Opening Cases

A 25-year-old female patient – gravida 1, para 0, 26 weeks pregnant – presents to the Emergency Department with a fever of 101°F and myalgias. Her symptoms began 72 hours prior to presentation and include vomiting and shortness of breath. She has noted no change in fetal movement, contractions, vaginal bleeding, or rush of amniotic fluid. The triage nurse documents that the patient is tachycardic, tachypneic, and hypoxic with an oxygen saturation of 85% on room air. On your examination, you note that the patient has crackles at the right lung base. What historical factors are critical in evaluating this patient?

A 21-year-old female, gravida 0, presents to the emergency room with vaginal discharge. She is sexually active with one male partner with whom she does not use barrier contraception. Although she does note some dysuria, she has no pelvic pain and has noticed no vaginal lesions. In addition, she has not noted any systemic symptoms such as fevers or chills. On your examination, you note that she has erythema of the external vaginal canal and cervix, with homogenous thin white discharge. Based on her demographics, what sexually transmitted infection (STI) is she most likely to have? What are the implications of an STI diagnosis based on her gender?

Introduction

Infectious disease represents an important domain where gender differences are present in acute care presentation, diagnosis, and treatment. Most emergency physicians have an instinctive awareness of differences in which infectious disease can present more commonly or, in some cases, exclusively in either male or female patients. For example, numerous studies confirm that urinary tract infections are more common in female rather than male patients (Magliano, 2012; McLaughlin, 2004). What is less understood is that differences between male and female patients in infectious disease range beyond the epidemiology of presentation to host responses to various microbial pathogens, the resultant severity of illness, and the need for tailored approaches to therapy. Without such knowledge, emergency physicians may not appropriately manage both male and female patients who present with infectious disease.

Infectious diseases also are unique in the acute care setting in that their manifestation can directly relate to a means of transmission between male and female patients, namely STIs. Microbial pathogens that are transmitted sexually can manifest in a gender-specific manner, both related to clinical symptoms and severity. The additional social and behavioral factors that govern sexual transmission of infectious disease are directly relevant to ED practice as well. These epidemiologic factors affect the means of diagnosis, the duration of treatment, and the need to counsel patients on the risk of transmission to their sexual partner(s). Again, gender-specific knowledge on the nature of STIs is critical to proper management in the ED.

In this chapter, we review the existing evidence on gender-related differences and similarities in infectious disease epidemiology, diagnosis, and management. We present the literature that shows that variations in severity and treatment exist between men and women for specific pathogens. Given the robust literature on gender differences in STIs, this chapter is divided in its discussion between non-sexually transmitted and sexually transmitted infectious diseases. Finally, we discuss where there are gaps in the existing literature on gender differences in the acute management of infectious disease.

Epidemiologic Differences between Males and Females in Infectious Disease

As with many medical disorders, the differences between males and females in infectious diseases have a combination of genetic and behavioral explanations. Overall, males appear more susceptible to infectious diseases than females, and this susceptibility extends beyond humans to other species (Guerra-Silveira, 2013). Two hypotheses are proposed for why males may be more susceptible. The first hypothesis, termed the “physiologic hypothesis,” is based on genetic and hormonal differences between males and females. In this theory, the relationship between sex-specific hormones and immune system development affects how males and females respond to infectious pathogens. The second hypothesis, termed “the behavioral hypothesis,” focuses on varying gender-assigned roles in the past (e.g., hunter-gatherer for men, family nurturer for women) as a possible explanation for the male predominance in infectious disease presentations. In this theory, behavior-driven activities such as roles in hunting-gathering versus lack thereof may have led to evolutionary changes that drive susceptibility to particular pathogens (Guerra-Silveira, 2013).

