INTRODUCTION
More than 50 million people from industrialized western countries travel abroad and visit tropical developing countries every year. About 8% of these travelers require medical care during or after travel, especially for common diseases acquired while traveling as well as for infectious or tropical risks specifically related to the travel15,33.
Chikungunya virus (CHIKV) is an arbovirus (genus Alphavirus, family Togaviridae) identified in the 1950s in Africa, where it is maintained in a sylvatic cycle involving wild primates and forest-dwelling mosquitoes35,38,39. CHIKV is also prevalent in Asian countries, where it has been associated with Aedes aegypti, the main vector of dengue fever, in an urban epidemiologic cycle without a known animal reservoir29. There, the transmission has been suspected to be supplemented by A. albopictus26.
The name "chikungunya" comes from the Makonde language of Tanzania and Mozambique, although it is often erroneously described as derived from Swahili, the most widely spoken language of eastern Africa5,28. The meaning "that which contorts or bends up," refers to the contorted posture of infected patients suffering with severe joint pain associated with the disease and a dramatic limited ability to ambulate in daily life39. The disease has been rarely described in the medical literature, and has long been considered benign. Knowledge of its clinical features was based until recently on the descriptions of South African teams after local epidemics in the late 1970s8,14,22. The acute stage includes brief fever, headache and myalgia, occasional evanescent rash, and subacute bilateral and symmetric inflammatory polyarthralgia or arthritides that can last for months. Brighton et al8 determined that 87.9% of 107 serologically confirmed infected patients declared themselves cured 3 years after disease onset, while 12.1% mentioned persistent symptoms including occasional discomfort, persistent joint stiffness, or stiffness and pain and effusion (3.7%, 2.8%, and 6% respectively). Brighton and colleagues9 also reported a case of late articular destruction after decades of post-CHIKV chronic rheumatism, but did not attribute direct cause to the virus.
Since 1952, CHIKV has caused outbreaks in East Africa (Tanzania and Uganda), in Austral Africa (Zimbabwe and South Africa), in West Africa (Senegal and Nigeria), and in Central Africa (Central African Republic and Democratic Republic of the Congo). In 1999-2000, a re-emergence was documented in the Democratic Republic of the Congo, where an estimated 50,000 persons were infected during an urban epidemic after 39 years without any isolation of the virus35. Serosurveys conducted in Cameroon have suggested that interepidemic infection is also common24. In Asia, since the first documented outbreak in 1958 in Thailand, other outbreaks have been documented in Thailand, Cambodia, Vietnam, Laos, Burma (Myanmar), Malaysia, the Philippines, and Indonesia25,29. The most recent epidemic re-emergence was documented in 2001-2003 in Indonesia, after a near 20-year hiatus of epidemic CHIKV activity in the country26. Both in Africa and Asia, CHIKV is characterized by the potential for major epidemics that re-emerge after an unpredictable period of apparent absence.
At the beginning of 2005, an outbreak of CHIKV fever emerged in the southwestern islands of the Indian Ocean4,13. More than 5000 cases were reported in Comoros Islands, and thereafter the virus has circulated in other islands including Reunion and Mayotte (2 French territories), Mauritius, and the Seychelles12,20,42. At the beginning of 2006, after a period of lower transmission during the winter and with the arrival of the Southern Hemisphere summer, Reunion Island suffered an explosive outbreak. By September 18, 2006, an estimate of 266,000 residents (population 770,000) infected with CHIKV was reported, and 248 death certificates gave CHIKV as the possible cause of death21. Evidence for intrauterine infection in pregnant women and vertical transmission has been documented27. A. albopictus is the incriminated local vector2,37. More recently, circulation of the virus has also been documented in Madagascar and in India where CHIKV is spreading rapidly with more than 1,100,000 cases reported by the health authorities since December 2005, including 101,500 laboratory-confirmed cases20,49. Recently, the virus responsible for the massive outbreak in the Indian Ocean islands and India has been characterized, indicating that the outbreak was initiated by a virus related to East African CHIKV isolates, from which new variants may have evolved31,40,49.
