Emerging Viral Infections in Rheumatic Diseases

INFECTIOUS ARTHRITIS

Emerging Viral Infections in Rheumatic Diseases Atul A. Khasnis, MD,* Robert T. Schoen, MD,† and Leonard H. Calabrese, DO‡

Objectives: To review the current literature regarding emerging viral pathogens in the context of rheumatic diseases with the intent of increasing awareness among rheumatologists and treating physicians, aiming at early recognition and treatment of these patients. Methods: We reviewed case reports, case series, review articles, and original reports from PubMed (www.pubmed.gov) regarding various aspects influencing spread of infectious diseases including epidemiology and viral and human factors that are potentially responsible for the emergence of new viral pathogens. By consensus, we generated a list of emerging viral pathogens pertinent regarding presentation with rheumatologic manifestations and then short-listed several with particular clinical relevance including hepatitis B, human immunodeficiency virus, and Chikungunya viruses for discussion in greater detail. Results: There has been a change in the epidemiology and clinical rheumatic manifestations of previously known viral pathogens as well as the emergence of new viral pathogens as a consequence of factors such as changes in environmental temperature and its consequences, changes in vector and parasite biology, and human influences such as treatment and immunization. Conclusions: Rheumatologists need to be cognizant of the changing landscape of emerging viral pathogens as they may present with myriad clinical features. Recognition of these pathogens is important to guide correct treatment and prognosis. Given the current scenario of global epidemiologic factors that influence viral emergence, we should expect a growing number of future emerging pathogens. Ongoing research directed at understanding pathogenesis and transmission as well as developing better preventive strategies may help counter the threat posed by emerging pathogens. © 2011 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:236-246 Keywords: emerging viral infections, epidemiology, alphavirus, Chikungunya, rheumatic diseases

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mere generation ago, the rheumatologist thought of infectious diseases in the context of bacterial and less frequently mycobacterial and fungal pathogens. With advances in clinical and laboratory virology, the number of identified viral pathogens associated with rheumatic manifestations has grown dramatically (1); in fact, new pathogens continue to be identified and

*Fellow, Center for Vasculitis Care and Research, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH. †Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT. ‡Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, RJ Fasenmyer Chair of Clinical Immunology Vice Chairman; Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH. The authors have no conflicts of interest to disclose. Address reprint requests to: Leonard Calabrese, DO, 9500 Euclid Avenue, A50, Cleveland, OH 44195. E-mail: [email protected].

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the epidemiology and clinical expression of “older” pathogens continue to transform themselves. Emerging infections have been defined as diseases that have expanded their range of hosts, have spread beyond their presumed geographic territories, have altered their pathogenic characteristics, or are caused by agents not previously deemed as pathogenic (2). A clear understanding of emerging pathogens by rheumatologists is clinically important as these pathogenic agents have been responsible for new rheumatic syndromes that can pose formidable challenges to diagnose and treat. Awareness of the factors that contribute to their emerging nature also gives us insights into the profound effects of factors such as the effect of public health measures and modern medical practice as well as the effects of factors such as global warming, which has and continues to play a key role in the emergence of viral pathogens (3). In this review, we focus specifically on emerging viral infections (EVI) that present with rheuma-

