Michael Hawkes

Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis

Objective:To determine the utility of angiopoietin-1 and angiopoietin-2 as potentially novel biomarkers of morbidity and mortality in patients with severe sepsis. Design:Multicenter longitudinal cohort study. Setting:Three tertiary hospital intensive care units in Hamilton, Ontario, Canada. Patients:A total of 70 patients with severe sepsis were enrolled within 24 hrs of meeting the inclusion criteria for severe sepsis and followed until day 28, hospital discharge, or death. Interventions:Clinical data and plasma samples were obtained at intensive care unit admission for all 70 patients and then daily for 1 wk and weekly thereafter for a subset of 43 patients. Levels of angiopoietin-1 and angiopoietin-2 in stored plasma samples were measured and compared with clinical characteristics, including the primary outcomes of 28-day mortality and morbidity measured by the Multiple Organ Dysfunction score. Measurements and Main Results:Lower angiopoietin-1 plasma levels (≤5.5 ng/mL) at admission were associated with increased likelihood of death (relative risk 0.49 [95% confidence interval of 0.25–0.98], p = .046). Lower angiopoietin-1 levels remained a significant predictor of 28-day mortality in a multiple logistic regression model (adjusted odds ratio of 0.282 [95% confidence interval of 0.086–0.93], p = .037). Analysis of serial data using linear mixed models confirmed that sepsis survivors had higher levels of angiopoietin-1 (p = .012) and lower daily levels of angiopoietin-2 (p = .022) than nonsurvivors. Furthermore, survivors had higher peak angiopoietin-1 levels (median 13 vs. 10 ng/mL, p = .019) and lower nadir angiopoietin-2 levels (median 2.8 vs. 6.2 ng/mL, p = .013) than nonsurvivors. A score incorporating angiopoietin-1 and angiopoietin-2 and three other markers of endothelial activation discriminated with high accuracy between fatal and nonfatal cases (c-index of 0.80 [95% confidence interval of 0.69–0.90], p < .001). Plasma levels of angiopoietin-2 correlated with clinical markers of organ dysfunction and molecular markers of endothelial cell activation. Conclusions:Angiopoietin-1 levels at admission and both angiopoietin-1 and angiopoietin-2 levels measured serially correlated with 28-day mortality in severe sepsis. Angiopoietin-2 levels also correlated with organ dysfunction/injury and a validated clinical sepsis score. These results suggest the use of angiopoietins as clinically informative biomarkers of disease severity and patient outcome in severe sepsis.

Advances in malaria diagnosis

Malaria is a leading cause of mortality worldwide and accurate diagnostic testing for malaria can potentially save an estimated 100,000 lives annually. New technologies have the potential to circumvent limitations of the traditional diagnostic method, light microscopy, which is labor intensive and requires considerable technician expertise. Immunochromatographic tests, which are easy to use in field conditions and relatively inexpensive, offer a potential solution to the problem of malaria overtreatment in resource-poor endemic countries. Assays based on the PCR are highly sensitive, can be used for unambiguous species identification and, thus, may increasingly complement or even replace light microscopy in developed countries. Experimental diagnostics using flow cytometry and mass spectrometry are currently under investigation for high-throughput screening.

Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria: a retrospective case-control study

Objective:To investigate the relationship among the angiopoietin–Tie-2 system, retinopathy, and mortality in children with cerebral malaria. Design:A case–control study of retinopathy-positive vs. retinopathy-negative children with clinically defined cerebral malaria. Setting:Queen Elizabeth Central Hospital in Blantyre, Malawi. Subjects:One hundred fifty-five children presenting with severe malaria and meeting a strict definition of clinical cerebral malaria (Blantyre Coma Score ⩽2, Plasmodium falciparum parasitemia, no other identifiable cause for coma) were included in the study. Interventions:None. Measurements and Main Results:Clinical and laboratory parameters were recorded at admission and funduscopic examinations were performed. Admission levels of angiopoietin-1, angiopoietin-2, and a soluble version of their cognate receptor were measured by enzyme-linked immunosorbent assay. We show that angiopoietin-1 levels are decreased and angiopoietin-2 and soluble Tie-2 levels are increased in children with cerebral malaria who had retinopathy compared with those who did not. Angiopoietin-2 and soluble Tie-2 were independent predictors of retinopathy (adjusted odds ratio [95% CI], angiopoietin-2, 4.3 [1.3–14.6], p = .019; soluble Tie-2, 9.7 [2.1–45.8], p = .004). Angiopoietin-2 and soluble Tie-2 were positively correlated with the number of hemorrhages, the severity or retinal whitening, and the extent of capillary whitening observed on funduscopic examination (p < .05 after adjustment for multiple comparisons). Angiopoietin-2 and soluble Tie-2 levels were elevated in children with cerebral malaria who subsequently died and angiopoetin-2 was an independent predictor of death (adjusted odds ratio: 3.9 [1.2–12.7], p = .024). When combined with clinical parameters, angiopoetin-2 improved prediction of mortality using logistic regression models and classification trees. Conclusions:These results provide insights into mechanisms of endothelial activation in cerebral malaria and indicate that the angiopoietin–Tie-2 axis is associated with retinopathy and mortality in pediatric cerebral malaria.

