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1.  Correlates of illness severity in infectious mononucleosis 
Infectious mononucleosis is caused by Epstein-Barr virus and can lead to complications, including hepatitis and hematological abnormalities, in a subset of patients. The authors of this article assessed measures of illness severity as well as viral load at presentation and six weeks later among a cohort of individuals <25 years of age for the purpose of informing the management of patients with infectious mononucleosis.
INTRODUCTION:
Understanding the spectrum and frequencies of Epstein-Barr virus (EBV) complications and markers of illness severity in immunocompetent patients with primary EBV infection will inform management of patients with EBV-related illnesses.
OBJECTIVES:
To determine the clinical and laboratory correlates of illness severity among infants, children and youth with infectious mononucleosis (IM).
METHODS:
Study subjects with confirmed IM were prospectively enrolled. Illness severity was assessed at baseline and at six weeks using a scoring tool. Peripheral blood viral loads served as a measure of viral burden.
RESULTS:
Among 32 children and young adults with IM, the median age was 16 years (range two to 24 years). The predominant clinical findings were lymphadenopathy (23 of 32 [72%]), pharyngitis (16 of 32 [50%]), fever (nine of 32 [28%]) and splenomegaly (six of 32 [19%]). With respect to symptoms or signs that persisted to at least six weeks after illness onset, the predominant complaint was lymphadenopathy in 35% of subjects available for reassessment. Deranged liver function tests were present at presentation in up to 44% of subjects. Patients with the highest viral loads at presentation had significantly higher illness severity scores associated with fatigue (P=0.02). Other than the scores associated with fatigue, viral load values were not significantly correlated with the illness severity scores at baseline and at six weeks.
CONCLUSION:
In IM, viral loads are not necessarily correlated with illness severity, with the exception of fatigue. EBV-related hepatitis is common in IM, confirming the status of this virus as a relatively common cause of transient hepatitis in children and youth. This entity is not necessarily a marker of disease severity.
PMCID: PMC4211352  PMID: 25371691
Epstein-Barr virus; Hepatitis; Mononucleosis; Viral load
2.  Clostridium difficile in paediatric populations 
Paediatrics & Child Health  2014;19(1):43-48.
An increase in Clostridium difficile infection incidence has been observed among hospitalized children in the United States. The present statement, targeted at clinicians caring for infants and children in community and institutional settings, summarizes the relevant information relating to the role of C difficile in childhood diarrhea and provides recommendations for diagnosis, prevention and treatment. Significant differences between adult and paediatric risk factors and disease are discussed, along with emerging therapies. The relationship between age and disease severity in children with a newly emergent and more fluoroqinolone-resistant strain of C difficile (North American Pulse-field type-1 [NAP1]) remains unknown. The importance of antimicrobial stewardship as a preventive strategy is highlighted. This statement replaces a previous Canadian Paediatric Society position statement on C difficile published in 2000.
PMCID: PMC3938221  PMID: 24627655
CDI; Colitis; Diarrhea; Immunocompromise; Megacolon; Metronidazole; NAP1; Vancomycin
4.  Prevention and management of neonatal herpes simplex virus infections 
Paediatrics & Child Health  2014;19(4):201-206.
Human herpes simplex virus (HSV) infection in neonates can result in devastating outcomes, including mortality and significant morbidity. All infants are potentially at risk for neonatal HSV infection. This position statement reviews epidemiology, transmission and risk factors, with a focus on intrapartum infection. It considers diagnosis and prognosis according to infection category, along with testing modalities and limitations. Recommendations for managing newborns known to have been exposed intrapartum to HSV are based on expert opinion because a randomized trial to compare management options is not feasible. Guidance is provided for the empirical management of infants with suspected clinical sepsis, including those who do not respond to antibacterial therapy. The present statement replaces a 2006 position statement by the Canadian Paediatric Society.
PMCID: PMC4028647  PMID: 24855418
Acyclovir; CNS; Encephalitis; SEM; Sepsis
6.  The Use of Antiviral Drugs for Influenza: Recommended Guidelines for Practitioners 
The present document outlines current guidelines and supporting literature relating to the use of antiviral drugs for chemoprophylaxis and influenza illness therapy in paediatric and adult settings. The focus is on the management of influenza in interpandemic periods. Where appropriate, the areas in need of additional research are identified. It will be necessary to update aspects of these guidelines as new information emerges. The recommendations that follow represent the results of a joint effort supported by the Canadian Paediatric Society and the Association of Medical Microbiology and Infectious Disease Canada.