0049-0172/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2011.01.008

A.A. Khasnis, R.T. Schoen, and L.H. Calabrese

tologic manifestations and from this group we focus on 4 select pathogens that exemplify 1 or more features contributing to their emergence, including (1) virus-related factors, (2) vector-related factors; (3) host factors; and (4) the effects of modern medicine and public health. METHODS We reviewed case reports, case series, review articles, and original reports from PubMed (www.pubmed.gov) regarding various aspects influencing spread of infectious diseases. Our search terms for PubMed included “emerging viral infections,” “emerging viral pathogens,” “epidemiology,” “human immunodeficiency virus,” “hepatitis B virus,” “Dengue virus,” “Chikungunya virus,” “rheumatic manifestations,” “human factors,” “global warming,” “alphaviruses,” “progressive multifocal leukoencephalopathy,” “immunization,” and “prevention.” We attempted to focus on identifying potential risk factors and mechanisms responsible for the emergence of new viral pathogens. We then generated a list of emerging viral pathogens that present with rheumatologic manifestations that was sorted to list pathogens with particular clinical relevance, including hepatitis B, human immunodeficiency virus (HIV), and Chikungunya viruses (CHIKV), for further discussion regarding epidemiology, preventive measures, and clinical manifestations, and to understand how these have been modified by treatment as well as changes in viral and vector factors. We also chose to touch on newer viral infections that are emerging related to patients with preexisting rheumatic diseases as a consequence of their disease and immunosuppressive treatments. RESULTS Factors Contributing to the Emergent Nature of Viral Infections Background The factors contributing to EVI can be thought of as viral-related, vector-related, and environment-related (Table 1). The evolutionary biology of viruses is an area of great interest in EVI. A combination of “natural selection” and “genetic drift” contributes to the initial development and later spread of viruses. RNA viruses emerge more often compared with DNA viruses, but the latter stands a better chance at long-term success in transmission (4,5). RNA viruses are more transmissible and therefore more likely to spread rapidly among human hosts within a short span of time. Geographic spread of DNA viruses depends more on actual host migration. HIV and Dengue virus are successful RNA viruses, whereas JC virus and human papilloma virus are notable DNA viruses that have crossed the barriers of time and space in affecting human populations. Cleaveland and coworkers analyzed a large database of 1922 infectious pathogens (compiled from textbooks)

237 Table 1 Determinants of Emerging Viral Infections and Their Spread ●

Viral factors Œ Mutability Œ Mutational robustness Œ Transmissibility Œ Genetic composition (DNA/RNA) Œ Ability to infect multiple species Œ Short lived vs persistent infection Œ Ability to elicit immune response in host ● Vector factors Œ Increased breeding Œ Migration Œ Increased extrinsic incubation rate Œ Decreased extrinsic incubation period Œ Altered biting behavior Œ Ability to harbor new pathogens Œ Environmental adaptability ● Human and ecologic factors Œ Increased population density Œ Limited cultivable land Œ Decreased crop returns Œ Natural disasters Œ Strained health resources Œ Limited financial resources Œ Working conditions Œ Immune status and response

affecting domestic mammals and humans. Among these, 1415 were human pathogens; 15% of these were viruses and 62.7% were able to infect multiple hosts. One hundred seventy-five pathogens were deemed associated with “emerging human diseases,” of which viruses were the most likely species to emerge (relative risk, 4.34) (4). Retroviruses represent the bridge between RNA and DNA viruses and owing to their shared biology may have survived in human and primate hosts due to their “mutational robustness” (6,7). Viruses preferentially infect certain host cells and therefore are likely to spread to hosts harboring similar cells, such as related species (8). The ability to infect across multiple species is a strong survival strategy of most successful pathogens. The ability of the CHIKV to exist in multiple animal hosts ensures its long-term sylvatic survival until it encounters a human host (9). It is also difficult to predict the effects co-infection with multiple viruses on the human host (synergy vs interference). Global warming may benefit vectors of several viral infections in terms of expanding numbers, their ability to infect unusual hosts, and their ability to transmit infection and spread their territory. Viral spread across continents is attributed to a combination of vector and host migration. Environmental disasters such as flood and famine could favor the breeding and spread of vectors such as mosquitoes (10). The spread of the West Nile Virus genotype WN02 and the extrinsic incubation rate of the Western equine encephalomyelitis and St. Louis

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Emerging viral infections in rheumatic diseases

Table 2 Factors Influencing the Emergence of Specific Emerging Viral Infections Virus

Vector

Vertebrate Reservoir

Viral Factors

HBV

None

Humans

DNA virus Mutability

HCV

None

Humans

RNA virus Chronicity Mutability High replication rate HIV important cofactor in transmission

