Search

Acute gastrointestinal intestinal GVHD (aGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation, and the intestinal microbiota is known to impact on its severity. However, an association between treatment response of aGI-GVHD and the intestinal microbiota has not been well-studied. In a cohort of patients with aGI-GVHD (n=37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and loss of Bacteroides ovatus from the microbiome. In a mouse model of carbapenem-aggravated GVHD, introducing Bacteroides ovatus reduced severity of GVHD and improved survival. Bacteroides ovatus reduced degradation of colonic mucus by another intestinal commensal, Bacteroides thetaiotaomicron, via its ability to metabolize dietary polysaccharides into monosaccharides, which then inhibit mucus degradation by Bacteroides thetaiotaomicron and reduce GVHD-related mortality.

A variety of tyrosine kinase inhibitors (TKIs) are currently approved for the treatment of solid tumors and hematological cancers. However, TKIs are often associated with gastrointestinal (GI) adverse effects (AEs), especially diarrhea. Therefore, in the present study, we aimed to describe the clinical features and outcomes of TKI-associated lower GI AEs.This was a retrospective single-center cohort study of patients with cancer treated with TKIs from March 2016 to September 2020 who experienced diarrhea without other identifiable causes. Basic and GI AE-related characteristics and outcomes were compared using χOf 2172 patients who received TKIs over the study period, we included 228 in the final analysis. Of these, 166 (72.8%) had hematological cancers. Besides diarrhea, GI symptoms included nausea (36.4%), vomiting (21.9%), abdominal pain (15.4%), and bleeding (3.1%). Symptoms were typically mild, with 209 patients (91.7%) presenting with Common Terminology Criteria for Adverse Events grade 1-2 diarrhea. Only 5 patients (2.2%) received immunosuppressants for diarrhea treatment, 83 (36.4%) received no treatment, 29 (12.7%) received antibiotics, 101 (44.3%) received supportive antidiarrheal medications, and 17 patients (7.5%) needed TKI dose reduction or cessation of TKI use. When compared with patients with hematological cancers, those with solid tumors had a higher rate of hospitalization (29.0% vs. 7.2%; p 0.001) and mortality (75.8% vs. 43.4%; p 0.001) but a lower rate of recurrence of GI AEs (21.0% vs. 42.8%; p = 0.003. Only 15 patients (6.6%) underwent colonoscopy, with normal endoscopic findings in 8 patients (53.3%) and nonulcerative inflammation in 5 patients (33.3%). The inflammation universally involved the left colon. Twelve of the 15 patients who underwent colonoscopy had active colitis. In the hematological cancer group, patients with acute myeloid leukemia had a lower GI AE recurrence rate than did patients with other hematological cancers (7.2% vs. 30.1%; p = 0.001).Ten percent of cancer patients receiving TKIs experienced lower GI AEs, which were usually mild. Symptoms TKI-related GI adverse effects were nonspecific, often overlapping those of other cancer therapy-related GI AEs. Treatment of GI AEs was largely supportive, with limited roles for antibiotics and immunosuppressants.

Background Yersinia enterocolitica is usually transmitted through ingesting or handling undercooked pork products and is an uncommon cause of diarrhea, mesenteric adenitis and bacteremia in the United States. There is limited information regarding its clinical course in immunosuppressed and cancer patients. We describe the clinical presentation and outcomes of cancer patients diagnosed with Y. enterocolitica at a Comprehensive Cancer Center in the United States before and after the use of nucleic acid amplification testing (NAAT) using GI multiplex panel (GIMP). Methods We studied all patients with Y. enterocolitica isolated from cultures or identified by NAATs. We then obtained demographic information, comorbidities, co-infections, clinical characteristics, treatment and overall mortality at 30 days post diagnosis. Results Sixteen cases were identified (Table 1). The most common symptom of Y. enterocolitica infection was diarrhea [10/16 (62%)], followed by abdominal pain [8/16 (50%)] and fever [4/16 (25%)]. Ten of the cases were identified by NAAT over a 2-year period, compared with six cases identified prior to April 2016 over 70 years. Stool cultures confirmed Y. enterocolitica infection in two cases identified by NAAT (20%). Three patients had co-infection with Clostridium difficile, and four patients had a history of C. difficile infection. All but one patient was treated, mostly with a fluoroquinolone. Thirty-day mortality was 7.7%. Cause of death was most often a complication of advanced cancer. The one patient who did not receive antibiotics had maxillary sinus squamous cell cancer and had spontaneous resolution of symptoms. Conclusion GIMP NAATs have increased the rates of Y. enterocolitica identification in patients with cancer, suggesting that this disease was underdiagnosed or is now more common as patients receive increasingly intensive immunosuppression. GIMP NAATs will likely re-define the epidemiology of Y. enterocolitica infection in cancer patients. In patients with Y. enterocolitica who are at high risk for C. difficile relapse and in whom no recent immunosuppression or evidence of systemic illness is present, it may be reasonable to consider observation or shorter course of antibiotics. Disclosures All authors: No reported disclosures.

BACKGROUND AND OBJECTIVES Bacterial pneumonia still contributes to morbidity/mortality in HIV infection despite effective combination antiretroviral therapy (cART). Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial (ESPRIT), a trial of intermittent recombinant interleukin-2 (rIL-2) with cART vs. cART alone (control arm) in HIV-infected adults with CD4 counts ≥300cells/μL, offered the opportunity to explore associations between bacterial pneumonia and rIL-2, a cytokine that increases the risk of some bacterial infections. METHODS Baseline and time-updated factors associated with first-episode pneumonia on study were analysed using multivariate proportional hazards regression models. Information on smoking/pneumococcal vaccination history was not collected. RESULTS IL-2 cycling was most intense in years 1-2. Over ≈7 years, 93 IL-2 [rate 0.67/100 person-years (PY)] and 86 control (rate 0.63/100 PY) patients experienced a pneumonia event [hazard ratio (HR) 1.06; 95% confidence interval (CI) 0.79, 1.42; P=0.68]. Median CD4 counts prior to pneumonia were 570cells/μL (IL-2 arm) and 463cells/μL (control arm). Baseline risks for bacterial pneumonia included older age, injecting drug use, detectable HIV viral load (VL) and previous recurrent pneumonia; Asian ethnicity was associated with decreased risk. Higher proximal VL (HR for 1 log(10) higher VL 1.28; 95% CI 1.11, 1.47; P

Udgivelsesdato: 2009-Jan-2 BACKGROUND: Cystatin C has been proposed as an alternative marker of renal function. We sought to determine whether participants randomized to episodic use of antiretroviral therapy guided by CD4 cell count (drug conservation) had altered cystatin C levels compared with those randomized to continuous antiretroviral therapy (viral suppression) in the Strategies for Management of Antiretroviral Therapy trial, and to identify factors associated with increased cystatin C. METHODS: Cystatin C was measured in plasma collected at randomization, 1, 2, 4, 8 and 12 months after randomization in a random sample of 249 and 250 participants in the drug conservation and viral suppression groups, respectively. Logistic regression was used to model the odds of at least 0.15 mg/dl increase in cystatin C (1 SD) in the first month after randomization, adjusting for demographic and clinical characteristics. RESULTS: At randomization, mean (SD) cystatin C level was 0.99 (0.26 mg/dl) and 1.01 (0.28 mg/dl) in the drug conservation and viral suppression arms, respectively (P = 0.29). In the first month after randomization, 21.8 and 10.6% had at least 0.15 mg/dl increase in cystatin C in the drug conservation and viral suppression arms, respectively (P = 0.0008). The difference in cystatin C between the treatment arms was maintained through 1 year after randomization. After adjustment, participants in the viral suppression arm had significantly reduced odds of at least 0.15 mg/dl increase in cystatin C in the first month (odds ratio 0.42; 95% confidence interval 0.23-0.74, P = 0.0023). CONCLUSION: These results demonstrate that interruption of antiretroviral therapy is associated with an increase in cystatin C, which may reflect worsened renal function.