PMCID: PMC2095091  PMID: 18382639
Antiviral therapy; Influenza; M2 inhibitors; Neuraminidase inhibitors
7.  Medical decision analysis in infectious diseases 
Medical decision analysis (MDA) has played an important role in assisting infectious disease physicians make decisions associated with varying levels of complexity. Clinicians are often uncomfortable with some aspects of MDA, particularly when utilities are used as outcome measures. However, as the present paper outlines, MDA may use other outcome variables, including costs and disease complications. In this context, this explicit, reproducible analytic framework is an important tool in the area of infectious diseases, and is frequently applied to many situations, including cost effectiveness analyses, studies involving assessment of risks versus benefits of preventive and treatment strategies, and other situations. The objective of this paper is to assist infectious diseases clinicians to understand better the role of MDA in clinical practice. In this regard, the principles of MDA are reviewed and a common clinical example is used for illustrative purposes.
PMCID: PMC2094783  PMID: 18159308
Decision analysis; Infectious diseases
8.  Minimizing infection risks after paediatric organ transplants: Advice for practitioners 
Paediatrics & Child Health  2013;18(3):143-148.
Paediatric patients who have undergone an organ transplant face risks associated with different infectious diseases. Their susceptibility is increased by treatment with immunosuppressive medications. More of these patients are being cared for in community settings. This practice point provides guidance on key aspects in the prevention and treatment common infections.
PMCID: PMC3680288  PMID: 24421679
Antibiotics; Immunosuppression; Infection; Transplantation; Vaccines
10.  The use of antiviral drugs for influenza: Guidance for practitioners, 2012/2013; Paediatric summary 
Paediatrics & Child Health  2013;18(3):155-158.
This practice point summarizes the use of antiviral drugs to manage influenza illness in children and youth for the 2012/2013 season. It excerpts a recently published, full-length update of Canadian recommendations for clinicians on the use of antiviral drugs for the prevention and treatment of influenza, with a focus on paediatric antiviral therapy. Detailed information on the selective use of chemoprophylaxis can be found in the source document, which also highlights the importance of secondary bacterial infections (Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus and methicillin-resistant S aureus) in cases of severe influenza illness.
PMCID: PMC3680290  PMID: 24421680
Antiviral therapy; Children; Influenza; Neuraminidase inhibitors
12.  Cytomegalovirus infection in childhood-onset systemic lupus erythematosus 
Systemic lupus erythematosus (SLE) is a multisystem disease with significant morbidity and even mortality. Cytomegalovirus (CMV) is a ubiquitous herpesvirus that, similar to SLE, can also lead to significant morbidity and mortality in the immunocompromised host. The relationship between SLE and CMV is complex, with observations suggesting that CMV induces the autoimmunity of SLE in addition to occurring in the immunocompromised host with known SLE. In this article, we first consider CMV infection in the immunocompetent host, and further examine how this infection differs in the patient with SLE. We focus on disease mechanisms, CMV detection and treatment. We review the differences between CMV infection, syndrome and disease, as identifying the correct state will determine the appropriate treatment. We propose guidelines for the screening and management of CMV infection in childhood-onset SLE, and recognize that further study in this population is required to increase our understanding of the interplay between these disease entities.
doi:10.2217/ijr.12.82
PMCID: PMC3920748  PMID: 24527062
childhood; CMV; complication; Cytomegalovirus; detection; guidelines; infection; lupus; pediatric
13.  The use of antiviral drugs for influenza: Guidance for practitioners 2012/2013 
The present article addresses the use of antiviral drugs in the management of seasonal influenza illness for the 2012/2013 season. It updates the previous document published in 2011 (1). Noteworthy guidance updates since 2011 include the following: Seasonal influenza in 2012/2013 is predicted to be caused by two human influenza A and one influenza B strain, all of which are anticipated to remain generally susceptible to oseltamivir.The predicted strains are A/California/7/2009 (H1N1) pdm09-like, A/Victoria/361/2011 (H3N2)-like and B/Wisconsin/1/2010-like (Yamagata lineage). All are included in the seasonal influenza vaccine and are susceptible to oseltamivir.Swine-variant H3N2v, which has rarely caused infection in humans exposed to infected swine within the past year in the United States, is susceptible to oseltamivir. It is not included in the current seasonal influenza vaccine.It is still considered that initiation of antiviral therapy more than 36 h to 48 h after onset of symptoms is beneficial in patients hospitalized with complicated influenza and severe illness.Oseltamivir continues to be recommended for the treatment of influenza in pregnant women.The use of antiviral drugs among measures to control outbreaks of influenza in closed facilities such as correctional institutions is now included in the present document.
