Sophie Cohen

A child with severe relapsing Kawasaki disease rescued by IL-1 receptor blockade and extracorporeal membrane oxygenation

Kawasaki disease (KD) is an acute inflammatory vasculitis that predominantly occurs in children under 5 years of age.1 It is associated with the development of coronary artery aneurysms (CAA) in 15–25% of untreated cases.2 Standard treatment consists of high-dose intravenous immunoglobulins (IVIG) along with aspirin.3 About 15% of patients do not respond to a single dose of IVIG and need retreatment.4 When ongoing signs of active disease are present, methylprednisolone pulses are often administered.5 If there is a lack of response, alternative anti-inflammatory medication such as infliximab or plasmapheresis have been suggested in individual case series.6 ,7 We report, for the first time, the beneficial use of an interleukin-1 receptor antagonist (IL-1RA) in relapsing KD. A 2-year-old boy was presented with persistent fever, coughing and swollen cervical lymph nodes. The boys condition had not improved with empirical antibiotic treatment. He developed a rash, conjunctivitis and swollen extremities. Upon admission the …

Severe malaria is associated with a deficiency of von Willebrand factor cleaving protease, ADAMTS13

Severe falciparum malaria remains a major killer in tropical countries. Central in the pathophysiology is mechanical obstruction in the microcirculation caused by cytoadherence and sequestration of parasitized erythrocytes. However, the pathogenesis of many features complicating severe malaria, including coma, renal failure and thrombocytopenia, remains incompletely understood. These disease manifestations are also key features of thrombotic thrombocytopenic purpura, a life-threatening disease strongly associated with a deficiency of the von Willebrand factor (VWF) cleaving protease, ADAMTS13. We measured plasma ADAMTS13 activity, VWF antigen and VWF propeptide levels in 30 patients with severe falciparum malaria, 12 patients with uncomplicated falciparum malaria and 14 healthy Bangladeshi controls. In patients with severe malaria ADAMTS13 activity levels were markedly decreased in comparison to normal controls (mean [95%CI]: 23% [20-26] vs. 64% [55-72]) and VWF antigen and propeptide concentrations were significantly elevated (VWF antigen: 439% [396-481] vs. 64% [46-83]; VWF propeptide: 576% [481-671] vs. 69% [59-78]). In uncomplicated malaria VWF levels were also increased compared to healthy controls but ADAMTS13 activity was normal. The results suggest that decreased ADAMTS13 activity in combination with increased VWF concentrations may contribute to the complications in severe malaria.

Poorer cognitive performance in perinatally HIV-infected children versus healthy socioeconomically matched controls

BACKGROUND Despite the declining incidence of severe neurological complications such as HIV encephalopathy, human immunodeficiency virus (HIV) infection in children is still associated with a range of cognitive problems. Although most HIV-infected children in industrialized countries are immigrants with a relatively low socioeconomic status (SES), cognitive studies comparing HIV-infected children to SES-matched controls are lacking. METHODS This cross-sectional study included perinatally HIV-infected children and controls matched for age, sex, ethnicity, and SES, who completed a neuropsychological assessment evaluating intelligence, information processing speed, attention, memory, executive function, and visual-motor function. Multivariate normative comparison was used to assess the prevalence of cognitive impairment in the HIV-infected group. Multivariable regression analyses were performed to identify HIV- and combination antiretroviral therapy-related factors associated with cognitive performance. RESULTS In total, 35 perinatally HIV-infected children (median age, 13.8 years; median CD4 count, 770 × 10(6) cells/L; 83% with undetectable HIV RNA) and 37 healthy children (median age, 12.1 years) were included. HIV-infected children scored lower than the healthy controls on all cognitive domains (eg, intelligence quotient [IQ], 76 [standard deviation {SD}, 15.7] vs 87.5 [SD, 13.6] for HIV-infected vs healthy children; P = .002). Cognitive impairment was found in 6 HIV-infected children (17%). The Centers for Disease Control and Prevention (CDC) clinical category at HIV diagnosis was inversely associated with verbal IQ (CDC clinical category C: coefficient -22.98; P = .010). CONCLUSIONS Our results show that cognitive performance of HIV-infected children is poor compared with that of SES-matched healthy controls. Gaining insight into these cognitive deficits is essential, as subtle impairments may progress to more pronounced complications that will influence future intellectual performance, job opportunities, and community participation of HIV-infected children.

