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Fever, Rash, and Severe Arthralgias in Travelers Returning from India
By Sheela Shenoi, MD, and Albert Shaw, MD, Dr. Shenoi is a Fellow in Infectious Diseases, and Dr. Shaw is an Assistant Professor of Medicine, Section of Infectious Diseases, both at the Yale School of Medicine, New Haven, CT
Drs. Shaw and Shenoi report no financial relationships relevant to this field of study. This article originally appeared in the January 2007 issue of Travel Medicine Advisor. It was edited by Frank Bia, MD, MPH, and peer reviewed by Lin H. Chen, MD. Dr. Bia is Professor of Medicine and Laboratory Medicine; Co-Director, Tropical Medicine and International Travelers' Clinic, Yale University School of Medicine, and Dr. Chen is Assistant Clinical Professor, Harvard Medical School; Director, Travel Resource Center, Mount Auburn Hospital in Cambridge, MA. Dr Bia is a consultant for Pfizer and Sanofi Pasteur, and receives funds from Johnson & Johnson. Dr. Chen reports no financial relationship relevant to this field of study.
A 56-year-old man, originally from India and with a history of hypertension, had developed bilateral red, swollen ankles while on a recent trip to Bangalore. Five days later, the patient developed severe fever and shaking chills that resolved within 48 hrs. He had stayed in his brother-in-law's house in an urban setting, with several children residing there. He had not been swimming or spent any time in rural areas or farmland, nor had he been in direct contact with animals. He saw a physician, was told that he had a viral syndrome, but was given an unknown antibiotic and pain medication. Two days later, he developed diarrhea with 5 loose bowel movements, with no blood or abdominal pain, so he stopped the antibiotics with resolution of the diarrhea. He arrived back in the United States, and 24 hrs later noticed worsening of the ankle swelling, dizziness, and "red dots" on the upper extremities, prompting emergency evaluation. He reported swelling of fingers in both hands, fatigue and mild discomfort in both ankles, but was otherwise asymptomatic. The patient reported numerous mosquito bites, but took no antimalarial prophylaxis. Of note, the patient's brother-in-law in India had also developed similar symptoms.
In the hospital, the patient was afebrile and examination was significant for peripheral edema 1/3 up the calves with associated erythema and mild tenderness, without effusion or warmth. On the hands, there was mild proximal interphalangeal joint swelling bilaterally without warmth, effusion, or synovial hypertrophy. The heart and lung sounds were within normal limits, and abdominal exam was unremarkable and without hepatosplenomegaly. There was no cervical, axillary, or inguinal lymphadenopathy, and the rash had resolved.
White blood cell count was 3,600 cells /uL with 41% segmented neutrophils, 34% lymphocytes, and 10% eosinophils. Platelets were 151,000/uL with normal hemoglobin. Peripheral blood smears were negative for malaria; urinalysis was unremarkable, and blood cultures were negative. Serum creatine phosphokinase (CK) was elevated at 357 IU with normal serum CK-MB and troponin levels. AST was elevated 70 U/L and ALT was 77 U/L (nl. for both 0 - 35 U/L) with normal serum bilirubin and alkaline phosphatase.
The presumptive diagnosis was chikungunya versus dengue virus infection. The patient was discharged home. At a follow up appointment ~10 days later, the patient reported persistent arthralgias in the ankles without effusion on exam. Fourteen days after discharge, serologies sent to CDC were reported as IgM-positive, IgG-negative for chikungunya virus and IgM-negative, IgG-positive for dengue.
The CDC's website (www.cdc.gov/travel/), as well as sites such as the WHO Weekly Epidemiological Record (www.who.int/wer/en/) and ProMED mail www.promedmail.org/pls/promed/) are useful resources. In this case, a relevant outbreak of chikungunya virus involving > 200,000 cases starting early 2005 and peaking in December 2005 had been noted in Reunion (Indian Ocean) with associated cases in Mauritius and Seychelles. More than 340 cases have been documented in France among tourists returning from islands in the Indian Ocean. Cases have also been reported in returning travelers in China and Germany. There have been 12 cases among travelers to the United States, diagnosed serologically at the CDC in 2005-2006. In India, since March 2006, there has been an epidemic of chikungunya virus, with thousands of cases reported in the central states of Maharashtra (home to Mumbai, or Bombay), Andrha Pradesh (home to Hyderabad), and Karnataka (home to Bangalore, where our patient resided during his trip).