To be valid, the physiologic hypothesis would predict that sex differences in infectious diseases would appear in infancy and in puberty, both times in development when changes in levels of sex hormones occur. In contrast, the behavioral hypothesis would not predict differences in infancy, as major variations between the genders in activities related to infectious disease susceptibility do not occur until later in life. The preponderance of evidence supports the physiologic rather than the behavioral hypothesis. A study of the epidemiology of 10 major pathogens in Brazil over three years found that the prevalence of these disorders, including leishmaniasis, schistosomiasis, and leprosy, follow the predictions of the physiologic hypothesis (Guerra-Silveira, 2013). Similarly, an Israeli study found that the prevalence of infectious diseases such as viral hepatitis, viral meningitis, salmonellosis, and shigellosis were higher among male children younger than age five than among female children, a finding that could not be explained by behavioral differences (Green, 1992). Yet both studies suggest that there are behavioral factors that are gender based that may increase the risk of infectious disease, especially in communities where presumed societal roles are ascribed based on traditional beliefs. Overall, the current state of the literature suggests that the physiologic hypothesis is stronger, but that behavioral-related susceptibilities exist in explaining the higher prevalence of infectious diseases among males when compared to females. Table 11.1 summarizes the differences between the physiologic and behavioral hypotheses; Table 11.2 provides an overview of gender differences in non-sexually transmitted infectious diseases discussed in this chapter.

Respiratory Infections

Respiratory infections, ranging from viral upper respiratory pathogens to bacterial pneumonias, are the fourth most common primary diagnosis given to patients from the ED and represent the cause of 3.2% of all ED visits in the United States (Centers for Disease Control, 2010). This high incidence has allowed a number of studies to evaluate the differing epidemiology between males and females in respiratory infectious diseases. A longitudinal study of Danish children and adolescents observed that hospitalizations for respiratory infectious diseases were approximately 1.5 times more common in males than females in early childhood. At later ages, the ratio reversed, with males being hospitalized for respiratory ailments at a ratio of 0.8 to 1 female. This reversal in hospitalization ratio extended across respiratory ailments, including viral upper respiratory infections, influenza, and otitis media. The authors note that the nature of Danish child care, with most children being cared for in similar types of day care situations, makes it unlikely that behavioral differences would explain the gender difference observed. Rather, the previously discussed physiologic changes that occur in infancy and puberty in males and females are more likely factors that contribute to this changing epidemiology (Jensen-Fangel, 2004).

Studies of the nature of respiratory infectious diseases in males and female also indicate that the type of ailments that most commonly affect each population differs based on gender. A review of available studies on the subject found that female patients are more likely to present with upper respiratory infections, while male patients were more likely to present with lower respiratory infections, including pneumonia. These differences in the anatomical location of respiratory infectious diseases may also explain the observation that males have worse outcomes than females when afflicted by respiratory pathogens, given that pneumonia is generally more virulent than upper respiratory infections. Other potential mechanisms for the worse outcomes in male patients with respiratory infections include sex hormone differences and their role in host immune response and behavioral factors, such as workplace environmental exposures (Falagas, 2007).

Male patients also appear more likely to experience pneumonia after trauma. Data from 26 trauma centers in Pennsylvania showed that for moderate and severely injured patients (Injury Severity Score >15), males were more likely to develop pneumonia than females. However, the same study found no evidence that there were mortality differences in post-injury pneumonia between the genders (Gannon, 2004).

Overall, the literature on pneumonia shows evidence that males are more likely to be diagnosed with pneumonia than females. Evidence on outcomes from pneumonia is less robust; males may have poorer outcomes when afflicted with community-acquired pneumonia but may have equal outcomes to females when diagnosed with nosocomial pneumonia (Falagas, 2007; Gannon, 2004).

Tuberculosis is another respiratory disease for which gender epidemiologic differences have been observed. Observational evidence from passive reporting (based on patient presentation to health care services as opposed to active surveillance that evaluates for the presence of cases outside the health care system) suggests that beginning in adolescence, males are more likely than females to develop clinically evident tuberculosis. The criticism of this evidence is that it might be attributable to national health resources in underdeveloped nations being disproportionately accessible to males than females (Holmes, 1998). However, studies based on sputum positivity have also found that males are more likely to develop pulmonary tuberculosis than females with age (Borgdorff, 2000).