HIV-1

None

Humans

RNA virus Mutability Chronicity

Chikungunya virus

Aedes aegypti Aedes albopictus

Humans

Other alpha viruses

Birds, mammals, humans, primates, marsupials, rodents

Parvovirus B19

Mosquitoes (Culex spp., Aedes spp., Haemagogus spp., Psorophora spp., Ochlerotatus spp., Verrallina spp., Ochlerotatus spp.) None

RNA virus Ability to survive in multiple hosts Mutability (E1-A226V) Single-stranded positive RNA Ability to affect multiple cell types within the host Mutability

Humans

Single-stranded DNA virus Ability to infect erythrocyte precursors, megakaryocytes, synovium, heart, liver, lung, and kidney, transplacental transmission Highly resilient and can withstand denaturation, even at high temperatures

Dengue virus

Aedes aegypti

Humans

Flavivirus Pathogenesis depends on cell and tissue specificity with possible differential targeting of vascular beds

HTLV-1

None

Humans

Retrovirus Induces production of protein “Tax-1” in host cells Oncogenic potential

encephalitis viruses by laboratory strains of Culex mosquitoes increases at elevated temperatures (11,12), whereas that of Dengue 2 and 4 viruses decreases at higher temperatures (13). The combination of longer periods of warmer temperatures (increased survival and biting peri-

ods) combined with shorter viral incubation periods and increased incubation rates could have multiplicative effects in perpetrating EVI. The spread of CHIKV from its proposed epicenter in Africa has been proposed to be from a spread of the viral strain itself as well as of its vector, the

A.A. Khasnis, R.T. Schoen, and L.H. Calabrese

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Table 2 Continued Vector Factors

Human Factors

Public Health Measures

None

Travel, high-risk behavior, reactivation risk with immunosuppression

None

Travel, high-risk behavior, reactivation risk with immunosuppression

None

Travel, high-risk behavior, reactivation risk with immunosuppression

Breeding sites

Ecologic changes, travel/migration Artificial ecosystems

Breeding sites

Migration and travel Artificial ecosystems with modern infrastructures, irrigation, solid waste production

None

Genetic (arthropathy in HLA-DR4, HLA-B27-positive individuals) Severe disease can occur in pregnancy and immunocompromised individuals (HIV, transplant recipients) In general, absolute risk of infection and poor outcome in an individual are low International travel Unusual modes of transmission include vertical, transfusion related, transplantation related, and needlestick-related Abnormal host immune response responsible in part for tissue damage

Vaccination since 1991 has successfully led to 82% reduction in number of new cases Blood screening for HBV since 1972 No vaccine available Reduced transmission since 1987 due to advanced methods for manufacturing blood products Reduced transmission since 1992 following transfusions or solid organ transplants due to better testing of donors No vaccine available Availability of HAART has led to prolonged survival (80% reduction in mortality) Decreasing number of new cases in United States Drug resistance No vaccine available Potential use of Chikungunya immunoglobulin under study Candidate vaccine for Ross river virus successful in animal trials, no human data reported Full-length cDNA clones containing the entire viral genome done Screening not routine in pregnancy or donated blood Recombinant vaccine of VP1 and VP2 capsid proteins under study

Tropical mosquito Closely associated with human habitation Adult females preferentially feed on humans Feeds on multiple hosts during a single gonotrophic cycle Eggs can withstand desiccation for up to a year Survival influenced by temperature, humidity, rainfall, photoperiod, and wind velocity None

First retrovirus known to cause human disease Transmitted through breastfeeding, sexual intercourse, transfusion, and sharing of needles and syringes

Aedes mosquito (9,14). Favorable locations for mosquito breeding include bodies of stagnant water such as cesspools, pits, open drains, construction sites, used cans/tins, tires, abandoned car parts, and tree holes (15). Global warming will also impact human travel and migration;

Vaccines against domain III of the envelope protein and nonstructural proteins under study In the Americas, efforts by the Pan American Health Organization led to a marked decline and successful eradication of A. aegypti in Central and South America by 1970s followed by resurgence Biological interventions may have a role

