Post-infectious fatigue following Puumala virus infection

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Furberg, M., Anticona Huaynate, C., Schumann, B. (2019) Post-infectious fatigue following Puumala virus infection Infectious Diseases, 51(7): 519-526

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Post-infectious fatigue following Puumala virus infection

Maria Furberg, Cynthia Anticona & Barbara Schumann

To cite this article: Maria Furberg, Cynthia Anticona & Barbara Schumann (2019) Post- infectious fatigue following Puumala virus infection, Infectious Diseases, 51:7, 519-526, DOI:

10.1080/23744235.2019.1605191

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INFECTIOUS DISEASES, 2019; VOL. 51, NO. 7, 519–526

https://doi.org/10.1080/23744235.2019.1605191

ORIGINAL ARTICLE

Post-infectious fatigue following Puumala virus infection

Maria Furberg^a , Cynthia Anticona^b and Barbara Schumann^b

aDepartment of Clinical Microbiology, Umea University, Umea, Sweden;^bDepartment of Epidemiology and Global Health, Umeå University, Umeå, Sweden

ABSTRACT

Background: Puumala virus infection or nephropathia epidemica (NE) is common in northern Sweden. NE causes haemorrhagic fever with renal syndrome. Most patients make a full recovery, but a convalescent phase with fatigue has been reported. Although post-infectious fatigue has been demonstrated for other viral infections, it is not well studied in relation to NE. This study assessed recovery time and levels of fatigue in former NE patients, as compared to the general population.

Methods: NE patients diagnosed in northern Sweden between 2007 and 2011, together with a comparison sample from the general population, answered a questionnaire on demographic and health-related factors, including the Fatigue Severity Scale (FSS), and characteristics of NE infection. Self-reported recovery time was assessed, and fatigue levels were compared across the two groups by multiple linear regression, stratified by gender.

Results: In total, 1132 NE patients and 915 comparison group subjects participated. Time to complete recovery was reported to exceed 3 months for 47% and 6 months for 32% of the NE patients. Recovery time differed by gender and age. NE patients had significantly higher FSS scores than the comparison group. Differences were greater among women than men, and adjustments for current illness, body mass index, smoking and current residence only slightly modified the estimates.

Conclusions: Individuals with previous NE infection show higher fatigue scores than non-infected individuals, even 5 years following the infection. Full recovery takes half a year or longer for a substantial proportion of former NE patients.

KEYWORDS Puumala virus

nephropathia epidemica post-infectious fatigue recovery time Northern Sweden

ARTICLE HISTORY Received 30 November 2018 Revised 26 February 2019 Accepted 4 April 2019

CONTACT Maria Furberg

maria.furberg@umu.se

Department of Clinical Microbiology, Umea University, Umea, Sweden

ß 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

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Background

Northern Sweden has a high incidence of Puumala virus (PUUV) infection, also known as nephropathia epidemica (NE) or vole fever. The causative agent, PUUV, is a hantavirus that causes haemorrhagic fever with renal syndrome. The virus is spread by bank vole (Myodes glareolus) excreta, although the voles themselves remain unaffected by the infection. Transmission to humans is believed to occur via the inhalation of infectious aero- sols; no human-to-human transmission of PUUV has been reported [1].

Following an incubation period of 1–8 weeks (median 4) PUUV causes a sudden onset and mild form of haemorrhagic fever with renal syndrome, varying from sub- clinical cases to severe disease requiring haemodialysis [2]. The symptoms include high fever, malaise, headache, abdominal and back pain, dizziness, vomiting, blurred vision, thrombocytopenia, proteinuria, haematuria and transient renal failure. Case fatality is low (<0.5%) [3,4].

No specific treatments are available, and the infection creates lifelong immunity [5].

