Severe and fatal forms of COVID-19 in children.

OBJECTIVES: The aim of this study was to describe severe forms of novel coronavirus disease 2019 in children, including patient characteristics, clinical, laboratory, and imaging findings, as well as the disease management and outcomes. METHODS: This was a retrospective, single-center, observational study conducted in a pediatric intensive and high-dependency care unit (PICU, HDU) in an urban hospital in Paris. All patients, aged from 1 month to 18 years, admitted for confirmed or highly suspected SARS-CoV-2 were included. RESULTS: We analyzed the data of 27 children. Comorbidities (n=19, 70%) were mainly neurological (n=7), respiratory, (n=4), or sickle cell disease (n=4). SARS-CoV-2 PCR results were positive in 24 children (nasopharyngeal swabs). The three remaining children had a chest CT scan consistent with COVID-19. Respiratory involvement was observed in 24 patients (89%). Supportive treatments were invasive mechanical ventilation (n=9), catecholamine (n=4), erythropheresis (n=4), renal replacement therapy (n=1), and extracorporeal membrane oxygenation (n=1). Five children died, of whom three were without past medical history. CONCLUSION: This study highlighted the large spectrum of clinical presentation and time course of disease progression as well as the non-negligible occurrence of pediatric life-threatening and fatal cases of COVID-19 mostly in patients with comorbidities. Additional laboratory investigations are needed to further analyze the mechanism underlying the variability of SARS-Cov-2 pathogenicity in children.

Management of 35 critically ill hyperammonemic neonates: Role of early administration of metabolite scavengers and continuous hemodialysis.

Neurological involvement is frequent in inherited metabolic disease of the intoxication type. Hyperammonemic coma related to these diseases may cause severe neurological sequelae. Early optimal treatment is mandatory combining metabolite scavengers (MS) and sometimes continuous veno-venous hemodialysis (CVVHD). We aimed to describe the therapeutic management of hyperammonemia in neonates upon diagnosis of their metabolic disease and to compare neonates managed with MS alone or with both MS and CVVHD. We conducted a retrospective study including all neonates admitted for initial hyperammonemia to the pediatric intensive care unit of a Reference Center of Inherited Metabolic Diseases, between 2001 and 2012. The study included 35 neonates. Before admission, MS were initiated for 11 neonates. At admission, the median ammonia levels were 391 µmol/L and were significantly lower in neonates who received MS before admission. At admission, ammonia levels were 644 µmol/L in dialyzed and 283 µmol/L in non-dialyzed neonates. The median time to reach a 50% decrease of the initial ammonia levels was significantly shorter in dialyzed neonates; however, the normalization of ammonia levels was similar between dialyzed and non-dialyzed neonates. Hemodynamic disorders were more frequent in dialyzed neonates. CONCLUSION: MS represent an effective treatment for hyperammonemia and should be available in all pediatric units to avoid the need for CVVHD. Although CVVHD enhances the kinetics of toxic metabolite decrease, it is associated with adverse hemodynamic effects.

[Clowns in the pediatric intensive care unit in France]. / Les clowns en réanimation pédiatrique : état des lieux en France.

INTRODUCTION: In recent years, in children's hospitals, clowns are involved in pediatric intensive care units (PICUs), at the bedside of the most severely ill children. This study is the first that addresses the work of professional clowns in the PICU. Its aim is to describe this practice in French hospitals. METHODS: This study is a descriptive and prospective study conducted in December 2013 involving all the pediatric PICUs in French hospitals. A survey was emailed to all the PICU department heads in France. RESULTS: Questionnaires were sent to 32 PICUs (21 pediatric and neonatal intensive care units and 11 pediatric intensive care units). The response rate was 81.2% (26 questionnaires completed). Among the 26 units that responded to the survey, clowns intervened in 13 of them (50%). Eight had an exclusive pediatric activity and five had both pediatric and neonatal activities. The clown visit was twice a week in six units and once in seven (missing data: one unit). The head doctor was satisfied or very satisfied in 92.3% of the cases (n=12/13). Medical clowns were trained and professional artists in all of the units. They worked in duo in most units (n=12/13) and solo in one unit. The clown rounds were preceded by a meeting with a healthcare worker in 12 of the 13 PICUs in which the clowns worked. They dialogued with a doctor in four and a nurse (or head nurse) in eight. DISCUSSION: Prior to implementation, the clowns' work should be understood, accepted, and supported by each PICU team, to be validated in the overall care plan for each child. CONCLUSION: Despite the severity of the situations met in the PICU, the instability of patients and the technical environment, clowning in PICUs appears to be a common and worthwhile practice in most French pediatric hospitals.