Blood donor screening for HTLV-1 antibodies using EIA assay approved by FDA in 1997 Vaccine directed at B-cell and T-cell activation through structural viral targets under study

with scarce inhabitable land resources, de novo overcrowding is likely to occur and worsen in preexistent congested areas. Increased population density favors human transmission of viral infections through contact, aerosols, food, water, and fomites. This impact of vector-borne

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diseases is likely to be imbalanced as certain populations may not be as vulnerable due to previous exposure leading to semi-immunity (16). The landscape of EVI is also likely to be influenced by public health interventions that include but are not limited to vaccination, public sanitary measures, use of universal precautions, tracing of contacts, advising patients and contacts against social interaction and travel, public campaign to encourage early self-diagnosis, antiviral prophylaxis, and disinfection strategies (17). The impact of modern medicine by creating vulnerable populations such as immunosuppressed hosts is also important in enhancing the emergence of viral pathogens. While efficacious, the infectious risk that immunosuppression portends may not be immediately estimated and long-term data continue to be reported. Treating the viral infection may result in viral suppression and dormancy as well as possible generation of resistance. Antiviral treatment may also be complicated by the development of immune reconstitution inflammatory syndrome (IRIS), a paradoxical immune activation that has been well described in patients on highly active antiretroviral therapy (HAART) and also in solid organ transplant patients, patients in the postpartum period, neutropenic patients, and patients on tumor necrosis factors inhibitors (18). There are no large reported studies of EVI in immunosuppressed patients, but Dengue infection has been reported to be not severe in a series of 6 patients with renal transplants (19). SPECIFIC VIRAL INFECTIONS Cleaveland and colleagues have identified 1415 species of infectious organisms known to be pathogenic for humans and among these 175 were considered to be emerging. From these by far the largest taxonomic group were viral and prion. Table 2 lists those emerging viral pathogens that we consider to have prominent rheumatic manifestations, the majority of which are alpha viruses (4). Table 2 also notes those features of each virus that contribute to its emerging classification. In selecting specific pathogens to discuss under the heading of “emerging,” we have focused on a selective few that have either recently entered human populations (eg, HIV-1) or have likely been present in humans historically, but which have recently had dramatic shifts in incidence (eg, alpha viruses). Similarly some pathogens such as HIV-1 by virtue of advances in therapy have evolved in their host–pathogen relationship, which has altered the expression of rheumatic complications. Other newly described viral pathogens with prominent rheumatic manifestations, such as B19, hepatitis C, and human T-cell lymphotropic virus (HTLV-1), are often cited as emerging but as with many other viral pathogens are recently described but not necessarily displaying the above features and have been recently reviewed elsewhere (20-22).

Emerging viral infections in rheumatic diseases

Hepatitis B Virus While natural attention is generally directed at pathogens spreading into new populations, it is also important to focus on some that are disappearing and, as a result, their associated rheumatic disease manifestations are accordingly affected. Hepatitis B virus (HBV) remains a widespread problem and 1 of the most prevalent viral infections with an estimated 350 million people chronically infected worldwide. HBV is associated with a variety of rheumatic manifestations including acute polyarthritis and vasculitis of the polyarteritis variety (22). Global endemicity ranges from areas considered high with prevalence rates ⬎8% to low areas such as in the industrialized West, where rates are generally ⬍2%. Universal immunization, a product of public heath, beginning at birth, along with other strategies, has had a dramatic effect resulting in a dramatic decrease in new cases. As of 2008, 177 countries had incorporated HBV in their immunization strategies (23). As a result of such programs and the rigorous screening of blood and blood products, there has been a documented and dramatic decline in HBV-associated polyarteritis noted by several groups (24,25). Similarly it may be assumed that other rheumatic manifestations such as arthritis and arthritisdermatitis are becoming similarly rare, although no tracking data are available. HIV-1 Any discussion of EVI must begin with HIV-1, the etiologic agent for acquired immunodeficiency syndrome, which has infected over 60 million people and accounted for over 25 million deaths, ranking it among the great global killers of all time (26). In terms of its emergence, HIV-1 and its epidemiologically related virus, HIV-2, apparently display the influence of each contributing factor (ie, viral, vector, host, public health, and modern medicine). These viruses evolved in hosts genetically similar to man [(chimpanzee, Pan troglodytes, and the Sooty Mangabey (Cerocebus atys)] before jumping to humans 60-70 years ago (26). Viral spread appears to have been profoundly influenced by disruptions in social and economic patterns in post colonial sub-Saharan Africa combined with increased travel and changing norms in sexual behavior and drug use. While the number of people infected continues to grow, now reaching an estimated 35 million individuals, the infection itself and its clinical sequelae have been profoundly altered by the introduction and increasing use of increasingly effective combination antiviral therapy (HAART). As a result, particularly in the industrialized West, with increasing utilization in resource poor areas, life expectancy and access to therapy have been increased dramatically. Sentinel complications of advanced and complex opportunistic infections have similarly become less frequent. Of great interest is that rheumatic complications, which have always been relatively rare but clinically fascinating and often dramatic, have similarly been affected by

