Assessment of the duration of protection in Campylobacter jejuni experimental infection in humans.

A human Campylobacter jejuni infection model provided controlled exposure to assess vaccine efficacy and investigate protective immunity for this important diarrheal pathogen. A well-characterized outbreak strain, C. jejuni 81-176, was investigated using a volunteer experimental infection model to evaluate the dose range and duration of protection. Healthy Campylobacter-seronegative adults received C. jejuni strain 81-176 via oral inoculation of 10(5), 10(7), or 10(9) CFU (5 adults/dose), which was followed by clinical and immunological monitoring. Based on dose range clinical outcomes, the 10(9)-CFU dose (n = 31) was used to assess homologous protection at 28 to 49 days (short-term veterans [STV]; n = 8) or 1 year (long-term veterans [LTV]; n = 7) after primary infection. An illness dose effect was observed for naïve subjects (with lower doses, 40 to 60% of the subjects were ill; with the 10(9)-CFU dose, 92% of the subjects were ill) along with complete protection for the STV group and attenuated illness for the LTV group (57%). Partial resistance to colonization was seen in STV (25% of the subjects were not infected; 3-log-lower maximum excretion level). Systemic and mucosal immune responses were robust in naïve subjects irrespective of the dose or the severity of illness. In contrast, in STV there was a lack of circulating antibody-secreting cells (ASC), reflecting the local mucosal effector responses. LTV exhibited comparable ASC responses to primary infection, and anamnestic fecal IgA responses likely contributed to self-resolving illness prior to antibiotic treatment. Campylobacter antigen-dependent production of gamma interferon by peripheral blood mononuclear cells was strongly associated with protection from illness, supporting the hypothesis that TH1 polarization has a primary role in acquired immunity to C. jejuni. This study revealed a C. jejuni dose-related increase in campylobacteriosis rates, evidence of complete short-term protection that waned with time, and immune response patterns associated with protection.

beta-Blocker use in long-term dialysis patients: association with hospitalized heart failure and mortality.

BACKGROUND: beta-Blockers have been shown to be beneficial in the treatment and prevention of heart failure (HF) in the general population, but they have not been assessed for their association with nonfatal HF in a nationally representative population of long-term dialysis patients. METHODS: We conducted a retrospective cohort study of 2550 patients enrolled in the US Renal Data System (USRDS) Wave 2 who were Medicare eligible at the start of the study. Analysis was stratified by the presence or absence of a known diagnosis of HF, and patients followed up until December 31, 2000. Cox regression analysis, including propensity scores, was used to model adjusted hazard ratios for beta-blocker use (assessed separately by cardioselective activity and lipid solubility) with time to the first Medicare institutional claim for HF, cardiovascular-related death, or death from any cause. RESULTS: In patients without a previous history of HF, beta-blocker use was significantly associated with a lower adjusted risk of HF (adjusted hazard ratio, 0.69; 95% confidence interval, 0.52-0.91; P=.008), with a similar reduction in risk of cardiac-related and all-cause death. beta-Blocker use had no statistically significant associations with outcomes in patients with previous HF. CONCLUSIONS: In dialysis patients without a previous documented history of HF, beta-blocker use was associated with a lower risk of new HF, cardiovascular death, and death from any cause. No such associations were seen for dialysis patients with a previous history of HF. These results are hypothesis generating only and should be confirmed in randomized trials.

Safety, tolerability, and lack of antibody responses after administration of a PfCSP DNA malaria vaccine via needle or needle-free jet injection, and comparison of intramuscular and combination intramuscular/intradermal routes.

Introduction of a new vaccine requires choosing a delivery system that provides safe administration and the desired level of immunogenicity. The safety, tolerability, and immunogenicity of three monthly 2.5-mg doses of a PfCSP DNA vaccine were evaluated in healthy volunteers as administered intramuscularly (IM) by needle, IM by jet injection (Biojector or IM/intradermally (ID) by jet injection. Vaccine administration was well-tolerated. Adverse events were primarily mild and limited to the site of injection (98%). Jet injections (either IM or ID) were associated with approximately twice as many adverse events per immunization as needle IM, but nevertheless were strongly and consistently preferred in opinion polls taken during the study. No volunteers had clinically significant biochemical or hematologic changes or detectable anti-dsDNA antibodies. In conclusion, the injection of Plasmodium falciparum circumsporozoite (PfCSP) DNA vaccine appeared to be safe and well-tolerated when administered by any of the three modes of delivery. However, despite improved antibody responses following both jet injection and ID delivery in animal models, no antibodies could be detected in volunteers by immunofluorescence antibody test (IFAT) or enzyme-linked immunosorbent assay (ELISA) after DNA vaccination.

Survival by time of day of hemodialysis: analysis of United States Renal Data System Dialysis Morbidity and Mortality Waves III/IV.