The Swedish Communicable Diseases Act mandates that all NE cases must be reported [6]. The diagnostic criteria constitute either a positive PUUV–RNA PCR blood test or a positive test of specific PUUV IgM and IgG antibodies, consistent with current infection. The annual incidence of NE in Sweden varies considerably, with peaks every 3–4 years related to the bank vole population cycle. Recorded incidences are on average 20/

100,000 population per year, although the true incidence is considered to be at least eight times higher [7,8]. During a large NE outbreak in 2007, the incidence

reached 313 cases/100,000 population in the county of V€asterbotten [3] (Figure 1).

NE infection is considered a relatively benign disease, and its long-term consequences have been only briefly studied, with particular emphasis placed on hypertension, persisting haematuria and proteinuria and prolonged renal impairment. Initial studies indicated long-lasting health effect [9–11], although these are not corroborated by more recent studies, with the exception of the case of persisting haematuria [12].

Most patients make a full recovery following NE infection, although a convalescent phase of several weeks with fatigue has been reported [2,13]. Long recovery times associated with post-infectious fatigue have also been reported in other viral infections such as Epstein–Barr Virus (EBV, also called mononucleosis) [14], Dengue fever [15] and Ross River virus [16].

Fatigue following EBV infection has been most widely investigated, in both retrospective and prospective studies [16,17]. Post-infectious fatigue state does not exhibit specific diagnostic criteria or a commonly accepted definition, and is neither equal to chronic fatigue syndrome as defined by the Centers for Disease Control and Prevention [18], nor the less well- defined chronic fatigue (CF).

Thus, previous research has indicated a high prevalence of post-infectious fatigue for some viral infectious diseases, but only two small studies mention fatigue in relation to NE [2,13]. The aim of this study was to assess recovery times following NE infection and to examine levels of fatigue in former NE patients compared to the general population.

Figure 1. Cumulative incidence of NE in Sweden (dotted), Norrbotten (dashed), and V€asterbotten (solid) counties. Source: Public Health Agency of Sweden, 2018.

520 M. FURBERG ET AL.

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Methods Recruitment

We contacted all adult patients diagnosed with NE infection between 2007 and 2011 at the two laboratories serving northernmost Sweden: the Sunderby Clinical Microbiology Laboratory in Luleå and the Clinical Microbiology Laboratory at Norrlands University Hospital in Umeå. Quick-test ReaScan Puumala IgM [19] and immunofluorescence (IFA) IgM and IgG analyses [20]

were used at both laboratories to diagnose NE. All IgM tests had to be confirmed by IgG seroconversion or a four-fold titer increase in paired samples, to meet the reportable criteria.

A comparison sample from the general population was obtained from Statistics Sweden, matched by age, gender and municipality of current residence of the patients. Via their Swedish personal identification numbers, any previous diagnosis of NE in the two laboratories during the last 10 years could be ruled out for the individuals in the comparison group.

The sample of NE patients and individuals for comparison received a letter of invitation, a questionnaire and a written informed consent form by postal service.

All potential participants who did not respond received one reminder letter.

Questionnaire

The questionnaire consisted of three sections. Section 1 included demographic information and health-related factors. Section 2 (for patients only) included the characteristics of the NE infection, such as place of diagnosis, hospitalisation, time in bed, sick leave and time until complete recovery. In addition, patients were asked to identify which of the following symptoms dominated prior to their recovery: fatigue, pain or sleep disturb- ance, or any alternative symptom, which they were asked to name. Section 3 included a series of validated instruments to measure fatigue (FSS—Fatigue Severity Scale), general health (SF 36 – Short Form 36 Health Survey), sleep quality (PSQI – Pittsburgh Sleep Quality Index) and pain (BPI-SF – Brief Pain Inventory- Short Form).

In this paper, we report the findings of the fatigue assessment. The FSS is a nine-item, self-report questionnaire that assesses the effects of fatigue on daily living.

The final fatigue score is measured on a scale from 1 (low fatigue) to 7 (high fatigue). The FSS has been successfully used in clinical research to distinguish the

frequency and severity of fatigue between healthy subjects and patients with various infectious and non- communicable diseases [21].

