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Viral load and humoral immune response in association with disease severity in Puumala hantavirus-infected patients-implications for treatment
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.ORCID iD: 0000-0003-4030-0449
Department of medicine, Center for Infectious Medicine, Karolinska institutet, Stockholm.
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2014 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 20, no 3, 235-241 p.Article in journal (Refereed) Published
Abstract [en]

Hantaviruses are the causative agents of haemorrhagic fever with renal syndrome (HFRS) in Eurasia and of hantavirus cardiopulmonary syndrome (HCPS) in the Americas. The case fatality rate varies between different hantaviruses and can be up to 40%. At present, there is no specific treatment available. The hantavirus pathogenesis is not well understood, but most likely, both virus-mediated and host-mediated mechanisms are involved. The aim of the present study was to investigate the association among Puumala hantavirus (PUUV) viral RNA load, humoral immune response and disease severity in patients with HFRS. We performed a study of 105 PUUV-infected patients that were followed during the acute phase of disease and for up to 1-3 months later. Fifteen of the 105 patients (14%) were classified as having moderate/severe disease. A low PUUV-specific IgG response (p <0.05) and also a higher white blood cell count (p <0.001) were significantly associated with more severe disease. The PUUV RNA was detected in a majority of patient plasma samples up to 9 days after disease onset; however, PUUV RNA load or longevity of viraemia were not significantly associated with disease severity. We conclude that a low specific IgG response was associated with disease severity in patients with HFRS, whereas PUUV RNA load did not seem to affect the severity of HFRS. Our results raise the possibility of passive immunotherapy as a useful treatment for hantavirus-infected patients.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014. Vol. 20, no 3, 235-241 p.
Keyword [en]
age, disease severity, hantavirus, haemorrhagic fever with renal syndrome, humoral immune response, immunoglobulins, neutrophil, Puumala virus, viral load, white blood cell count
National Category
Microbiology in the medical area Infectious Medicine
Research subject
URN: urn:nbn:se:umu:diva-74938DOI: 10.1111/1469-0691.12259ISI: 000331024400018PubMedID: 23742660OAI: diva2:635009
Available from: 2013-07-02 Created: 2013-07-02 Last updated: 2016-05-24Bibliographically approved
In thesis
1. Study of pathogenesis and immune response in human Puumala virus infection
Open this publication in new window or tab >>Study of pathogenesis and immune response in human Puumala virus infection
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hantaviruses can cause two severe human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). Hantaviruses are spread to humans mainly through inhalation of infectious virions, secreted from infected rodents. The human diseases are characterized by an increased capillary leakage syndrome. Hantaviruses are known to infect endothelial cells, but they are non-cytopathogenic. The mechanism behind human disease is not well understood, but an overactive immune response is implicated in the pathogenesis. The aim of my thesis has been to investigate parts of innate and adaptive immune responses in Puumala virus-infected patients.

In paper I we found a sex difference in the cytokine profile during acute infection. Females had significantly higher plasma levels of IL-9, FGF-2, GM-CSF and lower levels of IL-8 and IP-10 compared to males. These differences may affect the activation and function of the immune response.

In paper II we studied the phenotype and kinetics of NK cells. We observed that CD56dim NK cells were elevated during acute infection and that these, predominantly NKG2C+ NK cells, remained elevated for at least two months after symptom debut. Our novel finding of a prolonged NK cell response, implicates that NK cells may possess adaptive immunity features. 

In paper III we observed a vigorous cytotoxic T cell (CTL) response during acute infection, which contracted in parallel with decrease in viral load. The CTL response was not balanced by an increase in regulatory T cells. The T cells expressed inhibitory immunoregulatory receptors, known to dampen intrinsic T cell activity. 

In paper IV, we found that a low IgG response in patients was significantly associated with more severe disease, while the viral load did not affect the outcome. Our findings support the use of passive immunization as a treatment alternative for hantavirus-infected patients.

