• 1.

    Powers AM , Brault AC , Tesh RB , Weaver SC , 2000. Re-emergence of Chikungunya and O’nyong-nyong viruses: evidence for distinct geographical lineages and distant evolutionary relationships. J Gen Virol 81: 471479.

    • Search Google Scholar
    • Export Citation
  • 2.

    Rezza G , Chen R , Weaver SC , 2017. O’nyong-nyong fever: a neglected mosquito-borne viral disease. Pathog Glob Health 111: 271275.

  • 3.

    Williams MC , Woodall JP , 1961. O’nyong-nyong fever: an epidemic virus disease in East Africa. II. Isolation and some properties of the virus. Trans R Soc Trop Med Hyg 55: 135141.

    • Search Google Scholar
    • Export Citation
  • 4.

    Shore H , 1961. O’nyong-nyong fever: an epidemic virus disease in East Africa: III. Some clinical and epidemiological observations in the Northern province of Uganda. Trans R Soc Trop Med Hyg 55: 361373.

    • Search Google Scholar
    • Export Citation
  • 5.

    Haddow AJ , Davies CW , Walker AJ , 1960. O’nyong-nyong fever: an epidemic virus disease in East Africa 1. Introduction. Trans R Soc Trop Med Hyg 54: 517522.

    • Search Google Scholar
    • Export Citation
  • 6.

    Sanders EJ et al. 1999. O’nyong-nyong fever in south-central Uganda, 1996–1997: description of the epidemic and results of a household-based seroprevalence survey. J Infect Dis 180: 14361443.

    • Search Google Scholar
    • Export Citation
  • 7.

    Kiwanuka N et al. 1999. O’nyong-nyong fever in south-central Uganda, 1996–1997: clinical features and validation of a clinical case definition for surveillance purposes. Clin Infect Dis 29: 12431250.

    • Search Google Scholar
    • Export Citation
  • 8.

    Rwaguma EB , Lutwama JJ , Sempala SD , Kiwanuka N , Kamugisha J , Okware S , Bagambisa G , Lanciotti R , Roehrig JT , Gubler DJ , 1997. Emergence of epidemic O’nyong-nyong fever in southwestern Uganda, after an absence of 35 years. Emerg Infect Dis 3: 77.

    • Search Google Scholar
    • Export Citation
  • 9.

    Powers AM , 2013. Chapter 23: Infection Patterns and Emergence of O'nyong'nyong Virus in Viral Infections and Global Change. Hoboken, NJ: John Wiley & Sons, Inc.

  • 10.

    LaBeaud AD et al. 2015. High rates of O’nyong nyong and Chikungunya virus transmission in coastal Kenya. PLoS Negl Trop Dis 9: e0003436.

  • 11.

    Tappe D , Kapaun A , Emmerich P , de Mendonca Campos R , Cadar D , Gunther S , Schmidt-Chanasit J , 2014. O’nyong-nyong virus infection imported to Europe from Kenya by a traveler. Emerg Infect Dis 20: 17661767.

    • Search Google Scholar
    • Export Citation
  • 12.

    Waggoner J , Heath CJ , Ndenga B , Mutuku F , Sahoo MK , Mohamed-Hadley A , Vulule J , Mukoko D , LaBeaud AD , Pinsky BA , 2017. Development of a real-time reverse transcription polymerase chain reaction for O’nyong-nyong virus and evaluation with clinical and mosquito specimens from Kenya. Am J Trop Med Hyg 97: 121124.

    • Search Google Scholar
    • Export Citation
  • 13.

    Hortion J , Mutuku FM , Eyherabide AL , Vu DM , Boothroyd DB , Grossi-Soyster EN , King CH , Ndenga BA , LaBeaud AD , 2019. Acute flavivirus and alphavirus infections among children in two different areas of Kenya, 2015. Am J Trop Med Hyg 100: 170173.

    • Search Google Scholar
    • Export Citation
  • 14.

    Vu DM , Mutai N , Heath CJ , Vulule JM , Mutuku FM , Ndenga BA , LaBeaud AD , 2017. Unrecognized dengue virus infections in children, western Kenya, 2014–2015. Emerg Infect Dis 23: 19151917.

    • Search Google Scholar
    • Export Citation
  • 15.

    Harris PA , Taylor R , Thielke R , Payne J , Gonzalez N , Conde JG , 2009. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomedical Informatics 42: 377381.

    • Search Google Scholar
    • Export Citation
  • 16.