According to the World Organization of Tourism, 719,000 tourists arrived in Mauritius, 430,000 in Reunion Island, 229,000 in Madagascar, and 121,000 in the Seychelles in 200448. During 2005-2006 several European countries reported imported cases in travelers returning from these islands, including to mainland France (808 imported cases from April 2005 to August 2006)19,23, where viremic patients have been diagnosed31; Germany, Italy, Norway, and Switzerland2. Recently cases have also been imported in the United States10.
We describe here the clinical and laboratory features of travelers with CHIKV infection diagnosed in Marseilles, France, returning from the Indian Ocean islands.
PATIENTS AND METHODS
Patients with suspected travel-acquired CHIKV infection were prospectively recorded between February 2005 and April 2006 in the infectious and tropical diseases units in Marseilles, located at the Laveran Hospital, a 300-bed military hospital where civilians are also admitted, and at the North Hospital, an 800-bed university-affiliated teaching hospital. Both units are reference centers for tropical diseases and travel-related illnesses in southern France and include an outpatient clinic. CHIKV infection was suspected in all patients who returned from Indian Ocean islands who complained of fever and/or arthralgia. The case definition was as follows: 1) a history of travel to an island in the western Indian Ocean, 2) positive serologic results defined as the presence of specific IgM or both IgM and IgG against CHIKV, and/or positive reverse transcription-polymerase chain reaction (RT-PCR) and/or isolation of CHIKV from blood, 3) no other etiology identified. In-house IgM-capture and IgG-capture enzyme-linked immunosorbent assays35 as well as immunofluorescence assay using CHIKV (Ross strain)-infected Vero cells were used to detect specific IgG and IgM31. RT-PCR and isolation in Vero-E6 cells of CHIKV from acute sera, were also attempted as described elsewhere31,34. Descriptions of demographic, clinical, and laboratory findings of both acute and chronic stages were registered for all patients at the first consultation and/or at the time of hospitalization and during follow-up. For patients seen more than 10 days after the onset of illness, clinical features of the early stage of the disease were identified by retrospective questioning. After the initial consultation or hospitalization, patients' status was actively followed by regular consultations and/or phone calls until October 2006.
RESULTS
Demographic and Epidemiologic Features
A total of 47 patients with confirmed imported CHIKV infection were identified (39 at the Laveran Hospital and 8 at the North Hospital). The mean age was 45.1 years (range, 0.5-73 yr), with 22 female patients and 25 males (Table 1). Places of infection and times of the first hospital consultation are presented in Figure 1. The 47 patients comprised the following: 1) 29 individuals permanently residing in metropolitan France who traveled for tourism, 2) 10 migrants of Comorian origin living in metropolitan France (including 2 pregnant woman) who traveled to visit friends and relatives, 3) 7 residents of an Indian Ocean island who traveled to metropolitan France, and 4) a 5-month-old Canadian child whose family stopped for a few days in France after visiting Reunion Island before returning to Canada. The length of stay in Indian Ocean islands, excluding residents of Reunion Island, ranged from 9 to 180 days (mean, 3.1 mo). Underlying conditions were present in 30 infected patients (see Table 1). The disease developed in 26 patients during travel and in 21, on their return. The mean interval between return and first symptoms was 2.4 days (range, 0-7 d).
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TABLE 1: Demographic and Medical Data of 47 Patients With Travel-Acquired Chikungunya Infection, Marseilles, France, March 2005-April 2006
FIGURE 1: Incidence of CHIKV-infected travelers returning from Indian Ocean islands to Marseilles, France, March 2005 to April 2006.
Clinical and Laboratory Features at the Early Stage of CHIKV Infection
Twelve patients presented in Marseilles during the early stage (within 10 d of the disease onset), and 8 were hospitalized. The reason for hospitalization was a febrile illness accompanied by painful and disabling polyarthritis in all patients. Of these hospitalized patients, an immunocompromised 71-year-old man also had severe pancytopenia and Gram-negative septicemia31, and a previously healthy 22-year-old woman also had transient myocarditis.
