Mechanisms and consequences of sex differences in immune responses.

Biological sex differences refer to differences between males and females caused by the sex chromosome complement (that is, XY or XX), reproductive tissues (that is, the presence of testes or ovaries), and concentrations of sex steroids (that is, testosterone or oestrogens and progesterone). Although these sex differences are binary for most human individuals and mice, transgender individuals receiving hormone therapy, individuals with genetic syndromes (for example, Klinefelter and Turner syndromes) and people with disorders of sexual development reflect the diversity in sex-based biology. The broad distribution of sex steroid hormone receptors across diverse cell types and the differential expression of X-linked and autosomal genes means that sex is a biological variable that can affect the function of all physiological systems, including the immune system. Sex differences in immune cell function and immune responses to foreign and self antigens affect the development and outcome of diverse diseases and immune responses.

A Clinical Model to Predict the Occurrence of Select High-risk Infections in the First Year Following Heart Transplantation.

Background: Invasive infection remains a dangerous complication of heart transplantation (HT). No objectively defined set of clinical risk factors has been established to reliably predict infection in HT. The aim of this study was to develop a clinical prediction model for use at 1 mo post-HT to predict serious infection by 1 y. Methods: A retrospective cohort study of HT recipients (2000-2018) was performed. The composite endpoint included cytomegalovirus (CMV), herpes simplex or varicella zoster virus infection, blood stream infection, invasive fungal, or nocardial infection occurring 1 mo to 1 y post-HT. A least absolute shrinkage and selection operator regression model was constructed using 10 candidate variables. A concordance statistic, calibration curve, and mean calibration error were calculated. A scoring system was derived for ease of clinical application. Results: Three hundred seventy-five patients were analyzed; 93 patients experienced an outcome event. All variables remained in the final model: aged 55 y or above, history of diabetes, need for renal replacement therapy in first month, CMV risk derived from donor and recipient serology, use of induction and/or early lymphodepleting therapy in the first month, use of trimethoprim-sulfamethoxazole prophylaxis at 1 mo, lymphocyte count under 0.75 × 103cells/µL at 1 mo, and inpatient status at 1 mo. Good discrimination (C-index 0.80) and calibration (mean absolute calibration error 3.6%) were demonstrated. Conclusion: This model synthesizes multiple highly relevant clinical parameters, available at 1 mo post-HT, into a unified, objective, and clinically useful prediction tool for occurrence of serious infection by 1 y post-HT.

Sex- and age-based comparison of serum immunoglobulins following liver transplantation.

BACKGROUND: Over a quarter of organ transplant recipients have low immunoglobulin levels in their early post-transplant course, which is associated with increased risk of infection and mortality. Although immunoglobulin level varies by sex among healthy individuals, it is unknown how such differences are affected by transplant-related immunosuppression. This study compared post-liver transplant immunoglobulin G (IgG) between sexes at varying ages. METHODS: Serum specimens from a prospective cohort of 130 liver transplant recipients were analyzed. IgG was measured at time of transplant and from one-month post-transplant samples. Post-transplant IgG was compared between sexes using multivariable linear regression. Four age and sex categories were created (women<50, women≥50, men<50, men≥50) and the model repeated with this as the explanatory variable. The relationship between sex hormone concentrations and post-transplant IgG was also explored. Infection type and incidence were examined within groups. RESULTS: The cohort included 99 men, 31 women (mean age 53). In adjusted linear regression, post-transplant IgG was not significantly different by sex (p = 0.92). However, when broken into four categories by age and sex, the contrast in IgG levels between younger versus older patients was strikingly greater among women than among men. An interaction term including age and sex was statistically significant (p = 0.03). The combined age-sex categorical variable was also significantly associated with post-transplant IgG (p = 0.01). Finally, an association was identified between baseline estradiol level and post-transplant change in IgG (p = 0.04). CONCLUSIONS: Sex and age have an important relationship with post-transplant IgG with older women demonstrating lowest concentrations. Immunoglobulin levels have previously demonstrated association with post-transplant outcomes.

Female sex and advanced age are associated with invasive cytomegalovirus disease in solid organ transplant recipients.

BACKGROUND: Limited data exist to describe sex-based differences in the severity of cytomegalovirus (CMV) infection after solid organ transplant (SOT). We sought to identify if a difference exists in likelihood of tissue-invasive disease between male and female SOT recipients and to understand how age affects this relationship. METHODS: A retrospective cohort of 180 heart, liver, and kidney recipients treated for CMV was examined. A logistic regression model was developed to assess the relationship between female sex and CMV type (noninvasive vs. invasive). A secondary regression analysis looked at the relationship of invasive CMV with a variable combining sex with age above or below 50. RESULTS: There were 37 cases of proven or probable invasive CMV, occurring in 30% of females versus 16% of males. After adjustment for potential confounders, females with CMV infection were significantly more likely to have invasive disease (odds ratio (OR) 2.69, 95% confidence interval (CI) 1.25-5.90, p = .01). Females 50 years or older were at particular risk compared with males under 50 years (adjusted OR 4.54, 95% CI 1.33-18.83, p = .02). CONCLUSION: Female SOT recipients with CMV in our cohort were more likely than males to have tissue-invasive disease, with the highest risk among older females. Further prospective studies are warranted to explore underlying immunologic mechanisms.