Ethical approval

The study was approved by the Regional Ethical Review Board in Umeå, Sweden. Written informed consent was obtained from the participants.

Statistical analyses

Descriptive analyses of the study population were calcu- lated as frequencies and percentages for categorical variables, and means and standard deviations for continuous variables, separately for the patients and the comparison group. Patients’ disease-related characteristics were described, including hospitalisation, co-morbid- ity during the acute disease and recovery time.

The relationship between NE exposure and the fatigue score was explored via simple and multiple linear regression analyses. Multivariate models were adjusted for potential confounders such as current illness, body mass index (BMI), smoking and residence. All statistical analyses were stratified by gender, considering previous evidence of a higher frequency of post-infectious fatigue in women [15]. All analyses were per- formed at the 5% significance level using SPSS (v.24).

Results

Study population

In total, 1132 NE patients and 915 subjects in the comparison group returned the questionnaire, giving an overall response rate of 59.9% (65.8% among patients and 53.2%

among the comparison group), making a total sample of 2047. The study population is described in Table 1. The mean age was 60 years; no significant differences between the groups appeared regarding gender and age distribution, socioeconomic status or exercise habits. More NE patients had a current disease at the time of participation, and reported poor health to a greater extent than participants from the comparison group. There were significantly more current smokers among patients.

Disease-related characteristics of NE patients

The vast majority had received their NE infection diagnosis during the large outbreak in 2006–2007, with no difference by gender. More than 90% of the patients were bedridden during the acute NE episode, but fewer

INFECTIOUS DISEASES 521

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than half had to be hospitalised. More women than men were in bed or hospital, although the difference was significant only for bed confinement. Twenty-three per cent of the patients reported that they had another disease when contracting NE; significantly more women than men had some concurrent disease (Table 2).

Recovery time

For 32% of the patients, 6 months or longer were required for a full recovery, nearly half, 47%, experienced a recovery time of at least 3 months. In this group, the vast majority named fatigue as the main symptom preventing recovery; one-fifth of the 47% (98 individuals) spontaneously used the same, very specific Swedish word for ‘feebleness’ (‘orkesl€oshet’) to describe the pre- dominant symptom that prevented a complete recovery (data not shown).

Recovery time differed by gender and age. More men than women recovered within the first month, but no gender difference could be identified thereafter (Table 2). Among women (but not men), young and old patients exhibited contrasting recovery times, with younger women (<60 years) tending to report longer recovery times than elderly women (60 years or older), who more often recovered within the first 3 months (Figure 2).

Association between fatigue and NE infection

Among both men and women, NE patients exhibited higher FSS scores than the comparison group. One-fifth (21.6%) of the former NE patients reported high fatigue levels (score 5 or higher) whereas only 10.6% of the comparison group reported such a high score. The difference was more pronounced among women than men (Figure 3).

A statistically significant difference in the FSS score was identified between NE patients and the comparison group among both men and women, with larger effects for women. Adjustment for current diseases, BMI, smoking habits and current residence reduced the effect only slightly (Table 3). Additional models adjusting for other potential confounders (age and physical activity) changed the effect estimates only marginally (data not shown).

Discussion

This study on the long-term outcomes of NE has shown that almost half of the NE patients reported a recovery time of at least 3 months. This is in line with the prospective study by Settergren et al., which reported a full recovery after 3 months for 46 out of 74 NE patients (62%). After 6 months, all 66 evaluated patients had recovered fully (6 were lost to follow up) [2]. In 1971, L€ahdevirta reported fatigue lasting 1–5 months for 17%

(6 out of 36) of NE patients evaluated [13]. To contrast that, in the present study, 6 months following the acute Table 2. Disease-related characteristics of NE patients.