At this early stage, fever was present in 45 of 47 patients (mean duration, 3.7 d; range, 2-9 d) (Table 2). Twenty-four patients had a rash in the first week of illness, mostly located on the face, the trunk, and the extremities (Figure 2). Rashes included papules, macules, and diffuse redness. The rash was transient with a mean duration of 2.5 days (range, 1-4 d). Two patients developed temporary bilateral conjunctivitis. Edema of the face or pruritus accompanying the rash was common (see Figure 2). Two patients reported spontaneous gingival bleeding. Arthralgia and/or arthritis were constantly present during the acute stage (100%), sometimes asynchronous with fever and rash. In adults, arthralgia was mostly bilateral and symmetric (40/46), and involved more than 8 peripheral joint groups (35/46). The most frequently affected joints were distal joints of fingers, wrists, toes, and ankles, often in association with periarticular inflammatory edema (19/46) (see Figure 2). Pain also affected knees, hips, shoulders, and elbows. Temporomandibular and sternocostoclavicular joints and heels were involved in 7/46, 2/46, and 2/46, respectively. Five patients with asymmetric arthralgia complained of pain at a previously injured joint (postsurgery or posttrauma). Large joint effusions were present in 7 of 46 cases, mostly in the knee (including 2 cases with Baker cysts and 1 with lymphocytic arthritis with presence of IgM anti-CHIKV in synovial fluid). Hygromas and/or bursitis were present in 3 patients (Figure 3). Two patients presented with multiple symmetrical wrist and finger tenosynovitis. Axial pain was also present for 22 adults, located in lumbar (13/22), cervical (13/22), and/or thoracic (2/22) segments, especially in areas with previous arthritis or trauma. As a consequence, all patients had a dramatically limited ability to ambulate and undertake their activities of daily living for 2 or 3 days.
TABLE 2: Clinical Features of 47 Patients at First Stage of Travel-Acquired Chikungunya Infections, Marseilles, France March 2005-April 2006
FIGURE 2: Skin manifestations in patients with CHIKV infection returning from Reunion Island to Marseilles in 2006, including a 45-year-old woman with rash of the face (A) and abdomen (B) and edema of the face (A) and hand (C); and a 36-year-old man with rash that blanches with pressure on the right arm (D, E).
FIGURE 3: Joint manifestations in patients with CHIKV infection returning from Reunion Island to Marseilles in 2006, including bilateral tenosynovitis of extensors of wrists and fingers (A), of wrists flexors (B), tenosynovitis of peroneus longus and brevis muscles (C), and elbow hygroma (D).
Common early laboratory findings in both mild and severe cases included elevation of liver and muscle enzymes (lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, and gamma-glutamyl transpeptidase) (50%), mild thrombocytopenia (50%), and leukopenia (75%). One patient presented with extreme cytopenias including thrombocytopenia (17 × 109/L), leukopenia (0.7 × 109/L), neutropenia (0.3 × 109/L), and nonregenerative anemia (Hb 9.5 g/dL, reticulocytes 10 × 109/L)31. Serology demonstrated the presence of anti-CHIKV IgM in 12 patients seen within the first 10 days. In 3 patients, CHIKV has been detected by RT-PCR and isolated in cell culture31.
All patients received short-term symptomatic treatment (painkillers and/or antiinflammatory drugs) during the acute stage. One patient described epistaxis while taking aspirin. Whatever treatment they had, all patients mentioned at least partial improvement 7-10 days after the onset of symptoms. Six of the patients seen in the early stage had recurrent symptoms during follow-up after the tenth day, while 3 were asymptomatic after that time (3 patients were lost to follow-up).
