During December 2013, the first locally transmitted chikungunya virus (CHIKV) infections in the Americas were reported in the Caribbean. Although CHIKV infection is rarely fatal, risk for severe disease increases with age and medical comorbidities. Herein we describe characteristics of Veterans Health Administration (VHA) patients with CHIKV infection and, among those with infections diagnosed in Puerto Rico, investigated risk factors for hospitalization. We queried VHA’s national electronic medical records to identify patients with CHIKV testing during 2014. Demographics, clinical history, laboratory results, and outcomes were abstracted. We investigated risk factors for hospitalization among patients with laboratory-confirmed CHIKV infection in Puerto Rico. We identified 180 laboratory-confirmed CHIKV infections; 148 (82. 2%) were diagnosed in Puerto Rico, and 32 (17. 8%) were diagnosed among returning travelers elsewhere in the United States. In Puerto Rico, where more patients were hospitalized (55. 4% versus 20. 0%) and died (4. 1% versus 0%), risk for hospitalization increased with age (relative risk [RR]/each 10-year increase, 1. 19; 95% confidence interval [CI], 1. 06–1. 32) and, adjusted for age, increased among patients with congestive heart failure (RR, 1. 58; 95% CI, 1. 25–1. 99), chronic kidney disease (RR, 1. 52; 95% CI, 1. 19–1. 94), diabetes mellitus (RR, 1. 39; 95% CI, 1. 06–1. 84), or chronic lung disease (RR, 1. 37; 95% CI, 1. 03–1. 82). CHIKV infection is an emerging problem among Veterans residing in or visiting areas with CHIKV transmission. Although overall mortality rates are low, clinicians in affected areas should be aware that older patients and patients with comorbidities may be at increased risk for severe disease.
Chikungunya virus (CHIKV), an alphavirus most commonly transmitted by Aedes species mosquitoes, causes chikungunya fever (CHIK), characterized by acute-onset of fever and what is frequently described as incapacitating polyarthralgia [1,2]. Since CHIKV was first identified in Tanzania in 1953 [2], epidemics have occurred in South and Southeast Asia, Africa, and Europe [1,3, 4]. Three distinct genotypes have been described, including East/Central/South African, Asian, and West African [1,5]. In December 2013, locally transmitted infection in the Western Hemisphere was first reported; the predominant strain is closely related to the Asian genotype [6–8]. CHIKV has rapidly disseminated among this largely immunologically naïve population; the Pan American Health Organization (PAHO) reported >1. 1 million suspect cases, involving the majority of Western Hemisphere countries by the end of 2014 [9]. During 2014, over 31,000 cases (14% laboratory-confirmed) were reported in Puerto Rico [10] and over 1,500 cases (17% laboratory-confirmed) were reported in the U. S. Virgin Islands [11]; these figures are thought to underestimate disease burden because they do not include patients who did not present for care nor those who presented, but were not reported or for whom diagnostic testing was not completed [12]. During 2014,2, 811 laboratory-confirmed infections in the United States were reported to the Centers for Disease Control and Prevention (CDC) through the ArboNET surveillance system; the majority were among returning travelers, except for 12 persons in Florida with locally transmitted infection [13]. CHIK is usually self-limited, with the majority of symptoms typically resolving in 7–10 days [1]; however, patients can have prolonged rheumatologic symptoms [14,15]. CHIKV infection can also be associated with severe illness, involving neurologic, cardiovascular, respiratory, renal, and ocular manifestations [16]. Although overall mortality is low, estimated at 0. 3/1,000 population per year on Réunion Island [17], risk for severe disease and death increases with age and is higher among patients with certain comorbidities [17–19]. The Veterans Health Administration (VHA) has health care facilities throughout the United States and U. S. territories. Because 45% of all U. S. Veterans and 62% of Veterans in Puerto Rico are aged ≥65 years [20], and VHA patients have more comorbidities than Veterans who receive care at non-VHA facilities or non-Veterans [21], VHA patients might be at higher risk for severe CHIK than those in the general U. S. population exposed to the virus (i. e. returning travelers and those living in areas with CHIKV transmission). VHA’s Public Health Surveillance and Research Group (PHSR) performs surveillance for emerging infections among VHA patients. After the CHIK epidemic involved U. S. territories, PHSR began performing CHIK epidemiologic surveillance in July 2014 of all patients with laboratory-confirmed CHIKV infection diagnosed at VHA facilities during 2014. Herein, we describe characteristics of these patients, compare clinical findings with patients who tested negative, investigate risk factors for hospitalization, and report phylogenetic analysis of CHIKV strains detected.