    Bessaud M , Peyrefitte CN , Pastorino BA , Gravier P , Tock F , Boete F , Tolou HJ , Grandadam M , 2006. O’nyong-nyong virus, Chad. Emerging Infectious Diseases 12: 1248.

    • Search Google Scholar
    • Export Citation
  • 17.

    Posey DL , O’rourke T , Roehrig JT , Lanciotti RS , Weinberg M , Maloney S , 2005. O’nyong-nyong fever in West Africa. Am J Trop Med Hyg 73: 32.

    • Search Google Scholar
    • Export Citation
  • 18.

    Johnson B , Gichogo A , Gitau G , Patel N , Ademba G , Kirui R , Highton R , Smith D , 1981. Recovery of O’nyong-nyong virus from Anopheles funestus in Western Kenya. Trans R Soc Trop Med Hyg 75: 239241.

    • Search Google Scholar
    • Export Citation
  • 19.

    Johnson B , Chanas A , Shockley P , Squires E , Gardner P , Wallace C , Simpson D , Bowen E , Platt G , Way H , 1977. Arbovirus isolations from, and serological studies on, wild and domestic vertebrates from Kano Plain, Kenya. Trans R Soc Trop Med Hyg 71: 512517.

    • Search Google Scholar
    • Export Citation
  • 20.

    Olaleye O , Omilabu S , Fagbami A , 1988. Igbo-Ora virus (an alphavirus isolated in Nigeria): a serological survey for haemagglutination inhibiting antibody in humans and domestic animals. Trans R Soc Trop Med Hyg 82: 905906.

    • Search Google Scholar
    • Export Citation
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No Evidence of O’nyong-nyong Viremia among Children with Febrile Illness in Kenya (2015–2018)

Melisa M. Shah Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California;

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Bryson A. Ndenga Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya;

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Francis M. Mutuku Department of Environment and Health Sciences, Technical University of Mombasa, Mombasa, Kenya;

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Victoria Okuta Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya;

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Charles O. Ronga Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya;

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Philip K. Chebii Msambweni County Referral Hospital, Msambweni, Kenya;

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Priscilla Maina Msambweni County Referral Hospital, Msambweni, Kenya;

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Zainab Jembe Diani Health Center, Ukunda, Kenya;

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Malaya K. Sahoo Department of Pathology, Stanford University School of Medicine, Stanford, California;

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ChunHong Huang Department of Pathology, Stanford University School of Medicine, Stanford, California;

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Jenna Weber Department of Pathology, Stanford University School of Medicine, Stanford, California;

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Benjamin A. Pinsky Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California;
Department of Pathology, Stanford University School of Medicine, Stanford, California;

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Angelle Desiree LaBeaud Division of Infectious Disease, Department of Pediatrics, Stanford University School of Medicine, Stanford, California

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ABSTRACT

O’nyong-nyong virus (ONNV) is a little-known arbovirus causing intermittent, yet explosive, outbreaks in Africa. It is closely related to chikungunya virus, an emerging infectious disease. O’nyong-nyong virus causes a self-limited illness characterized by bilateral polyarthritis, rash, low-grade fever, and lymphadenopathy. In 1959, an extensive outbreak of ONNV occurred in East Africa, and decades later, another large outbreak was documented in Uganda in 1996. Limited evidence for interepidemic transmission is available, although serologic studies indicate a high prevalence of exposure. 1,045 febrile child participants in western and coastal Kenya were tested for the presence of ONNV using a multiplexed real-time reverse transcriptase–PCR assay. More than half of the participants had malaria parasitemia, and there was no evidence of active ONNV viremia in these participants. Further work is required to better understand the interepidemic circulation of ONNV and to reconcile evidence of high serologic exposure to ONNV among individuals in East Africa.

O’nyong-nyong virus (ONNV) is a mosquito-borne alphavirus in the Togaviridae family. ONNV is phylogenetically related to other Old World alphaviruses causing arthritis including chikungunya virus (CHIKV), Mayaro, and Ross River viruses. 1,2 ONNV is a relatively recent discovery and was first isolated in Uganda during the 1959–1962 outbreak in which ONNV spread from Uganda to surrounding countries infecting more than two million people. 3,4 The disease was named by the Ugandan Acholi tribe and means “weakening of the joints.” 5 In 1996, ONNV infected an estimated 21,000 individuals in Uganda. 6 This outbreak started in the Rakai district of southern Uganda, with the infection rate 68% and the attack rate 41% in some villages. 6 ONNV historically causes large epidemics followed by long periods of disappearance. ONNV may circulate in an enzootic cycle during interepidemic periods, but the hosts within such a cycle have not been characterized. 2

The most common symptoms of ONNV infections are fever, arthritis of the knees and ankles, posterior cervical lymphadenopathy, pruritic rash, and headache. 7,8 The signs of ONNV are often described as a triad of fever, arthralgia, and rash. 7 Symptoms are self-limited, and the febrile period lasts approximately five days. 6 There have been no reported fatalities from ONNV to date.

