A 20-year Study of Intracranial Pyogenic Complications of Sinusitis in Children.

BACKGROUND: Intracranial pyogenic complications of sinusitis in children can lead to serious sequelae. We characterize the clinical, epidemiologic and microbiologic characteristics of children with such complications over a 20-year period. METHODS: Single-center retrospective chart review. Cases were identified based on International Classification of Diseases diagnostic codes (ICD)-9 and ICD-10 depending on the year and by reviewing all intracranial microbiological samples. RESULTS: A total of 104 cases of complicated sinusitis were included after review of 1591 charts. Median age was 12 (IQR 9-14); 72 were male (69%). The most frequent complications were epidural empyema (n = 50, 48%), subdural empyema (n = 46, 44%) and Pott's puffy tumor (n = 27, 26%). 52% (n = 54) underwent neurosurgery and 46% (n = 48) underwent otolaryngological surgery. The predominant pathogen isolated from sterile site specimens was Streptococcus anginosus (n = 40, 63%), but polymicrobial growth was common (n = 24; 38%). The median duration of intravenous antibiotic therapy was 51 days (IQR 42-80). Persistent neurological sequelae (or death, n = 1) were found in 24% (n = 25) and were associated with the presence of cerebritis and extensive disease on neuroimaging ( P = 0.02 and P = 0.04, respectively). CONCLUSIONS: Intracranial complications of sinusitis continue to cause significant morbidity in children. Polymicrobial infections are common, which reinforces the need for broad-spectrum empiric antibiotic therapy and cautious adjustment of the antibiotic regimen based primarily on sterile site cultures. The association of neurologic sequelae with the presence of cerebritis and extensive intracranial involvement on neuroimaging suggest that delayed diagnosis may be a contributor to adverse outcome.

A Prolonged Outbreak of Human Adenovirus A31 (HAdV-A31) Infection on a Pediatric Hematopoietic Stem Cell Transplantation Ward with Whole Genome Sequencing Evidence of International Linkages.

A surge in hematopoietic stem cell transplantation (HSCT) human adenovirus A31 (HAdV-A31) infections was initially observed in late 2014/2015 at SickKids (SK) Hospital, Toronto, Canada. In response, enhanced laboratory monitoring for all adenovirus infections was conducted. Positive samples underwent genotyping, viral culture, and, in selected cases, whole-genome sequencing (WGS). HAdV-A31 specimens/DNA obtained from four international pediatric HSCT centers also underwent WGS. During the SK outbreak period (27 October 2014 to 31 October 2018), 17/20 HAdV-A31 isolates formed a distinct clade with 0 to 8 mutations between the closest neighbors. Surveillance before and after the outbreak detected six additional HAdV-A31 HSCT cases; three of the four sequenced cases clustered within the outbreak clade. Two SK outbreak isolates were identical to sequences from two patients in an outbreak in England. Three SK non-outbreak sequences also had high sequence similarity to strains from three international centers. Environmental PCR testing of the HSCT ward showed significant adenovirus contamination. Despite intense infection control efforts, we observed re-occurrence of infection with the outbreak strain. Severe but nonfatal infection was observed more commonly with HAdV-A31 compared to other genotypes, except HAdV-C1. Our findings strongly implicate nosocomial spread of HAdV-A31 over 10 years on a HSCT unit and demonstrate the value of WGS in defining and mapping the outbreak. Close linkages among strains in different countries suggest international dissemination, though the mechanism is undetermined. This large, extended outbreak emphasizes the pre-eminent role of HAdV-A31 in causing intractable pediatric HSCT outbreaks of severe illness worldwide.

Assessment of panfungal PCR performance with formalin-fixed paraffin-embedded tissue specimens†.

We reviewed the performance of a panfungal ITS-2 PCR and Sanger sequencing assay performed on 88 FFPE specimens at The Hospital for Sick Children (Toronto, Canada) in 2019. A potential fungal pathogen was identified by ITS PCR in 62.7 and 2.9% of positive and negative direct slide examination of tissue specimens, respectively. ITS amplicons were detected in 87/88 specimens, with 53/88 (60.2%) considered as 'positive-contaminants' and 34/88 (38.6%) as 'positive-potential pathogen' upon sequencing. Potential pathogens included Blastomyces dermatitidis (17.1%), Cryptococcus neoformans (17.1%), Histoplasma capsulatum (14.3%) and Mucormycetes (11.4%). Laboratories should only perform ITS PCR on FFPE tissues if fungal elements have been confirmed on histopathology slides. LAY SUMMARY: In this study, we examined how well a DNA-based test could detect DNA from fungi in archived human biopsy tissues. The best performance was achieved if fungi were seen in the tissue under a microscope before being tested. Our results indicate that we should only use this test if these conditions are met.

