Download Increased Risk for Lymphoma Following Hemorrhagic Fever With

BRIEF REPORT
Increased Risk for Lymphoma
Following Hemorrhagic Fever
With Renal Syndrome
Jonas Klingström,1 Fredrik Granath,3 Anders Ekbom,3
Niklas K. Björkström,1,2 and Hans-Gustaf Ljunggren1
1
Hemorrhagic fever with renal syndrome (HFRS) is a severe
acute disease. Although long-term consequences to public
health have been reported, no association with cancer is
known. We examined the risk of cancer development after
HFRS in the Swedish population between 1997 and 2011
(n = 6582) and report a 73% increased risk for lymphoma.
Keywords.
lymphoma; HFRS; hantavirus; Puumala virus.
Several viruses are linked with increased risks for various forms
of cancer. For example, infections with Epstein-Barr virus
(EBV), hepatitis C virus (HCV), human immunodeficiency
virus type 1 (HIV-1), and human T-lymphotrophic virus type 1
(HTLV-1) have been associated with increased risk of developing lymphoma [1].
Viral hemorrhagic fevers (VHFs) are a cluster of zoonotic
emerging infectious diseases caused by viruses of the Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae families.
Although the pathogenic mechanisms behind different VHF
are diverse, a common feature is that these viruses cause systemic infection and often interfere with normal immune cell functions in manners that lead to impaired or aberrant immune
responses [2]. Rodent-borne hantaviruses (family Bunyaviridae,
genus Hantavirus) are the causative agent of hemorrhagic fever
with renal syndrome (HFRS) in Eurasia. In the Americas,
Received 25 March 2014; accepted 18 June 2014; electronically published 25 June 2014.
Correspondence: Jonas Klingström, PhD, Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
([email protected]).
Clinical Infectious Diseases 2014;59(8):1130–2
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases
Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@
oup.com.
DOI: 10.1093/cid/ciu488
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METHODS
HFRS is a notifiable disease in Sweden. Diagnosis is based on
seroconversion, that is, detection of PUUV-specific antibodies
in patient samples by either enzyme-linked immunosorbent
assay or an indirect immunofluorescence method [5]. All diagnosed cases are, with their National Registration Number
(NRN), reported to the Public Health Agency of Sweden (formerly Swedish Institute for Communicable Disease Control).
Using NRNs, individuals diagnosed with HFRS between 1997
and 2011 were followed up by linkage to the Swedish Cancer
Registry through 31 December 2011. Age- and sex-standardized
incidence ratios (SIRs) and associated 95% confidence intervals
(CIs) were calculated against corresponding incidence rates for
the entire Swedish population. The study was approved by the
Regional Ethical Review Board in Stockholm, Sweden.
RESULTS
Of the 6603 individuals diagnosed with PUUV-associated
HFRS in Sweden from 1997 to 2011, 21 were excluded from
the present analyses because of death before the diagnostic report (n = 11), emigration (n = 5), or missing citation of age in
the report (n = 5). The majority of the patients were male
(59.7%), and the median age at HFRS diagnosis was 52.0
years (range, 2–94 years). Of the 6582 individuals included in
the study, with an accumulated 42 136 person-years (mean
person-years of follow-up, 6.4 [range, 0–15 years]), 353 were
diagnosed with cancer. The overall risk for development of
cancer among the HFRS-diagnosed individuals did not differ
significantly compared with the general population (SIR, 0.95
Downloaded from http://cid.oxfordjournals.org/ at Rowan University on November 3, 2014
Center for Infectious Medicine, and 2Liver Immunology Laboratory, Division of
Gastroenterology and Hepatology, Department of Medicine, Karolinska University
Hospital Huddinge, Karolinska Institutet, and 3Clinical Epidemiology Unit,
Department of Medicine Solna, Karolinska University Hospital, Karolinska Institutet,
Stockholm, Sweden
hantaviruses cause hantavirus pulmonary syndrome (HPS;
also called hantavirus cardiopulmonary syndrome). HFRS and
HPS are, like most VHFs, severe acute diseases with case-fatality
rates of up to 15% for HFRS and approximately 40% for HPS [3,
4]. Currently, no specific treatment is available and no US Food
and Drug Administration–approved vaccine exists. In Europe,
including Sweden, Puumala virus (PUUV) is the predominant
causative agent of HFRS. Infection results in a relatively mild
variant of the disease with case-fatality rates normally <1%
[4]. Following the specific diseases HFRS and HPS, several
long-term consequences of human hantavirus infection have
been reported, including effects on the cardiovascular, renal,
and endocrine systems [3, 4]. Here, we investigated the possibility of an association between HFRS and cancer.
