Mosquito Arthritis Save

In the last two years there have been increasing reports of mosquito-borne infectious arthritides.  Dengue fever was best known until the introduction of viral infections due to chikungunya and Zika. 

All three of these are unified by linkage with the vector (the Aedes egypti mosquito), increasing numbers in the Caribbean and topics (with spillover exposure and illness in US travelers), and clinical features that include fever, rash, and arthritis. 

While reports of Zika viral infections have proliferated recently, all three entities are possible for those living in or traveling to, endemic regions. This review will compare and contrast each, with a focus on diagnosis, testing and treatment options.

Chikungunya
Since the 2013 outbreaks in the Caribbean, the chikungunya virus (CKV) has affected more than 1.5 million people worldwide – affecting 44 countries and territories in the Caribbean and Americas. 

As of 2015, there were over 2,344 United States citizens infected, usually after traveling to the Caribbean. This infection is still a concern for those traveling to the Caribbean, South and Central American countries (Argentina) and the Pacific islands (Cook and Marshall Islands).

CKV is the etiologic agent of chikungunya fever and belongs to the Togaviridae family. The global spread of CKV is due to two mosquito vectors: A. aegypti and A. albopictus. In the US, Caribbean and Western hemisphere, Aedes aegypti accounts for nearly all cases. Similar to Dengue fever, human CKV infection is initiated by the bite of an infected female mosquito. Nearly 85% of inoculated patients will develop symptomatic disease. Characteristic features include fever over 39⁰C, headache, myalgia, rash, and severe joint pain.

The disease has an abrupt onset, and this acute phase that lasts 7 to 10 days. Soon after, the majority of patients will improve. Improvement coincides with the appearance of neutralizing IgM antibodies and the end of viremia. IgM antibody production persists for 1 to 3 months, and IgM production confers long-term immunity to reinfection.

Joint pain occurs in all patients during the acute phase of the illness. Typically, this manifests as an acute bilateral, symmetrical involvement of large and small joints. Up to 80% of patients may develop musculoskeletal manifestations that persist longer than 3 months. The most common manifestations are persistent or relapsing-remitting polyarthralgias, polyarthritis, and myalgias. Fingers, wrists, knees, ankles, and toes are the most frequently involved, but proximal joints and axial involvement can occur in the chronic stage. Tendinitis and enthesitis are also common.

Chronic manifestations of CKV infection may resemble RA or seronegative spondylarthrosis. Severe, limiting myalgias and arthralgias may be accompanied by a transient maculopapular rash (usually days 2-5) on the trunk, face, arms, and legs. Children have been reported with bullous or blistering lesions. The elderly and children are among the most severely affected.

Musculoskeletal symptoms may last for weeks or months and few (5-10%) have been reported to last for nearly 2 years. A chronic relapsing arthritis syndrome characterized by distal polyarthritis or monarthritis and tenosynovitis in the hands has been reported. Chronic arthritis can be erosive.

CKV complications may include encephalitis, meningitis, seizures, encephalopathy, myocarditis, hepatitis, and multiorgan failure. Fatal outcomes with chikungunya are rare - with an estimated case fatality ratio of 1/1,000.  That equates to nearly 200 CKV deaths in the western hemisphere.

Diagnosis can be confirmed by serum or blister fluid PCR testing during the acute phase. Later, an IgM serologic diagnosis can be made after the first week and for up to the first 3 to 8 days of symptom onset up to 1 to 3 months’ symptom onset.  IgG titers rise in the first few weeks and persist for years. A 4-fold increase in IgG titers may also be considered diagnostic. Testing is available from several commercial labs (Focus Diagnostics, ARUP Laboratories, Quest Diagnostics) who can do ELISA, IgG or IgM immunoassays or PCR assays for chikungunya virus or dengue virus.

Symptomatic treatment and even DMARDs have been used to treat those with chronic arthritis. Currently, there is no vaccine or curative treatment. If Dengue is in the differential diagnosis, NSAIDs or aspirin should not be used if the patient is afebrile for 48 hours. Severe dengue infection differs by having severe abdominal pain, persistent vomiting, mucosal bleeding, edema, lethargy, enlarged liver, increased hematocrit and low platelet counts.  Zika viral infections may have more rash or conjunctivitis.

Zika
Zika virus infection an acute systemic infection manifest as fever, rash, arthritis, myalgias and conjunctivitis. Zika virus is a single-stranded RNA virus of the Flaviviridae family. The Zika virus is spread to humans via the bite of an infected Aedes species mosquito. It was discovered in 1947, named after the Zika Forest in Uganda. Since, outbreaks of Zika have been reported in tropical Africa, Southeast Asia, and the Pacific Islands. One of the challenges of diagnosing Zika has been its similarity with other infections (Dengue, CKV) and milder spectrum of symptoms. 