Influenza Vaccine Effectiveness Among Patients With Cancer: A Population-Based Study Using Health Administrative and Laboratory Testing Data From Ontario, Canada.

PURPOSE: Seasonal influenza vaccination is recommended for patients with cancer despite concerns of disease or treatment-associated immunosuppression. The objective of this study was to evaluate vaccine effectiveness (VE) against laboratory-confirmed influenza for patients with cancer. PATIENTS AND METHODS: We conducted an observational test-negative design study of previously diagnosed patients with cancer 18 years of age and older who underwent influenza testing during the 2010-2011 to 2015-2016 influenza seasons in Ontario, Canada. We linked individual-level cancer registry, respiratory virus testing, and health administrative data to identify the study population and outcomes. Vaccination status was determined from physician and pharmacist billing claims. We used multivariable logistic regression to estimate VE, adjusting for age, sex, rurality, income quintile, cancer characteristics, chemotherapy exposure, comorbidities, previous health care use, influenza season, and calendar time. RESULTS: We identified 26,463 patients with cancer who underwent influenza testing, with 4,320 test-positive cases (16%) and 11,783 (45%) vaccinated. Mean age was 70 years, 52% were male, mean time since diagnosis was 6 years, 69% had solid tumor malignancies, and 23% received active chemotherapy. VE against laboratory-confirmed influenza was 21% (95% CI, 15% to 26%), and VE against laboratory-confirmed influenza hospitalization was 20% (95% CI, 13% to 26%). For patients with solid tumor malignancies, VE was 25% (95% CI, 18% to 31%), compared with 8% (95% CI, -5% to 19%) for patients with hematologic malignancies (P = .015). Active chemotherapy usage did not significantly affect VE, especially among patients with solid tumor cancer. CONCLUSION: Our results support recommendations for influenza vaccination for patients with cancer. VE was decreased for patients with hematologic malignancies, and there was no significant difference in VE among patients with solid tumor cancer receiving active chemotherapy. Strategies to optimize influenza prevention among patients with cancer are warranted.

The yield of monitoring adenovirus in pediatric hematopoietic stem cell transplant patients.

Human adenovirus (HAdV) is recognized as a serious pathogen after allogeneic hematopoietic stem cell transplantation (HSCT), causing morbidity and mortality. Currently, there is no universal agreement regarding routine HAdV surveillance after HSCT. We assessed the impact of HAdV weekly monitoring by polymerase chain reaction (PCR) on HAdV viremia rates and the risk factors that influence survival. Three-hundred and fifty-six pediatric allogeneic HSCT were done between 2007 and 2015. Until July 2011, HAdV testing was performed based on clinical suspicion (cohort 1, n = 175) and from August 2011, weekly blood-HAdV monitoring was done (cohort 2, n = 181) until day +100. Twenty-three patients (4 [2.3%] from cohort 1 and 19 [10.5%] from cohort 2, p = .001) were found with HAdV viremia and seven of them died. Both cohorts had a similar incidence of HAdV-associated mortality (3/175; 1.7% in cohort 1 and 4/181; 2.2% in cohort 2). Respiratory failure was the cause of death in all patients. Clinical symptoms appeared prior to or within 5 days of HAdV detection in cohort 2. In summary, weekly monitoring was associated with higher detection of HAdV. The study could not assess survival benefit due to small numbers of HAdV-positive cases. In many instances, symptoms occurred with the development of positive HAdV blood PCR results and hence, symptomatology could have triggered the test. Future studies are needed to provide data that help establishing a uniform approach for regular monitoring of HAdV post-transplant.

Adenovirus-Associated Central Nervous System Disease in Children.

OBJECTIVE: To characterize the spectrum and salient clinical features of adenovirus-associated neurologic disease in immunocompetent children. STUDY DESIGN: Previously healthy children (aged 1 month-18 years) with central nervous system (CNS) disease associated with adenovirus infection were identified via the Encephalitis Registry (1996-2016) and Microbiology Database (2000-2016) at The Hospital for Sick Children, Toronto, and by systematic review of the literature. The data were pooled and analyzed to identify the spectrum of illness, clinical outcome, and risk factors for death or neurologic impairment. RESULTS: Neurologic complications associated with adenovirus infection in our institution included febrile seizures, encephalitis, acute disseminated encephalomyelitis, and aseptic meningitis. A total of 48 immunocompetent children with adenovirus-associated CNS disease were included in the pooled analysis-38 from the literature and 10 from our institution. In 85% of cases, the virus was detected in the respiratory or gastrointestinal tract, but not the cerebrospinal fluid. Eighteen of the 48 (38%) patients either died or suffered permanent neurologic sequelae. Predictors of adverse outcome included younger age, coagulopathy, the absence of meningismus, serotype 2 virus, and the presence of seizures. After multivariable adjustment, only seizures remained a significant risk factor. CONCLUSION: Adenovirus is a rare cause of CNS disease in immunocompetent children. Disease spectrum is variable, ranging from mild aspetic meningitis and fully reversible encephalopathy to severe, potentially fatal, acute necrotizing encephalopathy.