This study was reviewed by CDC for human subjects protection and was deemed to be non-research. It was also approved by the Stanford University Institutional Review Board and fulfilled the requirements of regulation OHRP 45 CFR 46. 116 (d) for waiver of informed consent. Patient data was anonymized after data abstraction.
Patients with CHIKV infection frequently reported oligoarthralgia or polyarthralgia (88. 3%), subjective fever (84. 4%), generalized malaise (76. 7%), myalgia (69. 4%), and rash (44. 4%), and reported these symptoms more often than CHIKV-negative patients (Table 2). Among 165 patients with laboratory-confirmed CHIKV infection who had recorded temperatures during their acute illness, only 53 (32. 1%) demonstrated objective fever (>38. 0°C or >100. 4°F) [9], and only 48 (29. 1%) had both objective fever and arthralgia. Subjective fever and arthralgia was reported for 140 (77. 8%) of 180 patients and subjective fever or any arthralgia for 174 (96. 7%). Among CHIKV-positive patients, 37. 0% of 173 had leukopenia (<4,000 white blood cells [WBC]/μL) and 71. 4% of 171 had lymphopenia (<1,000 lymphocytes/μL); these findings occurred more frequently compared with CHIKV-negative patients (Table 3). Thrombocytopenia (<150,000 platelets/μL) occurred among 80 (46. 5%) of 172 patients with CHIKV infection, with mean nadir platelet count of 104,000/μL. Acute kidney injury (AKI) (≥0. 3 mg/dL or 26. 5 μmol/L increase in serum creatinine from last level [28]) was experienced by 33 (21. 6%) of 153 patients, 4 (12. 1%) of whom had stage III AKI. Hepatic transaminitis (aspartate aminotransferase >40 U/L or alanine aminotransferase >45 U/L) was experienced by 52 (40. 3%) of 129 patients, 16 (30. 8%) of whom had transaminases >3 times the upper limit of normal. In Puerto Rico, 82 (55. 4%) of 148 patients with laboratory-confirmed CHIKV infection were hospitalized, including 10 (6. 8%) who required intensive care; elsewhere in the United States, 6 (20. 0%) of 30 returning travelers with known hospitalization status were hospitalized (p =. 0004). Whereas the hospitalization rate increased with age among patients in Puerto Rico (relative risk [RR]/ each 10-year increase in age, 1. 19; 95% confidence interval [CI], 1. 06–1. 32), it did not increase with age among returning travelers. Because only 6 returning travelers were hospitalized, analysis is only presented for patients in Puerto Rico (Table 4). After adjusting for age, a significantly higher risk for hospitalization associated with having congestive heart failure (CHF) (RR, 1. 58; 95% CI, 1. 25–1. 99), chronic kidney disease (CKD) (RR, 1. 52; 95% CI, 1. 19–1. 94), diabetes mellitus (RR, 1. 39; 95% CI, 1. 06–1. 84), or chronic lung disease (RR, 1. 37; 95% CI, 1. 03–1. 82) remained. Adjusted for age, patients had a greater risk for hospitalization if they were tachycardic (>100 beats/minute; RR, 1. 49; 95% CI, 1. 12–1. 98), had leukocytosis (>11,000 WBC/μL; RR, 1. 65; 95% CI, 1. 34–2. 03), AKI (RR, 1. 64; 95% CI, 1. 33–2. 04), or hepatic transaminitis (RR, 1. 38; 95% CI, 1. 07–1. 80) at presentation. Two patients with CHIKV infection, confirmed by RT-PCR, developed septic shock without another identified etiology. One patient, with CHIKV infection confirmed by RT-PCR of serum, developed meningitis with a CSF profile consistent with a viral etiology, demonstrating pleocytosis (30 WBC/mm3) with initial predominant monocytosis and elevated protein (88 mg/dL). CSF was not submitted for CHIKV testing and no CSF was recovered for diagnostic testing by VA PHRL. One patient presented with Guillain-Barré syndrome one month after CHIK; recent CHIKV infection was confirmed by positive IgM serology. Two patients with CHIKV infection, confirmed by RT-PCR, presented with diabetic ketoacidosis; one patient with CHIKV infection, confirmed by RT-PCR, presented with pancreatitis; one patient with CHIKV infection, confirmed by RT-PCR, presented with colitis, and one patient with CHIKV infection, confirmed by RT-PCR of serum, experienced monomicrobial nonneutrocytic ascites (recovered peritoneal fluid collected 20 days after symptom onset was CHIKV IgM and RT-PCR negative). Seven patients with CHIKV infection (6 confirmed by RT-PCR and 1 by IgM) experienced pneumonia during their clinical course. Four patients with CHIKV infection, confirmed by RT-PCR, experienced congestive heart failure exacerbations; three patients with CHIKV infection, confirmed by RT-PCR, presented with syncope; and one patient with CHIKV infection, confirmed by RT-PCR, experienced a non ST-elevation myocardial infarction. One patient with CHIKV infection, confirmed by RT-PCR, presented with epididymitis. Among the 148 patients with laboratory-confirmed CHIKV infection, 6 (4. 