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Sex Differences in Clinical Leptospirosis in Germany: 1997–2005

  1. Andreas Jansen1,
  2. Klaus Stark1,
  3. Thomas Schneider2, and
  4. Irene Schöneberg1
  1. 1Department for Infectious Disease Epidemiology, Robert Koch Institute, Berlin, Germany
  2. 2Department for Infectious Diseases, Charité, Campus Benjamin Franklin, Berlin, Germany
  1. Reprints or correspondence: Dr. Andreas Jansen, Dept. for Infectious Disease Epidemiology, Robert Koch Institute, Seestrasse 10, 13353 Berlin, Germany (JansenA{at}rki.de).
 
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Abstract

Background. Although the majority of patients with reported leptospirosis are male, several seroepidemiologic studies demonstrated that leptospirosis seroprevalences are at least identical between both sexes. To study the effect of sex on the severity—and possibly, recognition—of leptospirosis, we conducted a sex-specific analysis of the clinical manifestations of the disease among patients with reported leptospirosis in Germany during 1997–2005.

Methods. Data on demographic characteristics, symptoms, place of infection and place of residence when infection occurred, possible exposure risks, infecting serovars, and mortality were evaluated for patients with laboratory-confirmed leptospirosis reported in Germany during 1997–2005. Mantel-Haenszel odds ratios (ORMH), adjusted for age, were used to determine the association between sex and the frequency of reported symptoms.

Results. Among 338 patients with leptospirosis (263 male patients and 75 female patients) reported in Germany during 1997–2005, male patients were more likely than female patients to be hospitalized (OR, 2.6; P < .01) and to exhibit symptoms of severe leptospirosis with jaundice (ORMH, 3.7; P < .01), renal impairment (ORMH, 3.4; P < .01), and hemorrhage (ORMH, 7.8; P < .05). These sex-related differences were not associated with differences in exposure risks, presumptive infecting serogroups, or health-seeking behavior.

Conclusions. Our results indicate that male sex is associated with a higher severity of clinical leptospirosis. Reports on male predominance in leptospirosis may thus reflect sex-related variability in the incidence of severe disease, rather than different infection rates. In clinical practice, sex differences in the manifestation of leptospirosis may cause systematic underinvestigation and undertreatment of the disease in female patients.

Leptospirosis is a reemerging zoonotic disease of global importance. In countries where leptospirosis is a notifiable disease, the vast majority of patients with laboratory-confirmed clinical cases are male individuals, with an incidence ratio of male to female subjects of 5:1 in Germany and 10:1 in France and Italy [1]. This difference in sex-specific incidence is traditionally explained by male subjects having a higher exposure to leptospirosis risk factors associated with “typical” male occupations, such as livestock farming, fishing, and butchering [2]. Contradictory to this view, seroepidemiologic studies from these countries demonstrated that leptospirosis seroprevalences were almost identical between both sexes, or even higher in female patients [3–5]. In addition, it has been recognized that the importance of occupational risks favoring infections in male subjects has decreased in developed countries over recent past decades. These historical exposure risks are progressively replaced by environmental, recreational, and travel-associated risk factors, which are not primarily related to sex [6]. A number of reports have shown that sex influences the severity and outcome of several infectious diseases, including tuberculosis, listeriosis, Q fever, and amebiasis [7–9]. Consequently, it was asked whether the difference in sex-specific incidences of leptospirosis may also result from differences in the severity of the clinical disease [10, 11]. Thus far, however, the impact of sex on the clinical course of leptospirosis has not been investigated. To address this question, we conducted a sex-specific analysis of epidemiologic and clinical data on the manifestations of leptospirosis reported in Germany during 1997–2005.

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Methods

In Germany, leptospirosis is a notifiable disease, and cases of human leptospirosis are reported to the Robert Koch Institute (Berlin). During 1997–2000, detailed data on demographic characteristics (age, sex, and residence), symptoms, place of infection and place of residence when infection occurred, possible exposure risks, infecting serovars, and mortality were evaluated by standardized questionnaires sent to local health departments for every reported case of leptospirosis. During 2001–2005, similar data were transmitted to the Robert Koch Institute within the framework of the newly implemented Infectious Disease Control Act. A case definition, demanding both clinical signs of leptospirosis and laboratory confirmation [6], was applied to all reported infections. Renal function impairment was defined as an acute malfunction of the kidneys, indicated by increased plasma creatinine levels, oliguria (urine production, <500 mL/24 h), anuria (urine excretion, <100 mL/24 h), proteinuria, or haematuria. Hemorrhage included pulmonary, gastrointestinal, or subconjunctival hemorrhage, or hemorrhage into skin and mucous membranes. Flulike symptoms included headache, myalgia, and joint pain.

For comparison of categorical variables between groups, we used the summary χ2 test and Fisher's exact test. For comparison of quantitative variables, the Student's t test or nonparametric tests were applied, as appropriate. Mantel-Haenszel odds ratios (ORMH), adjusted for age, were used to determine the association between sex and the frequency of reported symptoms. The patients were divided into pediatric or adolescent (age, ⩽19 years) and adult groups. Patients from the adult group were further classified according to the following age categories: 20–29, 30–39, 40–49, 50–59, and ⩾60 years. All calculations were performed using Intercooled Stata software, version 9 (Stata). A P value <.05 was considered to be statistically significant. Results are expressed as means (±SD), as percentages, or as ORMH with 95% CIs.

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Results

Complete data on sex, age, place of residence, and clinical symptoms were available for 338 (82%) of 441 patients leptospirosis reported to the Robert Koch Institute during 1997–2005. Of these 338 patients, 263 (78%) were male. The mean age was 46.6 ± 15.0 years for male subjects and 41.2 ± 16.0 years for female subjects (P = .01). Among female subjects, the age distribution of the patients showed a predominance in the age groups of <40 years, and in male subjects, the age group of ⩾60 years dominated (figure 1). Cases were reported from all 16 German federal states. During 1997–2005, the mean incidence of leptospirosis in Germany was 0.06 cases per 100,000 inhabitants/year, with the highest incidences in the state of Mecklenburg Western-Pomerania for both male subjects (0.2 cases per 100,000 inhabitants/year) and female subjects (0.06 cases per 100,000 inhabitants/year).

Figure 1
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Figure 1

Age distribution (%) of patients with reported leptospirosis in Germany during 1997–2005, stratified by sex (263 male subjects and 75 female subjects).

The frequency of clinical symptoms and physical findings, stratified by sex, is presented in table 1. In age-adjusted analysis, jaundice (ORMH, 3.7; P < .01), renal impairment (ORMH, 3.4; P < .01), and hemorrhage (ORMH, 7.8; P < .05) were more frequent among male subjects. Of the 338 patients, 294 (87%) were hospitalized. The hospitalization rate was significantly lower for female patients than for male patients (75% vs. 90%; OR, 2.6; P < .01). The time period between onset of symptoms and outpatient treatment was 4.5 days for both male (n = 97) and female patients (n = 22; P = 1.0); the time period between onset of symptoms and hospitalization was 6.0 days for male patients (n = 205) and 5.5 days for female patients (n = 45; P = .7). Data on possible exposure risks were available for 185 patients (54%). For both male (n = 152) and female patients (n = 33), nonoccupational exposure risks (including traveling abroad, swimming, gardening, and canoeing; 85% for female patients vs. 75% for male patients; P = .2) dominated over occupational exposures (including farming, pig breeding, and sewer work; 15% for female patients vs. 25% for male patients; P = .2). Information on the place of infection (rural vs. urban) when infection occurred was available for 86 patients (65 male patients and 21 female patients). There was no significant association between sex and rural or urban place of residence (P = .3).

Table 1
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Table 1

Frequency of symptoms and age-adjusted Mantel-Haenszel OR (ORMH) for 338 patients with reported leptospirosis in Germany during 1997–2005, stratified by sex.

For 83 (31%) of 268 male subjects and 19 (27%) of 70 female subjects with serological confirmation of leptospirosis, identification of a single serovar was reported. Identification of the presumptive infecting leptospiral serovar was performed either by culture (for 9 patients) or by microscopic agglutination test (for 38 patients) in experienced laboratories. For 7 patients, a serovar-specific complement fixation test was used, and the method of antibody detection was not specified for 49 patients. Serovars in the Icterohaemorrhagiae serogroup were identified in 60 (72%) of 83 male and 8 (42%) of 19 female patients (P = .03) with reported serovar identification. None of the female patients with positive serologic results for serovars in the Icterohaemorrhagiae serogroup were reported to have jaundice (compared with 35 of 60 male patients) or hemorrhages (compared with 11 of 60 male patients), and one-eighth of female patients presented with renal failure (compared with 30 of 60 male patients). Leptospira species serovar Canicola was found in 3 female patients and 5 male patients (P = .2), and serovar Grippotyphosa was found in 4 female patients and 12 male patients (P = .5). Leptospira species serovar Bataviae was identified in 1 male patient and 1 female patient, and serovar Pomona was identified in 4 male patients; serovars Sejroe (in 1 female patient), Hardjo, Hebdomadis, Bratislava, and Australis (in 1 male patient) were found in single cases. Among all patients with serovar identification, no significant association between Leptospira species serovar Icterohaemorrhagiae and the presence of jaundice (P = .3), renal impairment (P = .2), and hemorrhage (P = .3) was found. Of the 338 patients with leptospirosis reported during 1997 to 2005, 13 male patients (case-fatality rate, 5%) and 1 female patient died (case-fatality rate, 1%; P = .3).