A.A. Khasnis, R.T. Schoen, and L.H. Calabrese

HAART. The classic rheumatic manifestations in the preHAART era (ie, before 1997) with descriptions of inflammatory arthritis, myositis, vasculitis, and other atypical connective tissue disorders have been extensively reviewed (27,28). These conditions, while clinically rare, posed challenges in both diagnosis and therapy as they occurred in individuals with progressive immunodeficiency states who were not ideal candidates for immunosuppression. In 1997, with the introduction of HAART not only was the natural history of nontreated or ineffectively treated HIV disease altered, but also the resultant spectrum of rheumatic complications. Several groups noted both a profound decrease in the incidence of rheumatic complications (20,27,29) and also an alteration of the clinical and pathologic manifestations (30). Similarly new rheumatic manifestations were described, in particular, new onset or flares of previously quiescent autoinflammatory states known as IRIS, resulting from a resurgence of Tcell-mediated immunity (29) and an increase in metabolic disorders, including avascular necrosis of bone (20). Some of these disorders may arise due to the alteration of host pathogen relationship and the resurgence of a failing immune system (ie, IRIS), while others may appear because patients on effective treatment may be living far longer and suffering sequelae that develop over prolonged periods (ie, avascular necrosis or osteoporosis). Since the etiology of these disorders is poorly understood, combinations of these and other factors may be involved. Thus HIV-1 as an emerging viral pathogen is exemplary of both a truly novel pathogen invading the human species as well as an infection that has experienced a profound alteration of its pathogenicity, all within a quarter of a century. EMERGING VIRAL ARTHRITIS: ALPHAVIRUSES Alphaviruses are emerging in explosive epidemics in Asia and Africa and have spread to Europe with the potential to spread to North America. A genus in the family Togaviridae, alphaviruses are enveloped, single-stranded, positive sense RNA viruses found throughout the world (31). Alphaviruses originated as zoonotic pathogens, maintained in a sylvatic life cycle restricted to 1 arthropod vector, 1 animal host, and 1 geographic area (9,32,33). Humans maintained herd immunity against infection (34), but were occasionally infected as dead-end hosts. More recently, epidemic human-mosquito-human transmission cycles have occurred in which urban epidemics develop in the absence of an animal reservoir (35). These epidemics profoundly increase the global importance of alphavirus infections. All arboviruses associated with human disease are mosquito-borne and are often divided, based on nucleotide sequence and geography, into “Old World” alphaviruses associated with encephalitis and “New World” alphaviruses, associated with arthropathy (36,37). Unlike most other forms of viral arthritis, arthritis-associated alphaviruses infections cause arthritis in virtually 100% of clinically apparent cases (38).