Early and late complications after liver transplantation for propionic acidemia in children: a two centers study.

Propionic acidemia (PA) is a severe metabolic disorder with cardiac and neurologic complications and a poor quality of life. Liver transplantation (LT) was thus proposed in PA to increase enzyme activity. We studied retrospectively LT in PA in two European centers. Twelve patients underwent 17 LTs between 1991 and 2013. They developed severe, unusual and unexpected complications, with high mortality (58%). When present, the cardiomyopathy resolved and no acute metabolic decompensation occurred allowing dietary relaxation. Renal failure was present in half of the patients before LT and worsened in all of them. We suggest that cardiac and renal functions should be assessed before LT and monitored closely afterward. A renal sparing immunosuppression should be used. We speculate that some complications may be related to accumulated toxicity of the disease and that earlier LT could prevent some of these consequences. As kidney transplantation has been performed successfully in methylmalonic acidemia, a metabolic disease in the same biochemical pathway, the choice of the organ to transplant could be further discussed.

[French law related to patient's rights and end of life: pediatric intensive care unit's health professionals' opinions]. / Opinions des soignants des réanimations pédiatriques françaises sur l'application de la loi Léonetti.

INTRODUCTION AND OBJECTIVES: To identify the knowledge of caregivers of pediatric intensive care units (PICUs) on the French law related to patients' rights and end of life, their views on withholding/withdrawing life-sustaining treatment (WWLST) decisions, and their feelings about how these decisions were made and implemented. MATERIALS AND METHODS: A multicenter survey in 24 French PICUs during the fourth trimester 2010. RESULTS: One thousand three hundred and thirty-nine professional healthcare workers (1005 paramedics and 334 physicians) responded. Over 85% of caregivers had good knowledge of the WWLST decision-making processes required by law. More than 80% of caregivers accepted mechanical ventilation, hemodiafiltration, or hemodynamic support withdrawal or withholding. Nevertheless, the withdrawal of artificial nutrition and hydration generated reluctance or opposition for the majority of respondents. While paramedics' participation in the decision-making process was deemed necessary by all caregivers, paramedics found more often than physicians that they were insufficiently involved. The quality of end-of-life care was judged very positively by caregivers. The answers on how WWLST was applied suggest very different interpretations of the law. Some caregivers respect the principles of palliative care as stated in the public health code and 40% of doctors and 64% of caregivers consider it "acceptable" to hasten death if resulting from a collaborative decision-making process. CONCLUSION: This study is the first to show that caregivers of French PICUs have good knowledge of the French law concerning the end of life. Yet, there is still confusion about the limits of practice during the end-of-life period.

[Implementation of morbidity and mortality conferences in French intensive care units: a survey]. / Enquête nationale sur la pratique des "Revues de morbi-mortalité" en réanimation.

