IFNγ Response to Mycobacterium tuberculosis, Risk of Infection and Disease in Household Contacts of Tuberculosis Patients in Colombia

OBJECTIVES: Household contacts (HHCs) of pulmonary tuberculosis patients are at high risk of Mycobacterium tuberculosis infection and early disease development. Identification of individuals at risk of tuberculosis disease is a desirable goal for tuberculosis control. Interferon-gamma release assays (IGRAs) using specific M. tuberculosis antigens provide an alternative to tuberculin skin testing (TST) for infection detection. Additionally, the levels of IFNgamma produced in response to these antigens may have prognostic value. We estimated the prevalence of M. tuberculosis infection by IGRA and TST in HHCs and their source population (SP), and assessed whether IFNgamma levels in HHCs correlate with tuberculosis development. METHODS: A cohort of 2060 HHCs was followed for 2-3 years after exposure to a tuberculosis case. Besides TST, IFNgamma responses to mycobacterial antigens: CFP, CFP-10, HspX and Ag85A were assessed in 7-days whole blood cultures and compared to 766 individuals from the SP in Medellín, Colombia. Isoniazid prophylaxis was not offered to child contacts because Colombian tuberculosis regulations consider it only in children under 5 years, TST positive without BCG vaccination. RESULTS: Using TST 65.9% of HHCs and 42.7% subjects from the SP were positive (OR 2.60, p<0.0001). IFNgamma response to CFP-10, a biomarker of M. tuberculosis infection, tested positive in 66.3% HHCs and 24.3% from the SP (OR = 6.07, p<0.0001). Tuberculosis incidence rate was 7.0/1000 person years. Children <5 years accounted for 21.6% of incident cases. No significant difference was found between positive and negative IFNgamma responders to CFP-10 (HR 1.82 95% CI 0.79-4.20 p = 0.16). However, a significant trend for tuberculosis development amongst high HHC IFNgamma producers was observed (trend Log rank p = 0.007). DISCUSSION: CFP-10-induced IFNgamma production is useful to establish tuberculosis infection prevalence amongst HHC and identify those at highest risk of disease. The high tuberculosis incidence amongst children supports administration of chemoprophylaxis to child contacts regardless of BCG vaccination

Correlation between TST and IFNγ production in response to CFP and CFP-10 by age in household contacts (HHCs) and individuals from source population (SP).

<p>*Spearman correlation coefficient <i>r</i>. All p values<0.001.</p><p>†TST (mm of induration); IFNγ (pg/mL).</p

Characteristics of household contacts (HHCs) of pulmonary tuberculosis cases and individuals from their source population (SP).

<p>*Only index cases that lead to household contacts included.</p><p>†p value (two tailed) refers to comparison of characteristics in HHCs and individuals from SP.</p><p>‡SES categories as defined in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008257#s2" target="_blank">Methods</a>.</p

Hazard of TB development according to IFNγ production.

<p>Hazard levels of tuberculosis development taking the modified version of IFNγ production categories proposed by Andersen et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008257#pone.0008257-Andersen1" target="_blank">[11]</a> as baseline predictors of disease. Negative: <22pg/mL, Low: 22–99 pg/mL Medium: 100–999 pg/mL, High: ≥1000 pg/mL. HHCs: Household Contacts SP: Source Population.</p

Incidence of active tuberculosis in household contacts and IFNγ production levels at baseline.

<p>*Negative: <22pg/mL, Low: 22–99 pg/mL Medium: 100–999 pg/mL, High: ≥1000 pg/mL.</p><p>†Total positive: (Negative + Low + Medium + High).</p

Incidence of active tuberculosis in household contacts according to age.

<p>Incidence of active tuberculosis in household contacts according to age.</p

Study profile.

<p>HHCs = Household contacts, IGRA = IFNγ Release Assay, TST = Tuberculin Skin Test, SP = source population, CFP-10 = Culture Filtrate Protein-10.</p

Comparison of baseline IFNγ production by TB incident and non–incident HHCs in response to the antigens used.

<p>*Student t - test.</p><p>†Chi-square (χ²) test.</p

IFNγ production levels by age.

<p>Geometric means of IFNγ production in response to CFP (A) and CFP-10 (B) by age in household contacts (HHCs) and individuals from source population (SP). Horizontal lines depict the cut-off value (22 pg/mL).</p

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit