Endothelial activation is associated with intestinal epithelial injury, systemic inflammation and treatment regimen in children living with vertically acquired HIV-1 infection.

BACKGROUND: Premature development of cardiovascular disease in children living with HIV-1 (CLWH) may be associated with compromised gut barrier function, microbial translocation, immune activation, systemic inflammation and endothelial activation. Biomarkers of these pathways may provide insights into pathogenesis of atherosclerotic disease in CLWH. METHODS: This was a cross-sectional study of CLWH enrolled in the multicentre Early Pediatric Initiation-Canadian Child Cure Cohort (EPIC4 ) who were on antiretroviral therapy (ART) with undetectable viral load. Plasma biomarkers of intestinal epithelial injury [intestinal fatty acid binding protein-1 (IFABP)], systemic inflammation [tumour necrosis factor (TNF) and interleukin-6 (IL-6)] and endothelial activation [angiopoietin-2 (Ang2), soluble vascular endothelial growth factor-1 (sVEGFR1) and soluble endoglin (sEng)] were quantified by enzyme-linked immunosorbent assay. Correlation and factor analysis of biomarkers were used to examine associations between innate immune pathways. RESULTS: Among 90 CLWH, 16% of Ang2, 15% of sVEGFR1 and 23% of sEng levels were elevated relative to healthy historic controls. Pairwise rank correlations between the three markers of endothelial activation were statistically significant (ρ = 0.69, ρ = 0.61 and ρ = 0.65, P < 0.001 for all correlations). An endothelial activation index, derived by factor analysis of the three endothelial biomarkers, was correlated with TNF (ρ = 0.47, P < 0.001), IL-6 (ρ = 0.60, P < 0.001) and intestinal fatty acid binding protein-1 (ρ = 0.67, P < 0.001). Current or past treatment with ritonavir-boosted lopinavir (LPV/r) was associated with endothelial activation (odds ratio = 5.0, 95% CI: 1.7-17, P = 0.0020). CONCLUSIONS: Endothelial activation is prevalent in CLWH despite viral suppression with combination ART and is associated with intestinal epithelial injury, systemic inflammation and treatment with LPV/r.

Breastfeeding by Women Living With Human Immunodeficiency Virus in a Resource-Rich Setting: A Case Series of Maternal and Infant Management and Outcomes.

The reduction in human immunodeficiency virus (HIV) transmission through breastmilk with maternal combination antiretroviral therapy (cART) has led many pregnant women living with HIV and healthcare providers to question exclusive formula feeding in resource-rich settings. Here, we describe cART prophylaxis in 3 breastfed infants whose mothers had sustained virologic suppression; all 3 of these infants remained uninfected.

Congenital anomalies following antenatal exposure to dolutegravir: a Canadian surveillance study.

OBJECTIVE: Dolutegravir is recommended worldwide as a first-line antiretroviral therapy (ART) for individuals living with HIV. A recent study reported increased rates of neural tube defects in infants of dolutegravir-treated women. This study examined rates of congenital anomalies in infants born to women living with HIV (WLWH) in Canada. DESIGN: The Canadian Perinatal HIV Surveillance Programme captures surveillance data on pregnant WLWH and their babies and was analysed to examine the incidence of congenital anomalies. SETTING: Paediatric HIV clinics. POPULATION: Live-born infants born in Canada to WLWH between 2007 and 2017. METHODS: Data on mother-infant pairs, including maternal ART use at conception and during pregnancy, are collected by participating sites. MAIN OUTCOME MEASURES: Congenital anomalies. RESULTS: Of the 2423 WLWH, 85 (3.5%, 95% CI 2.85-4.36%) had non-chromosomal congenital anomalies. There was no evidence of a significant difference in rates of congenital anomalies between women who were on ART in their first trimester (3.9%, CI 1.7-7.6%) or later in the pregnancy (3.9%, 95% CI 2.6-5.6%). Four of the 80 (5.0%, 95% CI 1.4-12.3%) neonates born to WLWH on dolutegravir during the first trimester had congenital anomalies, none were neural tube defects (95% CI 0.00-3.10%). CONCLUSION: Despite recent evidence raising a safety concern, this analysis found no signal for increased congenital anomalies. TWEETABLE ABSTRACT: Five percent of the infants of Canadian women living with HIV on dolutegravir at conception had congenital anomalies; none had neural tube defects.

Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium.

BACKGROUND: Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research. METHODS: In March 2012, the International Encephalitis Consortium, a committee begun in 2010 with members worldwide, held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study. RESULTS: We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed. CONCLUSIONS: We anticipate that this document, representing a synthesis of our discussions and supported by literature, will serve as a practical aid to clinicians evaluating patients with suspected encephalitis and will identify key areas and approaches to advance our knowledge of encephalitis.

Assessment of an infectious disease history preceding juvenile dermatomyositis symptom onset.

OBJECTIVES: A number of studies have looked at the role of infectious diseases in triggering juvenile dermatomyositis (JDM). Previous studies have found a moderately high frequency of infectious symptoms prior to disease onset; however, no specific pathogens could be identified. We sought to correlate preceding infectious symptoms with onset and outcomes of JDM. METHODS: We studied an inception cohort of all JDM cases diagnosed at The Hospital for Sick Children (SickKids) between 1988 and 2006. Data pertaining to symptoms at onset, diagnosis and disease outcomes were abstracted. Two independent paediatric infectious disease specialists reviewed all records of patients with symptoms or tests suggestive of infection. RESULTS: A total of 110 patients were reviewed; of these, 78 had sufficient information about disease onset for inclusion. Potential indications of an infectious process prior to JDM onset were found in 55/78 (71%) patients and were further evaluated for evidence of infection temporally associated with symptom onset. Features suggestive of infection prior to JDM symptom onset were found in 40/55 [probable (30/40) or possible (10/40)]. Most children with probable infections had respiratory illnesses [24/30 (80%)]. Fewer patients than expected had disease onset during summer months. The presence of an infection at onset was not found to be associated with differences in characteristics at diagnosis or disease outcomes. CONCLUSIONS: A substantial number of JDM patients have a clinical history consistent with an infection prior to onset. Newly diagnosed patients should undergo a full infectious disease assessment as part of their initial work-up; specific attention should be given to respiratory infections.

Acute childhood encephalitis and Mycoplasma pneumoniae.

In a prospective 5-year study of children with acute encephalitis, evidence of Mycoplasma pneumoniae infection was demonstrated in 50 (31%) of 159 children. In 11 (6.9%) of these patients, M. pneumoniae was determined to be the probable cause of encephalitis on the basis of its detection in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) or by positive results of serologic tests for M. pneumoniae and detection of the organism in the throat by PCR. CSF PCR positivity correlated with a shorter prodromal illness (P=.015) and lack of respiratory symptoms (P=.06). Long-term neurologic sequelae occurred in 64% of probable cases. Thirty children (18.9%) who were seropositive for M. pneumoniae but did not have the organism detected by culture or PCR had convincing evidence implicating other organisms as the cause of encephalitis, suggesting that current serologic assays for M. pneumoniae are not sufficiently specific to establish a diagnosis of M. pneumoniae encephalitis.

Measles inclusion-body encephalitis caused by the vaccine strain of measles virus.

We report a case of measles inclusion-body encephalitis (MIBE) occurring in an apparently healthy 21-month-old boy 8.5 months after measles-mumps-rubella vaccination. He had no prior evidence of immune deficiency and no history of measles exposure or clinical disease. During hospitalization, a primary immunodeficiency characterized by a profoundly depressed CD8 cell count and dysgammaglobulinemia was demonstrated. A brain biopsy revealed histopathologic features consistent with MIBE, and measles antigens were detected by immunohistochemical staining. Electron microscopy revealed inclusions characteristic of paramyxovirus nucleocapsids within neurons, oligodendroglia, and astrocytes. The presence of measles virus in the brain tissue was confirmed by reverse transcription polymerase chain reaction. The nucleotide sequence in the nucleoprotein and fusion gene regions was identical to that of the Moraten and Schwarz vaccine strains; the fusion gene differed from known genotype A wild-type viruses.