Unlike other alphaviruses, ONNV is transmitted via the Anopheles mosquito, the same night-biting vector carrying malaria. Anopheles gambiae and Anopheles funestus were the major vectors transmitting ONNV during the two documented, large epidemics. 9 In a 2015 serological study conducted in coastal Kenya, ONNV exposure as confirmed by plaque reduction neutralization (PRNT) assays among 1,848 participants was 22.6%. 10 Since the last known outbreak in this region ended in 1962, evidence for ONNV transmission was surprising and suggestive of unrecognized interepidemic transmission. Multiple children and young adults were also seropositive, demonstrating that ONNV transmission likely occurred recently and may be poorly reported within the clinical setting. A German individual returning from Kenya was also documented to have fever due to ONNV based on the presence of neutralizing antibody in 2014. 11 We hypothesize ongoing low-level ONNV transmission in Kenya, given available serologic reports and recent sporadic cases. 10

Stored blood samples from a study of children with fever in Kenya were tested for ONNV viremia using highly sensitive, multiplexed molecular diagnostics. Kenyan children with undifferentiated febrile illness from five outpatient clinics (Chulaimbo County Hospital, Mbaka Oromo Dispensary in Chulaimbo, Jaramogi Oginga Odinga Teaching and Referral Hospital in Kisumu, Msambweni County Hospital, Diani Health Center in Ukunda) were enrolled between July 14, 2015 and May 4, 2018. 13,14 The clinics serve a mix of urban and rural populations in western and coastal Kenya and are operated by the Kenyan Ministry of Health. Children ages 1–18 years with an acute febrile illness (defined as reported fever or observed temperature ≥ 38°C) and no localizing symptoms were enrolled. Participants were consented and underwent a clinical history and physical examination by a certified clinical officer. Whole blood from each of the study participants was collected for molecular testing. Thirty whole blood samples from this study overlapped with previously reported ONNV results from serum samples. 12 An additional 1,015 untested whole blood samples from febrile pediatric visits were included. A thick and thin blood smear for malaria parasite examination was prepared for all participants. Real-time reverse transcriptase–PCR (rRT-PCR) for ONNV targeting the nonstructural protein 1 gene was conducted as previously described. 12 The positive ONNV control was a 124-bp single-stranded synthesized DNA Ultramer within the assay target (Integrated DNA Technologies, Coralville, IA). This control was based on ONNV strain M20303 from GenBank. Data were stored in REDCap. 15

A total of 1,045 febrile participant outpatient visits were included. There were 602 visits from western Kenyan clinics and 443 visits from coastal Kenyan clinics for a total of 1,045 visits. The median age was 5.5 (range 1–18) years. Joint pain was reported as a symptom in 405/1,045 (38.8%) of visits. Lymphadenopathy was reported by the clinician in 167/1,045 (16.7%) of visits. At all sites, 438/857 (51.1%) of participants had documented malaria parasitemia at their febrile visit. None (0/1,045) of the participants had the presence of ONNV viremia by rRT-PCR.

Despite the presence of the Anopheles vector and literature suggesting high exposure to ONNV by serology, no evidence of ONNV viremia was found in more than 1,000 febrile children from western and coastal Kenya. Given the close relationship between CHIKV and ONNV, serosurveys can reflect cross-reactivity of ONNV to CHIKV. However, in serosurveys from Kenya, PRNT was performed to confirm ONNV-specific reactions. 10 In addition, rare human cases have been reported in interepidemic periods. 16,17 Limited undetected outbreaks followed by periods of quiescent could also explain the findings of high antibody titers to ONNV in human populations. A further possibility is that ONVV could be clinically mild or asymptomatic such that infected individuals would develop immunity without reporting to medical care. Further work is required to better understand the interepidemic circulation of ONNV and observations of high serologic exposure among individuals in East Africa.