Influenza represents the most commonly encountered respiratory pathogen for which female gender is associated with a more severe clinical presentation. It is well established that pregnant women represent a patient population with a particular susceptibility to morbidity and mortality from influenza. Prior to the advent of H1N1 influenza in 2009, epidemiologic survey evidence had confirmed that seasonal influenza from 1998 to 2005 in the United States affected pregnant women in a manner that warranted their labeling as a high-risk population that should be targeted for immunization (Callaghan, 2010). The H1N1 influenza pandemic was particularly virulent among pregnant women, who represented 5% of all deaths attributable to that pathogen. For emergency physicians and other acute care practitioners, these studies suggest that pregnant women with influenza should be treated aggressively with antiviral medications, even if presenting beyond the traditional 24 to 48 hours from symptom onset when these treatments are considered most effective.

Urinary Tract Infection

Infections of the urinary tract represent an extremely common reason for patients to present to the ED. Estimates suggest that 1 million visits to the ED annually are attributable to this disease process. Urinary tract infections also are a prototypical example of how the epidemiology of infectious diseases can vary between sexes. Under age 1 and above age 60, males and females have a similar incidence in urinary tract infections. However, between these two age groups, females are up to 40 times more likely to present with urinary tract infections. Half of all women experience a urinary tract infection during their lifetime. Anatomical (proximity of genitourinary tract to the rectum, shorter urethra), physiologic (gender variations in uroepithelial receptors for pathogenic bacteria), and behavioral (use of spermicidal contraception) factors all contribute to the female predominance in observed presentations for urinary tract infections (McLaughlin, 2004).

For emergency physicians, the higher prevalence in female patients of urinary tract infections can create a danger of overdiagnosis. A retrospective analysis of women age 70 and older diagnosed with urinary tract infections in the ED found that 43% had negative cultures. Obtaining a urine sample by straight catheterization rather than clean catch reduced the likelihood of a false positive diagnosis of urinary tract infection (Gordon, 2013).

Epidemiology varies between males and females with regard to urinary tract infections. Asymptomatic bacteriuria and acute cystitis in men are rare outside of the extremes of age (neonates and the elderly); when it occurs, it is often due to urinary tract anatomic abnormalities. The data on treatment of urinary tract infections in men are limited and often extrapolated from treatment studies in women. The emergency physician should be familiar with current treatment guidelines as well as local antimicrobial resistance patterns when prescribing empiric treatment for acute cystitis. Current expert treatment guidelines, written by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases, and cosponsored by the American Congress of Obstetricians and Gynecologists, the American Urological Association, the Association of Medical Microbioplogy and Infectious Diseases – Canada, and the Society for Academic Emergency Medicine, take into consideration both efficacy as well as collateral damage in the form of community antimicrobial resistance and the ecological adverse effects of antimicrobial therapy such as clostridium difficile colitis and colonization with multidrug-resistant organisms when recommending first-line empiric treatment for urinary tract infection in women. Current guidelines recommend first-line therapy with nitrofurantoin, trimethoprim/sulfamethoxizole, or fosfomycin for uncomplicated cystitis. Trimethoprim/sulfamethoxozole should not be chosen empirically if the local community resistance is greater than 20%, and neither nitrofurantoin nor fosfomycin should be chosen if early pyelonephritis is suspected since the tissue levels of these agents are not sufficient. The quinolones are effective, but second-line options due to the propensity for ecological adverse effects secondary to the broad spectrum nature of these agents (Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases, 2011).

Endocarditis and Staph aureus Bacteremia/Colonization

Unlike urinary tract infections, endocarditis and Staph aureus bacteremia are two infectious conditions for which gender differences in epidemiology and treatment are either not apparent or attributable to other disease-specific factors. In endocarditis, investigators suggested that women were more likely to die from this disease, probably due to a decreased likelihood of receiving surgical treatment (Sambola, 2010). However, as confounding factors such as diabetes mellitus, receiving hemodialysis, or being immunosuppressed are considered, gender differences in outcomes and surgical treatment seem to fall away (Aksoy, 2007). This suggests that observed gender variations in endocarditis are more a function of other patient-specific factors rather than biases due to sex.