Table 1. Cancer Risk Following Diagnosis of Hemorrhagic Fever
With Renal Syndrome
No. of Cases
Cancer Site
(ICD-7 Code)
Observed
Expected
SIR
95% CI
359
58
377.8
53.2
0.95
1.09
.85–1.05
.83–1.41
Lung (162)
Breast (170)
24
39
28.1
42.4
0.85
0.92
.55–1.27
.65–1.26
Prostate (177)
95
87.4
1.09
.88–1.33
Urinary system
(180–181)
26
27.4
0.95
.62–1.39
Nonmelanoma skin
cancer (191)
10
25.7
0.39
.19–.72
Lymphoma (200–
201 + 204.1)
26
15.0
1.73
1.13–2.54
Overall
Gastrointestinal
(150–154)
<1
1–4
4
13
1.95
7.22
2.05
1.80
.56–5.25
.96–3.08
5–9
7
4.25
1.65
.66–3.39
≥10
2
1.58
1.27
.15–4.57
Abbreviations: CI, confidence interval; ICD-7, International Classification of
Diseases, Seventh Revision; SIR, standardized incidence ratio.
[95% CI, .85–1.05]); however, and strikingly, the risk of developing lymphoma was significantly increased (SIR, 1.73 [95% CI,
1.13–2.54]). Except for a decreased risk of nonmelanoma skin
cancer (SIR, 0.39 [95% CI, .19–.72]), the risk for other forms
of cancer did not differ significantly between HFRS-diagnosed
individuals and the general population (Table 1).
The highest risk for lymphoma occurred early after HFRS diagnosis (Table 1). The risk for lymphoma remained higher than
expected during the entire time of follow-up, but decreased with
time after HFRS diagnosis (Table 1).
DISCUSSION
The finding that individuals diagnosed with PUUV-associated
HFRS exhibit an increased risk of lymphoma is new. After being
diagnosed with HFRS, in total 32 individuals were diagnosed
with lymphatic/hematopoietic malignancies (International
Classification of Diseases, Seventh Reviosion codes 200–205)
whereof 26 were diagnosed with lymphoma (Table 1). Although
there are indications that hantavirus-infected individuals can
experience long-term negative health effects [3, 4], no association with cancer has previously been reported. Moreover, to the
best of our knowledge, this is the first time that a virus of the
Bunyaviridae family, and a virus causing hemorrhagic fever,
has been associated with any form of cancer. The observed finding of an increased risk for lymphoma, and not for other forms
of cancer, suggests the possibility that a causal link exists
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Lymphoma, follow-up time, y
between HFRS and lymphoma development, possibly mediated
by the hantavirus infection.
Of the viruses that earlier have been associated with lymphoma [1], EBV is of particular interest because it can cause infectious mononucleosis that, like HFRS, has an acute onset [6].
Here, we observed a high risk for lymphoma early after HFRS
diagnosis (Table 1), resembling the pattern of infectious mononucleosis–associated Hodgkin lymphoma [7].
An interesting feature of human hantavirus infection is the
strong lymphocyte responses observed; long-lasting elevated levels of lymphocytes are frequently found in patients with HFRS [3,
4, 8]. Moreover, lymphocytes are potential target cells for hantaviruses [9], and hantaviruses have potent antiapoptotic capacities
in infected cells [10]. Hantaviruses inhibit apoptosis in general
and protect infected cells from cytotoxic granule-dependent induction of apoptosis. These effects can, at least partly, be attributed to the capacity of hantavirus nucleocapsid protein to inhibit
the enzymatic activities of both caspase 3 and granzyme B [10],
enzymes required for execution of apoptosis (caspase 3) and for
cytotoxic granule–dependent induction of apoptosis (granzyme
B). Furthermore, it was recently reported that the hantavirus nucleocapsid protein stimulates Mdm2-dependent degradation of
p53 [11]. Resisting cell death is an important hallmark of cancer,
and loss of p53 function has been shown to promote lymphoma
development [12]. Taken together, these observations suggest
that hantaviruses are equipped with mechanisms that, at least
theoretically, might be involved in carcinogenesis, an issue that
remains to be further investigated.
All known carcinogenic viruses establish chronic infection,
but they differ in how they induce cancer. The International
Agency for Research on Cancer classifies the lymphomaassociated viruses EBV and HTLV-1 as direct carcinogens,
whereas HCV and HIV-1 are indirectly carcinogenic—HCV
infection causes chronic inflammation and HIV-1 infection
mediates immune suppression in infected individuals [1].
Whether hantaviruses have any direct carcinogenic effect remains to be elucidated. Hantaviruses are zoonotic viruses that
establish chronic infection in the natural hosts, rodents [3].
Chronic hantavirus infections in humans have never been described; however, the possibility has not been extensively
investigated.
In summary, the present study demonstrates an increased risk
for lymphoma following PUUV-associated HFRS. Future investigations of other HFRS- and HPS-causing hantaviruses should
address if the association between HFRS and lymphoma is
PUUV-specific or a general feature of disease-causing hantaviruses in humans. Furthermore, the possibility that other viruses
within the Bunyaviridae family, and perhaps also other viruses
causing hemorrhagic fever, are associated with lymphoma remains to be investigated. The possibility that hantaviruses have
carcinogenic properties needs to be carefully considered.
Notes
Financial support. This work was supported by the Swedish Cancer
Society, the Swedish Research Council, the Swedish Foundation for Strategic
Research, the Karolinska Institutet, and the County Council of Stockholm.
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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