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Alphavirus Infections Summertime epidemics of polyarthritis caused by alphaviruses may have existed in Africa, Asia, and possibly the southern United States for 200 years (39). The first alphavirus associated with arthritis to be isolated was the CHIKV recovered in 1953 in Tanzania (40,41). “Chikungunya” means “that which contorts or bends up” in Kimakode, a Tanzanian vernacular language (42). Other important alphaviruses associated with arthritis include O’nyong-Nyong, the cause of past epidemics in Africa (43), the Sindbis virus group, identified in Sindbis, Egypt, but distributed throughout the world (44), and Ross River virus, the most common mosquito-borne illness in Australia (37,45). In this review, we concentrate on the emergence, geographic spread, vector ecology, and clinical and social impact of CHIKV, but recognize that other arthritis-associated alphaviruses have similar potential to develop globally important epidemics in the not distant future. The Emergence of CHIKV Evolutionary lineages of CHIKV exist in 3 clusters, ancestral West African, Asian, and Central/South/East African (C/S/E/A) from which the current epidemic CHIKV is derived (46). The virus originally circulated between forest-dwelling Aedes mosquitoes and nonhuman primates. Human cases were infrequent. An urban cycle developed in Africa and Asia, with human hosts and urban mosquitoes, Aedes aegypti and Aedes albopictus (9,32,33). This epidemic pattern of CHIKV infection became important in 2004 with an outbreak in the western Indian Ocean that began on Lamu Island in Kenya, where 13,500 individuals (3/4 of the population) were affected (47). Several months later, the nearby Union of Comoros had 225,000 cases (48), followed by outbreaks in Mayotte (49), Mauritius (50), and the Seychelles (35). As in previous CHIKV epidemics, A. aegypti was the vector (51). In 2005 to 2006, CHIKV spread to La Reunion Island and infected 266,000 individuals (1/3 of the population) (9,52). At the height of the epidemic, there were 40,000 new cases each week (33). In addition to fever and arthritis, neurological manifestations (33), hepatic failure (33), and peripartum maternal-fetal infections were described (53). There were 237 deaths attributed to this epidemic (approximately 1 per 1000 cases), primarily in newborns and the elderly (53,54). In the La Reunion outbreak, a new variant of CHIKV arose, demonstrating rapid adaptation to changing environmental conditions. Initially, CHIKV was transmitted by A. aegypti and had alanine at residue 226 of the envelope protein E1, resembling the C/S/E/A strain isolated from Tanzania 50 years earlier. Then a substitution of valine for alanine at position 226 (A226VAL) occurred (55). Because it is a single-stranded RNA virus, CHIKV RNA-dependent, RNA polymerase has no proofreading activity and variants occur commonly (56-58). Why did the new CHIKV variant emerge

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on La Reunion? On this island, A. albopictus is the dominant mosquito vector. The (A226VAL) mutation improved virus replication and transmission by A. albopictus, which lacks cholesterol, by eliminating cholesterol dependence for growth (58,59). Even more striking, phylogenetic analysis demonstrates that the (A226VAL) mutation occurred independently in India (2006-2007), in Cameroon (2006), and Gabon (2007), all locations where A. albopictus has displaced A. aegypti. This implies parallel, but independent, adaptive mutation driven by vector requirement, an example of evolutionary convergence resulting from extreme selective pressure (60). Aedes aegypti and Aedes albopictus A. aegypti is an urban African mosquito that spread around the world on ships (61). It is the primary vector of yellow fever and dengue. A. albopictus (“The Asian Tiger Mosquito”) originated in tropical and subtropical Asia, but spread to North America, Europe, as well as parts of Africa (62). Like A. aegypti, A. albopictus is an urban mosquito that breeds in containers such as tires, gutters, and other locations with standing water. However, A. albopictus is more difficult to eradicate since it is less dependent on an urban environment (63). Since its introduction in the United States in 1985, and elsewhere throughout the world, A. albopictus has somewhat displaced A. aegypti (64). The La Reunion CHIKV genotype reached India in 2005. The Indian epidemic, spread by both A. aegypti and A. albopictus, is ongoing with millions of cases (65). Unlike the island populations, India provides a continuous source of immunologically naive individuals unlikely to develop herd immunity (33). CHIKV in Europe and North America Once established in India, numerous CHIKV cases occurred in travelers returning to Europe (66-68) and North America (69). A. albopictus is found throughout southern Europe (70), including Italy, having been imported in automobile tires from a retread factory in Georgia, USA in 1990 (71). When an outbreak of febrile patients with arthritis occurred in the summer of 2007 in Ravenna, Italy, a low-lining marshy region once associated with a significant risk for malaria (72), CHIKV was suspected and detected in 205 individuals (73,74) with an attack rate in the 2 affected towns of 2.5% and 5.4%. Genetic sequencing confirmed that the La Reunion variant (A226Val) was introduced from India (75). Spread of CHIKV to Italy from India resulted from several factors (76). First, an acutely infected individual imported the virus during the viremic stage of illness. This was made increasingly likely by the rise of international travel. Since 1950, world population has increased by a factor of 2.6, but international travel has increased 35-fold (77). Second, a competent vector, A. albopictus, found throughout Italy, replicated the virus and spread secondary cases. Third, a sufficient viral load existed in newly infected

