Sex & Gender in Acute Care Medicine

1. Sex & Gender in Acute Care Medicine Chapter 11: Infectious Disease

2. Chapter 11: Infectious Disease Erica Hardy Mitchell Kosanovich ArvindVenkat

3. Case 1 • A 25-year-old female patient – gravida 1, para 0, 26 weeks pregnant – presents to the ED with a fever of 101°F and myalgias • Her symptoms began 72 hours prior and include vomiting and shortness of breath • She notes no change in fetal movement, contractions, vaginal bleeding, or rush of amniotic fluid

4. Case 1, continued • The triage nurse documents that the patient is tachycardic, tachypneic, and hypoxic with an O2 saturation of 85% on room air • On exam, you note that she has crackles at the right lung base • What historical factors are critical are in evaluating this patient?

5. Case 2 • A 21-year-old female, gravida 0, presents to the ED with vaginal discharge • She is sexually active with one male partner with whom she does not use barrier contraception • She does report some dysuria, but no pelvic pain and denies vaginal lesions • She denies fever or chills

6. Case 2, continued • On exam, 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 sex?

7. Introduction • Sex and gender differences exist in acute care presentation, diagnosis, and treatment of infectious disease • Most emergency physicians are aware of cases in which infectious disease presents more commonly in either male or female patients

8. Introduction • What is less understood is that differences between male and female patients in infectious disease range beyond the epidemiology of presentation • Sex and gender differences affect host responses to various microbial pathogens, resultant severity of illness, and response to therapy

9. Introduction • Infectious diseases are also unique in that their manifestation can directly relate to a means of transmission between male and female patients, namely sexually transmitted infections • Microbial pathogens that are transmitted sexually can manifest in gender- and sex-specific ways

10. Introduction • In this chapter, we review existing evidence on sex- and gender-related differences and similarities in infectious disease epidemiology, diagnosis, and management • Discussion is divided between non-sexually and sexually transmitted infectious diseases • Finally, we discuss gaps in existing literature on sex and gender differences in the acute management of infectious disease

11. Epidemiologic Differences • Differences between males and females in infectious disease have a combination of genetic and behavioral explanations • Overall, males appear more susceptible to infectious diseases than females • This extends beyond humans to other species • Two hypotheses are proposed for why males may be more susceptible

12. Epidemiologic Differences • The “physiologic hypothesis” – the relationship between sex-specific hormones and immune system development affects how males and females respond to pathogens • The “behavioral hypothesis” – behavior-driven activities such as hunting-gathering may have led to evolutionary changes that drive susceptibility to pathogens

13. Epidemiologic Differences • The preponderance of evidence supports the physiologic rather than behavioral hypothesis • For example, an Israeli study found that the prevalence of infectious diseases such as viral hepatitis and viral meningitis were higher among male children younger than age five than among female children • A finding that could not be explained by behavioral differences, which typically do not occur until later in life

14. Epidemiologic Differences • The current state of the literature suggests that the physiologic hypothesis is stronger • But that behavioral-related susceptibilities do exist

15. Epidemiologic Differences

16. Respiratory Infections • 4th most common primary diagnosis given to patients from the ED • Represent 3.2% of all ED visits in the US • A longitudinal study of Danish children found that hospitalizations for respiratory infections were 1.5 times more common in males than females in early childhood • At later ages, the ratio reversed, with males being hospitalized at a ratio of 0.8 to 1 female

17. Respiratory Infections • This reversal in hospitalization ratio extended across respiratory ailments, including viral upper respiratory infections, influenza, and otitis media • Authors note that the nature of Danish childcare, with most children being cared for in similar settings, makes it unlikely that behavioral differences would explain this

18. Respiratory Infections • One review found that female patients were more likely to present with upper respiratory infections • Males were more likely to present with lower respiratory infections, including pneumonia • These differences in anatomical location of infection may also explain the observation that males have worse outcomes than females

19. Respiratory Infections • Pneumonia is generally more virulent than upper respiratory infections • Other potential mechanisms for the worse outcomes in male patients include sex hormone differences and their role in host immune response • Behavioral factors, such as workplace environmental exposes, may also play a role

20. Respiratory Infections • 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 of mortality differences in post-injury pneumonia between the sexes