Clinical Features and Outcome at the Second Stage
Thirty-four patients presented more than 10 days after the onset of disease (including 2 patients symptom-free at this time), and 3 were hospitalized for severe persistent joint pains. Among the 46 adult patients, 38 (82.6%) remained symptomatic with persistent or recurrent joint pain after 10 days of illness (Table 3). None had recurrent fever or rash. All but 5 patients presented with persisting arthralgia and joint stiffness, although they were less pained and handicapped than during the acute stage. Proximal finger joints were still swollen in 50% of patients during the first month after disease onset. Symmetrical arthritis of the large joints was observed in 1 patient at this stage (see Figure 3). Physical examination identified tenosynovitis in 26 of 38 patients, commonly involving more than 2 tendons (Figure 4). The most frequently involved tendons were extensors and flexors of wrists and fingers (including thumbs), tendons of peroneus longus and brevis muscles, tibialis anterior muscle, and hallucis and digitorum longus muscles. Four male patients with pre-existing thickened and/or nodular aspects of palmar fascia, consistent with Dupuytren disease, presented with hand tenosynovitis. Eleven patients with hypertrophic tenosynovitis of wrist flexors described night dysesthesia and/or paresthesia in fingers during the second and third month. The symptoms were typical of carpal, tarsal, or cubital tunnel syndromes, (10, 2, and 1 patients, respectively), sometimes overlapping, and bilateral in 5 cases. Nine patients described de novo bilateral Raynaud phenomenon, erythermalgia, or severe coldness of fingers (5, 2, and 1 patients respectively) that lasted for a few weeks during the second and third months and that were not associated with wrist tenosynovitis; 3 of them underwent nailfold digital capillaroscopy that only showed nonspecific changes.
TABLE 3: Clinical Features of 47 Patients at First Stage of Travel-Acquired Chikungunya Infections, Marseilles, France March 2005-April 2006
FIGURE 4: MRI of the hand and wrist of a patient with imported CHIKV infection and severe pain, revealing carpitis and thumb arthritis (arrow on coronal section, left) associated with multiple tenosynovitis of extensors and flexors of fingers and wrist (arrow on sagittal section, right) (time-resolved contrast-enhanced T1-weighted sequence with fat suppression).
Standard laboratory findings (including blood cell count and erythrocyte sedimentation rate; lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, gamma-glutamyl transpeptidase, and C-reactive protein levels) were within normal limits in 38 patients sampled at the second stage.
Initial treatment of the patients remaining symptomatic after 10 days of evolution always included analgesic drugs (2/38 requiring morphine) and nonsteroidal antiinflammatory drugs (NSAIDs). The patient who presented initially with severe pancytopenia had persistent arthralgia despite the use of NSAIDs, but improved significantly after empirical oral chloroquine treatment. Short-term systemic corticosteroid therapy was given when NSAIDS were contraindicated or failed (19 cases). Dramatic improvement of locomotor status was observed with corticosteroids, especially in the presence of refractory inflammatory arthralgia, tenosynovitis, nerve entrapment syndromes, or Raynaud phenomenon.
At the end of October 2006, overall mean follow-up was 8 months (range, 1-19 mo), and 28 patients were still under follow-up. Most patients who complained of persistent pain described severe discomfort in daily life lasting weeks to months, particularly while walking and using the hands. Three patients reported depression. Among patients who have been followed up to 1, 3, and 6 months after disease onset, the percentages of symptomatic patients were 88%, 86%, and 48%, respectively. Among the 9 patients infected in the Comoros archipelago in the first months of 2005, 4 were symptom-free within 4 months after disease onset, while 2 had persistent symptoms for up to 15 months, and 3 were lost to follow-up.
DISCUSSION
Travelers and migrants can pose diagnostic problems to western physicians who are unfamiliar with tropical diseases15. Reports of CHIKV infection in travelers and expatriates were rarely described before 2005-20061,36,41,44,47, and this disease remains poorly known by western physicians. In the current study we report the largest series of CHIKV infection documented in returned travelers, to our knowledge.