Emerging viral infections in rheumatic diseases

patients for vector infection (78). This was possible since CHIKV causes high levels of viremia in immunologically naive patients (78). Fourth, the spread of CHIKV to India created a year-round outbreak in the northern hemisphere, allowing synchronization between A. albopictus infection in India (year-round) and Europe and North America (northern hemisphere summer) (66). Although there have been no epidemics in the Americas, there have been numerous CHIKV cases imported in returning travelers (69,79). In 2006, 37 such travel-associated cases from 17 states were confirmed by the Centers for Disease Control (79). Also, A. aegypti and A. albopictus captured in Florida were found to be competent vectors, highly susceptible to CHIKV infection and transmission (80). Clinical Manifestations of CHIKV The estimated rate of asymptomatic CHIKV infection is 3 to 25% (33). Typically clinical manifestations occur in 2 phases (33,81,82). After an incubation period of 3 to 7 days, high fever, lasting up to 2 weeks, severe joint pain and swelling, and rash characterize the initial phase (33). Arthralgias and arthritis (Fig. 1) occur early, but during the second phase of the illness, patients often have severe, chronic polyarthritis (Fig. 2). Joint pain is usually symmetrical and commonly affects the wrists, elbows, fingers, knees, and ankles. Joint swelling can occur and disability is common (81-83). Fifteen percent of patients have Raynaud’s phenomenon (66). Throughout both of these phases, headache, fatigue, nausea, and myalgias continue. Rash is common, but reported in a variable percentage of patients. It typically occurs after onset of fever and may be nodular (Figs. 3 and 4), maculopapular, vesicular, bullous (84,85), or desquamative (32). Vasculitic and aphthous lesions have also been described (33). During recent outbreaks, extra-articular manifestations have included hemorrhage, myocarditis, neurological manifestations, including meningocephalitis, Guillain-Barre syndrome,

Figure 1 Acute arthritis involving wrist and interphalangeal joints in a patient with Chikungunya infection. (Color version of figure is available online.)

A.A. Khasnis, R.T. Schoen, and L.H. Calabrese

Figure 2 Chronic arthritis involving wrist and metacarpophalangeal and interphalangeal joints in a patient with Chikungunya infection. (Color version of figure is available online.)

paralysis, and palsies (33,86). Ocular manifestations including photosensitivity, uveitis, and retinitis have been described (33,87). Death directly attributable to CHIKV is rare, but crude death rates are increased (54,88), with the greatest risk in older individuals and neonates (53,54,84). In the La Reunion outbreak, CHIKV infected 10% of all pregnant women. Maternal-to-fetal transmission was found, but only in the intrapartum period, 2 days before to 2 days after delivery (53). Among 39 such neonates, however, 19 were infected and severe disease, including encephalopathy, shock, disseminated intravascular coagulation, and hemorrhage, occurred in 10 (53). Diagnostic Testing for CHIKV A variety of nonspecific laboratory abnormalities (89), including leukopenia, thrombocythemia, hypocalcemia, abnormal liver function tests, and cryoglobulinemia (33,90), can be seen. In addition, there are specific diag-

Figure 3 Nodule on pulp of thumb in a patient with chronic Chikungunya viral arthropathy. (Color version of figure is available online.)