The epidemiology of juvenile onset recurrent respiratory papillomatosis derived from a population level national database.

To develop a national database of cases of juvenile onset recurrent respiratory papillomatosis (JoRRP) in Canada, to calculate trends in incidence and prevalence of JoRRP from January 1994 to December 2007 at the national and regional level, and to mathematically model the natural history of JoRRP.

Sensitivity of Rapid Influenza Diagnostic Testing for Swine-Origin 2009 A (H1N1) Influenza Virus in Children

BACKGROUND: The rapidly evolving pandemic of novel 2009 swine-origin influenza A (H1N1) virus (S-OIV) demands that accurate and practical diagnostics be urgently evaluated for their potential clinical utility. OBJECTIVE: To determine the diagnostic accuracy of a rapid influenza diagnostic test (RIDT) and direct fluorescent antibody (DFA) assay for S-OIV by using reverse-transcription polymerase chain reaction (RT-PCR) as the reference standard. METHODS: We prospectively recruited children (aged 0–17 years) assessed in the emergency department of a pediatric referral hospital and a community pediatric clinic for influenza-like illness between May 22 and July 25, 2009. RIDT (performed on-site) and DFA were compared with RT-PCR to determine their sensitivity and specificity for S-OIV. We also compared the sensitivity of RIDT for S-OIV to that for seasonal influenza over 2 preceding seasons. RESULTS: Of 820 children enrolled, 651 were from the emergency department and 169 were from the clinic. RIDT sensitivity was 62% (95% confidence interval [CI]: 52%–70%) for S-OIV, with a specificity of 99% (95% CI: 92%–100%). DFA sensitivity was 83% (95% CI: 75%–89%) and was superior to that of RIDT (P < .001). RIDT sensitivity for S-OIV was comparable to that for seasonal influenza when using DFA supplemented with culture as the reference standard. RIDT sensitivity for influenza viruses was significantly higher in children 5 years of age or younger (P = .003) and in patients presenting ≤2 days after symptom onset (P < .001). CONCLUSIONS: The sensitivity of RIDT for detection of S-OIV is higher than recently reported in mixed adult-pediatric populations but remains suboptimal.

Community-associated MRSA: Superbug at our doorstep

While the potential for a devastating influenza pandemic has captured the imagination of the medical community and the population at large, another epidemic is currently raging in the United States and has already made inroads in Canada.[1][1] Clones of community-associated methicillin-resistant

Sexual Violence toward Children and Youth in War-Torn Eastern Democratic Republic of Congo

Background The epidemic of gender-based violence in the Democratic Republic of the Congo (DRC) has garnered popular media attention, but is incompletely described in the medical literature to date. In particular, the relative importance of militarized compared to civilian rape and the impact on vulnerable populations merits further study. We describe a retrospective case series of sexual abuse among children and youth in eastern DRC. Methods Medical records of patients treated for sexual assault at HEAL Africa Hospital, Goma, DRC between 2006 and 2008 were reviewed. Information extracted from the chart record was summarized using descriptive statistics, with comparative statistics to examine differences between pediatric (≤18 yrs) and adult patients. Findings 440 pediatric and 54 adult sexual abuse cases were identified. Children and youth were more often assaulted by someone known to the family (74% vs 30%, OR 6.7 [95%CI 3.6–12], p<0.001), and less frequently by military personnel (13% vs 48%, OR 0.14 [95%CI 0.075–0.26], p<0.001). Delayed presentation for medical care (>72 hours after the assault) was more common in pediatric patients (53% vs 33%, OR 2.2 [95%CI 1.2–4.0], p = 0.007). Physical signs of sexual abuse, including lesions of the posterior fourchette, hymeneal tears, and anal lesions, were more commonly observed in children and youth (84% vs 69%, OR 2.3 [95%CI 1.3–4.4], p = 0.006). Nine (2.9%) pediatrics patients were HIV-positive at presentation, compared to 5.3% of adults (p = 0.34). Interpretation World media attention has focused on violent rape as a weapon of war in the DRC. Our data highlight some neglected but important and distinct aspects of the ongoing epidemic of sexual violence: sexual abuse of children and youth.