The most common symptoms of Zika are fever, rash, joint pain, and conjunctivitis. The illness is usually mild with symptoms lasting for several days to a week after being bitten by an infected mosquito. Severe illness, hospitalization or death from Zika is quite rare.  Not all people infected with Zika will be symptomatic, as there are asymptomatic persons who have tested positive for the disease and hence may be carriers.  Once a person has been infected, he or she is likely to be protected from future infections.

The main concern arises with Zika virus infection during pregnancy wherein microcephaly as well as other severe fetal brain defects have been reported. CDC officials said the risk to pregnant women was greatest in the first trimester of pregnancy, and continued into the second trimester. There have been reports of miscarriage and fetal death due to microcephaly. Estimates are that one in every 100 pregnant women infected with the virus during the first trimester will give birth to a baby with the birth defect. There are reports of a sexual transmission of the virus. 

The spectrum and extent of the Zika virus is still evolving.  Lancet has reported 42 patients diagnosed with Guillain-Barre syndrome (GBS) during the Zika virus outbreak in French Polynesia. All of these patients experienced symptoms of Zika virus infection on average 6 days before neurological symptoms (acute-motor axonal neuropathy), and all carried Zika virus antibodies. These findings suggest that for every 100000 people were infected with Zika virus, 24 would develop GBS. 

Puerto Rico has been the hardest-hit for US citizens: 1,100 cases, including 139 pregnant women. CDC is currently following 122 pregnant women in PR and US 279 pregnant women with likely Zika virus infections across the USA.

The travel alert applies to the following countries: Brazil, Colombia, El Salvador, French Guiana, Guatemala, Haiti, Honduras, Martinique, Mexico, Panama, Paraguay, Suriname, Venezuela, and the U.S. Commonwealth of Puerto Rico.  Zika virus is transmitted by Aedes species mosquitoes, which also responsible for the spread dengue and chikungunya viruses common to these regions as well as Texas, Florida and elsewhere in the United States.

Ideally the diagnosis should be confirmed but there are limited testing resources for Zika. The CDC and several state laboratories are capable of testing viral infection by PCR (rRT-PCR) on serum or urine. Virus-specific IgM and neutralizing antibodies are present by the end of the first week of illness; cross-reaction with related flaviviruses (e.g., dengue and yellow fever viruses) is common and may prompt use of other methods.

Treatment of Zika is aimed at primary prevention, meaning avoiding exposure.  For athletes going to the upcoming Olympics in Rio, there will be recommendations for use of air conditioning, wearing long sleeves and long pants and using condoms. Currently there is no specific antiviral therapy and thus, supportive therapy is recommended. Patients suspected to have Zika infection should be evaluated for dengue or chikungunya infections.  Also, given the confusion with dengue, it would be best to avoid aspirin and NSAIDs, which have been associated with a risk of hemorrhage in dengue infected patients.

Dengue Fever
Dengue viral infection is a leading cause of illness and death in the tropics and subtropics worldwide. As many as 400 million people are infected yearly. Dengue is caused by any one of four related viruses transmitted by mosquitoes. 

Dengue has emerged as a worldwide problem only since the 1950s. Although dengue rarely occurs in the continental United States, it is endemic in Puerto Rico and in many popular tourist destinations in Latin America, Southeast Asia and the Pacific islands.

Dengue is an acute disorder with symptoms promptly following inoculation. Key features include high fevers, severe headaches, eye pain, arthritis, myalgias, rash, bleeding (e.g., nose or gum bleed, petechiae, or easy bruising), low white cell count.  Most will recover in about a week, and up to 5% of people infected will develop severe dengue. Severe dengue can result in shock, internal bleeding, and even death. Warning signs may appear as the fever declines and may include severe abdominal pain or persistent vomiting, vomiting blood, bleeding, purpura, petechiae, melena, altered mental status, dyspnea.

There is no specific medication for treatment of a dengue infection. The best way to prevent a dengue infection is to prevent mosquito bites. It is preferred to use analgesics with acetaminophen and avoid those aspirin or NSAIDs that may further hemorrhagic risks. When infected, early recognition and prompt supportive treatment can substantially lower the risk of medical complications and death. There are not yet any vaccines to prevent infection with dengue virus and the most effective protective measures are those that avoid mosquito bites.