BACKGROUND: Whether morning shift hemodialysis is associated with improved survival in comparison to patients receiving afternoon shift hemodialysis has not been shown for a representative sample of US chronic hemodialysis patients. METHODS: We conducted a historical cohort study of a national database (US Renal Data System Dialysis Morbidity and Mortality Waves III/IV) of 6,939 patients who started hemodialysis therapy from January 1, 1990, through December 31, 1993. Patients were followed up through April 9, 2000, and censored at the time of change to a different modality, including transplantation. We estimated the adjusted hazard ratio for all-cause mortality based on the time of day of hemodialysis (0500 to 1200 for morning shift, 1200 to 1800 for afternoon shift, 1800 to midnight for evening shift). Cox regression analysis was used to adjust for other factors associated with survival. RESULTS: For patients aged 60 years and older, the unadjusted 4-year survival rate for patients on morning shift hemodialysis was 28.8% versus 24.1% for patients on afternoon shift hemodialysis and 38.7% for patients on evening shift hemodialysis (P < 0.01 by log-rank test for both versus afternoon shift hemodialysis). Both morning shift (adjusted hazard ratio, 0.90; 95% confidence interval [CI], 0.83 to 0.98; P = 0.02) and evening shift hemodialysis (adjusted hazard ratio, 0.62; 95% CI, 0.48 to 0.80; P < or = 0.001) were independently associated with a lower risk for mortality compared with afternoon shift hemodialysis. No such differences were seen for patients younger than 60 years. Both morning shift and evening shift hemodialysis were independently associated with improved survival compared with afternoon shift hemodialysis in elderly chronic hemodialysis patients. No such association was found for younger patients.

Heart failure as a cause for hospitalization in chronic dialysis patients.

BACKGROUND: Risk factors for heart failure (HF) have not been reported previously in a nationally representative sample of dialysis patients. METHODS: We conducted a historic cohort study of 1,995 patients enrolled in the US Renal Data System Dialysis Morbidity and Mortality Study Wave 2 who were Medicare eligible at the study start and were followed up until December 31, 1999, or receipt of a renal transplant. Cox regression analysis was used to model associations with time to first hospitalization for both recurrent and de novo HF (International Classification of Diseases, Ninth Revision code 428.x), defined as patients with and without a history of HF, respectively. RESULTS: The incidence density of HF was 71/1,000 person-years. Angiotensin-converting enzyme inhibitors and beta-blockers were each used in less than 25% of patients with a known history of HF. A history of coronary heart disease was associated with an increased total risk for HF, as were hemodialysis (versus peritoneal dialysis), aspirin use, and a history of diabetes. However, hemodialysis and aspirin use were the only factors associated with both de novo and recurrent HF. Widened pulse pressure was associated with de novo HF. The mortality rate after HF was 83% at 3 years (adjusted hazard ratio for mortality, 2.10; 95% confidence interval, 1.80 to 2.45; P < 0.0001). CONCLUSION: In chronic dialysis patients, hemodialysis and aspirin use were associated with increased risk for both total and de novo HF. Hospitalized HF was associated with a significantly increased risk for death.

Arteriovenous fistula use and heart disease in long-term elderly hemodialysis patients: analysis of United States Renal Data System Dialysis Morbidity and Mortality Wave II.

BACKGROUND: There are some concerns that arteriovenous fistula (AVF) use or other dialysis specific factors may exacerbate cardiovascular disease in long-term hemodialysis (HD) patients. METHODS: We performed a historical cohort study of the United States Renal Data System Dialysis Morbidity and Mortality Wave II study, limited to 993 patients who started HD in 1996 with valid information on vascular access and who were primarily eligible for Medicare at the start of the study. We assessed the association between hemodialysis vascular access and heart disease, defined as Medicare Claims for heart failure (HF, International Classification of Diseases (ICD9) code 428.x) and acute coronary syndromes (ACS, ICD9 code 410.x and 411.x). Cox proportional hazards regression (using propensity analysis) was used to model adjusted hazard ratios (AHR) for the association between patients factors and heart disease after dialysis. RESULTS: The rate of HF per 100 person years at risk (PYAR) was 19.6 among AVF users, 25.7 among patients using polytetrafluoroethylene grafts (grafts), and 31.1 among patients using temporary catheters. Corresponding rates of ACS were 8.2 among AVF users, 11.0 among users of grafts, and 12.4 among users of temporary catheters. In Cox Regression analysis, there was no significant association between AVF use and either HF or ACS. This lack of association was consistent across gender, diabetes, race, and age. CONCLUSIONS: We found that AVF use had no significant association with the incidence of HF or ACS. We conclude that use of AVF by 60 days after the start of dialysis is not associated with an increased risk of later non-fatal cardiovascular outcomes in long-term hemodialysis patients.

Scleroderma at end stage renal disease in the United States: patient characteristics and survival.