The word chikungunya, a Makonde term meaning "that which bends up," was given in reference to the joint pain and contortions associated with severe infections. A classic paper by Robinson et al (1955) described the illness among 115 patients along the border of modern day Tanzania and Mozambique. Since then, it has been considered responsible for multiple epidemics in Africa, southeast Asia, and the Philippines, such as in Peace Corps volunteers in 1986. Retrospective studies attribute many epidemics of fever, rash, and arthralgias from Indonesia (1779) to east Africa, to India, and possibly even to the southwestern United States (1827) to chikungunya infections.
Epidemiological studies done by Robinson, Ross, and Lumsden (1955) during chikungunya outbreaks in Uganda that examined the various mosquito species in an infected village and viral infectivity demonstrated that the most likely vector was the Aedes aegyptimosquito, an aggressive daytime feeding species. In recent outbreaks (2/06) among the islands of the Indian Ocean, the vector is Aedes albopictus (the Asian tiger mosquito). Serologic studies indicate that > 20% of people in various regions of tropical Africa have evidence of infection. Clinical similarity to dengue may represent under diagnosis and underreporting of chikungunya infections.
Among the alphaviruses, chikungunya is antigenically distinct from the encephalitis viruses, WEE, EEE, and VEE, and is grouped in the Semliki Forest virus antigenic complex.
Chikungunya infections may be asymptomatic, or may appear as an abrupt illness similar in presentation to dengue infection, with fever, headache, myalgias, malaise, and severe polyarticular arthralgias, especially of the small joints and also of those which have been previously injured. Incubation period is 1-8 days. The joints become swollen, without significant effusions, and usually resolve within 1-2 weeks. Often a maculopapular rash erupts over the face and neck in the first few days of the illness, and may later reappear on the trunk, limbs, face, palms, and soles. Petechial lesions have also been frequently reported, though their pathogenesis is unclear. Lymphadenopathy is mild or absent. Conjunctivitis is frequently reported. Rare but serious CNS manifestations such as seizures, and meningoencephalitis have been reported, particularly in children. The acute fevers usually resolve within 3 days, though low-grade temperatures may recur later in the course. Arthritis is frequently the most prominent symptom, and has been characterized as a symmetric polyarthritis that may affect the MCP joints, wrists, elbows, knees, ankles and MTP joints.
The differential diagnosis includes non-hemorrhagic dengue, which is often clinically indistinguishable from chikungunya virus infections. Dengue usually has less rash, headache and arthralgia, but more adenopathy, especially long term. There are several additional arboviruses that can cause fever and arthralgias, including O'nyong-nyong, which is antigenically closely related to chikungunya, but is found primarily in Africa.
Laboratory studies reveal relative leukopenia with lymphocytosis, mild thrombocytopenia, and slightly elevated ESR/CRP. A mild elevation in hepatocellular enzymes is often found. As the level of viremia and fever trend down, hemagglutinin inhibition and serum antibodies rise. An antibody capture IgM ELISA is available through CDC (CDC Arboviral Diseases Branch: 970-221-6400; instructions for shipping specimens: www.cdc.gov). A reverse transcription PCR (E1 protein and non-structural protein 1) has been developed which takes less than 48 hours but is not widely available in the United States. Generally, diagnosis is made on clinically grounds.
Many patients recover uneventfully with supportive care, including rest, hydration, acetaminophen and/or NSAIDS. However, arthritis may be persistent and occasionally incapacitating in adults; 4 months later, up to 50% may have musculoskeletal findings such as morning stiffness, decreased grip strength, tenosynovitis, and periarticular soft tissue swelling, especially involving the proximal interphalangeal joints (Kennedy et al, 1980). Of the 4 patients presented in the CDC case series, one patient's arthralgias persisted for approximately one month, whereas another patient's joint symptoms persisted for up to 5 months. Cardiac involvement, including arrhythmias or cardiomyopathy and heart failure, has been rarely suggested to be associated with chikungunya infections. The development of a live-attenuated vaccine in a phase II trial has been reported, though it is still in trial.
As Aedes albopictus, the chikungunya vector in the Indian Ocean outbreak, is prevalent worldwide, including the Americas, there is risk that infected returning travelers may introduce chikungunya into local mosquito populations and cause outbreaks, especially in temperate areas of the United States. Patients with suspicion for infection should be reported and should avoid introduction of the virus to local mosquitoes by staying indoors as much as possible, wearing long sleeves, and using insect repellents during the first week of illness.
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