1%) died. All had viremia demonstrated by RT-PCR (Table 5). In addition to these six patients, there were 15 patients who died after presenting with an illness compatible with CHIK that may have contributed to death; specimens for these patients were submitted for CHIKV testing but were not processed. Although attempts were made to obtain these specimens submitted to non-VHA laboratories, they were not recovered for testing. These 15 patients are thus considered suspect cases (data available upon request). The mean age of patients with laboratory-confirmed CHIKV infection in Puerto Rico who died was 78 years (range, 66–99 years), compared with 68 years (range, 23–94 years) for those in Puerto Rico who survived (p = 0. 12). All 6 patients who died were afebrile on presentation (only one had a recorded temperature >100. 4°F or >38. 0°C during hospitalization); four were tachycardic on presentation. Of 5 with known medical history, all had multiple comorbidities. CHIKV E1 envelope glycoprotein gene sequences (GenBank accession numbers: KU724228-KU724266) for 39 patients in Puerto Rico were closely related (<0. 5% nucleotide difference) and nearly identical to strains in GenBank from St. Martin and the British Virgin Islands (Fig 3) [6,7].
Our study is the first to characterize U. S. Veterans with laboratory-confirmed CHIKV infection. The majority received a diagnosis in Puerto Rico, although 32 were returning travelers who received a diagnosis elsewhere in the United States. Although the majority reported subjective fever, only one-third had objective fever, indicating that use of recommended CHIK case definitions, requiring objective fever, might underestimate disease burden among VHA patients [24]. Among returning travelers, approximately one-fifth were hospitalized, whereas in Puerto Rico, where patients were older and had more comorbidities, approximately half of laboratory-confirmed patients were hospitalized, 6. 8% required intensive care, and 4. 1% died. The fatality rate was higher among VHA patients compared with a preliminary report from Puerto Rico in December 2014 that described only 4 deaths identified by passive surveillance on the island [12]. Although we performed population sequencing of only a portion of the E1 envelope glycoprotein gene, we did not find substantial difference among sequences from Puerto Rico compared with other strains circulating in the Western Hemisphere [6,7]. As in previous studies [18,19], we report that age was associated with increased risk for hospitalization. After adjusting for age, CHF (but not coronary heart disease), CKD, diabetes, and chronic lung disease were associated with increased risk for hospitalization. While we cannot be certain of the individual physicians' criteria for hospitalization in many cases, we do know that patients were more likely to be hospitalized if they had unstable vital signs (e. g. tachycardia) or had abnormal laboratory results (e. g. leukocytosis, acute kidney injury, or hepatic transaminitis) at presentation. Although literature review demonstrates low overall mortality, among persons with CHIKV infection presenting for care, the case fatality rate is not insignificant. During the CHIKV outbreak on Réunion Island (East/Central/South African genotype) [29], among 157 patients with laboratory-confirmed infection who presented to a medical center, 61. 8% were hospitalized and 3. 2% died [18]. Although patients in that study were >10 years younger and fewer had comorbidities, hospitalization and case fatality rates were similar to VACHS. They reported that diabetes and ischemic heart disease, unadjusted for age, was associated with increased odds of hospitalization [18]; only 11 patients in that study had CKD. Economopoulou et al. reported that among a subset of hospitalized patients with CHIK, cardiac disease, respiratory disease, as well as hypertension were associated with increased risk for severe disease [19]. Because our study included patients with laboratory-confirmed CHIKV infection, we cannot assess the overall burden of CHIKV infection among Veterans, only those who presented to VHA facilities and had appropriate diagnostic testing completed. During 2014, investigation of households surrounding laboratory-positive cases demonstrated that 28% of participants were laboratory-positive for current or recent CHIKV infection, and only 63% of symptomatic persons had sought care [12]. Although our query was robust, any patient with results not entered into the laboratory component of the electronic medical record (e. g. , scanned or recorded in a progress note) would not have been captured. Sample size limited analysis of returning travelers, and in Puerto Rico, prevented inclusion of >1 comorbidity in age-adjusted models or assessment of risk factors for intensive care or death among patients with laboratory-confirmed infection. This study identified the lack of testing availability for VACHS, as well as deficiencies in CHIKV diagnostic testing across VHA. We identified 11 patients (4 in Puerto Rico and 7 elsewhere in the United States) with inadequate testing to diagnose CHIKV infection, which may have contributed to