Invasive Fusariosis: A Single Pediatric Center 15-Year Experience.

Invasive fungal infection (IFI) is an important cause of mortality in immunocompromised children, particularly after hematopoietic stem cell transplantation. We describe 5 cases of Fusarium IFI in immunocompromised children seen at our institution over a 15-year period. A summary of all published pediatric cases of invasive Fusarium infection is presented. A focus on antifungal management challenges in these patients will be discussed.

The yield of monitoring for HSV and VZV viremia in pediatric hematopoietic stem cell transplant patients.

Reactivation of HSV and VZV is common following HSCT. Consensus guidelines do not support the use of routine screening for viremia following HSCT in adults, but no such clear guidelines exist in pediatrics. In our center, routine practice was to screen patients weekly for HSV and VZV viremia until engraftment in autologous transplant patients and up to day +100 in allogeneic transplant patients. We conducted a retrospective study of over 500 patients to establish whether this screening identified any patients with HSV or VZV viremia who would not have been identified by clinical signs or symptoms. Over a 4.5-yr period, routine screening identified three cases of HSV viremia and one case of VZV viremia. Two patients had persistent, unexplained fever and two patients had skin or mucosal lesions suggestive of HSV/VZV. We conclude that routine screening for HSV and VZV viremia in pediatric HSCT patients has a very low yield and that viremia can be reliably identified by targeted testing in patients with vesicular skin lesions, oral or genital ulceration, unexplained fever, neurological symptoms, or unexplained abnormal liver transaminases.

Utility of gastric aspirates for diagnosing tuberculosis in children in a low prevalence area: predictors of positive cultures and significance of non-tuberculous mycobacteria.

BACKGROUND: In countries with low rates of tuberculosis (TB), yields of gastric aspirates (GAs) for Mycobacterium tuberculosis (MTB) culture are low. The significance of non-tuberculous mycobacteria (NTM) isolated from GA is uncertain. METHODS: We reviewed clinical, microbiologic and radiologic data for children who underwent GA between 1999 and 2011 at Sick Kids, Toronto. Radiologic features of cases were compared with those of age matched controls. RESULTS: 785 GAs were obtained from 285 patients of whom 20 (7%) had positive MTB cultures: in 15 patients the GA was the only positive culture for MTB. Of 15 culture-positive patients who underwent exactly 3 GAs, MTB was isolated from the first lavage in 10 (67%), only from the second in 3 (20%) and only from the third in 2 (13%). On univariate analysis, miliary disease and intrathoracic lymphadenopathy were associated with a positive GA MTB culture. On multiple conditional logistic regression analysis, adenopathy remained significant (OR 10.2 [95% CI 2.0-51.4] p =0.005). Twelve patients had NTM isolated, most commonly M. avium complex: none had evidence of invasive NTM disease during a median duration of 12 months of follow-up. Causal pathogens different from the GA NTM culture were isolated from biopsies or bronchoalveolar lavage in 3. CONCLUSIONS: GAs continue to be important for TB diagnosis in children. Three GAs have a yield better than 1. Those with miliary or disseminated TB and intrathoracic lymphadenopathy have highest yields. NTM isolates from GA are likely unimportant and can be clinically misleading.

Herpes simplex virus lymphadenitis: the elusive doppelganger in immunocompromised patients.

Herpes simplex virus has protean manifestations and is an important cause of morbidity in the immunocompromised host. We report a case of recurrent lymphadenopathy and rash in a patient with chronic lymphocytic leukemia. The elusive clinical diagnosis eventually required core biopsy of a lymph node with immunohistochemistry and confirmation by polymerase chain reaction. This case illustrates the challenging clinical and laboratory diagnosis of herpes simplex virus lymphadenitis and the need to maintain a high index of suspicion for infection when treating an immunocompromised patient with unusual and/or persistent symptoms.

Human metapneumovirus (hMPV) infection in children with cancer.

