EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM

SNOWMASS, COLO. (FRONTLINE MEDICAL NEWS) – The continental United States is vulnerable to an epidemic of chikungunya virus disease, an event which would have profound consequences for rheumatologists, Robert T. Schoen, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

“We certainly have all the factors in place where we could have a major epidemic of chikungunya, particularly in Florida, Texas, and neighboring states. As rheumatologists, I think we can own this infection if we want to because it causes an arthritis that is a true arthritis in a significant percentage of patients,” said Dr. Schoen , a rheumatologist at Yale University in New Haven, Conn.

He cited a recent meta-analysis by Colombian investigators who concluded, on the basis of 18 published studies involving more than 5,700 subjects, that roughly 25% of patients with acute chikungunya go on to develop long-term disabling arthritis, his most conservative estimate. Reanalyzing the data after limiting consideration to the most representative studies – those with at least 200 patients – the investigators upped their estimate to 34% ( Arthritis Care Res. 2016 Dec;68[12]:1849-58 ).

“That’s a major impact when you think that these epidemics affect tens of thousands of individuals. If 25% of them develop long-term arthritis disability, that’s a whole new world for us,” the rheumatologist observed.

Chikungunya is a single-stranded RNA virus in the togaviridae family, which also contains rubella. The infection is transmitted by Aedes aegypti and A. albopictus, also known as the yellow fever and Asian tiger mosquitoes, respectively. Both mosquitoes are established inhabitants of much of the United States.

“This infection is a one-bite deal. These are very aggressive mosquitoes,” Dr. Schoen observed. “If you haven’t seen a case of chikungunya yet, you will soon,” he added.

In 2014, at the height of a massive Caribbean epidemic which included half a million cases in Puerto Rico, roughly 2,800 cases of chikungunya were imported into 46 U.S. states. In 2015, however, as the Caribbean epidemic waned and herd immunity developed, that figure fell to 653 imported cases. But the epidemic in India, which began in 2008, remains ongoing with no end in sight. Several of Dr. Schoen’s patients with chikungunya had recently returned from India when they first became ill.

“India provides an unlimited reservoir of immunologically naive patients to perpetuate the infection,” he observed.

Course of illness

The rate of asymptomatic infection has been variously estimated at 3%-25%. Symptomatic chikungunya is a biphasic illness. After a 2- to 6-day incubation period, patients develop rapid-onset fever with severe joint pain and muscle aches. Indeed, chikungunya means “bent over” in Makonde, an African Bantu language.

Roughly 60% of patients develop a rash during the acute febrile phase of the illness, which lasts about a week. The dermatitis is most often a maculopapular rash on the trunk which is “absolutely indistinguishable” from the rash caused by Zika virus infection, transmitted by the same vectors, Dr. Schoen noted.

During this acute phase, almost all patients develop a severe polyarthritis which can last for weeks or, less commonly, for months or years. This polyarthritis mimics seronegative rheumatoid arthritis. It is usually symmetric and often affects the hands, wrists, and feet.

The acute febrile phase is characterized by high levels of viremia, with up to 1 billion viral particles per milliliter of blood. During this period, definitive diagnosis of chikungunya can be made through reverse transcriptase–polymerase chain reaction testing or viral culture.

Typically, though, patients make their way to a rheumatologist only well after the viremic period is over. In that situation, the diagnostic mainstay is serologic testing. Antichikungunya virus Immunoglobulin M is detectable starting on about day 5 after symptom onset, and it persists for the next 1-3 months. Immunoglobulin G (IgG) antibodies become detectable in the same time frame and remain elevated for years.

Dr. Schoen highlighted a small but intriguing study from Singapore that suggests that the early appearance of chikungunya-specific neutralizing IgG3–antibodies may constitute a marker for favorable long-term prognosis. The observational study involved 30 patients hospitalized for severe acute chikungunya infection. The investigators classified them into two groups: 14 patients had low levels of acute viremia, a less severe acute illness, and late development of IgG3 antibodies; the other 16 had a high initial viral load, a more severe acute phase, and a rapid IgG3 and interleukin-6 response to infection.

The patients with a robust early IgG3 response cleared the virus faster and none of them developed chronic arthritis. In contrast, those without early, chikungunya-specific IgG3 had a high rate of persistent arthralgia ( J Infect Dis. 2012 Apr 1;205[7]:1147-54 ).

Treatment

No evidence-based treatment for chikungunya exists. Treatment in the acute phase is primarily supportive care. Rheumatologists on the Caribbean island of Martinique have reported a favorable experience using methotrexate at doses up to 25 mg/week or with standard doses of anti–tumor necrosis factor agents in chikungunya patients with severe bilateral symmetric chronic inflammatory joint disease arising during the 2013-2015 epidemic. The treatment response and tolerability were comparable with the results typically obtained in rheumatoid arthritis patients, according to the rheumatologists ( Arthritis Rheumatol. 2016 Nov;68[11]:2817-24 ).

Dr. Schoen found the report from Martinique to be reassuring. He too has resorted to familiar rheumatologic medications in his severely affected patients. Anecdotally, his greatest success involved a patient with a 5-year history of disabling chikungunya polyarthritis who showed marked improvement after several months on hydroxychloroquine.

The Martinique investigators also reported on 22 patients who developed chikungunya while on biologic agents for rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, or systemic lupus erythematosus. The biologics weren’t protective against the viral disease in these patients. All 22 of them developed severe acute chikungunya polyarthritis with a mean swollen joint count of 9.6 ( Joint Bone Spine. 2016 Mar;83[2]:245-6 ).

Infection during pregnancy

There is a legitimate concern about chikungunya infection occurring during pregnancy, but, based on the experiences documented on Reunion Island, the risk to the baby is confined to intrapartum exposure in a viremic mother.

Reunion Island is a French region in the Indian Ocean off the eastern coast of Africa. It has first-world medical care. Much of the best documented early work on chikungunya outbreaks grew out of the 2005-2006 epidemic there, which affected more than one-third of the island’s 800,000-plus residents.

In a prospective study of 7,504 deliveries on the island during a 22-month period, mother-to-child transmission of chikungunya occurred only in the context of intrapartum viremia, with 19 cases of vertical transmission occurring among 39 affected mothers who delivered at a median 38 weeks of gestation. Cesarean section had no protective effect. All 19 infected neonates were asymptomatic at birth, with median onset of pain, fever, and thrombocytopenia on day 4. Nine of the 19 infected neonates developed encephalopathy with pathologic MRI findings, including cerebral hemorrhage in two cases ( PLoS Med. 2008 Mar 18;5[3]:e60 ).

The case fatality rate for chikungunya is low at 0.1%. Most deaths occur in young children or elderly individuals with major comorbid conditions. Despite this low mortality, interest in chikungunya vaccine development is being driven by the infection’s impact on tourism, its spread to temperate climates, the economic impact of the considerable time lost from work, and military need. A promising attenuated, virus-like, particle-based vaccine is currently in phase II testing in the Caribbean.

Dr. Schoen reported having no financial conflicts.

bjancin@frontlinemedcom.com

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