Cerebral injury in perinatally HIV-infected children compared to matched healthy controls

Objective: The current study aims to evaluate the neurologic state of perinatally HIV-infected children on combination antiretroviral therapy and to attain a better insight into the pathogenesis of their persistent neurologic and cognitive deficits. Methods: We included perinatally HIV-infected children between 8 and 18 years and healthy controls matched for age, sex, ethnicity, and socioeconomic status. All participants underwent a 3.0 T MRI with 3D-T1-weighted, 3D–fluid-attenuated inversion recovery, and diffusion-weighted series for the evaluation of cerebral volumes, white matter hyperintensities (WMH), and white matter (WM) diffusion characteristics. Associations with disease-related parameters and cognitive performance were explored using linear regression models. Results: We included 35 cases (median age 13.8 years) and 37 controls (median age 12.1 years). A lower gray matter and WM volume, more WMH, and a higher WM diffusivity were observed in the cases. Within the HIV-infected children, a poorer clinical, immunologic, and virologic state were negatively associated with volumetric, WMH, and diffusivity markers. Conclusions: In children with HIV, even when long-term clinically and virologically controlled, we found lower brain volumes, a higher WMH load, and poorer WM integrity compared to matched controls. These differences occur in the context of a poor cognitive performance in the HIV-infected group, and larger, longitudinal studies are needed to increase our understanding of the pathogenesis of cerebral injury in perinatally HIV-infected children.

Central venous catheter use in severe malaria: time to reconsider the World Health Organization guidelines?

BackgroundTo optimize the fluid status of adult patients with severe malaria, World Health Organization (WHO) guidelines recommend the insertion of a central venous catheter (CVC) and a target central venous pressure (CVP) of 0-5 cmH2O. However there are few data from clinical trials to support this recommendation.MethodsTwenty-eight adult Indian and Bangladeshi patients admitted to the intensive care unit with severe falciparum malaria were enrolled in the study. All patients had a CVC inserted and had regular CVP measurements recorded. The CVP measurements were compared with markers of disease severity, clinical endpoints and volumetric measures derived from transpulmonary thermodilution.ResultsThere was no correlation between the admission CVP and patient outcome (p = 0.67) or disease severity (p = 0.33). There was no correlation between the baseline CVP and the concomitant extravascular lung water (p = 0.62), global end diastolic volume (p = 0.88) or cardiac index (p = 0.44). There was no correlation between the baseline CVP and the likelihood of a patient being fluid responsive (p = 0.37). On the occasions when the CVP was in the WHO target range patients were usually hypovolaemic and often had pulmonary oedema by volumetric measures. Seven of 28 patients suffered a complication of the CVC insertion, although none were fatal.ConclusionThe WHO recommendation for the routine insertion of a CVC, and the maintenance of a CVP of 0-5 cmH2O in adults with severe malaria, should be reconsidered.

The reliability of the physical examination to guide fluid therapy in adults with severe falciparum malaria: an observational study