21. Respiratory Infections • Sex differences have also been observed in the epidemiology of tuberculosis • Observational evidence from passive reporting suggests that beginning in adolescence, males are more likely to develop clinically evident tuberculosis • Criticism of this evidence is that it might be attributable to health resources in developing nations being more accessible to males than females

22. Respiratory Infections • Influenza is the most commonly encountered respiratory pathogen for which female sex is associated with more severe clinical presentation • It is well established that pregnant women represent a population with particular susceptibility to morbidity and mortality from influenza

23. Respiratory Infections • The H1N1 influenza pandemic was particularly virulent among pregnant women, who represented 5% of all attributable deaths • For ED physicians, studies suggest that pregnant women with influenza should be treated aggressively with antiviral medications • Even if presenting beyond the traditional 24-48 hours from symptom onset, when treatment is considered most effective

24. Urinary Tract Infection • Estimates suggest that 1 million visits to the ED annually are attributable to UTI • Under age 1 and above age 60, males and females have a similar incidence of UTI • Between these two age groups, however, females are up to 40 times more likely to present with UTI • Half of all women experience a UTI during their lifetime

25. Urinary Tract Infection • Anatomical (proximity of genitourinary tract to the rectum, shorter urethra), physiologic (sex variations in uroepithelial receptors for pathogenic bacteria), and behavioral (use of spermicidal contraception) factors all contribute to increased incidence of UTI in women

26. Urinary Tract Infection • For ED physicians, the higher prevalence of UTI in female patients can lead to overdiagnosis • A retrospective analysis of women age 70 and older diagnosed with UTI in the ED found that 43% had negative cultures • Obtaining a urine sample by straight catheterization rather than clean catch reduced the likelihood of false positive diagnosis

27. Urinary Tract Infection • Asymptomatic bacteriuria and acute cystitis in men are rare outside of extremes of age (neonates and the elderly) • When they occur, it is often due to urinary tract anatomic abnormalities • Data on treatment of UTI in men is limited and often extrapolated from studies of women • ED physicians should be familiar with current treatment guidelines and local antimicrobial resistance patterns

28. Urinary Tract Infection • Current guidelines take into account efficacy as well as community antimicrobial resistance • Also, ecological adverse effects of antimicrobial therapy such as clostridium difficile and colonization with multidrug resistant organisms

29. Urinary Tract Infection • Current guidelines recommend first-line therapy with nitrofurantoin, trimethoprim/sulfamethoxazole, or fosfomycin • Trimethoprim/sulfamethoxazole should not be chosen empirically if local community resistance is greater than 20%

30. Endocarditis and Staph AureusBacteremia • Sex differences in epidemiology and treatment are either not apparent or attributable to other disease-specific factors • Investigators suggested that women were more likely to die from endocarditis • However, as confounding factors such as diabetes and immunosuppression are considered, sex differences in outcomes and treatment seem to fall away

31. Endocarditis and Staph AureusBacteremia • Where sex differences do exist in endocarditis is in the heart valves affected • In registry studies, both sexes had a similar percentage of cases in native valves (70%) versus prosthetic (20%) • However, among patients with native endocarditis, men were more likely than women to be affected in their aortic valve

32. Endocarditis and Staph AureusBacteremia • Among patients with prosthetic valve endocarditis, women were more likely to be affect in their artificial mitral valve • Knowledge of sex variations in the potential location of endocarditis may allow physical exam findings to guide risk assessment • Sex differences have not been found in the incidence of Staph aureusbacteremia or methicillin-resistant Staph aureuscolonization

33. Diarrheal Illness • There is a paucity of literature on sex differences in pathogens that cause infectious diarrhea • Among the organisms for which sex and gender as risk factors have not been widely assessed are: • Salmonella • Shigella • Campylobacter • Ova and parasites

34. Diarrheal Illness • In contrast, emerging evidence suggests that women who are postpartum are at risk for Clostridium difficileinfections • Case control studies have found that otherwise healthy postpartum females who received prophylactic antibiotics or delivered by caesarian section were most at risk • Particularly if they were treated with ampicillin, gentamicin, or clindamycin