Background In the general population, raised levels of inflammatory markers are stronger predictors of fatal than nonfatal cardiovascular disease ( CVD ) events. People with HIV have elevated levels of interleukin‐6 ( IL ‐6), high‐sensitivity C‐reactive protein (hs CRP ), and D‐dimer; HIV ‐induced activation of inflammatory and coagulation pathways may be responsible for their greater risk of CVD . Whether the enhanced inflammation and coagulation associated with HIV is associated with more fatal CVD events has not been investigated. Methods and Results Biomarkers were measured at baseline for 9764 patients with HIV and no history of CVD . Of these patients, we focus on the 288 that experienced either a fatal (n=74) or nonfatal (n=214) CVD event over a median of 5 years. Odds ratios ( OR s) (fatal versus nonfatal CVD ) (95% confidence intervals [ CIs ]) associated with a doubling of IL ‐6, D‐dimer, hs CRP , and a 1‐unit increase in an IL ‐6 and D‐dimer score, measured a median of 2.6 years before the event, were 1.39 (1.07 to 1.79), 1.40 (1.10 to 1.78), 1.09 (0.93 to 1.28), and 1.51 (1.15 to 1.97), respectively. Of the 214 patients with nonfatal CVD , 23 died during follow‐up. Hazard ratios (95% CI ) for all‐cause mortality were 1.72 (1.28 to 2.31), 1.73 (1.27 to 2.36), 1.44 (1.15 to 1.80), and 1.88 (1.39 to 2.55), respectively, for IL ‐6, D‐dimer, hs CRP , and the IL ‐6 and D‐dimer score. Conclusions Higher IL ‐6 and D‐dimer levels reflecting enhanced inflammation and coagulation associated with HIV are associated with a greater risk of fatal CVD and a greater risk of death after a nonfatal CVD event. Clinical Trial Registration URL: http://www.clinicaltrial.gov Unique identifier: SMART: NCT00027352, ESPRIT: NCT00004978, SILCAAT: NCT00013611.

Summary Background Travel is thought to be a risk factor for the acquisition of sexually transmitted infections (STIs), but no multicentre analyses have been done. We aimed to describe the range of diseases and the demographic and geographical factors associated with the acquisition of travel-related STIs through analysis of the data gathered by GeoSentinel travel medicine clinics worldwide. Methods We gathered data from ill travellers visiting GeoSentinel clinics worldwide between June 1, 1996, and Nov 30, 2010, and analysed them to identify STIs in three clinical settings: after travel, during travel, or immigration travel. We calculated proportionate morbidity for each of the three traveller groups and did logistic regression to assess the association between STIs and demographic, geographical, and travel variables. Findings Our final analysis was of 112 180 ill travellers—64 335 patients seen after travel, 38 287 patients seen during travel, and 9558 immigrant patients. 974 patients (0·9%) had diagnoses of STIs, and 1001 STIs were diagnosed. The proportionate STI morbidities were 6·6, 10·2, and 16·8 per 1000 travellers in the three groups, respectively. STIs varied substantially according to the traveller category. The most common STI diagnoses were non-gonococcal or unspecified urethritis (30·2%) and acute HIV infection (27·6%) in patients seen after travel; non-gonococcal or unspecified urethritis (21·1%), epididymitis (15·2%), and cervicitis (12·3%) in patients seen during travel; and syphilis in immigrant travellers (67·8%). In ill travellers seen after travel, significant associations were noted between diagnosis of STIs and male sex, travelling to visit friends or relatives, travel duration of less than 1 month, and not having pretravel health consultations. Interpretation The range of STIs varies substantially according to traveller category. STI preventive strategies should be particularly targeted at men and travellers visiting friends or relatives. Our data suggest target groups for pretravel interventions and should assist in post-travel screening and decision making. Funding US Centers for Disease Control and Prevention, and International Society of Travel Medicine.

