No gender-related differences in the severity of nephropathia epidemica, Germany

The epidemiology of zoonotic diseases is complex due to the multifaceted factors influencing occurrence of host species and thereby the risk of exposure to humans [1]. Besides these factors that have an impact on the transmission rate, infectious diseases often exert a broad spectrum of clinic severity. Hantavirus infection causes disease whose clinical picture varies in humans. The infection with hantaviruses in the Old World causes hemorrhagic fever with renal syndrome (HFRS). The mortality rate ranges from < 1% for Nephropathia epidemica (NE) caused by Puumala virus to 12% for infections with Hantaan and Dobrava-Belgrade virus [2]. The infection is characterized by sudden onset with fever, thrombocytopenia, hematuria, elevated levels of serum creatinine, and decreased serum albumin levels. The infection often results in acute renal failure with massive proteinuria.

Aside from virus-specific differences, the severity of symptoms depends on patient-specific characteristics. The high seroprevalence in comparison to the number of clinical cases indicates that infections are often undiagnosed because of mild or subclinical presentation. In Germany, the seroprevalence for hantavirus antibodies is 1–2% [3] and the average number of annually recorded hantavirus cases with an incidence of 0.87/100000 (range 0.09/100000–3.45/100000) persons from 2001 through 2012 [4].

Factors that have been described to be associated with disease severity include genetic predisposition and differences in immune response [5, 6]. Gender-specific differences in symptoms, clinical parameters and mortality rates were identified for NE in Sweden and Finland and for HFRS in China [7‐10]. Therefore, we analyzed the epidemiology and the clinical course of NE cases in Germany with regard to gender-related differences.

The underlying mechanisms for the variety of severity of infectious diseases are still not completely understood. For hantavirus infections, several patient-specific characteristics such as specific alleles for HLA and TNF-α that are associated with the clinical courses have been identified [5, 6, 11‐15]. Numerous gender-specific differences in hantavirus disease were also often discussed. The most striking difference is the higher incidence of hantavirus disease in males that is observed in countries with hemorrhagic fever with renal syndrome [16] as well as in New World countries with hantaviral cardiopulmonary syndrome (HCPS) [17]. Several other sex-dependent differences were reported that may influence the outcome of the disease. Studies in Scandinavian patients suffering from infection with Puumala virus analyzed cytokine response and expression of the estrogen receptor [7, 8]. Furthermore, a higher risk for young male patients for severe central nervous system complications during infection with Puumala virus was described [9]. Interestingly, despite higher incidence in men a higher fatality rate for women was observed in patients with HFRS in China and with NE in Sweden [10, 18]. Underlying gender-dependent differences in the clinical course of hantavirus disease leading to fatal outcome could not be identified so far. As reported for hantavirus disease in other countries, the imbalanced distribution of cases is also observed in Germany and in the cohort that was treated in our department. However, symptoms, laboratory parameters and clinical course do not differ enormously between men and women in our patient cohort. Solely, the median level of minimum serum albumin was lower in female than in male patients. Renal findings such as oliguria/anuria, proteinuria and hematuria as well as the requirement of dialysis were more often observed in women. However, these observations do not reach statistical relevance. The imbalanced male to female ratio of hantavirus disease is often explained by the higher risk of exposition for men. Analysis of the M:F ratio for notifiable infectious diseases in Germany reveals a strong relationship between the mode of transmission and the number of infections in men and women. These findings indicate that men are more often affected by vector-borne diseases due to a higher expositional risk. Interestingly, seroprevalence in forestry workers of a non-endemic area in Germany shows no difference between men and women [19]. This would support our observation that differences in behavioral factors such as occupational and leisure activities account for the unequal gender distribution and not a higher susceptibility of men for arthropod-borne and an even higher for rodent-borne diseases. In contrast, equal seroprevalences for males and females were observed in randomly selected individuals in endemic areas in Sweden and Germany [3, 20]. This would lead to the conclusion that hantavirus infection in women is subclinical or less severe. Therefore, general gender-related differences in the susceptibility, severity or course of hantavirus infection could not be identified so far. Studies differ in hantavirus species and geographic area. Additional limitations are often the small size of cohorts with few women and the lack of information about the mode of transmission. The characteristics of host reservoir populations are also important for the analysis of risk factors for human infection. Further studies are necessary to define the relationship between gender and risk factors for severe courses of hantavirus disease caused by Old World hantaviruses Hantaan, Puumala and Dobrava-Belgrade virus as well as for HCPS-causing New World hantavirus species.

Gender-related differences in infectious diseases were often discussed. For hantavirus infection caused by diverse species several differences in regard to severe complications and clinical parameters were described. However, the sole difference that we could observe in our cohort is the unequal distribution of Puumala virus induced hantavirus disease between men and women. Differences in the symptoms or severity of hantavirus disease were not present between the male and female group. We observed a strong association between gender ratio and mode of transmission of infectious diseases. Further epidemiological studies on larger cohorts will be necessary to clarify the role of the mode of transmission in gender-specific differences of vector-borne diseases.