Alison McGeer

Invasive group a streptococcal infections in Ontario, Canada

BACKGROUND Several reports suggest that the incidence of invasive group A streptococcal infections, including streptococcal toxic shock syndrome and necrotizing fasciitis, is increasing. METHODS During 1992 and 1993 we conducted prospective, population-based surveillance of invasive group A streptococcal disease in Ontario, Canada. We reviewed clinical and laboratory records, searched for secondary cases of invasive disease, and cultured specimens from household contacts. RESULTS We identified 323 patients with invasive group A streptococcal infections, for an annual incidence of 1.5 cases per 100,000 population. The rates were highest in young children and the elderly. Fifty-six percent of the patients had underlying chronic illness. Risk factors for disease included infection with the human immunodeficiency virus, cancer, diabetes, alcohol abuse, and chickenpox. The most common clinical presentations were soft-tissue infection (48 percent), bacteremia with no septic focus (14 percent), and pneumonia (11 percent). Necrotizing fasciitis occurred in 6 percent of patients, and toxic shock in 13 percent. The mortality rate was 15 percent overall, but it was 29 percent among those over 64 years of age (P<0.001) and 81 percent among those with toxic shock (P<0.001). Fourteen percent of the cases were nosocomial, and 4 percent occurred in nursing home residents, often in association with disease outbreaks. Invasive disease occurred in 2 household contacts of patients with infection, for an estimated risk of 3.2 per 1000 household contacts (95 percent confidence interval, 0.39 to 12 per 1000). CONCLUSIONS The elderly and those with underlying medical conditions are at greatest risk for invasive group A streptococcal disease, toxic shock, and necrotizing fasciitis. Invasive steptococcal infection is associated with a substantial risk of transmission in households and health care institutions.

Population-based active surveillance for neonatal group B streptococcal infections in Alberta, Canada: implications for vaccine formulation.

Background. Knowledge of circulating serotypes of group B Streptococcus (GBS) is important for formulation of vaccines. There are no Canadian data on the serotype distribution of neonatal GBS isolates. Methods. Using a retrospective laboratory and health record survey between 1993 and 1994 (before introduction of Canadian prevention guidelines) and prospective active laboratory-based surveillance from 1995 to 1999 of all laboratories in Alberta, we identified 168 cases of invasive neonatal GBS infections including stillbirths among 262 398 total births; 118 of 123 (96%) isolates from 1995 to 1999 were serotyped, and the corresponding neonatal health records were reviewed. Results. The average annual incidence was 0.64 of 1000 total births/year. Of these 95 (57%) had early onset disease (EOD), 15 (9%) were still births and 58 (34%) had late onset disease (LOD). Eighty-one percent of EOD cases were caused by serotypes Ia, Ia/c, Ia/c/R, III, III/R and V, V/R, whereas 81% of LOD cases were caused by serotypes III and III/R. GBS serotypes containing the C protein along with serotypes III and V as a group constituted 91% (107 of 118) of all GBS cases in our population. The most common clinical presentation was bacteremia without focus (74%) followed by meningitis (14%) and pneumonia (12%). During 1995 to 1999, in addition to 13 stillbirths, there were 6 of 64 (9%) neonatal deaths among EOD cases and 1 of 46 (2%) neonatal death among LOD cases. Conclusions. In this population-based study stillbirths account for a proportion of cases that are not routinely counted and represent a group for which intrapartum antibiotics would likely not be effective, but potentially preventable by vaccination. Inclusion of serotypes Ia, III and V in a conjugate vaccine or serotypes III and V conjugated with the C protein in a GBS vaccine could theoretically provide protection against the majority of GBS invasive disease in Alberta neonates.

Antibodies to Capsular Polysaccharides of Group B Streptococcus in Pregnant Canadian Women: Relationship to Colonization Status and Infection in the Neonate

In a cohort study of 1207 pregnant women in Alberta, Canada, the serotype distributions of vaginal-rectal group B Streptococcus (GBS) isolates were compared with all isolates from neonates with invasive GBS disease identified by population-based surveillance. Serum concentrations of Ia, Ib, II, III, and V capsular polysaccharide (CPS)-specific IgG also were determined, according to serotype of the vaginal-rectal colonizing GBS strain. GBS colonization was detected in 19.5% (235 of 1207) of women. Serotype III accounted for 20.6% (48 of 233) of colonizing strains available for typing but for 37% (27 of 73) of invasive isolates from neonates (P<.01). Maternal colonization with type III was least likely to be associated with moderate concentrations of III CPS-specific IgG. Serotype III GBS is more invasive than other serotypes in this population; this may be due, at least in part, to poor maternal type III CPS-specific antibody response.

Association of Human Leukocyte Antigen with Outcomes of Infectious Diseases: The Streptococcal Experience

The role of host genetic factors in determining susceptibility to infections has become more evident. Certain individuals appear to be predisposed to certain infections, whereas others are protected. By studying the immune response and the genetic makeup of susceptible and resistant individuals a better understanding of the disease process can be achieved. Infections caused by group A streptococci offer an excellent model to study host-pathogen interactions and how the host genetic variation can influence the infection outcome. These studies showed that the same clone of these bacteria can cause severe or non-severe invasive disease. This difference was largely related to the human leukocyte antigen class II type of the patient. Certain class II haplotypes present the streptococcal superantigens in a way that results in responses, whereas others present the same superantigens in a way that elicits very potent inflammatory responses that can lead to organ failure and shock. These findings underscore the role of host genetic factors in determining the outcome of serious infections and warrants further investigations into how the same or different genetic factors affect susceptibility to other emerging and re-emerging pathogens.

