BACKGROUND AND OBJECTIVE:Reltecimod, a CD 28 T-lymphocyte receptor mimetic, inhibits T-cell stimulation by an array of bacterial pathogens. A previous phase 2 trial demonstrated improved resolution ...of organ dysfunction after NSTI. We hypothesized that early administration of reltecimod would improve outcome in severe NSTI.
METHODS:Randomized, double-blind, placebo-controlled trial of single dose reltecimod (0.5 mg/kg) administered within 6 hours of NSTI diagnosis at 65 of 93 study sites. Inclusionsurgical confirmation of NSTI and organ dysfunction modified Sequential Organ Failure Assessment Score (mSOFA) score ≥3. Primary analysis was modified Intent-to-Treat (mITT), responder analysis using a previously validated composite endpoint, necrotizing infection clinical composite endpoint, defined asalive at day 28, ≤3 debridements, no amputation beyond first operation, and day 14 mSOFA ≤1 with ≥3 point reduction (organ dysfunction resolution). A prespecified, per protocol (PP) analysis excluded 17 patients with major protocol violations before unblinding.
RESULTS:Two hundred ninety patients were enrolled, mITT (Reltecimod 142, Placebo 148)mean age 55 ± 15 years, 60% male, 42.4% diabetic, 28.6% perineal infection, screening mSOFA mean 5.5 ± 2.4. Twenty-eight-day mortality was 15% in both groups. mITT necrotizing infection clinical composite endpoint success was 48.6% reltecimod versus 39.9% placebo, P = 0.135 and PP was 54.3% reltecimod versus 40.3% placebo, P = 0.021. Resolution of organ dysfunction was 65.1% reltecimod versus 52.6% placebo, P = 0.041, mITT and 70.9% versus 53.4%, P = 0.005, PP.
CONCLUSION:Early administration of reltecimod in severe NSTI resulted in a significant improvement in the primary composite endpoint in the PP population but not in the mITT population. Reltecimod was associated with improved resolution of organ dysfunction and hospital discharge status.
BACKGROUND
Necrotizing soft tissue infections (NSTIs) are an acute surgical condition with high morbidity and mortality. Timely identification, resuscitation, and aggressive surgical management have ...significantly decreased inpatient mortality. However, reduced inpatient mortality has shifted the burden of disease to long-term mortality associated with persistent organ dysfunction.
METHODS
We performed a combined analysis of NSTI patients from the AB103 Clinical Composite Endpoint Study in Necrotizing Soft Tissue Infections randomized-controlled interventional trial (ATB-202) and comprehensive administrative database (ATB-204) to determine the association of persistent organ dysfunction on inpatient and long-term outcomes. Persistent organ dysfunction was defined as a modified Sequential Organ Failure Assessment (mSOFA) score of 2 or greater at Day 14 (D14) after NSTI diagnosis, and resolution of organ dysfunction defined as mSOFA score of 1 or less.
RESULTS
The analysis included 506 hospitalized NSTI patients requiring surgical debridement, including 247 from ATB-202, and 259 from ATB-204. In both study cohorts, age and comorbidity burden were higher in the D14 mSOFA ≥2 group. Patients with D14 mSOFA score of 1 or less had significantly lower 90-day mortality than those with mSOFA score of 2 or higher in both ATB-202 (2.4% vs. 21.5%;
p
< 0.001) and ATB-204 (6% vs. 16%:
p
= 0.008) studies. In addition, in an adjusted covariate analysis of the combined study data sets D14 mSOFA score of 1 or lesss was an independent predictor of lower 90-day mortality (odds ratio, 0.26; 95% confidence interval, 0.13–0.53;
p
= 0.001). In both studies, D14 mSOFA score of 1 or less was associated with more favorable discharge status and decreased resource utilization.
CONCLUSION
For patients with NSTI undergoing surgical management, persistent organ dysfunction at 14 days, strongly predicts higher resource utilization, poor discharge disposition, and higher long-term mortality. Promoting the resolution of acute organ dysfunction after NSTI should be considered as a target for investigational therapies to improve long-term outcomes after NSTI.
LEVEL OF EVIDENCE
Prognostic/epidemiology study, level III
In a cohort of 1028 children and adolescents infected with human immunodeficiency virus type 1 (HIV-1), the use of combination therapy including protease inhibitors increased from 7 percent in 1996 ...to 73 percent in 1999. Over the four-year period, mortality declined from 5.3 percent to 0.7 percent. This analysis was adjusted for multiple potentially confounding variables; the authors estimate that the use of combination therapy including protease inhibitors in HIV-1–infected children reduces the risk of death by 67 percent.
The use of combination therapy reduces the risk of death by 67 percent.