Where differences do exist in endocarditis between the sexes is in the heart valves affected. In registry studies, both genders had a similar percentage of cases in native valves (70%) versus prosthetic valves (20%) with the remainder being unidentified. However, among patients with native endocarditis, men were more likely than women to be affected in their aortic valve. Among patients with prosthetic valve endocarditis, women were more likely to be affected in their artificial mitral valve (Sevilla, 2010). These predilections are of relevance to emergency physicians when assessing patients who are at risk for endocarditis. Knowledge of gender variations in the potential location of endocarditis may allow physical examination findings to guide a risk assessment of the presence of endocarditis in males versus females. Diagnostic criteria and modalities for endocarditis are similar between the genders.

Gender differences have not been found in the incidence of Staph aureus bacteremia (Hanses, 2010) or methicillin-resistant Staph aureus colonization in hospitalized patients (Forster, 2013). For emergency physicians, the evidence to date does not suggest that patient sex should serve as a risk assessment factor for the diagnosis of these conditions.

Diarrheal Illness, Traveler’s Infectious Diseases, and Malaria

There is a paucity of literature on the subject of gender differences in pathogens that cause infectious diarrhea. Among the organisms for which gender as a risk factor has not been assessed in a widespread fashion are Salmonella, Shigella, Campylobacter, and ova and parasites. For emergency physicians, there is essentially no evidence to guide whether male versus female patients may be at higher risk for diarrhea due to these conditions.

In contrast, emerging evidence suggests that women who are postpartum are at risk for Clostridium difficile infections. Case control studies have found that otherwise healthy postpartum females who received prophylactic antibiotics, especially ampicillin, gentamicin, or clinidamycin, or delivered by caesarean section were most at risk for this condition. Given that emergency physicians generally consider C. difficile infections to be more present in either hospitalized or debilitated patients, this observed association in generally healthy and young postpartum women is an important epidemiologic risk factor that should be considered in assessing this patient population in the ED (Garey, 2008; Unger, 2011).

Traveler’s infections are an area where gender differences have been established, in terms of both pathogens and symptom presentation. In a large retrospective study of more than 58,000 patients worldwide who presented to traveler’s clinics over a decade, women were more likely to present with diarrheal symptoms, upper respiratory infections, and urinary tract infections. In contrast, men were more likely to present with febrile illnesses, vector-borne illnesses, STIs, and viral hepatitis. Again, however, no evidence suggests that once a particular traveler’s infectious disease diagnosis is made that management should vary between male and female patients (Schlagenhauf, 2010).

Malaria is one of the most common infectious diseases globally. Unfortunately, despite its widespread prevalence, there are few studies on gender differences in the presentation or complications related to malaria. One single center study from Thailand found that women were more likely to develop shock in Plasmodium falciparum malaria at rate of 77% versus 35% in males (Arnold, 2013). However, a smaller earlier single center study from Europe did not find such a difference (Bruneel, 1997). Further studies are needed to establish whether gender differences in either the presentation or management of malaria exist.

Hepatitis C

Hepatitis C is a viral infection whose acute phase is often asymptomatic, but in up to 75% of patients may lead to chronic infection with risk for liver fibrosis or cirrhosis. For emergency physicians, there are no established protocols for prophylaxis or acute treatment. However, evidence suggests that women are more likely to spontaneously clear the virus in comparison to males. This is especially evident in Caucasian women with an IL28B genetic polymorphism rs12979860 (van den Berg, 2011; Grebely, 2013). In Asian women, the evidence suggests that different IL28B genetic polymorphisms are synergistic with hepatitis C viral clearance (Rao, 2012). This research does indicate that female gender and particular genetic factors can be used to provide risk counseling on the likelihood of spontaneous hepatitis C clearance after exposure, although this will likely occur in referral to subspecialty evaluation after ED evaluation.