PMCID: PMC3597404  PMID: 24294283
14.  Breakthrough filamentous fungal infections in pediatric hematopoetic stem cell transplant and oncology patients receiving caspofungin 
BACKGROUND:
Caspofungin is an echinocandin class antifungal medication that is commonly used empirically in immunocompromised patients at high risk for invasive fungal disease.
OBJECTIVE:
To describe the clinical characteristics of breakthrough fungal infections in pediatric hematopoetic stem cell transplant recipients, and oncology and hematology patients receiving caspofungin.
METHODS:
A five-year retrospective review, from 2004 through 2008, of all cases of proven invasive filamentous fungal infection of children admitted to The Hospital for Sick Children (Toronto, Ontario) was conducted. A breakthrough infection was defined as new onset of symptoms that were later proven to be due to an invasive mold infection on day 3 or later after initiation of caspofungin therapy.
RESULTS:
Six confirmed positive cultures (Aspergillus fumigatus [two cases], Aspergillus niger, Fusarium oxysporum, Alternaria infectoria and Rhizomucor pusillus) met the criteria for breakthrough filamentous mold infection while on caspofungin therapy. Underlying immunocompromising conditions included acute lymphoblastic leukemia (two cases), acute myeloid leukemia (two cases), Burkitt’s lymphoma and aplastic anemia. Four of the patients underwent a hematopoetic stem cell transplant. All patients received a lipid amphotericin B product as part of their treatment for breakthrough infection. Five patients also received voriconazole and one received posaconazole. Four of the six patients died and two responded with a clinical and microbiological cure.
DISCUSSION:
There are few descriptions of breakthrough fungal infections in pediatric patients receiving caspofungin. The six cases presented here, all microbiologically proven, are likely only a fraction of the total number of possible breakthrough invasive fungal infections that occured over the study period.
CONCLUSION:
Clinicians must remain aware that breakthrough fungal infections by species not covered by particular antifungals, including caspofungin, do occur and may have poor outcomes.
PMCID: PMC3597394  PMID: 24294271
Breakthrough; Caspofungin; Fungal infection; Mold; Pediatric
15.  Incomplete Kawasaki disease associated with complicated Streptococcus pyogenes pneumonia: A case report 
A three-year-old boy presented with community-acquired pneumonia complicated by empyema. Streptococcus pyogenes (group A streptococcus) was identified on culture of the pleural fluid. The patient improved with antibiotic therapy and drainage of the empyema.
During his convalescence, the patient developed persistent fever, lethargy and anorexia. His inflammatory markers were elevated, and repeat cultures were negative. Although the patient had none of the classical mucocutaneous features of Kawasaki disease, an echocardiogram was performed, which revealed coronary artery dilation.
The patient was diagnosed with incomplete Kawasaki disease and treated with intravenous immunoglobulin and high-dose acetylsalicylic acid. The fever subsided within 48 h.
To the authors’ knowledge, the present report is the first report of Kawasaki disease associated with complicated S pyogenes pneumonia. It emphasizes the importance of considering incomplete Kawasaki disease among children with persistent fever, the role of echocardiography in diagnosis, and the potential link between Kawasaki disease and superantigen-producing organisms such as S pyogenes.
PMCID: PMC3476559  PMID: 23997782
Coronary arteritis; Group A streptococcus; Intravenous immunoglobulin; Kawasaki disease; Streptococcus pyogenes
16.  A retrospective cross-sectional study of risk factors and clinical spectrum of children admitted to hospital with pandemic H1N1 influenza as compared to influenza A 
BMJ Open  2012;2(2):e000310.
Objective
To compare risk factors for severe disease as measured by admission to hospital and intensive care unit (ICU) and other clinical outcomes in children with pandemic H1N1 (pH1N1) versus those with seasonal influenza.
Design
Retrospective analysis of children admitted to hospital with pH1N1 versus seasonal influenza A.
Setting
Canadian tertiary referral children's hospital.
Participants
All laboratory-identified cases of pH1N1 in children younger than 18 years admitted to hospital in 2009 (n=176) and all seasonal influenza A cases admitted to hospital from influenza seasons 2004–2005 to 2008–2009 (n=200). Children with onset of symptoms more than 3 days after admission were excluded.
Primary and secondary outcome measures
Primary outcomes include admission to hospital and ICU and need for mechanical ventilation. Secondary outcomes include length of stay in hospital and duration of supplemental oxygen requirement.