Background: Despite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist. Methods: We performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1:1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls. Results: Cases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm3. Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively). Conclusions: In patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.

Udgivelsesdato: 2009-Sep-15 BACKGROUND: Activation and coagulation biomarkers were measured within the Strategies for Management of Antiretroviral Therapy (SMART) trial. Their associations with opportunistic disease (OD) in human immunodeficiency virus (HIV)-positive patients were examined. METHODS: Inflammatory (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], amyloid-A, and amyloid-P) and coagulation (D-dimer and prothrombin-fragment 1+2) markers were determined. Conditional logistic regression analyses were used to assess associations between these biomarkers and risk of OD. RESULTS: The 91 patients who developed an OD were matched to 182 control subjects. Patients with an hsCRP level > or =5 microg/mL at baseline had a 3.5 higher odds of OD (95% confidence interval [CI], 1.5-8.1) than did those with an hsCRP level or =3 pg/mL at baseline had a 2.4 higher odds of OD (95% CI, 1.0-5.4) than did those with an IL-6 level or =5 microg/mL (compared with a level or =6 mg/L (compared with a level or =3 pg/mL (compared with a level

Background and methodsThe SMART study compared 2 strategies for using antiretroviral therapy—drug conservation (DC) and viral suppression (VS)—in 5472 human immunodeficiency virus (HIV)–infected patients with CD4+ cell counts >350 cells/μL. Rates and predictors of opportunistic disease or death (OD/death) and the relative risk (RR) in DC versus VS groups according to the latest CD4+ cell count and HIV RNA level are reported ResultsDuring a mean of 16 months of follow-up, DC patients spent more time with a latest CD4+ cell count 400 copies/mL (71% vs. 28%) and had a higher rate of OD/death (3.4 vs. 1.3/100 person-years) than VS patients. For periods of follow-up with a CD4+ cell count ConclusionsThe higher risk of OD/death in DC patients was associated with (1) spending more follow-up time with relative immunodeficiency and (2) living longer with uncontrolled HIV replication even at higher CD4+ cell counts. Ongoing HIV replication at a given CD4+ cell count places patients at an excess risk of OD/death Trial registrationClinicalTrials.gov identifier: NCT00027352

Udgivelsesdato: 2008-Nov-12 BACKGROUND: Interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimen is often necessary, but must be performed with caution because NNRTIs have a low genetic barrier to resistance. Limited data exist to guide clinical practice on the best interruption strategy to use. METHODS: Patients in the drug-conservation arm of the Strategies for Management of Antiretroviral Therapy (SMART) trial who interrupted a fully suppressive NNRTI-regimen were evaluated. From 2003, SMART recommended interruption of an NNRTI by a staggered interruption, in which the NNRTI was stopped before the NRTIs, or by replacing the NNRTI with another drug before interruption. Simultaneous interruption of all antiretrovirals was discouraged. Resuppression rates 4-8 months after reinitiating NNRTI-therapy were assessed, as was the detection of drug-resistance mutations within 2 months of the treatment interruption in a subset (N = 141). RESULTS: Overall, 601/688 (87.4%) patients who restarted an NNRTI achieved viral resuppression. The adjusted odds ratio (95% confidence interval) for achieving resuppression was 1.94 (1.02-3.69) for patients with a staggered interruption and 3.64 (1.37-9.64) for those with a switched interruption compared with patients with a simultaneous interruption. At least one NNRTI-mutation was detected in the virus of 16.4% patients with simultaneous interruption, 12.5% patients with staggered interruption and 4.2% patients with switched interruption. Fewer patients with detectable mutations (i.e. 69.2%) achieved HIV-RNA of 400 copies/ml or less compared with those in whom no mutations were detected (i.e. 86.7%; P = 0.05). CONCLUSION: In patients who interrupt a suppressive NNRTI-regimen, the choice of interruption strategy may influence resuppression rates when restarting a similar regimen. NNRTI drug-resistance mutations were observed in a relatively high proportion of patients. These data provide additional support for a staggered or switched interruption strategy for NNRTI drugs.