Total Men Women p-value

Time since diagnosis,N (%) .161

3 to<6 months 27 (2.4) 17 (2.8) 10 (2.0) 6 to<12 months 52 (4.6) 25 (4.1) 27 (5.3) 1 to<2 years 120 (10.7) 64 (10.4) 56 (11.1)

2–3 years 202 (18.0) 106 (17.2) 96 (19.0)

4 years 721 (64.3) 404 (65.6) 317 (62.6)

Total 1122 (100) 616 (100) 506 (100)

Confinement in bed,N (%) .015

Yes 1000 (91.2) 537 (89.4) 463 (93.5)

No 96 (8.8) 64 (10.6) 32 (6.5)

Total 1096 (100) 601 (100) 495 (100)

Hospitalisation,N (%) .116

Yes 454 (41.2) 235 (39.0) 219 (43.7)

No 648 (58.8) 367 (61) 281(56.3)

Total 1102 (100) 602 (100) 500 (100)

Concurrent disease during NE,N (%) .012

Yes 247 (23.4) 118 (20.5) 129 (27.0)

No 808 (76.6) 458 (79.5) 350 (73)

Total 1055 (100) 576 (100) 479 (100)

Recovery time,N (%) <.001

1–4 weeks 282 (26.2) 185 (31.5) 97 (19.9)

1 to<3 months 290 (27.0) 149 (25.3) 141 (28.9) 3 to<6 months 159 (14.8) 71 (12.1) 88 (18.0) 6 to<12 months 166 (15.4) 86 (14.6) 80 (16.4)

1 year 179 (16.6) 97 (16.5) 82 (16.8)

Total 1076 (100) 588 (100) 488 (100)

NE: Nephropathia epidemica. Differences between sums of subgroups and total numbers are due to missing values. P-values are for gender differences (Chi2 test).

Table 1. Study population.

NE patients Comparison group p-value

Total,N (%) 1132 (55.3) 915 (44.7) .827

Gender,N (%) .827

Men 623 (55.0) 508 (55.5)

Women 509 (45.0) 407 (44.5)

Age, mean (SD) 58.5 (14.1) 58.3 (13.9) .682

Residence,N (%) <.001

Rural (10,000) 863 (77.8) 595 (67.3)

Urban (>10,000) 246 (22.2) 289 (32.7)

Education,N (%) .171

Primary/elementary 338 (31.2) 261 (29.5) Senior high school 346 (32.0) 274 (30.9) College/university 272 (25.1) 261 (29.5) Other higher education 126 (11.6) 90 (10.2)

Employment status,N (%) .191

Working 528 (47.2) 464 (51.1)

Not working 509 (45.5) 387 (42.6)

Other 82 (7.3) 57 (6.3)

Current illness,N (%) 432 (40.6) 311 (35.1) .012

Smoking habits,N (%) <.001

Current smoker 189 (16.9) 95 (10.5)

Ex-smoker 408 (36.5) 329 (36.2)

Never smoker 521 (46.6) 484 (53.3)

BMI, mean (SD) 26.4 (4.1) 26.2 (4.0) .146

Poor health,N (%) 336 (29.8) 184 (20.2) <.001

NE: nephropathia epidemica; SD: standard deviation; BMI: body mass index.

Difference between sums of subgroups and total numbers are due to missing values. P-values are for difference between NE patients and the comparison group (Chi-squared test for categorical variables, t-test for continuous variables).

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infection one-third of the NE patients still did not feel completely recovered.

Fatigue appears to be a common problem preventing recovery. In the Dubbo prospective cohort study the prevalence of post-infectious fatigue syndrome was 27%

at 3 months and 12% at 6 months following the acute episode [16]. Another prospective cohort study found a prevalence of physical fatigue in 40% of patients 6 months after acute EBV infection [17]. Previous work on EBV-associated post-infectious fatigue has demonstrated a relationship with the severity of the initial infection [16]. Such an association was not found in our data, using hospitalisation as a proxy for severity (data not shown), nor in a study of Dengue fever [15].