Difference in absolute lymphocyte count among male and female heart transplant recipients.

The impact of sex on immune composition in the setting of solid organ transplantation is unknown. Immunocompetent men and women have quantitative differences in multiple markers of immunity, including lymphocyte subsets. Lymphocytes are of particular interest given the routine use of medications targeted at cell-mediated immunity. The objective of this retrospective cohort study was to compare absolute lymphocyte count (ALC) measurements of male and female heart recipients immediately before, and 1 month after, transplantation. Data was collected on 375 adult recipients (104 female and 271 male) from 2000 to 2018 at a single center. Mean ALC was compared using Student's t-test. Women had higher mean ALC both at baseline (female 1.6 × 103 cells/µl vs. male 1.3 × 103 cells/µl; P < .001) and at 1 month post-transplantation (mean 1.2 × 103 cells/µl vs. .8 × 103 cells/µl; P < .001). This finding could have important implications for sex-based differences in predisposition to rejection or response to infection or vaccination.

Association Between Lymphopenia at 1 Month Posttransplant and Infectious Outcomes or Death in Heart Transplant Recipients.

BACKGROUND: Cell-mediated immunity is a specific target of several medications used to prevent or treat rejection in orthotopic heart transplantation. Low absolute lymphocyte count (ALC) has potential to be a useful and accessible clinical indicator of overall infection risk. Though some studies have demonstrated this association in other transplant populations, it has not been assessed in heart transplant recipients. METHODS: A single-center retrospective cohort study examined adult heart transplant recipients transplanted between 2000 and 2018. The exposure of interest was ALC ≤0.75 × 103 cells/µL at 1 month posttransplant, and the primary endpoint was a composite outcome of infection (including cytomegalovirus [CMV], herpes simplex I/II or varicella zoster virus [HSV/VZV], bloodstream infection [BSI], invasive fungal infection [IFI]) or death occurring after 1 month and before 1 year posttransplant. A multivariable Cox proportional hazards model was created to control for confounders identified using clinical judgment and statistical criteria. RESULTS: Of 375 subjects analyzed, 101 (27%) developed the composite outcome (61 CMV, 3 HSV/VZV, 19 BSI, 10 IFI, 8 deaths). Lymphopenia (ALC ≤0.75 × 103 cells/µL) at 1 month was associated with a >2-fold higher rate of the composite outcome (hazard ratio [HR], 2.26 [95% confidence interval {CI}, 1.47-3.46]; P < .001) compared to patients without lymphopenia at 1 month. After adjustment for confounding variables, the presence of lymphopenia remained statistically significantly associated with the composite outcome (HR, 1.72 [95% CI, 1.08-2.75]; P = .02). CONCLUSIONS: ALC measured at 1 month after heart transplant is associated with an increased risk of infectious outcomes or death in the ensuing 11 months. This is a simple, accessible laboratory measure.

Prospective Observational Study Comparing Sepsis-2 and Sepsis-3 Definitions in Predicting Mortality in Critically Ill Patients.

BACKGROUND: Sepsis definitions have evolved, but there is a lack of consensus over adoption of the most recent definition, Sepsis-3. We sought to compare Sepsis-2 and Sepsis-3 in the classification of patients with sepsis and mortality risk at 30 days. METHODS: We used the following definitions: Sepsis-2 (≥2 systemic inflammatory response syndrome criteria + infection), Sepsis-3 (prescreening by quick Sequential Organ Failure Assessment [qSOFA] of ≥2 of 3 criteria followed by the complete score change ≥2 + infection), and an amended Sepsis-3 definition, iqSOFA (qSOFA ≥2 + infection). We used χ 2 or Wilcoxon rank-sum tests, receiver-operator characteristic curves, and survival analysis. RESULTS: We enrolled 176 patients (95% in an intensive care unit, 38.6% female, median age 61.4 years). Of 105 patients classified by Sepsis-2 as having sepsis, 80 had sepsis per Sepsis-3 or iqSOFA (kappa = 0.72; 95% confidence interval [CI], 0.62-0.82). Twenty-five (14.8%) died (20 of 100 with sepsis per Sepsis-2 [20%], and 20 of 77 [26.0%] with sepsis per Sepsis-3 or iqSOFA). Results for Sepsis-3 and iqSOFA were identical. The area under the curve of receiver-operator characteristic (ROC) curves for identifying those who died were 0.54 (95% CI, 0.41-0.68) for Sepsis-2, 0.84 (95% CI, 0.74-0.93) for Sepsis-3, and 0.69 (95% CI, 0.60-0.79) for iqSOFA (P < .01). Hazard ratios for death associated with sepsis were greatest for sepsis or septic shock per Sepsis-3. CONCLUSIONS: Sepsis-3 and iqSOFA were better at predicting death than Sepsis-2. Using the SOFA score might add little advantage compared with the simpler iqSOFA score.