The lack of ONNV viremia in a large group of febrile children, although a negative finding, is an important data point in understanding the ONNV reservoir. If ONNV is maintained at very low levels in human populations, the current sample size may not have been adequate to detect such circulation. Alternatively, given that the median age of participants was 5.5 years, human circulation could be sporadic with primary circulation being in an unknown enzootic cycle. During one interepidemic period in 1978, ONNV was isolated from an A. funestus mosquito, suggesting that mosquitoes may be involved in the interepidemic maintenance of the virus. 18 Apart from serosurveys in domestic livestock and rodents, little information is available about other vertebrates involved in the enzootic maintenance of ONNV. 19,20

The rapid spread during epidemic periods, the high attack rate, morbidity of illness, and potential demands on healthcare resources make ONNV an emerging pathogen with significant public health implications warranting close surveillance. Curiously, little is known about what maintains ONNV during interepidemic periods. The mechanism by which the ONNV reservoir is maintained is a key knowledge gap requiring further study. Understanding the combination of viral host immunity, enzootic interepidemic maintenance, ecological factors, and mosquito dynamics that tip the balance toward an ONNV epidemic is greatly needed to decrease the future burden of epidemics.

REFERENCES

  • 1.

    Powers AM , Brault AC , Tesh RB , Weaver SC , 2000. Re-emergence of Chikungunya and O’nyong-nyong viruses: evidence for distinct geographical lineages and distant evolutionary relationships. J Gen Virol 81: 471479.

    • Search Google Scholar
    • Export Citation
  • 2.

    Rezza G , Chen R , Weaver SC , 2017. O’nyong-nyong fever: a neglected mosquito-borne viral disease. Pathog Glob Health 111: 271275.

  • 3.

    Williams MC , Woodall JP , 1961. O’nyong-nyong fever: an epidemic virus disease in East Africa. II. Isolation and some properties of the virus. Trans R Soc Trop Med Hyg 55: 135141.

    • Search Google Scholar
    • Export Citation
  • 4.

    Shore H , 1961. O’nyong-nyong fever: an epidemic virus disease in East Africa: III. Some clinical and epidemiological observations in the Northern province of Uganda. Trans R Soc Trop Med Hyg 55: 361373.

    • Search Google Scholar
    • Export Citation
  • 5.

    Haddow AJ , Davies CW , Walker AJ , 1960. O’nyong-nyong fever: an epidemic virus disease in East Africa 1. Introduction. Trans R Soc Trop Med Hyg 54: 517522.

    • Search Google Scholar
    • Export Citation
  • 6.

    Sanders EJ et al. 1999. O’nyong-nyong fever in south-central Uganda, 1996–1997: description of the epidemic and results of a household-based seroprevalence survey. J Infect Dis 180: 14361443.

    • Search Google Scholar
    • Export Citation
  • 7.

    Kiwanuka N et al. 1999. O’nyong-nyong fever in south-central Uganda, 1996–1997: clinical features and validation of a clinical case definition for surveillance purposes. Clin Infect Dis 29: 12431250.

    • Search Google Scholar
    • Export Citation
  • 8.

    Rwaguma EB , Lutwama JJ , Sempala SD , Kiwanuka N , Kamugisha J , Okware S , Bagambisa G , Lanciotti R , Roehrig JT , Gubler DJ , 1997. Emergence of epidemic O’nyong-nyong fever in southwestern Uganda, after an absence of 35 years. Emerg Infect Dis 3: 77.

    • Search Google Scholar
    • Export Citation
  • 9.

    Powers AM , 2013. Chapter 23: Infection Patterns and Emergence of O'nyong'nyong Virus in Viral Infections and Global Change. Hoboken, NJ: John Wiley & Sons, Inc.

  • 10.

    LaBeaud AD et al. 2015. High rates of O’nyong nyong and Chikungunya virus transmission in coastal Kenya. PLoS Negl Trop Dis 9: e0003436.

  • 11.

    Tappe D , Kapaun A , Emmerich P , de Mendonca Campos R , Cadar D , Gunther S , Schmidt-Chanasit J , 2014. O’nyong-nyong virus infection imported to Europe from Kenya by a traveler. Emerg Infect Dis 20: 17661767.

    • Search Google Scholar
    • Export Citation
  • 12.