The usual treatment of NE patients at the Clinic of Infectious Diseases, Umeå University Hospital in V€asterbotten, involves signing off NE patients for up to 1 month and longer sick leave is unusual (personal com- munication). Our study results indicate a far longer-lasting effect on the wellbeing of a large proportion of NE patients. During major outbreak years such as 2006–2007, when the incidence rate reached 313 reported cases/100,000 inhabitants in V€asterbotten County, and the true incidence is believed to be eight times as high, the potential public health and health economic effects can be substantial [3,8].

The present study was conducted in order to fill a knowledge gap regarding the association between Figure 2. Self-reported recovery time in men and women by age group.

Figure 3. Fatigue scores in the study population by gender.

Table 3. Fatigue score differences by NE status and co-variates (regression coefficient with 95% confidence intervals).

Simple model Adjusted model 1 Adjusted model 2

Men Women Men Women Men Women

NE exposure 0.37 (0.20; 0.54) 0.49 (0.28; 0.69) 0.34 (0.18; 0.50) 0.41 (0.22; 0.61) 0.37 (0.20; 0.53) 0.44 (0.24; 0.64)

Current illness – – 0.81 (0.64; 0.98) 0.89 (0.69; 1.09) 0.80 (0.62; 0.97) 0.83 (0.62; 1.04)

BMI – – – – 0.02 (–0.01; 0.04) 0.03 (0.007; 0.05)

Smoking – – – – 0.04 (–0.17; 0.20) 0.13 (–0.07; 0.33)

Urban residence 0.02 (–0.17; 0.20) 0.06 (–0.17; 0.29)

Model 1, adjusted for current illness. Model 2, adjusted for current illness, BMI, smoking (current or former smokers; reference: never smokers) and current urban residence (reference: rural). NE: nephropathia epidemica; BMI: body mass index.

INFECTIOUS DISEASES 523

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fatigue and NE infection. The results show that NE patients displayed significantly higher FSS scores than the comparison group in both men and women. The proportion with high scores (5 or above) was twice as high in the NE patients as in the comparison group (22% versus 11%). Even when adjusting for potential confounders, this association was not altered. Moreover, the effect was stronger among women than men, with exposure to NE infection increasing the FSS score (ranging from 1 to 7) by 0.37 units in men and by 0.44 units in women, adjusted for current illness, BMI, smoking and recidence. A prospective study following acute NE infection found chronic overt hormonal deficiencies in 17%

(9 out of 54) of the patients. Hormonal alterations could provide some explanation to the higher levels of fatigue;

however, the hormonal changes were more common among men (22.9%) than women (12%) [22].

In the present study, women generally displayed higher FSS scores than men in both groups. A perform- ance test of FSS in a general Swedish setting has yet to be conducted, but other fatigue assessment tools have also indicated significantly higher fatigue scores among women than men in Sweden [23]. A Norwegian validation of FSS suggested a cut-off of 5 or higher (on the fatigue scale ranging from 1 to 7) for high fatigue and the same cut-off was used in the present study. In their sample of 1893 respondents from the general population, high fatigue scores were found in 23.1%. In our comparison group, only 10.6% reported a fatigue score of 5 or higher, whereas 21.6% of the former NE patients reported high fatigue. The Norwegian study reported that more women (26.2%) than men (19.8%) in the general population experienced high fatigue [24]. In our study, gender differences were more pronounced in the patient than the comparison group, suggesting an inter- action between gender and NE exposure. In a study on Dengue fever, fatigue was significantly more common among women [15].

Differences between men and women did not constitute the focus of our study, but became evident in the data. Gender differences in prolonged fatigue (as demonstrated for a number of viral infections) pose ques- tions regarding potential mechanisms. For hantaviruses as a group, research has shown that even though such infections are more prevalent among males, mortality is higher in females [25]. In our study, younger women (under 60 years) were more prone to long recovery times than were older women and men. One could hypothesise that sex hormones represent a contributor to the recovery time differences seen in our data. It is

likely that the pathogenesis of post-infectious fatigue is multifactorial and that the onset may be a consequence of immune alterations triggered by the viruses.