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Discussion

This study describes significant sex-specific differences in the clinical characteristics of leptospirosis, including a lower hospitalization rate and a lower frequency of jaundice, renal impairment, and hemorrhage in female patients. Given that these symptoms are reliable signs of severe leptospirosis [2], our results indicate that female patients more frequently experience a milder course of the disease. Because surveillance systems based on passive reporting are almost always biased towards including the more severe cases [12], if female patients present with milder symptoms, they may consequently be underreported more frequently than male patients. This would explain the inconsistency of male patients having a much higher incidence of notified leptospirosis than female patients in several countries, although seroprevalences among both sexes were found to be at least identical or higher among female patients in numerous cross-sectional studies [3–5]. Several factors may contribute to the sex-specific differences in the clinical manifestation of leptospirosis observed in this study. Severity and outcome of leptospirosis has been shown to depend on timely access to medical treatment [13], and sex-specific medical care—seeking behavior might influence the course and outcome of the disease. However, no significant differences in care-seeking behavior (using the time periods between onset of symptoms and outpatient treatment and hospitalization as a proxy) were documented between the sexes in our study.

It is generally accepted that specific leptospiral serovars or serogroups are not particularly associated with severe manifestations of leptospirosis [14]. Although serologic identification of specific serovars or serogroups using microscopic agglutination testing can only give a broad idea of the common serovars or serogroups in a certain population and has to be interpreted cautiously [15], our data indicate that the different clinical courses we documented are unlikely to be explained by different infecting serogroups among male or female patients. In fact, Leptospira species serovar Icterohaemorrhagiae was reported more frequently in male patients than in female patients. However, the predominance of this serovar in male patients does not explain the sex-specific clinical differences, because we found no significant association between the presence of jaundice, renal impairment, or hemorrhages and infection with Leptospira species serovar Icterohaemorrhagiae. In addition, none of the 8 female patients with presumptive infection with Leptospira species serovar Icterohaemorrhagiae showed signs of jaundice or hemorrhage, thus indicating that this serogroup is not necessarily related to severe leptospirosis in Germany.

In many epidemiologic studies, different infection rates for leptospirosis in male and female patients are explained by sex-related occupations. With respect to the frequency of occupational versus nonoccupational exposure risks, we found no significant differences between the sexes. In both male and female patients, recreational risk factors, like swimming, gardening, or traveling abroad, predominate over occupational risk factors, including farming, keeping livestock, or fishing. It is therefore unlikely that the observed differences in number of cases (or disease severity) are related to different sex-specific occupational risk factors. Apart from exogenous causes, the possibility that female patients experience less severe disease than male patients because of biological factors (e.g., steroid sex hormones) needs to be seriously considered. A potential role of intrinsic factors is certainly supported by the fact that the discrepancies between incidence and seroprevalence of leptospirosis are evident not only in different European countries, but also in developing countries with completely different socioeconomic and behavioral characteristics [5]. Thus far, however, no studies of sex-specific differences in leptospirosis with respect to course and outcome of disease have been conducted in countries where it is highly endemic.

Potential study limitations have to be considered. Firstly, although leptospirosis is mandatorily notifiable in Germany, cases are reported via a passive surveillance system. This means that the data on leptospirosis used in this study may be incomplete with respect to both case ascertainment (i.e., that less severe cases are less likely to be diagnosed) and data quality. With regard to the severity of the disease, however, this selection effect equally applies for both male and female patients.

Secondly, we cannot entirely rule out the possibility that the association between sex and clinical outcome was confounded by variables that were not investigated. Although we took into account important confounders, such as age, serovar distribution, exposure risks, and admission delay, information on other potential confounding factors, such as route of infection (e.g., mucosal, abrasions, and ingestion), differing pathogenicity of serovars (or clonal strains of serovars) in circumscribed areas, and inoculum size was lacking. A recent study from Peru demonstrated that the quantity of leptospires in surface waters (which served as potential sources of infection) was related to the outcome of the disease in humans and that the concentration of leptospires was higher in urban water sources [16]. These findings might explain different clinical outcomes of leptospirosis if the place of exposure (i.e., urban vs. rural) differs between male and female patients. Such sex-specific exposures, however, were not found in our study.

To conclude, the frequencies of severe symptoms in clinical leptospirosis significantly differ between sexes in Germany, and these differences are not associated with different exposure risks, leptospiral serovars, or treatment delays. Whatever may be the underlying cause, these findings have implications for future clinical and epidemiological studies of leptospirosis, because comparing groups with different proportions of male or female subjects may introduce a confounding effect. Additionally, in treatment or vaccine trials with unequal proportions of each sex in the study groups, data should be stratified by sex to avoid confounding. In clinical practice, sex differences in the manifestation of leptospirosis may cause systematic underinvestigation and undertreatment of the disease in female patients. If epidemiologically plausible, physicians should consider leptospirosis in female patients with fever of unknown origin, when indicative symptoms, such as jaundice or renal failure, are lacking.

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Acknowledgments

Financial support. Deutsche Forschungsgemeinschaft (KFO 104 to T. S.).

Potential conflicts of interest. All authors: no conflicts.

  • Received November 15, 2006.
  • Accepted January 15, 2007.
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  1. Clin Infect Dis. (2007) 44 (9): e69-e72. doi: 10.1086/513431
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