In conclusion, my thesis contributes to an increased knowledge about the immune response in hantavirus-infected patients. The findings, combined with future studies, will hopefully lead to a better understanding of the pathogenesis and possible treatment alternatives.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2013. 60 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1577
Hantavirus, puumala virus, immune response, viral load, NK cells, T cells, cytokines, disease severity
National Category
Basic Medicine
Research subject
Infectious Diseases
urn:nbn:se:umu:diva-76706 (URN)978-91-7459-681-6 (ISBN)
Public defence
2013-09-20, E04, byggnad 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Available from: 2013-08-30 Created: 2013-07-11 Last updated: 2013-09-03Bibliographically approved
Open this publication in new window or tab >>TRANSMISSION AND PATHOGENESIS OF HANTAVIRUS
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Abstract [en]

Hantaviruses are the causative agents of hemorrhagic fever with renal syndrome (HFRS) in Eurasia, and of hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Transmission to humans usually occurs by inhalation of aerosolized virus-contaminated rodent excreta. To date, human-to-human transmission has only been described for the Andes hantavirus. The mode of transmission of Andes hantavirus is not yet known, but transmission through saliva has been suggested. In Sweden, we have one hantavirus that is pathogenic to humans, Puumala virus (PUUV), which is endemic in Central and Northern Europe. It induces a relatively mild form of HFRS, also called nephropathia epidemica (NE). The rodent reservoir is the bank vole (Myodes glareolus). The mechanism behind the pathogenesis of hantavirus is complex and probably involves both virus-mediated and host-mediated mechanisms. The aim of this project was to investigate the transmission mechanisms and pathogenesis of hantavirus disease in humans.

In our first study, we described the largest outbreak of PUUV so far in Sweden. We investigated factors that might be important for causing the outbreak, and suggested that a peak in the bank vole population together with concurrent extreme weather conditions most probably contributed to the outbreak.

Our next studies concentrated on human-to-human transmission of hantaviruses. We found PUUV RNA in saliva from PUUV-infected patients, suggesting that there is PUUV in the saliva of infected humans, although no person-to person transmission appears to occur with PUUV.  In the studies that followed, we showed that human saliva and human salivary components could inhibit hantavirus replication. We also found PUUV-specific IgA in the saliva of PUUV-infected patients, which might prevent person-to-person transmission of the virus. 

In the final study, we focused on the pathogenesis of NE. One hundred five patients were included in a prospective study.  They were divided into a group with mild disease and a group with moderate or severe disease. We found that the immune response had a dual role in disease development. It was partly responsible for development of severe disease, with significantly higher amounts of neutrophils in severely ill patients, but it was also protective against severe disease, because patients with mild disease had higher levels of PUUV-specific IgG.

In conclusion, a peak in the bank vole population in combination with extreme weather will increase the risk of human infection, PUUV RNA is present in saliva, PUUV-specific IgA and salivary components inhibit person-to-person transmission of PUUV, and the immune response is important for the pathogenesis of PUUV and the severity of the disease.

Abstract [sv]

Hantavirus är en grupp av virus som finns hos gnagare som bär på viruset utan att själva bli märkbart sjuka. Varje hantavirus har anpassat sig till sin egen art av gnagare som de infekterar (kallas virusets reservoar). Hantaviruset kan överföras till människor från gnagare och kallas då för en zoonos eftersom detsprids från djur till människa. I människa orsakar hantavirus blödarfeber med njurpåverkan i Eurasien och blödarfeber med med hjärt och lungpåverkan i Nord- och Sydamerika.

I Sverige har vi bara ett hantavirus som är sjukdomsframkallande hos människor, Puumala-viruset som även finns i delar av övriga Europa. Det framkallar en relativt mild form av blödarfeber, som kallas sorkfeber eller Nephropathia epidemica. Puumala-virusets reservoar är skogssorken (Myodes glareolus).