The combination of human immunodeficiency virus (HIV)–specific protease inhibitors with nucleoside reverse-transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, or both has been demonstrated in adults to slow the progression of HIV type 1 (HIV-1) disease dramatically and to lower mortality.
1
,
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Recent studies provide some evidence of the efficacy and safety of these regimens in children and adolescents,
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–
6
but there is only limited evidence of reductions in mortality and morbidity.
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,
8
Current guidelines for the treatment of HIV infection in both adults and children recommend combination therapy including protease inhibitors.
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,
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We undertook the present study to estimate the effect of . . .
CONTEXT Combination anti-retroviral therapy or highly active antiretroviral therapy (HAART) has resulted in a dramatic decline in the incidence of opportunistic and other infections in human ...immunodeficiency virus (HIV)–infected adults and children. OBJECTIVES To estimate the incidence of 29 targeted opportunistic and other infections occurring in the era of HAART—between January 1, 2001, and December 31, 2004—in HIV-infected infants, children, and adolescents followed up in Pediatric AIDS Clinical Trials Group (PACTG) 219C; to compare incidence rates in the HAART era to those of the pre-HAART era; and to test for linear trends over time in the HAART era. DESIGN, SETTING, AND PARTICIPANTS Ongoing, multicenter, prospective cohort study designed to examine long-term outcomes in HIV-infected children. The study population included 2767 children enrolled between September 15, 2000, and December 31, 2004, with information entered in the database up to August 1, 2005, when data analysis was conducted. The pre-HAART era comparison population included 3331 children enrolled in 13 PACTG protocols from October 1988 to August 1998. MAIN OUTCOME MEASURES First occurrence of each of the 29 targeted infections. RESULTS Seventy-five percent of the children were enrolled in 2000 and 2001, 90% acquired HIV perinatally, 52% were girls, and 59% were black. The median age was 8.2 years (range, 6-13 years). The median duration of follow-up was 3.4 years. Overall, 553 first episodes of a specific infection occurred among 395 (14%) of the study participants. The number of events for the 4 most common first-time infections and their incidence rates (IRs) per 100 person-years were 123 bacterial pneumonia (IR, 2.15; 95% confidence interval CI, 1.79-2.56), 77 herpes zoster (IR, 1.11; 95% CI, 0.88-1.39), 57 dermatophyte infections (IR, 0.88; 0.67-1.14), and 52 oral candidiasis (IR, 0.93; 95% CI, 0.70-1.22). Incidence rates of first bacteremia, Pneumocystisjeroveci pneumonia, disseminated Mycobacteriumavium complex, lymphoid interstitial pneumonitis, systemic fungal infection, cytomegalovirus retinitis, and tuberculosis were all less than 0.50 per 100 person-years. There were no statistically significant linear trends in incidence for any of the 29 infections over the 4 calendar years. However, infection rates were significantly lower than those reported in the PACTG in the pre-HAART era. The pre-HAART IRs were as follows: for bacterial pneumonia, IR, 11.1; 95% CI, 10.3-12.0; bacteremia, IR, 3.3; 95% CI, 2.9-3.8; herpes zoster, IR, 2.9; 95% CI, 2.6-3.3; disseminated Mavium complex, IR, 1.8; 95% CI, 1.5-2.1; Pjeroveci, IR, 1.3; 95% CI, 1.1-1.6; oral candidiasis, IR, 1.2; 95% CI, 1.0-1.5; cytomegalovirus retinitis, IR, 0.5; 95% CI, 0.3-0.6; and tuberculosis, IR, 0.2; 95% CI, 0.1-0.4. CONCLUSIONS Opportunistic infections and other related infections are uncommon in children in the HAART era, and infection rates continue to be lower than those reported in the pre-HAART era. Continued surveillance is important to assess the long-term effect of HAART on the occurrence of opportunistic and other related infections in children.
To determine the role of Mycobacterium bovis in active pediatric tuberculosis (TB) in a United States-Mexico border region.
We reviewed all new cases of pediatric (<15 years old) TB presenting to San ...Diego hospitals and clinics from 1980 to 1997. Patients were categorized by age, ethnicity, country of origin, culture results, and disease manifestations. Case definitions were similar to those used by the Centers for Disease Control and Prevention. M bovis was distinguished from Mycobacterium tuberculosis by standard biochemical tests.
The median age of the 563 identified patients was 4.1 years old. The yearly incidence began rising in 1989 and peaked in the mid-1990s. Hispanics constituted 78.9% of the patients, but they were less likely to be foreign-born (21.6%) than were black children and Asian/Pacific Islanders. Overall, M bovis caused 10.8% of all TB during this period. Of the 180 patients with positive culture results, however, M bovis accounted for 33.9% and M tuberculosis 66. 1%. This high percentage of M bovis infections was largely attributable to its contribution to extrapulmonary TB (55.2% of all culture-positive specimens). M bovis patients were also even more likely to be Hispanic (90.2%), to present with extrapulmonary disease (95.1%), and to be older than 12 months (96.8%).