BACKGROUND: The patient characteristics and mortality associated with scleroderma have not been characterized for a national sample of end stage renal disease (ESRD) patients. METHODS: 364,317 patients in the United States Renal Data System initiated on ESRD therapy between 1 January 1992 and 30 June 1997 with valid causes of ESRD were analyzed in an historical cohort study of scleroderma. RESULTS: Of the study population, 820 (0.22%) had scleroderma. The mean age of patients with scleroderma was 56.38 +/- 13.93 years vs. 60.48 +/- 16.51 years for patients with other causes of ESRD (p<0.01 by Student's t-test). In histogram analysis, there were two age peaks: 45-49 and 65-69. In logistic regression, patients with scleroderma, compared to patients with other causes of ESRD, were significantly more likely to be women, Caucasian, younger, and more likely to have congestive heart failure but less likely to have ischemic heart disease, stroke, and receive predialysis erythropoietin. The unadjusted two-year survival of patients with scleroderma during the study period was 49.3% vs. 63.8% in all other patients (adjusted hazard ratio, 1.96, 95% CI 1.70-2.26, p=0.0001 by Cox Regression). CONCLUSIONS: Among patients with ESRD, the demographics of patients with scleroderma were similar to those of patients with scleroderma in the general population. Patients with scleroderma had decreased survival compared to patients with other causes of ESRD, despite being equally likely to be wait listed and receive renal transplantation adjusted for other factors.

HIVAN and medication use in chronic dialysis patients in the United States: analysis of the USRDS DMMS Wave 2 study.

BACKGROUND: The use and possible effects of factors known to improve outcomes in patients with human immunodeficiency virus associated nephropathy (HIVAN), namely of angiotensin converting enzyme inhibitors (ACE) and antiretroviral therapy, has not been reported for a national sample of dialysis patients. METHODS: We conducted a historical cohort study of the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave 2 to identify risk factors associated with increased mortality in these patients. Data were available for 3374 patients who started dialysis and were followed until March 2000. Cox Regression analysis was used to model adjusted hazard ratios (AHR) with HIVAN as a cause of end stage renal disease (ESRD) and its impact on mortality during the study period, adjusted for potential confounders. RESULTS: Of the 3374 patients who started dialysis, 36 (1.1%) had ESRD as a result of HIVAN. Only 22 (61%) of patients with HIVAN received antiretroviral agents, and only nine patients (25%) received combination antiretroviral therapy, and only 14% received ACE inhibitors. Neither the use of multiple antiretroviral drugs (AHR, 0.62, 95% CI, 0.10, 3.86, p = 0.60), or ACE inhibitors were associated with a survival advantage. Patients with HIVAN had an increased risk of mortality (adjusted hazard ratio, 4.74, 95% Confidence Interval, 3.12, 7.32, p < 0.01) compared to patients with other causes of ESRD. CONCLUSIONS: Medications known to improve outcomes in HIV infected patients were underutilized in patients with HIVAN. Adjusted for other factors, a primary diagnosis of HIVAN was associated with increased mortality compared with other causes of ESRD.

Atrial fibrillation in chronic dialysis patients in the United States: risk factors for hospitalization and mortality.

BACKGROUND: The incidence and risk factors for hospitalized atrial fibrillation have not been previously assessed in a national population of dialysis patients. METHODS: We analyzed the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave II in a historical cohort study of hospitalized atrial fibrillation. Data from 3374 patients who started dialysis in 1996 with valid follow-up times were available for analysis, censored at the time of renal transplantation and followed until November 2000. Cox Regression analysis was used to model factors associated with time to first hospitalization for atrial fibrillation (ICD9 code 427.31x) adjusted for comorbidities, demographic factors, baseline laboratory values, blood pressures, dialysis modality, and cardioprotective medications. RESULTS: The incidence density of atrial fibrillation was 12.5/1000 person years. Factors associated with atrial fibrillation were older age (> or = 71 years vs. <48 years), extremes (both high and low) of pre-dialysis systolic blood pressure, dialysis modality (hemodialysis vs. peritoneal dialysis), and digoxin use. Baseline use of coumadin was associated with reduced mortality in patients later hospitalized for atrial fibrillation. CONCLUSIONS: Dialysis patients had a high incidence of atrial fibrillation. This risk was largely segregated among those with established risk factors for atrial fibrillation, and hemodialysis patients. Use of coumadin was associated with improved survival among patients later hospitalized for atrial fibrillation.

Incident acute coronary syndromes in chronic dialysis patients in the United States.