underdiagnosis of CHIKV-infection. In Puerto Rico this was because of underuse of serology for patients who presented >8 days after symptom onset. Outside Puerto Rico this was because of underuse of CHIKV RT-PCR or convalescent serology for patients who presented during the first week of symptom onset. Among returning travelers, many of whom presented for care in the U. S. during the convalescent period, when diagnosis is dependent upon serology, some diagnoses could have been missed as CHIKV IgM typically declines after several weeks to months [1]. Only 4 of the returning travelers had CHIKV IgM performed without simultaneous CHIKV IgG, and no patients had a negative CHIKV IgM and positive CHIKV IgG, however, suggesting that few cases may have been missed for this reason. Outside Puerto Rico, only 44% of patients tested for CHIKV had laboratory-confirmed infection; this not only reflects the lower prevalence of CHIKV infection outside Puerto Rico, but also improper testing of patients without symptom-onset after travel to an area with CHIKV transmission. Our surveillance activities determined that CHIKV testing availability for VACHS was lacking and resulted in VHA PHRL offering CHIKV (and dengue virus) testing. Further education of VHA providers regarding CHIKV infection, correct diagnostic testing (RT-PCR versus serology) on the basis of time from symptom onset, and available testing through VHA is needed. Lessons learned from Puerto Rico are important for areas in the Western Hemisphere with ongoing CHIKV transmission as well as countries, including the United States, with similarly immunologically naïve populations and Aedes aegypti or Aedes albopictus vectors [6]. For clinical management, newly required CHIK public health reporting, and surveillance, having adequate laboratory testing capacity for timely results is helpful. Although testing all symptomatic persons might be infeasible, sufficient capacity to test those with severe (e. g. hospitalized patients) or atypical illness is needed. Clinicians practicing in areas with CHIKV transmission should be aware that CHIKV infection among elderly patients and patients with comorbidities, including CHF, CKD, diabetes, and chronic lung disease may be associated with more severe disease. To determine whether the risk of atypical complications is greater for CHIKV infection compared with other viral infections, a larger cohort of patients presenting with a viral syndrome would need to be studied. Further work to examine risk factors for intensive care and death among a larger sample of patients with laboratory-confirmed infection is needed to provide closer monitoring for those at greatest risk and to investigate the effect of prevention strategies [30] targeted to populations at greatest risk should they acquire CHIKV infection.
Infection with mosquito-borne chikungunya virus causes fever and severe diffuse joint pain—an illness known as chikungunya fever, or" that which bends up." Epidemics of chikungunya fever have occurred in Asia, Africa, and Europe. Not until December 2013 were there reports of chikungunya virus infection occurring in the Americas. Since then, it has involved most countries in the Western Hemisphere with >1. 1 million cases reported by the end of 2014. Previous data from the Réunion Island outbreak demonstrated that older patients and patients with certain chronic medical conditions may have a higher risk of severe disease. The Veterans Health Administration is the largest health care system in the United States and has facilities in U. S. territories, including Puerto Rico, which has been heavily affected by this epidemic. Among Veterans in Puerto Rico, we investigated risk factors for severe disease and described all chikungunya-associated deaths. Risk for hospitalization increased with age, and for patients of the same age, was increased among those with congestive heart failure, chronic kidney disease, diabetes, or chronic lung disease. Further work is needed to determine whether prevention strategies targeted to those who may be at greatest risk for severe disease could help decrease morbidity and mortality among these populations.
reverse transcriptase-polymerase chain reaction
medicine and health sciences
pathology and laboratory medicine
togaviruses
chikungunya infection
respiratory infections
pathogens
tropical diseases
microbiology
geographical locations
alphaviruses
pulmonology
viruses
north america
chikungunya virus
rna viruses
signs and symptoms
neglected tropical diseases
molecular biology techniques
caribbean
research and analysis methods
infectious diseases
serology
artificial gene amplification and extension
medical microbiology
microbial pathogens
molecular biology
people and places
puerto rico
diagnostic medicine
polymerase chain reaction
fevers
viral pathogens
biology and life sciences
viral diseases
organisms
Chikungunya Fever Cases Identified in the Veterans Health Administration System, 2014