However, further research is required for clarification.

Some findings from the descriptive analysis may par- tially explain the higher fatigue scores among former NE patients. The patient group comprised significantly more current smokers than the comparison group. This finding is to be expected, because previous studies have identified smoking as a risk factor for NE infection [26,27].

However, adjusting for smoking in the analyses reduced the effect of NE exposure on fatigue to a negligible extent, suggesting the involvement of other pathogenic mechanisms. The patient group reported poor health and current diseases to a greater extent than the comparison group. In both groups, as expected, fatigue scores were higher among those reporting current illness, but the difference was larger in the patient group than in the comparison group; hence, NE infection appears to have an additional effect on fatigue.

This study had several limitations. The most important one is the retrospective design, prone to both recall bias and selection bias. The participation rate was low (60%

in total), and was lower in the comparison group than in the patient group (53% and 66%, respectively). One rea- son may have been individuals’ reluctance to participate where they felt high levels of fatigue, resulting in selection bias. Furthermore, a large number of patients con- tracted their disease during the outbreak of 2006–2007, several years before the study was conducted, and so recall bias (in particular regarding disease characteristics such as recovery time) may have affected our data.

Individuals in the comparison group were checked for reported previous NE infection diagnosed in the two laboratories included in the study, but did not undergo laboratory tests to rule out any undiagnosed NE. Thus, undiagnosed infections might have been included in the comparison group, posing the potential for bias due to misclassification. Their number is however likely to be small. Finally, one major limitation is the lack of information regarding patient participants’ health status or levels of fatigue prior to the NE infection.

The major strength of this study is its large study group from a well-defined geographical study area of two counties in Sweden. The involvement of a matched comparison group enabled us to compare former patients and their fatigue scores with individuals from a similar context.

The findings highlight the importance of further investigation into fatigue-affected former NE patients. A

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prospective study to reduce recall bias and examine the extent and properties of post-infectious fatigue following acute NE infection would thus be valuable.

Conclusions

A prolonged state of post-infectious fatigue is very common following acute NE infection. People with previous NE infection show higher fatigue scores than non- infected individuals, even 5 years after the infection. The underlying mechanisms are unclear and merit further investigation into the nature and extent of fatigue in this population.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

V€asterbotten County Council This study was financially supported by V€asterbotten County Council.

ORCID

Maria Furberg http://orcid.org/0000-0002-7580-6485 Cynthia Anticona http://orcid.org/0000-0001-9321-6174 Barbara Schumann http://orcid.org/0000-0002-9722-0370

References

[1] Leduc JW. Epidemiology of hemorrhagic fever viruses. Rev Infect Dis. 1989;11:S730.

[2] Settergren B, Juto P, Trollfors B, et al. Clinical characteristics of nephropathia epidemica in Sweden: prospective study of 74 cases. Rev Infect Dis. 1989;11:921–927.

[3] Pettersson L, Boman J, Juto P, et al. Outbreak of Puumala virus infection, Sweden. Emerg Infect Dis. 2008;14:808–810.

[4] Hjertqvist M, Klein SL, Ahlm C, et al. Mortality rate patterns for hemorrhagic fever with renal syndrome caused by Puumala virus. Emerg Infect Dis. 2010;16:1584–1586.

[5] Settergren B, Ahlm C, Juto P, et al. Specific Puumala IgG virus half a century after haemorrhagic fever with renal syndrome. Lancet. 1991;338:66.

[6] Folkh€alsomyndigheten Public Health Agency of Sweden 2018. Notifiable diseases 2018 [20181207]. Available from:

https://www.folkhalsomyndigheten.se/the-public-health- agency-of-sweden/communicable-disease-control/surveil- lance-of-communicable-diseases/notifiable-diseases/

[7] Olsson GE, Dalerum F, Hornfeldt B, et al. Human hantavirus infections, Sweden. Emerg Infect Dis. 2003;9:1395–1401.