Human metapneumovirus (hMPV) has recently emerged as an important cause of lower respiratory tract infections in hospitalized children, causing severe pneumonia and respiratory failure among immunocompromised patients. We retrospectively examined 30 children diagnosed with cancer whose nasopharyngeal swabs were positive for hMPV by direct fluorescent testing over a 5-year period. In 16/30 (53.3%) children, infection was confined to the upper respiratory tract, whereas lower respiratory tract infection occurred in 46.7%. The median duration of respiratory illness was 6.5 days with a hospital admission rate of 66.6%. No mechanical ventilation was required because of hMPV infection. Bronchoalveolar lavage tested positive for hMPV in 1 patient requiring prolonged inhaled steroid and bronchodilator therapy. All children recovered completely from hMPV infection. hMPV causes upper and lower respiratory tract infections in immunocompromised children. Infections may result in significant disease but is usually not fatal. In the absence of specific anti-viral drug, good symptomatic therapy appears to be the optimal therapy.

Role of respiratory viruses in pulmonary exacerbations in children with cystic fibrosis.

BACKGROUND: The role of respiratory viruses in cystic fibrosis (CF) exacerbations is incompletely understood. METHODS: Cross-sectional study of CF children with a pulmonary exacerbation. Mid-turbinate swabs were tested by a direct immunofluorescent antibody assay and a multiplex PCR panel (ResPlex II v2.0, Qiagen). Resplex II was also applied to sputum or throat swab samples. Pulmonary function tests and quality of life and severity scores were recorded. Sputum cell counts, bacterial density and cytokines were measured. RESULTS: 26/43 (60.5%) subjects tested positive for at least one respiratory virus by any diagnostic method applied to any sample type. Virus-positive patients were younger (p=0.047), more likely to be male (p=0.029), and had higher CF clinical severity (p=0.041) and lower quality of life (physical) scores (p=0.023) but similar IL-8, neutrophil percentage and elastase levels. CONCLUSIONS: Compared to non-viral exacerbations, viral-related exacerbations were associated with worse severity and quality of life scores but similar pulmonary inflammation.

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.

HISTORIQUE: La caspofongine est un antifongique de la classe des échinocandines souvent utilisée de manière empirique chez les patients immunodéficients très vulnérables à une maladie fongique envahissante. OBJECTIF: Les auteurs visaient à décrire les caractéristiques cliniques des infections fongiques perthérapeutiques chez des receveurs de greffe de cellules souches hématopoïétiques (GCSH) ou des patients traités en oncologie ou en hématologie qui prennent de la caspofongine. MÉTHODOLOGIE: Les auteurs ont procédé à l'analyse rétrospective de tous les dossiers après avoir repéré les cas d'infection fongique filamenteuse envahissante démontrés grâce aux dossiers de microbiologie d'enfants hospitalisés au Hospital for Sick Children sur une période de cinq ans, entre 2004 et 2008. Une infection perthérapeutique est définie comme l'apparition de nouveaux symptômes qui sont ultérieurement attribués à une infection à champignon envahissante, laquelle se manifeste à compter du troisième jour suivant le début du traitement à la caspofongine. RÉSULTATS: Six cultures positives confirmées (Aspergillus fumigatus [deux cas], Aspergillus niger, Fusarium oxysporum, Alternaria infectoria et Rhizomucor pusillus) respectaient les critères d'infection fongique filamenteuse perthérapeutique pendant un traitement à la caspofongine. Les troubles d'immunodéficience sous-jacents incluaient la leucémie lymphoblastique aiguë (deux cas), la leucémie myéloïde aiguë (deux cas), le lymphome de Burkitt et l'anémie aplastique. Quatre patients ont reçu une GCSH. Tous les patients ont reçu un produit d'amphotéricine B en formulation lipidique dans le cadre du traitement de l'infection perthérapeutique. Cinq patients ont également reçu du voriconazole et un, du posaconazole. Quatre des six cas sont décédés et deux ont répondu à un traitement clinique et microbiologique. EXPOSÉ: Il existe peu de descriptions d'infections fongiques perthérapeutiques chez les patients d'âge pédiatrique qui prennent de la caspofongine. Les six cas, tous confirmés par examen microbiologique, représentent probablement une fraction du total des infections fongiques envahissantes perthérapeutiques possibles tout au long de la période de l'étude. CONCLUSION: Les cliniciens doivent savoir que des infections fongiques perthérapeutiques causées par des espèces qui ne sont pas éradiquées par un antifongique précis, y compris la caspofongine, se produisent bel et bien et peuvent s'associer à une issue sombre.

Candida bracarensis bloodstream infection in an immunocompromised patient.