35. Traveler’s Infectious Diseases • In a large retrospective study of more than 58,000 patients worldwide who presented to traveler’s clinics: • Women were more likely to present with diarrheal symptoms, upper respiratory infections, and UTIs • Men were more likely to present with febrile illnesses, vector-borne illnesses, sexually transmitted infections, and viral hepatitis

36. Traveler’s Infectious Diseases • No evidence suggests that once a particular traveler’s infectious disease diagnosis is made that management should vary between males and females

37. Malaria • Despite its prevalence, there are few studies on sex and gender differences in 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 a rate of 77% versus 35% in males • However, a smaller, earlier single center study from Europe did not find such a difference

38. Hepatitis C • Hepatitis C is a viral infection whose acute phase is often asymptomatic • But in 75% of patients it may lead to chronic infection with risk for liver fibrosis or cirrhosis • For ED physicians, there are no established protocols for prophylaxis or acute treatment • Evidence suggests that women are more likely to spontaneously clear the virus than men • Particularly Caucasian women with an IL28B genetic polymorphism

39. Cutaneous Infections • Cellulitis and diabetic foot infections are two common cutaneous infections • Although evidence is limited to retrospective analysis, no data suggests that sex alone is a factor associated with poor outcome • For cellulitis, single-center evidence suggests that an apparent observed male predominance in development of abscess is better explained by alcohol use and delayed antimicrobial treatment

40. Cutaneous Infections • For diabetic foot infections, initial increased ulcer size is the most clearly associated factor with poor outcome • in comparison to sex, age, or degree of diabetic control • For ED physicians, these studies suggest that it is not necessarily to consider sex as a separate epidemiologic factor associated with poor outcome

41. Leptospirosis • Leptospirosis is a zoonotic infectious disease caused by a spirochete-type bacterium • Humans typically acquire this disease through exposure to animal urine • Causes flulike symptoms followed by a more severe second phase after apparent recovery • Second phase can cause meningitis,renal or liver failure

42. Leptospirosis • Worldwide, 80-90% of cases are reported in males • This was initially presumed to be due to behavioral explanations, such as occupational exposures (i.e., 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

43. Leptospirosis • This supports physiological hypothesis explanation for sex difference in this disease • Decreased severity of leptospirosis in females may lead to lower rates of reporting in this population • Current evidence does not support the need for treatment differences by sex • Doxycycline is considered first-line therapy

44. Lyme Disease • In the US, there is a male predominance of Lyme disease cases • In Europe, there is a female predominance • The driving factors behind this difference in incidence are unclear • Possibilities include behavioral factors associated with tick vector exposure and likelihood of seeking treatment

45. Lyme Disease • In a 20-year retrospective study from Slovenia, female patients were more likely to present with early dermatologic manifestations, erythema migrans and acrodermatitischronicaatrophicans • In contrast, men were more likely to present with Lyme neuroborreliosis and arthritis, later manifestations of the disease

46. Lyme Disease • It is unclear whether this difference is a function of behavioral factors, with male patients delaying seeking care • Or physiologic factors such as sex-specific genetic background and host response • Some support for a physiologic explanation comes from studies that show that males manifest a more severe form of Q fever, another spirochete disease

47. Cryptococcal Meningitis • Caused by Cryptococcus neoformans • Male AIDS patients experience this opportunistic infection at a higher rate than females with AIDS • A seminal study of HIV patients from Botswana noted that this is not a function of worse HIV control • Males in this study had higher CD4 counts compared to females and yet were still more likely to contract cryptococcal meningitis

48. Cryptococcal Meningitis • Investigators found that sex hormones and sex-specific macrophage activity were likely explanations • With testosterone causing higher fungal activity and male macrophages experiencing more cell death • For ED physicians, knowledge of this pathophysiology should lead to a sex-specific risk assessment in AIDS patients with suspected infection

49. Onchocerciasis • Onchocerciasis, or river blindness, represents a disease for which gender differences in eradication are profound • Caused by a parasitic nematode, river blindness is readily treated with ivermectin • However, eradication programs in endemic areas tend to follow patterns where males are in positions of authority

50. Onchocerciasis • This leads to decreased female participation in these programs • In general, there is a paucity of medical literature on the role that gender plays in treatment programs of endemic and epidemic infectious diseases