Cutaneous Infections

Cellulitis and diabetic foot infections are two common cutaneous infections. The danger with cellulitis is that the patient will not respond to typical antibiotics and will develop an abscess or other systemic infection. For diabetic foot infections, the danger is the development of a deeper space infection requiring surgical debridement or amputation. Although the evidence is limited to retrospective analyses, for both conditions, no data suggest that gender alone is a factor associated with either poor outcome. Rather, for cellulitis, single-center evidence suggests that an apparent observed male predominance in development of abscess after cellulitis is better explained by alcohol use and delayed antimicrobial treatment (Picard, 2013). Similarly, for diabetic foot infections, initial increased ulcer size is the most clearly associated factor with poor outcome in comparison to gender, age, or degree of diabetic control (Oyibo, 2001). For emergency physicians, these studies suggest it is not necessary to consider gender as a separate epidemiologic factor associated with poor outcome.

Other Infectious Diseases

Leptospirosis is a zoonotic infectious disease caused by a spirochete-type bacterium. Humans typically acquire this disease through exposure to animal urine and experience initial flulike symptoms followed by a more severe second phase after apparent recovery. The second phase can cause meningitis or renal or liver failure. Worldwide, 80% to 90% of cases are reported in males. This was initially presumed to be due to behavioral hypothesis explanations, such as occupational tendencies and exposures. For example, males were assumed to be more at risk through traditional roles in farming and butchering. However, it is now clear from seroprevalence studies that women are as commonly exposed to leptospirosis as men but experience a less severe phenotype, supportive of a physiologic hypothesis explanation for gender differences in this disease. The decreased severity of leptospirosis in females may also lead to lower rates of reporting in this population relative to males. Existing evidence does not support the need for treatment differences between the genders, with doxycycline serving as first-line therapy (Jansen, 2007).

Lyme disease is another entity for which gender differences have been observed in both the incidence of illness and symptom manifestation, although the difference varies by geographic location. In the United States, there is a male predominance of cases; in Europe, there is a female predominance. It is unclear what the driving factors behind this differing incidence are. Possibilities include behavioral factors associated with tick vector exposure and likelihood of seeking treatment. Lyme disease also seems to show variability in how it manifests between males and females. In a 20-year retrospective study from Slovenia, female patients were more likely to present with erythema migrans and acrodermatitis chronica atrophicans, early dermatologic manifestations of Lyme disease. In contrast, men were more likely to present with Lyme neuroborreliosis and Lyme arthritis, which are later manifestations of the disease. Again, it is unclear whether this difference is a function of behavioral factors, with male patients not seeking care until later symptoms manifest, or physiologic factors, such as gender-specific genetic background and host response (Strle, 2013). Some support for a physiologic hypothesis explanation comes from studies that show that males manifest a more severe form of Q fever, another spirochete disease, and that sex hormones play a role in its pathogenesis (Raoult, 2000; Leone, 2004).

Cryptococcal meningitis, caused by Cryptococcus neoformans, is another infectious disease for which gender differences in disease incidence and prevalence have been observed. Male AIDS patients experience this opportunistic infection at a higher rate than female AIDS patients. A seminal study of HIV patients from Botswana noted that this is not a function of worse HIV control. In fact, male patients in this study were found to have higher CD4 counts compared to female patients, but they still were more likely to experience cryptococcal meningitis. Instead, the investigators found that sex hormones and gender-specific macrophage activity were likely explanations, with testosterone leading to higher fungal activity and male macrophages experiencing more cell death (McClelland, 2013). For emergency physicians, knowledge of this pathophysiology supports the epidemiologic evidence of a male predominance in cryptococcal meningitis and should lead to a gender-specific risk assessment in AIDS patients suspected of manifesting this disease process.

Finally, onchocerciasis, or river blindness, represents an infectious disease for which gender differences are profound not in pathophysiology but in societal efforts in eradication. Caused by a parasitic nematode, river blindness is readily treated with ivermectin. However, eradication programs in endemic areas tend to follow patterns where males, especially older men, are in positions of authority. This leads to decreased female participation in these programs, which may have an effect on long-term adherence and sustainability (Clemmons, 2002). In general, there is a paucity of medical literature on the role that gender plays in treatment programs of endemic and epidemic infectious diseases.

Sexually Transmitted Infections and Gender

The relationship between gender, biomedical risk, and STIs is complex, with local epidemiology playing an equally important role. The emergency physician must take all of this into consideration when evaluating a patient for a potential STI. Women are uniquely at increased risk of STIs in several ways, including susceptibility to infection, severity of infection, and the difficulty in screening and diagnosis.