The dynamics of our cases paralleled the spread of the explosive outbreak in the Indian Ocean. In 2005 we initiated a national alert and disseminated medical information when the first CHIKV cases imported from Comoros in the early phase of the epidemics were diagnosed in Marseilles14,23, where there is a significant community of migrants originating from Comoros. This illustrated the importance of travelers and migrants visiting friends and relatives in their country of origin as unwitting sentinels for the surveillance of infectious disease32,33. Later, the spread of the epidemic in the western Indian Ocean brought numerous acute and chronic patients among travelers back to Europe, with an incidence proportional with local epidemic peaks. Our patients chose to present to the hospital and the use of this self-selected patient population, without a control or comparison group, makes it difficult to draw firm conclusions about the full spectrum of disease, particularly in those who did not become sufficiently ill to seek medical attention. About one-quarter of the patients who complained of a history of arthralgia and/ or fever after visiting Reunion Island tested negative for CHIKV infection (as well as for dengue), up to 1 month after return. A comparison of seropositive and seronegative patients showed no differences in their demographics. Among the seronegative patients, some patients sought evaluation for CHIKV to learn if they had been exposed, and some suffered symptoms similar to the confirmed CHIKV patients.
The current series among travelers brings new data on clinical presentation, including the presence of severe cases and "2-phased" disease evolution. Most patients presented with a typical acute stage with a febrile polyarthritis8,14,22. A rash, as reported in other recent published imported cases18,30, was inconstant. All of the patients suffered from severe bilateral and symmetric joint pains that lasted for about 1 week before improvement. Two-thirds of the infected travelers who presented during the acute stage of the disease had to be hospitalized, including 2 cases for a life-threatening event. Therefore, CHIKV should not be considered a benign disease in tropical areas or when imported to developed countries. The link between the potential severity of the cases and the emergence of new CHIKV variants has to be considered40.
Most infected travelers presented at least 10 days after the onset of illness, mostly after having consulted several physicians who were not aware of this emerging disease. This stage of the disease, often following transient improvement, is characterized by chronic rheumatism that can last for months with unpredictable fluctuations and so-called relapses requiring transitory intensification of symptomatic treatment. We identified 3 types of late to chronic CHIKV-rheumatic manifestations that can coexist in 1 patient: 1) finger and toe polyarthritis with morning pain and stiffness; 2) severe subacute tenosynovitis of wrists, hands, and ankles; and 3) exacerbation of mechanic pain in previously injured joints and bones. The main clinical feature was a dramatically limited ability to ambulate and carry out routine activities in daily life, with impaired strength in hands and pain in walking. We point out the high incidence of tenosynovitis during the second stage, although this clinical event was only described by Kennedy et al22 and Thonnon et al44. Tenosynovitis was more common than arthritis during the first months of rheumatism associated with CHIKV. When the anterior wrist was affected (the most frequent location), multiple hypertrophic tenosynovitis commonly induced carpal or cubital tunnel syndromes. It is noteworthy that patients with preexisting Dupuytren disease could be more susceptible to late tenosynovitis when infected with CHIKV. Magnetic resonance imaging (MRI) (with time-resolved coronal contrast-enhanced T1-weighted sequences and fat suppression) appears to be an excellent tool to demonstrate CHIKV-related tenosynovitis, arthritis, and periosteum inflammation, while bone scintigraphy is also of great interest in CHIKV rheumatism31. The current study identified the possibility of Raynaud phenomenon and Raynaud-like phenomenon, to our knowledge for the first time, which were observed during the second and third months of the CHIKV infection.