BackgroundAdults with severe malaria frequently require intravenous fluid therapy to restore their circulating volume. However, fluid must be delivered judiciously as both under- and over-hydration increase the risk of complications and, potentially, death. As most patients will be cared for in a resource-poor setting, management guidelines necessarily recommend that physical examination should guide fluid resuscitation. However, the reliability of this strategy is uncertain.MethodsTo determine the ability of physical examination to identify hypovolaemia, volume responsiveness, and pulmonary oedema, clinical signs and invasive measures of volume status were collected independently during an observational study of 28 adults with severe malaria.ResultsThe physical examination defined volume status poorly. Jugular venous pressure (JVP) did not correlate with intravascular volume as determined by global end diastolic volume index (GEDVI; rs = 0.07, p = 0.19), neither did dry mucous membranes (p = 0.85), or dry axillae (p = 0.09). GEDVI was actually higher in patients with decreased tissue turgor (p < 0.001). Poor capillary return correlated with GEDVI, but was present infrequently (7% of observations) and, therefore, insensitive. Mean arterial pressure (MAP) correlated with GEDVI (rs = 0.16, p = 0.002), but even before resuscitation patients with a low GEDVI had a preserved MAP. Anuria on admission was unrelated to GEDVI and although liberal fluid resuscitation led to a median hourly urine output of 100 ml in 19 patients who were not anuric on admission, four (21%) developed clinical pulmonary oedema subsequently. MAP was unrelated to volume responsiveness (p = 0.71), while a low JVP, dry mucous membranes, dry axillae, increased tissue turgor, prolonged capillary refill, and tachycardia all had a positive predictive value for volume responsiveness of ≤50%. Extravascular lung water ≥11 ml/kg indicating pulmonary oedema was present on 99 of the 353 times that it was assessed during the study, but was identified on less than half these occasions by tachypnoea, chest auscultation, or an elevated JVP. A clear chest on auscultation and a respiratory rate <30 breaths/minute could exclude pulmonary oedema on 82% and 72% of occasions respectively.ConclusionsFindings on physical examination correlate poorly with true volume status in adults with severe malaria and must be used with caution to guide fluid therapy.Trial registrationClinicaltrials.gov identifier: NCT00692627

Neurometabolite Alterations Associated With Cognitive Performance in Perinatally HIV-Infected Children

AbstractDespite treatment with combination antiretroviral therapy (cART), cognitive impairment is still observed in perinatally HIV-infected children. We aimed to evaluate potential underlying cerebral injury by comparing neurometabolite levels between perinatally HIV-infected children and healthy controls. This cross-sectional study evaluated neurometabolites, as measured by Magnetic Resonance Spectroscopy (MRS), in perinatally HIV-infected children stable on cART (n = 26) and healthy controls (n = 36).Participants were included from a cohort of perinatally HIV-infected children and healthy controls, matched group-wise for age, gender, ethnicity, and socio-economic status. N-acetylaspartate (NAA), glutamate (Glu), myo-inositol (mI), and choline (Cho) levels were studied as ratios over creatine (Cre). Group differences and associations with HIV-related parameters, cognitive functioning, and neuronal damage markers (neurofilament and total Tau proteins) were determined using age-adjusted linear regression analyses.HIV-infected children had increased Cho:Cre in white matter (HIV-infected = 0.29 ± 0.03; controls = 0.27 ± 0.03; P value = 0.045). Lower nadir CD4+ T-cell Z-scores were associated with reduced neuronal integrity markers NAA:Cre and Glu:Cre. A Centers for Disease Control and Prevention (CDC) stage C diagnosis was associated with higher glial markers Cho:Cre and mI:Cre. Poorer cognitive performance was mainly associated with higher Cho:Cre in HIV-infected children, and with lower NAA:Cre and Glu:Cre in healthy controls. There were no associations between neurometabolites and neuronal damage markers in blood or CSF.Compared to controls, perinatally HIV-infected children had increased Cho:Cre in white matter, suggestive of ongoing glial proliferation. Levels of several neurometabolites were associated with cognitive performance, suggesting that MRS may be a useful method to assess cerebral changes potentially linked to cognitive outcomes.

Retinal Structure and Function in Perinatally HIV-Infected and cART-Treated Children: A Matched Case-Control Study.