    Waggoner J , Heath CJ , Ndenga B , Mutuku F , Sahoo MK , Mohamed-Hadley A , Vulule J , Mukoko D , LaBeaud AD , Pinsky BA , 2017. Development of a real-time reverse transcription polymerase chain reaction for O’nyong-nyong virus and evaluation with clinical and mosquito specimens from Kenya. Am J Trop Med Hyg 97: 121124.

    • Search Google Scholar
    • Export Citation
  • 13.

    Hortion J , Mutuku FM , Eyherabide AL , Vu DM , Boothroyd DB , Grossi-Soyster EN , King CH , Ndenga BA , LaBeaud AD , 2019. Acute flavivirus and alphavirus infections among children in two different areas of Kenya, 2015. Am J Trop Med Hyg 100: 170173.

    • Search Google Scholar
    • Export Citation
  • 14.

    Vu DM , Mutai N , Heath CJ , Vulule JM , Mutuku FM , Ndenga BA , LaBeaud AD , 2017. Unrecognized dengue virus infections in children, western Kenya, 2014–2015. Emerg Infect Dis 23: 19151917.

    • Search Google Scholar
    • Export Citation
  • 15.

    Harris PA , Taylor R , Thielke R , Payne J , Gonzalez N , Conde JG , 2009. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomedical Informatics 42: 377381.

    • Search Google Scholar
    • Export Citation
  • 16.

    Bessaud M , Peyrefitte CN , Pastorino BA , Gravier P , Tock F , Boete F , Tolou HJ , Grandadam M , 2006. O’nyong-nyong virus, Chad. Emerging Infectious Diseases 12: 1248.

    • Search Google Scholar
    • Export Citation
  • 17.

    Posey DL , O’rourke T , Roehrig JT , Lanciotti RS , Weinberg M , Maloney S , 2005. O’nyong-nyong fever in West Africa. Am J Trop Med Hyg 73: 32.

    • Search Google Scholar
    • Export Citation
  • 18.

    Johnson B , Gichogo A , Gitau G , Patel N , Ademba G , Kirui R , Highton R , Smith D , 1981. Recovery of O’nyong-nyong virus from Anopheles funestus in Western Kenya. Trans R Soc Trop Med Hyg 75: 239241.

    • Search Google Scholar
    • Export Citation
  • 19.

    Johnson B , Chanas A , Shockley P , Squires E , Gardner P , Wallace C , Simpson D , Bowen E , Platt G , Way H , 1977. Arbovirus isolations from, and serological studies on, wild and domestic vertebrates from Kano Plain, Kenya. Trans R Soc Trop Med Hyg 71: 512517.

    • Search Google Scholar
    • Export Citation
  • 20.

    Olaleye O , Omilabu S , Fagbami A , 1988. Igbo-Ora virus (an alphavirus isolated in Nigeria): a serological survey for haemagglutination inhibiting antibody in humans and domestic animals. Trans R Soc Trop Med Hyg 82: 905906.

    • Search Google Scholar
    • Export Citation

Author Notes

Address correspondence to Melisa M. Shah, Division of Infectious Diseases and Geographic Medicine, Stanford University, 300 Pasteur Dr., Lane 134, Stanford, CA 94305. E-mail: melisa.shah@gmail.com

Authors’ addresses: Melisa M. Shah, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, E-mail: melisa.shah@gmail.com. Bryson A. Ndenga, Victoria Okuta, and Charles O. Ronga, Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya, E-mails: bndenga@yahoo.com, victoriaokuta7@gmail.com, and rongacharles@yahoo.com. Francis M. Mutuku, Department of Environment and Health Sciences, Technical University of Mombasa, Mombasa, Kenya, E-mail: fmutuku73@gmail.com. Philip K. Chebii and Priscilla Maina, Msambweni County Referral Hospital, Msambweni, Kwale County, Kenya, E-mails: chebiik@yahoo.com and pirimaina@gmail.com. Zainab Jembe, Diani Health Center, Ukunda, Kwale County, Kenya, E-mail: zainabjembe@gmail.com. Malaya K. Sahoo, ChunHong Huang, and Jenna Weber, Department of Pathology, Stanford University School of Medicine, Stanford, CA, E-mails: mksahoo@stanford.edu, chhuang@stanford.edu, and jmicweber@gmail.com. Benjamin A. Pinsky, Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, E-mail: bpinsky@stanford.edu. Angelle Desiree LaBeaud, Department of Pediatrics Infectious Diseases, Stanford University School of Medicine, Stanford, CA, E-mail: dlabeaud@stanford.edu.

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