Nursing brain drain from India

In response to recent findings regarding migration of health workers out of Africa, we provide data from a survey of Indian nurses suggesting that up to one fifth of the nursing labour force may be lost to wealthier countries through circular migration.

Time course of juvenile onset recurrent respiratory papillomatosis caused by human papillomavirus.

Background: With the recent licensure of a new quadrivalent vaccine, many diseases caused by human papillomavirus (HPV) can now be prevented, including recurrent respiratory papillomatosis (RRP). The purpose of this study was to describe the burden and time course of juvenile onset RRP. Methods: A retrospective chart review was conducted of children with airway papillomatosis at the Hospital for Sick Children in Toronto, Canada, between 1994 and 2004. Statistical methods included descriptive statistics of the cohort, a repeated events survival model, and nonlinear modeling equations to describe the time course of illness. Results: Nine hundred twenty-six surgical procedures in 67 patients were identified through a review of surgical records. The median age at diagnosis was 3.2 years (range, 0.1–14.8 years) and the most common presenting symptom was hoarseness (75%). Adjuvant pharmacologic therapy (interferon or cidofovir) was used in 13 cases (19%). HPV types 6 or 11 were identified most commonly as the etiologic agent. Nonlinear modeling equations (exponential and quadratic) fit the observed data well, and were superior to linear models. Repeated events survival analysis identified significant prognostic variables: surgeon, adjuvant therapy, and anatomic score. A decision rule is presented that allows the time to next surgery to be predicted based on the previous surgery and the anatomic score. Conclusions: Most patients have a decelerating rate of debulking surgeries over time, well described by our nonlinear modeling equations. Factors affecting the time course of RRP include: intersurgeon variability, the extent and severity of papillomas at the time of laryngoscopy, and the use of adjuvant medical therapies.

Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria

Angiopoietin-1 is dysregulated in pediatric severe malaria, and targeting it prevents vascular dysfunction and death in a mouse model of cerebral malaria. Bolstering the host to beat malaria Cerebral malaria is a devastating disease associated with high death rates and brain injury despite the use of potent antimalarials. Understanding the role of the host response in determining the ability of the host to survive a severe malaria infection may enable development of host-based therapeutics to prevent infection-induced death. Higgins et al. now demonstrate how the loss of a key host vascular protective protein, angiopoietin-1, is associated with severe and fatal malaria in children and in a mouse model. Administering angiopoietin-1 to mice with cerebral malaria reinforced the blood-brain barrier and improved survival, even when initiated late in disease. Cerebral malaria is a leading cause of global morbidity and mortality. Interventions targeting the underlying pathophysiology of cerebral malaria may improve outcomes compared to treatment with antimalarials alone. Microvascular leak plays an important role in the pathogenesis of cerebral malaria. The angiopoietin (Ang)–Tie-2 system is a critical regulator of vascular function. We show that Ang-1 expression and soluble Tie-2 expression were associated with disease severity and outcome in a prospective study of Ugandan children with severe malaria and in a preclinical murine model of experimental cerebral malaria. Ang-1 was necessary for maintenance of vascular integrity and survival in a mouse model of cerebral malaria. Therapeutic administration of Ang-1 preserved blood-brain barrier integrity and, in combination with artesunate treatment, improved survival beyond that with artesunate alone. These data define a role for dysregulation of the Ang–Tie-2 axis in the pathogenesis of cerebral malaria and support the evaluation of Ang–Tie-2–based interventions as potential adjunctive therapies for treating severe malaria.