HIV-Associated Lymphoma of the Gastrointestinal Tract: The University of Toronto AIDS-Lymphoma Study Group Experience

We present a retrospective analysis of 31 (30 male) patients with HIV-associated gastrointestinal lymphoma which was undertaken to determine the natural history and response to therapy. Only seven patients had stage I or II lymphoma and 22 had stage IV. Pathology included diffuse large cell (13), immunoblastic (10), and small cell non-cleaved (7). The median age at presentation was 39 years (range 24-59), and the median CD4 count before treatment was 100/microL (range 4-1150). Eighty-seven percent of patients received systemic chemotherapy and significant response was seen in 84% (CR 38%; PR 46%). Hematologic toxicity was high (febrile neutropenia in 44% and dose reductions were required in 81%) and perforation occurred in five patients. Median survival for all patients was 6 months and death was secondary to lymphoma in 61%, treatment toxicity in 10%, other AIDS-related illnesses in 25% and other causes in 4%. Survival was shorter for patients with bone marrow involvement and for those with poor performance status. HIV-associated GI lymphoma has a poor prognosis despite good initial response to chemotherapy and is associated with a higher perforation rate than in HIV negative patients.

A Cluster of Surgical Wound Infections due to Unrelated Strains of Group A Streptococci

Group A streptococci account for less than 1% of all surgical wound infections but are an important cause of nosocomial outbreaks. We report here a cluster of four group A streptococcal infections that occurred within an 11-day period on a single surgical service. The index case presented with toxic shock-like syndrome. Epidemiologic investigation did not identify any relationship between infections. Restriction endonuclease analysis and M and T typing found the four isolates to be unrelated. Restriction endonuclease analysis is a useful tool for determining relatedness of nosocomial isolates of group A streptococci.

High-dose influenza vaccine to reduce clinical outcomes in high-risk cardiovascular patients: Rationale and design of the INVESTED trial

Background Influenza leads to significant cardiopulmonary morbidity and mortality—particularly in patients with cardiovascular disease—that may be prevented with a standard influenza vaccine. However, patients with cardiovascular conditions have a reduced immune response to influenza vaccine, potentially resulting in reduced effectiveness for preventing clinical events. High‐dose vaccine augments immune response in cardiac patients, suggesting that a high‐dose influenza vaccination strategy may further reduce morbidity and mortality. Alternatively, broader coverage with an influenza vaccine containing an increased number of viral strains is an alternative strategy without direct evaluation. Research design and methods INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated heart failure (INVESTED) is a pragmatic, randomized, double‐blind, parallel‐group, active‐controlled trial comparing the effectiveness of an annual vaccination strategy of high‐dose trivalent versus standard‐dose quadrivalent influenza vaccine in patients with a history of recent heart failure or myocardial infarction hospitalization. The trial will enroll approximately 9,300 patients over 4 influenza seasons. The primary hypothesis is that high‐dose influenza vaccine will reduce the composite outcome of all‐cause mortality and hospitalization from a cardiovascular or pulmonary cause compared with standard‐dose influenza vaccine within each enrolling season. Approximately 1,300 primary outcome events will provide >90% power to detect an 18% relative risk reduction at a 2‐sided &agr; level of .05. Conclusion INVESTED is the largest and longest study to assess whether high‐dose influenza vaccine is superior to standard‐dose influenza vaccine in reducing cardiopulmonary events in a high‐risk cardiovascular population (ClinicalTrials.gov Identifier: NCT02787044).

Kinetics of Serological Responses in Critically Ill Patients Hospitalized With 2009 Pandemic Influenza A(H1N1) Virus Infection in Canada, 2009–2011

Background The kinetics of the antibody response during severe influenza are not well documented. Methods Critically ill patients infected with 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09), confirmed by reverse-transcription polymerase chain reaction analysis or seroconversion (defined as a ≥4-fold rise in titers), during 2009-2011 in Canada were prospectively studied. Antibody titers in serially collected sera were determined using hemagglutinin inhibition (HAI) and microneutralization assays. Average antibody curves were estimated using linear mixed-effects models and compared by patient outcome, age, and corticosteroid treatment. Results Of 47 patients with A(H1N1)pdm09 virus infection (median age, 47 years), 59% had baseline HAI titers of <40, and 68% had baseline neutralizing titers of <40. Antibody titers rose quickly after symptom onset, and, by day 14, 83% of patients had HAI titers of ≥40, and 80% had neutralizing titers ≥40. Baseline HAI titers were significantly higher in patients who died compared with patients who survived; however, the antibody kinetics were similar by patient outcome and corticosteroid treatment. Geometric mean titers over time in older patients were lower than those in younger patients. Conclusions Critically ill patients with influenza A(H1N1)pdm09 virus infection had strong HAI and neutralizing antibody responses during their illness. Antibody kinetics differed by age but were not associated with patient outcome.