These data demonstrate the dramatic impact of this underappreciated cause of zoonotic TB on US children at the Mexican border and underscore the need for cross-collaboration to enforce existing Mexican pasteurization laws.
Once-daily losartan reduces BP in a dose-dependent manner and is well tolerated in hypertensive children aged 6-16 years. This study assessed the dose-response relationship, safety, and tolerability ...of losartan in hypertensive children aged 6 months to 6 years.
This was a 12-week, randomized, open-label, dose-ranging study, with a 2-year extension. Patients were randomized to losartan at the following dosages: 0.1 mg/kg per day (low), 0.3 mg/kg per day (medium), or 0.7 mg/kg per day (high). Losartan was titrated to the next dose level (to a 1.4 mg/kg per day maximum dosage, not exceeding 100 mg/d, which was not one of the three original doses offered at randomization) at weeks 3, 6, and 9 for patients who did not attain their goal BP and were not taking the highest dose. Dose response was evaluated by analyzing the slope of change in sitting systolic BP (SBP; primary end point) and diastolic BP (DBP; secondary end point) after 3 weeks compared with baseline. Adverse events (AEs) were recorded throughout.
Of the 101 patients randomized, 99 were included in the analysis (low dose, n=32; medium dose, n=34; and high dose, n=33). Mean sitting BP decreased from baseline in the low-, medium-, and high-dose groups by 7.3, 7.6, and 6.7 mmHg, respectively, for SBP and 8.2, 5.1, and 6.7 mmHg, respectively, for DBP after 3 weeks. No dose-response relationship was established by the slope analysis on SBP (P=0.75) or DBP (P=0.64). The BP-lowering effect was observed throughout the 2-year extension. The incidence of AEs was low and comparable between groups.
Hypertensive children aged 6 months to 6 years treated with losartan 0.1-0.7 mg/kg per day had clinically significant decreases from baseline in SBP and DBP, yet no dose-response relationship was evident. Losartan, at a dosage up to 1.4 mg/kg per day, was well tolerated.
Background. Trimethoprim-sulfamethoxazole (TMP-SMZ) has been used extensively for the prevention of Pneumocystis carinii (also referred to as “Pneumocystis jiroveci”) pneumonia (PCP) and other ...opportunistic infections in human immunodeficiency virus (HIV)—infected children. Because the efficacy of TMP-SMZ for treatment of bacterial infections is limited, it is sometimes poorly tolerated, and there is risk of emergence of drug-resistant strains associated with widespread use, we evaluated a regimen that included atovaquone and azithromycin. Methods. A randomized, double-blind, placebo-controlled trial was designed to determine whether atovaquone-azithromycin had equivalent efficacy to TMP-SMZ for the prevention of serious bacterial infections and to compare the long-term tolerance, PCP breakthrough rates, and nonserious bacterial infection rates among HIV-infected children aged 3 months to 19 years. Children qualified for PCP prophylaxis (on the basis of Centers for Disease Control and Prevention recommendations) were randomized to receive atovaquone-azithromycin or TMP-SMZ daily for ⩾2 years. Results. Data from 366 of the 369 eligible patients (median duration of follow-up, 3 years) showed that the estimated rates of serious bacterial infection—related events were lower among atovaquone-azithromycin recipients than among TMP-SMZ recipients (17.3 vs. 24.2 events per 100 patient-years; difference, 6.9 events per 100 patient-years; 95% confidence interval CI, -0.22 to 14.12). Rates for all end points (serious bacterial infection, PCP, Mycobacterium avium complex infection, and serious and nonserious bacterial infection—related deaths) were 19.7 and 27.7 events per 100 patient-years, respectively (difference, 7.9 events per 100 patient-years; 95% CI, -0.28 to 15.54 events per 100 patient-years). The results marginally favored atovaquone-azithromycin therapy statistically. Atovaquone-azithromycin and TMP-SMZ therapies had similar adverse event profiles. Conclusions. We conclude that, in HIV-infected children, atovaquone-azithromycin is as effective as TMP-SMZ for the prevention of serious bacterial infections and is similarly tolerated.
Opportunistic infections (OIs) are an important cause of morbidity and mortality in children infected with HIV. However, few data are available regarding the overall prevalence, incidence and ...immunologic correlates associated with these diseases in the pediatric HIV population. The Pediatric AIDS Clinical Trials Group (PACTG) has conducted multicenter studies in HIV-infected children since 1988 and through these studies has collected prospective data on the immunologic and virologic status of study participants and recorded complications, including infectious diseases, related to HIV infection and its treatments. Therefore data were analyzed from across 13 PACTG studies, performed before treatment with highly active antiretroviral therapy was given, to determine the rates of various infectious complications and the immunologic correlates, specifically CD4 cell counts, associated with these diseases.