Results
Children admitted with pH1N1 were older than seasonal influenza A admissions (hospital admission: 6.5 vs 3.3 years, p<0.01; ICU admission: 7.3 vs 3.6 years, p=0.02). Children hospitalised with pH1N1 were more likely to have a pre-existing diagnosis of asthma (15% vs 5%, p<0.01); however, there was no difference in the severity of pre-existing asthma between the two groups. After controlling for obesity, asthma (OR 4.59, 95% CI 1.42 to 14.81) and age ≥5 years (OR 2.87, 95% CI 1.60 to 5.16) were more common risk factors in admitted children with pH1N1. Asthma was a significant predictor of the need for intensive care in patients with pH1N1 (OR 4.56, 95% CI 1.16 to 17.89) but not in patients with seasonal influenza A.
Conclusion
While most pH1N1 cases presented with classic influenza-like symptoms, risk factors for severe pH1N1 disease differed from seasonal influenza A. Older age and asthma were associated with increased admission to hospital and ICU for children with pH1N1.
Article summary
Article focus
Young age and underlying medical conditions have traditionally been considered risk factors for severe influenza in children.
Children admitted with pH1N1 influenza are more likely to have asthma; however, the impact of asthma severity is unknown.
Key messages
The presence of asthma and increased age, but not severity of asthma, were more common risk factors for hospitalisation with severe H1N1 influenza than with seasonal influenza A.
These results suggest that in future pandemics, certain high-risk groups may be more adversely affected than expected with seasonal influenza.
Treatment of pH1N1 influenza with oseltamivir did not appear to be associated with differing outcomes or severity of disease.
Strengths and limitations of this study
The strength of this study is that it compares a large number of children admitted with microbiologically confirmed pH1N1 to those admitted over 5 years with seasonal influenza A. For each admitted child with suspected asthma, at least two physicians reviewed the case to confirm a diagnosis of pre-existing asthma and to grade the asthma as mild, moderate or severe.
The main limitations of this study include its retrospective design, single-centre site, the inability to calculate population-based rates and that the number of admitted patients with asthma, particularly to ICU, was small.
doi:10.1136/bmjopen-2011-000310
PMCID: PMC3307038  PMID: 22411932
17.  Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study 
The Lancet infectious diseases  2010;10(8):521-526.
Summary
Background
There are few data on the epidemiology and outcomes of influenza infection in recipients of solid-organ transplants. We aimed to establish the outcomes of pandemic influenza A H1N1 and factors leading to severe disease in a cohort of patients who had received transplants.
Methods
We did a multicentre cohort study of adults and children who had received organ transplants with microbiological confirmation of influenza A infection from April to December, 2009. Centres were identified through the American Society of Transplantation Influenza Collaborative Study Group. Demographics, clinical presentation, treatment, and outcomes were assessed. Severity of disease was measured by admission to hospital and intensive care units (ICUs). The data were analysed with descriptive statistics. Proportions were compared by use of χ2 tests. We used univariate analysis to identify factors leading to pneumonia, admission to hospital, and admission to an ICU. Multivariate analysis was done by use of a stepwise logistic regression model. We analysed deaths with Kaplan-Meier survival analysis.
Findings
We assessed 237 cases of medically attended influenza A H1N1 reported from 26 transplant centres during the study period. Transplant types included kidney, liver, heart, lung, and others. Both adults (154 patients; median age 47 years) and children (83; 9 years) were assessed. Median time from transplant was 3.6 years. 167 (71%) of 237 patients were admitted to hospital. Data on complications were available for 230 patients; 73 (32%) had pneumonia, 37 (16%) were admitted to ICUs, and ten (4%) died. Antiviral treatment was used in 223 (94%) patients (primarily oseltamivir monotherapy). Seven (8%) patients given antiviral drugs within 48 h of symptom onset were admitted to an ICU compared with 28 (22.4%) given antivirals later (p=0.007). Children who received transplants were less likely to present with pneumonia than adults, but rates of admission to hospital and ICU were similar.
Interpretation
Influenza A H1N1 caused substantial morbidity in recipients of solid-organ transplants during the 2009–10 pandemic. Starting antiviral therapy early is associated with clinical benefit as measured by need for ICU admission and mechanical ventilation.
doi:10.1016/S1473-3099(10)70133-X
PMCID: PMC3045703  PMID: 20620116
18.  Public health implications of MRSA in Canada 
doi:10.1503/cmaj.060480
PMCID: PMC1490018  PMID: 16804119
19.  Response to a protease-inhibitor (ritonavir)-containing combination antiretroviral regimen in HIV-infected children 
INTRODUCTION:
The number of antiretroviral agents available for children who are failing existing therapy is limited. Data are lacking on the use of various combination regimens and the resulting viral load dynamics in such children.