Women’s increased susceptibility to STIs is illustrated by the case of the adolescent patient. While adolescents ages 15 to 24 make up only a quarter of the US population, they represent nearly half of the STIs (CDC surveillance data, 2012). This phenomenon is partially explained by the increased susceptibility of the female adolescent to STIs due to biomedical reasons. Squamous epithelial cells are more resistant to chlamydia and gonorrhea, whereas columnar epithelium supports their growth. The adolescent cervix normally contains an area of ectopy, where columnar cells are located on the exposed portion of the cervix. It has been hypothesized that the exposure of these columnar cells (which are more susceptible to some STIs) places the adolescent at increased risk of these infections, whereas on the mature cervix, the exposed columnar cells are slowly replaced by squamous epithelium (more resistant to infection). Cervical mucous, which plays a protective role in STI prevention, is more easily penetrated by these organisms in early adolescence (Vickery, 1968). And while playing an important role in preventing unwanted pregnancy, oral contraceptives alter the local immunity by increasing the size of this squamocolumnar junction, thereby increasing susceptibility to STIs (Park, 1995).

In addition to these local factors in the female genital tract, STIs are often more efficiently transmitted from a male to his female partner(s). Genital herpes transmission from male to female is 19% compared to 5% from female to male (Mertz, 1992). Gonorrhea is transmitted from an infected male to his female partner 60% to 90% of the time, compared to 20% to 30% of the time from female to male (Hooper, 1978). Some of the proposed mechanisms for this disparity have been more infectious innoculum as a result of pooled semen in the vagina as well as greater trauma to the genital tract tissues during sexual intercourse.

It is known that male circumcision decreases the risk of STIs such as the human immunodeficiency virus (HIV) as well as the human papilloma virus (HPV). Interestingly, circumcision in a male partner also decreases the risk of cervical cancer in the female partner (Castellsague, 2002).

In addition to the baseline increased infection risk, women are disproportionately affected by the sequelae of STIs. Pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy, and infertility, affecting only women, are the end result of STIs, and decreasing these serious sequelae is the ultimate goal of prevention programs. Each subsequent infection increases a women’s risk for pelvic inflammatory disease and ectopic pregnancy. So breaking the chain of transmission is extremely important, and emergency medicine providers play an important role in interrupting this cascade.

Screening and diagnosis may also be more problematic in females, because infection in females is more likely to be asymptomatic. Gonorrhea and chlamydia infection are asymptomatic in up to 80% of females, compared to 10% to 20% of males, resulting in less diagnosis if only symptomatic individuals are tested for the disease (Zimmerman, 1990). Two things may occur as a result – asymptomatic infection may continue in women, placing them more at risk for serious sequelae, and screening programs focusing on women may fail to eliminate infection in men, which is then retransmitted to females partners, even after the woman has been treated. Prevention strategies such as expedited partner therapy, a strategy easily employed by the emergency medicine provider, have been proven in randomized controlled clinical trials to be effective at treating asymptomatic partners and decreasing the reinfection rate in females. Data have shown that men may be more likely to be tested for syphilis when an STI is suspected (Garfinkel, 1999), which has implications for a missed diagnosis in females, especially problematic given the serious sequelae of congenital syphilis.

Some have suggested that sexual behaviors, resulting from socialization into different gender roles, affected by culture, peer, and parental influences, may account for some of the gender differences in STIs. Males often have an earlier age at first sexual encounter (Institute of Medicine, 1997) and a higher rate of partner changes (Siegel, 1999). Women are more likely to have been forced into their first sexual encounter (Department of Health and Human Services, 1997). Women may be uncomfortable negotiating condom use, and dynamics of intimate partner violence against women may make it more difficult for women to advocate for themselves in protecting against STIs. If the provider is aware of these potential barriers to avoiding STIs in women, then screening is more likely to take place. Prevention programs that address gender roles have shown a significant reduction in STI rates (Kamb, 1998; Shain, 1999).

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