Människor smittas oftast av hantavirus när de andas in infekterat damm som innehåller utsöndringar (avföring, urin eller saliv) från gnagare som har torkat in och sedan blivit luftburet. Vad man vet hittills så finns det bara ett hantavirus som smittar från person till person, för övriga hantavirus är människan en ”dead end”. Det virus som kan smitta från person till person heter Andes hantavirus och finns i Sydamerika. Andes hantavirus har en mus som reservoar från vilken människor kan smittas, sedan har smittan i vissa fall förts vidare från människa till människa, som tur är har dessa utbrott gått att stoppa. Fastän utbrotten har varit små har många personer dött, eftersom dödligheten är så hög, ungefär 30-40% av de diagnostiserade fallen dör. Hur Andes hantavirus överförs från människa till människa är inte känt men överföring genom saliv har föreslagits.

Hur viruset ger upphov till sjukdom hos människa är inte klarlagt. Studier talar för att mekanismen bakom sjukdomsutvecklingen (den så kallade patogenesen) hos hantavirusorsakade blödarfebrar är komplex. Sannolikt beror patogenesen både på egenskaper hos viruset och värden d.v.s. människan som är smittad av viruset. Vårt mål med detta projekt var att undersöka vad som hindrar överföring av Puumala hantavirus från människa till människa och att undersöka hur virusinfektionen påverkar sjukdomsutvecklingen hos människan.

I vår första studie beskrev vi det största utbrottet av sorkfeber hittills i Sverige och vi undersökte faktorer som kan ha orsakat utbrottet. Vi föreslog att en topp i skogssorkpopulationen samtidigt med extremt varmt väder troligen bidrog till utbrottet. Utbrottet skedde i december och det extremt varma vädret medförde att snön smälte bort. Sorkarna bor vanligtvis under snön på vintern, vi tror att frånvaro av snötäcke fick sorkarna att söka sig till byggnader för att söka skydd och där kom i kontakt med människor.

Våra efterföljande studier fokuserade på överföring av hantavirus från människa till människa. Vi hittade Puumala-virusets arvsmassa (RNA) i saliv från sorkfeberpatienter, vilket tyder på att det finns Puumala-virus i saliven hos infekterade människor, även om ingen överföring från person till person verkar inträffa. I efterföljande studier visade vi att mänsklig saliv och mänskliga salivkomponenter minskar hantavirus smittsamhet. Vi fann också Puumala-virusspecifika IgA-antikroppar i saliven från sorkfeberpatienter, vilket kan förhindra överföring från person till person.

I den sista studien fokuserade vi på patogenesen hos människor efter hantavirusinfektion. 105 patienter ingick i en prospektiv studie och delades in i en grupp med mild sjukdom och en grupp med måttlig/svår sjukdom. Vi hittade en dubbel roll hos immunsvaret för sjukdomsutvecklingen. Immunsvaret var delvis ansvarig för utveckling av svår sjukdom med betydligt högre mängd neutrofiler hos svårt sjuka patienter, men det var också skyddande mot allvarlig sjukdom, eftersom patienter med en mild sjukdom hade högre nivåer av Puumalavirusspecifika IgG-antikroppar. Detta talar för att behandling med IgG-antikroppar specifikt riktade mot hantavirus skulle kunna vara effektiv hos hantavirusinfekterade patienter.

Sammanfattningsvis; en topp i skogssorkspopulationen i kombination med extremt väder ökar risken för infektion hos människor; Puumala-virus arvsmassa (RNA) finns i saliv; Puumala-virusspecifika IgA-antikroppar och salivkomponenter hämmar överföring av Puumalavirus från person till person; immunsvaret är viktigt för Puumala-virus patogenes och sjukdomens svårighetsgrad.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2015. 43 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1701
Puumala virus, Hantavirus, human-to-human transmission, saliva, nephropathia epidemica, NE, IgA, IgG, IgM, neutrophils, neutrophil, viremia, treatment, climate, snow cover, temperature.
National Category
Medical and Health Sciences
Research subject
Medical Virology
urn:nbn:se:umu:diva-99687 (URN)978-91-7601-225-3 (ISBN)
Public defence
2015-03-06, Betula, byggnad 6M, Umeå Universitet, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Available from: 2015-02-13 Created: 2015-02-11 Last updated: 2015-02-16Bibliographically approved

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