METHODS:
Between March 1998 and March 2000, HIV-infected children younger than 18 years of age were studied in an open trial. The study regimen included ritonavir, with at least two drugs to which the virus was known or presumed to be sensitive. Subjects were ritonavir-naive and were included if they had high viral loads while receiving antiretroviral therapy. Patients had clinical assessments, CD4 counts and viral load monitoring.
RESULTS:
Fifteen antiretroviral-experienced HIV-infected children were enrolled. Approximately 87% (13 of 15) had perinatally-acquired HIV; median age was 7.9 years (range 1.6 to 14.8). At enrolment, the median CD4 count was 557 cells/mm3 (range 57 to 1702) and the median viral load was 72,600 copies/mL (range 3626 to 796,440). The majority of children (73.3%) had increases in CD4 counts within 12 weeks. During this period, the median increase in CD4 counts over baseline was 30.0%. Approximately 73% (eight of 11) of subjects with initial improvements in CD4 counts had sustained increases at 32 to 48 weeks. Over the first 12 weeks, 60% (nine of 15) had greater than 0.5 log10 decreases in viral load. The improvement was sustained in 88.9% (eight of nine) of these patients at 32 to 48 weeks. Three patients discontinued therapy due to taste aversion.
CONCLUSIONS:
Among pediatric patients with high viral loads while on existing therapy, the ritonavir-containing regimen was generally well tolerated. In a significant proportion of patients, modification of therapy was associated with sustained improvements in viral loads and CD4 counts over 32 to 48 weeks.
PMCID: PMC2094910  PMID: 18159430
Antiretroviral therapy; HIV infection; HIV viral load; Pediatrics; Protease inhibitor
20.  CHRIMCY: A major step in the right direction 
Paediatrics & Child Health  2000;5(4):201-202.
PMCID: PMC2817791  PMID: 20177518
21.  Pneumocystis prophylaxis for all, some, or no HIV-infected infants less than one year of age: A decision analysis approach 
Pneumocystis carinii pneumonia (PCP) is associated with significant mortality and morbidity among infants infected with human immunodeficiency virus (HIV). The preferred prophylaxis strategy for such infants is a subject of debate. Medical decision analysis was used to determine the preferred strategy for primary PCP prophylaxis among asymptomatic HIV-infected infants less than one year of age, and to determine the thresholds at which different variables influence decision making. Utility measures (health state preference values) were used to determine whether prophylaxis should be given to all, some or no infants. In this regard, some infants would receive prophylaxis if baseline CD4 counts are fewer than 1500 cells/mm3. The results suggest that the preferred option is to give prophylaxis to all asymptomatic HIV-infected infants despite CD4 counts, if the risk of PCP is equal to or greater than 25%. However, if the risk of PCP is less than 25%, prophylaxis is recommended for those infants with CD4 counts of fewer than 1500 cells/mm3. The results complement current guidelines regarding PCP prophylaxis for HIV-infected infants.
PMCID: PMC3250776  PMID: 22346469
Decision analysis; Pneumocystis; Prophylaxis
23.  Acute rheumatic fever: Findings of a hospital-based study and an overview of reported outbreaks 
To review the characteristics of reported outbreaks of acute rheumatic fever in the United States, and to determine if there is an increase in the incidence of acute rheumatic fever in the population served by the Hospital for Sick Children, Toronto, Ontario, the authors conducted a literature search and a retrospective review of inpatients and outpatients, satisfying the revised Jones criteria for the diagnosis of acute rheumatic fever, from 1972 to 1988. Patients satisfying the revised Jones criteria for the time period 1972–88 were included in the study. There have been eight articles reporting an increase in acute rheumatic fever in the United States. In three, the majority of children were white and from middle class suburban/rural communities in different geographic locations. Mucoid strains of group A streptococci were implicated but not confirmed as being associated with the outbreaks in three. The results of the chart review at the Hospital for Sick Children revealed that 83 cases satisfied the revised Jones criteria. The number of cases per 100,000 children (aged 18 years or less) per year, decreased progressively over the study period. Polyarthritis was the most frequently seen major criterion occurring in 73% of patients (61 of 83). The most frequently affected ethnic groups were Italians 23%, Afro-Canadians 19% and Orientals 8%. The reported outbreaks in the United States are multifocal and predominantly confined to white middle class children residing in suburban/rural communities. There was no evidence of an increase in the number of cases of acute rheumatic fever seen in the population served by the Hospital for Sick Children; there was a progressive decline in number of cases over the study period. The results facilitate the characterization of acute rheumatic fever within North America into three different patterns of occurrence.
PMCID: PMC3327974  PMID: 22553445
Acute rheumatic fever; Jones criteria; Outbreaks; Pharyngitis; Streptococcal infection

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