Physicians should consider CHIKV when presented with a patient with an unusual rheumatic syndrome after traveling to the tropics. As viremia is shorter than the clinical phase, diagnostic confirmation is based on serology despite possible cross-reaction with other alphaviruses16,43,46. Distinguishing between all these arboviral diseases may be difficult. For example, an outbreak of an acute illness with fever and extreme joint pain occurred in Lamu in Kenya, beginning in June 2004, with an attack rate >50% and an estimated 13,500 persons infected3. Cases were then described in Mombasa, beginning in November 2004. At first, after having excluded malaria, this disease outbreak was suspected to be due to o'nyong-nyong fever virus, another member of the genus Alphavirus (PROMED Archive Number 20041214.331; http://www.promedmail.org). Recent molecular analysis has confirmed that it was caused by CHIKV6, however, and may have been the beginning of the subsequent massive outbreak in the Indian Ocean5. Furthermore, dengue virus is endemic in many of the same tropical locations where CHIKV epidemics have occurred, and usually overshadows CHIKV and other arboviral diseases. In the description of the disease by Robinson38 in 1955, proposed clinical findings that would improve the differential diagnosis of other febrile outbreaks with arthralgia and were more characteristic of CHIKV infection were the "absence of adenopathy, the frequent dissociation of the rash and the secondary rise of the temperature, the lack of post-orbital pain, or pain on moving the eyes, and the long continuance of chronic joint pains." The data presented here, particularly the "2-phased" disease evolution, the presence of multiple tenosynovitis, a typical pain on pressure to the wrists, and the delayed onset of Raynaud syndrome may also be helpful in diagnosis.
To date, treatment of CHIKV infection is still solely symptomatic against fever, pain, and handicap. During the acute stage, patients improved with paracetamol, analgesics, short-term systemic NSAIDs, or corticotherapy. Nevertheless, physicians must be aware of possible severe adverse effects such as aspirin-induced bleeding or paracetamol-induced fulminant hepatitis in patients with underlying chronic liver disease20. The management of chronic CHIKV rheumatism is based on analgesics, local and/or systemic NSAIDs, and physiotherapy. When NSAIDs are contraindicated or local treatment fail, short-term systemic corticotherapy is of interest and can lead to dramatic improvement, although a few patients experienced a painful relapse a few days after discontinuation.
In our experience, the management of the elderly infected travelers was more difficult because they had comorbidity and experienced more severe pain and handicap, as previously noticed by Brighton et al8,14,22, and sometimes depressive disorders. Most patients with tenosynovitis were poorly responsive to NSAIDs but dramatically improved after short-term systemic corticosteroids. Although some patients experienced relapses during the second stage requiring repeat short-term corticotherapy, we did not experience steroid-dependent CHIKV-associated rheumatism. In order to treat chronic CHIKV-associated rheumatism, Brighton7 conducted an open pilot study with chloroquine phosphate, in which 5 of 10 treated patients had significant improvement of Ritchie articular index and morning stiffness after a 20-week therapy. The single patient of the current study who initially received a 14-day chloroquine treatment improved in locomotion, but became symptom-free only after 6 months. Controlled studies are being conducted in Reunion to evaluate the efficacy of early chloroquine treatment in CHIKV infection (de Lamballerie, personal data).
In conclusion, the current series of CHIKV among travelers describes some new aspects of the 2-phased arboviral disease characterized by a severe febrile and eruptive polyarthritis, commonly followed by persisting handicapping peripheral rheumatism. Some life-threatening manifestations and unusual rheumatic symptoms (tenosynovitis, Raynaud syndrome) were also observed. CHIKV, which was classically located in Africa and in Southeast Asia, is now spreading to new territories in the western and eastern Indian Ocean and India11. CHIKV infection has now to be considered in the diagnosis in patients who live in or are traveling to and from endemic or epidemic regions. Furthermore, although A. albopictus, the Asian tiger mosquito, was implicated as the vector in Reunion, and is indigenous to Southeast Asia, the western Pacific and the Indian Oceans, it has recently spread to Africa, the Middle East, Europe, and the Americas, mainly because of transportation of dormant eggs in tires17. In some Mediterranean countries, such as Italy, A. albopictus is highly active during the summer17,45. Thus, emergence of autochthonous CHIKV is theoretically possible when coexistence of viremic patients and competent vectors occurs. Finally, nosocomial transmission has been documented in southern France, in a nurse who had direct contact with the blood of a viremic patient31. Considering all these recent data, CHIKV is an arboviral disease that all physicians should be prepared to encounter.
ACKNOWLEDGMENTS
We are grateful to Dr. Marimoutou for statistical support and to Drs. Lin Chen and Paul Newton for editing and helpful comments.
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