Stage-specific activity of pentavalent antimony against Leishmania donovani axenic amastigotes.

The standard treatment of human visceral leishmaniasis involves the use of pentavalent antimony (SbV) compounds. In recent years increasing numbers of clinical failures of treatment with SbV have been reported, probably due to the development of parasite resistance to this compound. The mode of action and mechanisms of resistance to SbV have not been fully elucidated. In the present study an axenic amastigote culture was used to study the in vitro responses of Leishmania donovani to SbV. Susceptibility to both sodium stibogluconate and meglumine antimoniate was found to be stage specific. Amastigotes were 73 to 271 times more susceptible to SbV than were promastigotes. As opposed to SbV, trivalent antimony (SbIII) was similarly toxic to both developmental stages. When promastigotes were transformed to amastigotes, susceptibility to meglumine antimoniate developed after 4 to 5 days, upon the completion of differentiation. In contrast, with transformation from amastigotes to promastigotes, resistance to meglumine antimoniate was acquired rapidly, within 24 h, before the completion of differentiation. The culture of promastigotes at an acidic pH (5.5) or at an elevated temperature (37 degrees C) alone did not lead to the appearance of SbV susceptibility, emphasizing the requirement of both these environmental factors for the development of SbV susceptibility. A previously isolated sodium stibogluconate (Pentostam)-resistant L. donovani mutant (Ld1S.20) is also resistant to meglumine antimoniate, indicating cross-resistance to SbV-containing compounds. In contrast, no cross-resistance was found with SbIII, suggesting a mechanism of SbV resistance different from that described in Leishmania tarentolae. These data show that L. donovani susceptibility to SbV is parasite intrinsic, stage specific, and macrophage independent.

Stachybotrys chartarum (atra) contamination of the indoor environment: Health implications.

In 1998, widespread contamination of water-damaged school portables with the toxigenic mold Stachybotrys chartarum was detected in the province of Ontario. This mold may cause human disease through direct irritation, type 1 hypersensitivity or the production of toxins. A variety of respiratory, dermatological, eye and constitutional symptoms have been associated with heavy and prolonged exposure to S chartarum. S chartarum has also been potentially implicated as a rare cause of idiopathic pulmonary hemorrhage in infants. Ingestion of food heavily contaminated with toxin-producing molds, including S chartarum, can cause bone marrow suppression and immunotoxicity. However, the level of toxin exposure that occurs following inhalation of S chartarum is very low; consequently, serious adverse health effects from such an exposure are extremely unlikely. In a child with symptoms felt to be temporally related to the school environment, an assessment of the child's school should be carried out by the public health authorities so that potential irritants and allergens can be identified. Avoidance of exposure is the most effective mode of therapy. Buildings found to be heavily contaminated with molds, particularly S chartarum, should undergo thorough cleaning and repair to remove the offending agent(s), and prevent further water damage and mold overgrowth.

Medical therapy of otitis media: use, abuse, efficacy, and morbidity.

OBJECTIVE: Otitis media (OM) is one of the most common paediatric disorders encountered by primary care physicians. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the principal pathogens responsible for OM. As a result of the increasing prevalence of antimicrobial resistance, the use of antimicrobial therapy in OM has come under close scrutiny. Amoxicillin remains the most appropriate option for initial empiric therapy of acute otitis media (AOM). The duration of therapy required for AOM depends on the age of the patient, the severity of disease, and the route of administration. In most cases, particularly in children older than 5 years of age, a 5-day course of antibiotic therapy should suffice. Antibiotic therapy is not required in most cases of otitis media with effusion (OME) and should be reserved for those with bilateral effusions persisting for longer than 3 months associated with significant hearing loss. Antibiotic prophylaxis for recurrent AOM should be minimized. Myringotomy with or without tympanostomy tube placement is an important therapeutic option in those with OME and recurrent AOM. Active immunization against S. pneumoniae and Influenza A is likely to play an increasingly important role in the prevention of OM.