Udgivelsesdato: 2008-Apr-15 BACKGROUND: The SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL to intermittent antiretroviral therapy (ART; the drug conservation [DC] group) versus continuous ART (the viral suppression [VS] group). In the DC group, participants started ART when the CD4+ cell count was or= 6 months (n=228) were analyzed. The following clinical outcomes were assessed: (i) opportunistic disease (OD) or death from any cause (OD/death); (ii) OD (fatal or nonfatal); (iii) serious non-AIDS events (cardiovascular, renal, and hepatic disease plus non-AIDS-defining cancers) and non-OD deaths; and (iv) the composite of outcomes (ii) and (iii). RESULTS: A total of 477 participants (228 in the DC group and 249 in the VS group) were followed (mean, 18 months). For outcome (iv), 21 and 6 events occurred in the DC (7 in ART-naive participants and 14 in those who had not received ART for >or= 6 months) and VS (2 in ART-naive participants and 4 in those who had not received ART for 6 months) groups, respectively. Hazard ratios for DC vs. VS by outcome category were as follows: outcome (i), 3.47 (95% confidence interval [CI], 1.26-9.56; p=.02); outcome (ii), 3.26 (95% CI, 1.04-10.25; p=.04); outcome (iii), 7.02 (95% CI, 1.57-31.38; p=.01); and outcome (iv), 4.19 (95% CI, 1.69-10.39; p=.002 ). CONCLUSIONS: Initiation of ART at CD4+ cell counts >350 cells/microL compared with

BACKGROUND: Episodic use of antiretroviral therapy guided by CD4+ cell counts is inferior to continuous antiretroviral therapy. OBJECTIVE: To determine whether reinitiating continuous antiretroviral therapy in patients who received episodic treatment reduces excess risk for opportunistic disease or death. DESIGN: Randomized, controlled trial. SETTING: Sites in 33 countries. PATIENTS: 5472 HIV-infected individuals with CD4(+) cell counts greater than 0.350 x 10(9) cells/L enrolled from January 2002 to January 2006. INTERVENTION: Episodic or continuous antiretroviral therapy initially, followed by continuous therapy in participants previously assigned to episodic treatment. MEASUREMENTS: Opportunistic disease or death was the primary outcome. RESULTS: Eighteen months after the recommendation to reinitiate continuous therapy, mean CD4+ cell counts were 0.152 x 10(9) cells/L (95% CI, 0.136 to 0.167 x 10(9) cells/L) less in participants previously assigned to episodic treatment (P > 0.001). The proportion of follow-up time spent with CD4+ cell counts of 0.500 x 10(9) cells/L or more and HIV RNA levels of 400 copies/mL or less was 29% for participants initially assigned to episodic therapy and 66% for those assigned to continuous therapy. Participants who reinitiated continuous therapy experienced rapid suppression of HIV RNA levels (89.7% with HIV RNA levels > or =400 copies/mL after 6 months), but CD4+ cell counts after 6 months remained 0.140 x 10(9) cells/L below baseline. The hazard ratio (episodic versus continuous treatment) for opportunistic disease or death decreased after the recommendation to reinitiate continuous therapy (from 2.5 [CI, 1.8 to 3.5] to 1.4 [CI, 1.0 to 2.0]; P = 0.033 for difference). The residual excess risk was attributable to failure to reinitiate therapy by some participants and slow recovery of CD4+ cell counts for those who reinitiated therapy. LIMITATION: Follow-up was too short to assess the full effect of switching from episodic t continuous antiretroviral therapy. CONCLUSION: Reinitiating continuous antiretroviral therapy in patients previously assigned to episodic treatment reduced excess risk for opportunistic disease or death, but excess risk remained. Episodic antiretroviral therapy, as used in the SMART study, should be avoided.