Candida bracarensis is a recently described Candida species which is phenotypically similar to Candida glabrata. A case of C. bracarensis bloodstream infection in a bone marrow transplant patient is described and confirms this organism as an opportunistic human pathogen. The organism can be distinguished from C. glabrata by its white color on CHROMagar and by DNA sequence analysis using D1/D2 and internal transcribed spacer (ITS) primers.

Utility of peripheral blood cultures in bacteremic pediatric cancer patients with a central line.

PURPOSE: The utility of peripheral blood cultures in febrile neutropenic children with cancer and central venous catheters (CVC) is controversial. Our primary objective was to describe true bloodstream infections detected only by peripheral culture. Our secondary objectives were to describe true bloodstream infections detected only by CVC culture and to describe probable contaminants detected in both types of blood cultures. METHODS: We included children with cancer who had peripheral and CVC cultures obtained on the same day in which at least one culture was positive. Only cultures obtained prior to the initiation of broad-spectrum antibiotics were included. We defined true bloodstream infections due to common contaminants (such as coagulase-negative Staphylococcus) as occurring if multiple cultures were positive for the same organism or if sepsis was present. RESULTS: Between January 2002 and July 2007, 318 episodes of bloodstream infection from 224 children were included. Of these, 228/318 (71.7%) were classified as true bloodstream infections while 90/318 (28.3%) were classified as contaminants. Importantly, 28/228 (12.3%) true bloodstream infections were detected only in peripheral culture while 85/228 (37.3%) true bloodstream infections were detected only by CVC cultures. Contaminants were identified in peripheral culture in 45/318 (14.2%) of episodes and in CVC culture in 45/318 (14.2%) episodes. CONCLUSIONS: True bloodstream infections frequently are only detected in the peripheral culture. These data support continuation of the practice of routine peripheral cultures in addition to CVC cultures at the onset of fever for children with cancer who are not already receiving broad-spectrum antibiotics.

Molecular identification of phaeohyphomycosis due to Alternaria infectoria in a patient with acute myeloid leukemia--a case report.

We report the case of a 15-year old with acute myeloid leukemia who developed breakthrough invasive fungal rhinitis. The fungus was identified as Alternaria infectoria by polymerase chain reaction (PCR) and successfully treated by surgical excision and combination antifungal therapy, emphasizing the utility of fungal PCR in timely diagnosis of invasive fungal infections.

Risk factors for infection-related outcomes during induction therapy for childhood acute lymphoblastic leukemia.

BACKGROUND: The primary objective was to describe microbiologically documented infections during induction therapy for acute lymphoblastic leukemia. The secondary objectives were to describe risk factors for microbiologically documented infections and for patients with a febrile episode, to identify risk factors for recurrence of fever or reinitiation of antibiotics. METHODS: This study was a retrospective review of children from 1 to 18 years of age who received induction chemotherapy between March 1997 and September 2006. Microbiologically documented infections were examined through the induction period. RESULTS: There were 425 children evaluated. The most common pre-existing risk factor for infection was Down syndrome in 11 children. Of the 425 children, 83 (19.5%) experienced at least one microbiologically documented infection. There were 85 infections consisting of 65 bacterial, 15 viral and 5 fungal infections.Variables significantly associated with a microbiologically documented infection were pre-existing risk factors (odds ratio [OR]: 3.63; P = 0.01) and neutropenia at initial infectious episode (OR: 1.86; P = 0.03). Factors associated with recurrence of fever and reinitiation of antibiotics after an initial infectious episode were receipt of a 4-drug induction, neutropenia at the initial infectious episode, initial fever documented in hospital, and lack of bone marrow recovery at the time of initial antibiotic cessation. CONCLUSIONS: About 20% of children with acute lymphoblastic leukemia have a microbiologically documented infection during induction. Those with pre-existing risk factors and neutropenia at the initial infectious episode were at higher risk of microbiologically documented infection. Continued efforts to refine risk groups may allow for risk-directed prophylactic or empiric strategies.

Comparison of human metapneumovirus infection with respiratory syncytial virus infection in children.

We aimed to validate a direct immunofluorescence assay (DFA) for the detection of human metapneumovirus (hMPV) from nasal swabs and to determine the incidence and clinical features of this viral infection in a pediatric population. One hundred twenty-one of 3026 nasal swabs were positive for hMPV by DFA (4.0%). Compared with reverse transcriptase polymerase chain reaction, the sensitivity and specificity of DFA were 90%, and 100%, respectively. Compared with RSV, hMPV infection was more common in children with congenital abnormalities, particularly those with cardio-pulmonary dysplasia and was associated with an increased ventilatory requirement.