[8] Ahlm C, Linderholm M, Juto P, et al. Prevalence of serum IgG antibodies to Puumala virus (haemorrhagic fever with

renal syndrome) in northern Sweden. Epidemiol Infect.

1994;113:129–136.

[9] Miettinen MH, Makela SM, Ala-Houhala IO, et al. Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis. Kidney Int. 2006;69:2043–2048.

[10] Miettinen MH, Makela SM, Ala-Houhala IO, et al. Tubular proteinuria and glomerular filtration 6 years after puumala hantavirus-induced acute interstitial nephritis. Nephron Clin Pract. 2009;112:c115–c120.

[11] Makary P, Kanerva M, Ollgren J, et al. Disease burden of Puumala virus infections, 1995–2008. Epidemiol Infect.

2010;138:1484–1492.

[12] Latus J, Schwab M, Tacconelli E, et al. Clinical course and long-term outcome of hantavirus-associated nephropathia epidemica, Germany. Emerg Infect Dis. 2015;21:76–83.

[13] L€ahdevirta J. Nephropathia epidemica in Finland. A clinical histological and epidemiological study. Ann Clin Res. 1971;3:1.

[14] Petersen I, Thomas JM, Hamilton WT, et al. Risk and predic- tors of fatigue after infectious mononucleosis in a large primary-care cohort. QJM. 2006;99:49–55.

[15] Seet RC, Quek AM, Lim EC. Post-infectious fatigue syndrome in dengue infection. J Clin Virol. 2007;38:1–6.

[16] Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non- viral pathogens: prospective cohort study. BMJ. 2006;333:

575–578.

[17] White PD, Thomas JM, Amess J, et al. Incidence, risk and prognosis of acute and chronic fatigue syndromes and psy- chiatric disorders after glandular fever [Research Support, Non-U.S.] Br J Psychiatry. 1998;173:475–481.

[18] Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953–959.

[19] Parviainen M, Kelo E, Sirola H, et al. Detection of acute hantavirus infections using novel instrument-readable rapid tests. Eur Infect Dis. 2011;5:35–37.

[20] Elgh F, Wadell G, Juto P. Comparison of the kinetics of Puumala virus specific IgM and IgG antibody responses in nephropathia epidemica as measured by a recombin- ant antigen-based enzyme-linked immunosorbent assay and an immunofluorescence test. J Med Virol. 1995;45:

146–150.

[21] Valko PO, Bassetti CL, Bloch KE, et al. Validation of the fatigue severity scale in a Swiss cohort. Sleep. 2008;31:1601.

[22] M€akel€a S, Jaatinen P, Miettinen M, et al. Hormonal deficiencies during and after Puumala hantavirus infection. Eur J Clin Microbiol Infect Dis. 2010;29:705–713.

[23] Engberg I, Segerstedt J, Waller G, et al. Fatigue in the general population- associations to age, sex, socioeconomic status, physical activity, sitting time and self-rated health:

the northern Sweden MONICA study. BMC Public Health.

2017;2014:17.

[24] Lerdal A, Wahl AK, Rustoen T, et al. Fatigue in the general population: a translation and test of the psychometric properties of the Norwegian version of INFECTIOUS DISEASES 525

(10)

the fatigue severity scale. Scand J Public Health. 2005;

33:123–130.

[25] Klingstr€om J, Ahlm C. Sex, gender, and hemorrhagic fever viruses. In Klein SL, Roberts CW, editors. Sex and gender differences in infection and treatments for infectious diseases. New York: Springer International Publishing; 2015. p.

211–230.

[26] Vapalahti K, Virtala AM, Vaheri A, et al. Case-control study on Puumala virus infection: smoking is a risk factor.

Epidemiol Infect. 2010;138:576–584.

[27] Gherasim A, Hjertqvist M, Lundkvist Å, et al. Risk factors and potential preventive measures for nephropatia epidemica in Sweden 2011–2012: a case–control study. Infect Ecol Epidemiol. 2015;5:27698.