that during the acute phase of infection, which lasted for 7-10 days, the most common symptoms were fevers and joint pain (6):

Of these, 10% of cases reported prolonged arthralgia of >3 weeks of duration. In a cohort of 69 travelers to the Reunion Island during their outbreak, 20 patients developed flu-like symptoms with fevers and arthralgias being the predominant symptoms (7):

One cohort evaluated 1154 patients during an outbreak in Mayotte, a French Territory near Madagascar, of which 425 reported an acute febrile illness. 440 were seropositive and of these, 72% had presented with symptoms (8). 

82% of these patients had complete recovery, while the rest had persistent polyarthralgia. When coupling fever with another sign to evaluate the diagnostic performance, fever and polyarthralgia had the highest sensitivity and NPV when compared to other pairings: 

In Gabon, 1208 confirmed cases of Chikungunya were evaluated, of which 19 had a co-infection (9). 85% of patients had fevers while 90.4% presented with arthralgias, which was abrupt in all patients. Joint pain was symmetrical, bilateral, and polyarticular and incapacitating in 158 patients.  When using fever and arthralgia as a diagnostic syndrome, the combination demonstrated a sensitivity and specificity of 73% and 41%, respectively. Other atypical presentations have been described. For instance, a retrospective study of 57 patients with CNS-associated disease found 6 patients with confirmed chikungunya-associated encephalitis along with 18 possible cases (10). One large cohort evaluated nearly 1100 atypical presentations (11):

Chronic Chikungunya

Within 10 days after disease onset, most patients present with acute fevers, polyarthritis, and rash (12). This is described as the acute phase of the disease. After transient improvement, many will then present with rheumatic manifestations such as edematous polyarthritis of fingers and toes, severe tenosynovitis of the wrists, hands, and ankles, and exacerbation of pain of previously injured joints. This can mimic seronegative rheumatoid arthritis. One of the earliest descriptions comes from a cohort of 107 patients. Here, 4 patients had occasional joint stiffness, 3 had persistent residual stiffness but no pain, and 6 had persistent joint pain and stiffness (13). In the last 6 cases, joint pain and stiffness was predominantly in the wrists and MP joints along with ankle joints.

A single-center cohort described 128 patients who developed chronic chikungunya syndrome, which fell into 4 distinct rheumatological patterns (14). 

Only 27 of these developed de novo symptoms, however all had symptoms equally distributed in the distal small joints with clinically perceptible symmetric synovitis. The overall prevalence varies depending on the study, however a review of 18 studies reported it to be around 40% (15):

A retrospective study found that in chronic arthritis, hand/wrists and ankle/foot were the most commonly affected joints (16):

One case series of 10 patients who had previous infection notes 8 of these met 2010 ACR/EULAR criteria for seronegative RA (17), while a prospective study from the Reunion Island outbreak (18) described 88 patients with persistent arthralgias with small polyarticular arthralgia being the most common manifestation:

What is pathophysiology here? Good question, and the answer to that is unclear. One review posits that chronic disease is mediated by persistent virus and inflammation, with areas of persistence being things like endothelial cells in liver and end organs, mononuclear cells, macrophages in synovial fluid and surrounding tissues. This leads to a chronically infected joint (19). 

Furthermore, it seems that early control of viral load is a key factor. One study of age- and gender-matched patients evaluated the cytokine response in those who had chikungunya and had developed (n = 121) or not (n = 121) chronic arthritis and found that higher cytokine response was associated with a decreased incidence in chronic joint pain (20):

This suggests there may be a role in early viral clearance with decreased risk for subsequent post-inflammatory changes i.e. if you clear the virus faster, the inflammatory response goes away faster. A retrospective study found that women were more likely to have persistent arthralgia after acute febrile illness (100% vs 27%). Further, peak creatinine was lower in those with persistent arthralgia (79.5 vs 91.9 umol/L) however peak viral load and duration of viremia were not found to be associated with development of arthralgia (21).One review highlights management methods in the acute and chronic phases:

References:

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