OIs were tabulated from 3331 HIV-infected children who participated in 13 clinic trials undertaken before highly effective antiretroviral therapy was available. Five OIs occurred at event rates of >1.0 per 100 patient years (person years): serious bacterial infections, 15.1; herpes zoster, 2.9; disseminated Mycobacterium avium complex (DMAC), 1.8; Pneumocystis carinii pneumonia, 1.3; and tracheobronchial and esophageal candidiasis, 1.2. Six other OIs evaluated, cytomegalovirus (CMV) disease, cryptosporidiosis, tuberculosis, systemic fungal infections, toxoplasmosis and progressive multifocal leukoencephalopathy, occurred at event rates of <1.0 per 100 person years. Pneumonia (11.1 per 100 person years) and bacteremia (3.3 per 100 person years) were the most common bacterial infections. An AIDS-defining OI before entry was a risk factor for the development of a new OI during a trial. Bacterial infections, herpes zoster and tuberculosis occurred frequently at all stages of HIV infection; whereas DMAC, P. carinii pneumonia, CMV and other OIs occurred primarily in children with severe immunosuppression.
The frequency of OIs in HIV-infected children in the pre-highly active antiretroviral therapy era varies with age, pathogen, prior OI and immunologic status. Analysis of CD4 counts at the time of DMAC, CMV and PCP provide validation for current prophylaxis guidelines in children > or =2 years old. This information on infectious complications of pediatric HIV will be especially valuable for contemporary management of HIV infection that is poorly responsive to highly active antiretroviral therapy.
BACKGROUND:HIV-infected individuals mount poor antibody responses to vaccines. We sought to identify the immunologic and virologic factors associated with a robust response to hepatitis A virus (HAV) ...vaccine in children on highly active antiretroviral treatment.
METHODS:One hundred fifty-two pediatric highly active antiretroviral treatment recipients immunized against HAV at weeks 0 and 24 had anti-HAV antibodies, CD4+, CD8+, and CD19+ cell percent assessed at weeks 0 and 32. Subgroups had HIV viremia, B- and T-cell subpopulations, and cell-mediated immunity (CMI) to HAV and other stimulants measured.
RESULTS:Anti-HAV antibodies after complete vaccination correlated positively with CD4+ percent and CD19+ percent and negatively with viremia and CD8+ percent at baseline, but not at 32 weeks. There were no significant correlations between anti-HAV antibodies and B- or T-cell-naïve, memory, or activated subpopulations or non-HAV CMI. Compared with children who remained HAV-CMI-negative, those who mounted HAV-CMI in response to vaccination had higher anti-HAV antibody titers and CD19+ CD21+ CD27+ memory B cell percent at 32 weeks, but no other differences.
CONCLUSIONS:In HIV-infected children on highly active antiretroviral treatment, control of viral replication and conserved or reconstituted CD19+ and CD4+ cell numbers and function determine a robust antibody response to anti-HAV primary immunization. Our data support a bidirectional B- and T-cell cooperation in the response to the HAV vaccine.
There is limited evidence about longer-term effects of combination antiretroviral therapy that includes protease inhibitors (PIs) on the immunological status of HIV-1-infected children. Better ...understanding might help to resolve questions on when to initiate treatment.
The change in percentage of CD4-positive T lymphocytes (CD4%) was investigated in 1012 previously treated HIV-1-infected children (aged 0–17 years) who were enrolled in research clinics in the USA before 1996 and followed up to 2000. 702 started PI-based combination therapy. Data analyses ignored subsequent treatment changes.
Among the 1012 children, the median CD4% increased from 22% to 28% between 1996, when PIs were first prescribed, and 2000. For the 702 who started PI-based therapy, the mean CD4% increase after 3 years was largest among participants with the greatest immunosuppression (15·7%, 10·6%, 5·1%, and 2·0% for participants with CD4% before therapy of <5%, 5–14%, 15–24%, and ⩾25%; p<0·0001)· After adjustment for pre-PI CD4%, the mean increase was largest among the youngest participants (9·2%, 8·0%, and 4·3% for ages <5 years, 5–9 years, and ⩾10 years; p=0·001). However, only a minority of significantly immunocompromised participants (33%, 26%, and 49% of those with pre-PI CD4% of <5%, 5·14%, or 15·24%) achieved CD4% values above 25%, whereas 84% of those with pre-PI values above 25% maintained such values.
Although PI-based therapy was associated with substantial improvements in CD4%, initiation before severe immunosuppression and at younger ages may be more effective for recovery or maintenance of normal CD4%. Randomised investigation of when to start combination therapy in children, particularly infants, is needed.
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