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Figure 4 Palmar nodules in a patient with chronic Chikungunya viral arthropathy. (Color version of figure is available online.)

nostic tests for CHIKV. These include viral culture, since CHIVK causes high levels of viremia (up to 1 billion plaque forming units per ml) 4 to 10 days after the onset of infection (33,78), and reverse transcriptase polymerase chain reaction testing on early disease specimens (33,78,91). During early- and late-stage disease, serologic testing by ELISA to detect anti-CHIKV IgM and IgG antibodies (33,78,92) and immunofluorescence testing are available (33,93). Prevention and Treatment of CHIKV The mainstay of treatment is supportive care including rest, fluids, antipyretics, and analgesics (32,33). Specific therapies including chloroquine, acyclovir, ribavirin, interferon-␣, and corticosteroids have been proposed, but demonstrated efficacy is lacking (32). Human polyvalent immunoglobulin from convalescent CHIKV donors exhibits high in vitro neutralizing activity and protects neonatal and immunocompromised mice from infection (94). Conceivably CHIKV IgG might be used to protect against CHIKV infection in neonates and elderly or immunocompromised patients (94). Worldwide attempts to eradicate Aedes mosquitoes have had limited success (32). In Italy, after the 2007 Ravenna outbreak, an aggressive mosquito eradication program may have contributed to the lack of new cases in 2008 (95). In the Americas, however, an A. aegypti control project in the 1990s was followed by prompt re-infestation after funding terminated (61). Vector eradication may not be practical in Asia and Africa, where resources are limited and mosquitoes survive year round. A. albopictus, which thrives in a variety of urban and nonurban habitats, may be especially difficult to control (32,96). In the absence of effective prevention, a CHIKV vaccine may be the best option. In a phase 2 study, a conventionally attenuated vaccine was protective, but caused arthralgias (97). Safer, recombinant chimeric

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vaccines (98), a DNA vaccine (99), and a particle-like vaccine (100,101) are all in development. EMERGING VIRAL INFECTIONS COMPLICATING RHEUMATIC DISEASES Finally, a new category of EVI should be considered, clearly reflecting the effects of modern medicine on our patients with rheumatic diseases, namely, the effects of immunosuppression creating a vulnerable population that previously was little affected by such organisms. For over 50 years and primarily since the introduction of cortisone to treat rheumatoid arthritis, the treatment of most rheumatic diseases has resulted in an immunosuppressed population that at times approximates patients receiving combination chemotherapy for cancer or those undergoing organ transplantation, often using many of the same drugs. Not surprisingly, patients with rheumatic diseases have been increasingly reported with similar infectious complications, many with viruses now considered emerging, including JC polyoma virus, human herpesvirus-6 and -7, and others (102). Perhaps no example is more striking than infection with JC virus, an agent only described in the past 50 years, and the etiologic agent for progressive multifocal leukoencephalopathy. This devastating opportunistic infection, previously seen only in oncology settings and in the setting of HIV infection, has been reported in both the prebiologic (103) and the biologic era (104) in patients with rheumatic diseases and serves to remind us that rheumatologists now practice in the domain of opportunistic infections once reserved for oncologists, transplantation specialists, and infectious disease specialists. Continued vigilance for new pathogens and diseases is clearly warranted. CONCLUSIONS Rheumatologists should sensitize themselves to the changing landscape of EVI as clinical rheumatologic manifestations may be altered as a consequence of changes in the host, the infecting pathogen, or its therapy as exemplified by HIV-1 infection and HAART. Improved recognition of these pathogens and their associated clinical syndromes is important to study their epidemiology and offer appropriate treatment. Given the current trends in globalization and travel, changes in vector and viral biology, and immunization and other preventive strategies, we are likely to observe a dynamically increasing spectrum of emerging pathogens. Research directed at an improved understanding of disease pathogenesis and transmission as well as better prevention are likely to influence future disease outcomes in patients with EVI. ACKNOWLEDGMENT We would like to thank Sapan Pandya, MD, D.M., Ahmedabad, Gujarat, India for providing the figures included in this article.

Emerging viral infections in rheumatic diseases

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