PURPOSE Subtle structural and functional neuroretinal changes have been described in human immunodeficiency virus (HIV)-infected adults without retinitis treated with combination antiretroviral therapy (cART). However, studies on this subject in HIV-infected children are scarce. This study aimed to assess the presence of (neuro)retinal functional and structural differences between a group of perinatally HIV-infected children on cART and age-, sex-, ethnicity-, and socioeconomically matched healthy controls. METHODS All participants underwent an extensive ophthalmological examination, including functional tests as well as optical coherence tomography, to measure individual retinal layer thicknesses. Multivariable mixed linear regression models were used to assess possible associations between HIV status (and other HIV-related parameters) and ocular parameters, while accounting for the inclusion of both eyes and several known confounders. RESULTS Thirty-three HIV-infected children (median age 13.7 years [interquartile range (IQR), 12.2-15.8], median CD4+ T-cell count 760 cells/mm3, 82% with an undetectable HIV viral load [VL]), and 36 controls (median age 12.1 years [IQR, 11.5-15.8]) were included. Contrast sensitivity (CS) was significantly lower in the HIV-infected group (1.74 vs. 1.76 logCS; P = 0.006). The patients had a significantly thinner foveal thickness (-11.2 μm, P = 0.012), which was associated with a higher peak HIV VL (-10.3 μm per log copy/mL, P = 0.016). CONCLUSIONS In this study, we found a decrease in foveal thickness in HIV-infected children, which was associated with a higher peak VL. Longitudinal studies are warranted to confirm our findings and to determine the course and clinical consequences of these foveal changes.

Country of Birth Does Not Influence Long-term Clinical, Virologic, and Immunological Outcome of HIV-Infected Children Living in the Netherlands : A Cohort Study Comparing Children Born in the Netherlands With Children Born in Sub-Saharan Africa

Background:Immigrant HIV-infected adults in industrialized countries show a poorer clinical and virologic outcome compared with native patients. We aimed to investigate potential differences in clinical, immunological, and virologic outcome in Dutch HIV-infected children born in the Netherlands (NL) versus born in Sub-Saharan Africa (SSA) in a national cohort analysis. Methods:We included all HIV-infected children registered between 1996 and 2013. Descriptive statistics, mixed-effects models, and Cox proportional hazard models were used to investigate differences between groups. Results:In total, 319 HIV-infected children were registered. The majority of these children were born in SSA (n = 148, 47%) or NL (n = 113, 36%) and most were black (n = 158, 61%). Children born in NL were diagnosed at a median age of 1.2 years and initiated combination antiretroviral therapy (cART) at a median age of 2.6 years, compared with 3.7 and 5.3 years, respectively, for children born in SSA (HIV diagnosis: P < 0.001; cART initiation: P < 0.001). Despite a lower initial CD4+ T-cell Z-score in children born in SSA, their immunological reconstitution was similar to children from NL. Virologic suppression was achieved in the majority of all cART-treated children (NL: 96%, SSA: 94%). There was no difference in the occurrence or timing of virologic failure. Conclusions:Most immigrant HIV-infected children living in NL were born in SSA. Children born in SSA were diagnosed and initiated cART at an older age than children born in NL. Despite initial differences in CD4+ T-cell counts and HIV viral load, the long-term immunological and virologic response to cART was similar in both groups.

Health-related quality of life in perinatally HIV-infected children in the Netherlands

Combination antiretroviral therapy (cART) can alter HIV infection in children into a chronic condition. Studies investigating health-related quality of life (HRQoL) in HIV-infected children are scarce, and lacking from Western Europe. This study aimed to compare the HRQoL of clinically stable perinatally HIV-infected children to healthy, socioeconomically (SES)-matched controls as well as the Dutch norm population, and to explore associations between HIV and cART-related factors with HRQoL. HIV-infected and healthy children aged 8–18 years completed the Pediatric Quality of Life Inventory™ 4.0 (PedsQL™). We determined differences between groups on PedsQL™ mean scores, and the proportion of children with an impaired HRQoL per group (≥1 SD lower than the Dutch norm population). Logistic regression models were used to explore associations between disease-related factors and HRQoL impairment. In total, 33 HIV-infected and 37 healthy children were included. There were no differences in the mean PedsQL™ subscales between HIV-infected children and both control groups. The proportion of children with an impaired HRQoL was higher in the HIV-infected group (27%) as compared to the healthy control group (22%) and the Dutch norm (14%) on the school functioning subscale (HIV vs. Dutch norm: P = .045). Mean scores of HRQoL of perinatally HIV-infected children in the Netherlands were not different from a SES-matched control group, or from the Dutch norm population. However, the HIV-infected group did contain more children with HRQoL impairment, suggesting that HIV-infected children in the Netherlands are still more vulnerable to a compromised HRQoL.