BACKGROUND: Patients on dialysis have a disproportionately high rate of cardiovascular disease (CVD). However, the incidence and risk factors for incident acute coronary syndromes (ACS) have not been previously assessed in dialysis patients. METHODS: We analyzed the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave II in a historical cohort study of ACS. Data from 3374 patients who started dialysis in 1996 with valid follow-up times were available for analysis, censored at the time of renal transplantation and followed until March 2000. Cox regression analysis was used to model factors associated with time to first hospitalization for ACS (ICD9 code 410.x or 411.x) adjusted for comorbidities, demographic factors, baseline laboratory values, blood pressures and cholesterol levels, type of vascular access, dialysis adequacy, and cardioprotective medications (angiotensin-converting enzyme inhibitors, calcium channel blockers, HMG-CoA reductase inhibitors (statins), beta blockers, and aspirin). Follow-up was 2.19 +/- 1.14 years. RESULTS: The incidence of ACS was 29/1000 person-years. Factors associated with ACS were older age, the extreme high and low ranges of serum cholesterol level, history of coronary heart disease (CHD), male gender, and diabetes. No cardioprotective medications including statins had a significant association with ACS in this study. However, medications known to reduce mortality after ACS were used in less than 50% of patients with known CHD at the start of the study, and statins were used in less than 10% of patients with CHD. CONCLUSIONS: Dialysis patients had similar risk factors for ACS compared to the general population. Cardioprotective medications were not associated with a significant benefit, possibly due to their striking underutilization in this at-risk population.

Body mass index, dialysis modality, and survival: analysis of the United States Renal Data System Dialysis Morbidity and Mortality Wave II Study.

BACKGROUND: The impact of obesity on survival in end-stage renal disease (ESRD) patients as related to dialysis modality (i.e., a direct comparison of hemodialysis with peritoneal dialysis) has not been assessed adjusting for differences in medication use, follow-up > or =2 years, or accounting for changes in dialysis modality. METHODS: We performed a retrospective cohort study of the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Wave II Study (DMMS) patients who started dialysis in 1996, and were followed until October 31 2001. Cox regression analysis was used to model adjusted hazard ratios (AHR) for mortality for categories of body mass index (BMI), both as quartiles and as > or =30 kg/m2 vs. lower. Because such a large proportion of peritoneal dialysis patients changed to hemodialysis during the study period (45.5%), a sensitivity analysis was performed calculating survival time both censoring and not censoring on the date of change from peritoneal dialysis to hemodialysis. RESULTS: There were 1675 hemodialysis and 1662 peritoneal dialysis patients. Among hemodialysis patients, 5-year survival for patients with BMI > or =30 kg/m2 was 39.8% vs. 32.3% for lower BMI (P < 0.01 by log-rank test). Among peritoneal dialysis patients, 5-year survival for patients with BMI >/=30 kg/m2 was 38.7% vs. 40.4% for lower BMI (P > 0.05 by log-rank test). In adjusted analysis, BMI > or = 30 kg/m2 was associated with improved survival in hemodialysis patients (AHR 0.89; 95% CI 0.81, 0.99; P= 0.042) but not peritoneal dialysis patients (AHR = 0.99; 95% CI, 0.86, 1.15; P= 0.89). Results were not different on censoring of change from peritoneal dialysis to hemodialysis. CONCLUSION: We conclude that any survival advantage associated with obesity among chronic dialysis patients is significantly less likely for peritoneal dialysis patients, compared to hemodialysis patients.

Two studies evaluating the safety and immunogenicity of a live, attenuated Shigella flexneri 2a vaccine (SC602) and excretion of vaccine organisms in North American volunteers.

We report the first community-based evaluation of Shigella flexneri 2a strain SC602, a live, oral vaccine strain attenuated by deletion of the icsA (virG) plasmid virulence gene, given at 10(4) CFU. The primary objectives of this trial were to determine the safety and immunogenicity of the vaccine and to determine the duration of colonization. Four of 34 volunteers experienced transient fevers, and three reported diarrhea during the first 3 days of the study. Half of the volunteers mounted a positive serum immunoglobulin A (IgA) response to S. flexneri lipopolysaccharide. All but one of the volunteers excreted the vaccine in their stools for 1 to 33 days, and this excretion was often intermittent. Data from the community-based study were supplemented with an inpatient trial in which three volunteers received 10(3) and nine received 10(4) CFU. All volunteers who received 10(3) CFU excreted SC602 and had an IgA antibody-secreting cell response. Two of these had a serum IgA response. Six of the nine volunteers who received 10(4) CFU excreted SC602. One vaccinee had a transient fever and two met the definition of diarrhea. Six volunteers that received 10(4) CFU had an antibody-secreting cell response, and four had a serum IgA response. SC602 has now been tested at 10(4) CFU in a total of 58 volunteers. The cumulative results of these clinical trials, reported here and previously (Coster et al., Infect. Immun. 67:3437-3443, 1999), have demonstrated that SC602 is a substantially attenuated candidate vaccine that can evoke protection against the most severe symptoms of shigellosis in a stringent human challenge model of disease.