OBJECTIVE: A national survey was conducted by the "Collège français d'anesthésie et de réanimation (CFAR)" and the "Collège des bonnes pratiques en réanimation (CBPR)", to analyze the implementation of morbidity and mortality conferences (MMCs) in French intensive care units (ICUs). STUDY DESIGN: An electronic questionnaire was set up. We directed the survey at French ICUs physicians registered in the two Colleges directories, only one form was filled in by each participating unit. RESULTS: From December 2009 to February 2010, Among the 170 replies, 120 ICUs (71%) practiced MMC. No difference in the typology of the two groups was found. The median annual number of MMCs was 4 per year (1-15). The perimeter of the MMCs concerned only the ICU unit in 70 cases (58%), more than one ICU unit in the same department in 11 cases (9.8%), more than one department of ICU in 16 cases (13%) and other departments in 57 cases (48%). The events analyzed were: all deaths in 45 cases (37.5%), unexpected deaths in 50 cases (41.7%), severe adverse events in 67 cases (55.8%) and other events in 19 cases (15.8%). At least one adverse event defined by the two colleges in the process of "accreditation" was analyzed in 86 cases (72%). Participation of a physician of at least one other unit was reported in 56 cases (47%) and of medical students in 62 cases (52%). The low rate of participation of ICU nurses was reported in 62 cases (69.2%) and their absence in 35 cases (29%). MMCs consequences were drafting of new procedure in 99 cases (83%), changes in procedures in 75 cases (63%), conducting training programs in 60 cases (50%), organizational changes in 86 cases (72%), adverse event declaration in 21 cases (18%) and monitoring indicators in 40 cases (33%). Among units which did not practice MMCs, Identified obstacles were organizational causes in 25 cases (50%), inexperience in seven cases (14%), lack of methodology in 4 cases (8%), realization of other methods of formative assessment in 4 cases (8%) and physician's refusal in three cases (6%). The fear of medico-legal problem was never reported as a barrier to MMCs practice. Forty-five units (90%) projected to practice MMR. CONCLUSION: This survey showed that the practice of MMR is common in French ICUs, allowing the identification of organizational problems, but also of training needs, joining one of the initial concerns that have led to their implementation. Expanding the participation to non-physician members of the units should be encouraged, without underestimating the difficulties particularly in the organizational domains that represent an obstacle to development of MMCs.

Renal transplantation in 4 patients with methylmalonic aciduria: a cell therapy for metabolic disease.

INTRODUCTION: Patients with methylmalonic acidemia (MMA) may develop many complications despite medical treatment, in particular, severe central nervous system damage and chronic kidney disease (CKD). A kidney transplant may partially correct the metabolic dysfunctions. Liver, kidney and combined liver-kidney transplantations have been advocated but no guidelines are available to identify the most suitable organ to transplant. PATIENTS AND METHODS: Four patients with MMA (mut° phenotype) received a kidney graft because of repeated metabolic decompensations, with progression to CKD in 3 patients (end-stage kidney disease in two patients and CKD stage III in one patient with an estimated glomerular filtration rate [eGFR] of 40ml/min/1.73m(2)) but normal renal function in one (eGFR of 93ml/min/1.73m(2)) before transplantation. RESULTS: The medium age at transplantation was 7.9y (5-10.2) and the median follow-up was 2.8years (1.8-4.6). Renal transplantation improved the relevant metabolic parameters in 4/4 patients and renal function in the patients with CKD. Plasma and urinary MMA levels immediately decreased and remained normal or subnormal (mean values of plasma MMA before transplantation 1530µmol/L versus 240µmol/L after transplantation, and mean values of urine MMA before transplantation 4700mmol/mol creatinine versus 2300mmol/mol creatinine after transplantation). No further acute metabolic decompensation was observed and protein-intake was increased from 0.60 to 0.83g/Kg/day. One patient transplanted at age 9.7years developed a hepatoblastoma at age 11years with subsequent neurological complications and eventually died. The three other patients are alive. Two of them remained neurologically stable. The 3rd patient who displayed choreoathetosis transiently improved his neurological condition immediately after transplantation and then remained stable. CONCLUSION: Kidney transplantation represents an interesting alternative therapeutic option in methylmalonic aciduria, for renal complications but also as a "cellular therapy" that may significantly reduce metabolic decompensations and hospitalizations. However, further neurological impairment remains possible.

[Local salicylate transcutaneous absorption: an unrecognized risk of severe intoxication: a case report]. / Application cutanée localisée d'acide salicylique : un risque méconnu d'intoxication : à propos d'un cas.

INTRODUCTION: Although rare, salicylate intoxication through the skin should not be ignored as it can be severely life-threatening. We describe an original case of accidental poisoning with salicylates topically applied to the scalp of a 6-week-old infant. CLINICAL REPORT: A 6-week-old infant, with no prior history, was admitted to the pediatric intensive care unit for treatment of severe disorders of consciousness associated with significant tachypnea. Laboratory results revealed metabolic acidosis with elevated anion gap, ketonuria, and normal glycemia. Initial assessment ruled out the hypothesis of accidental ingestion of salicylates. However, the presence of salicylic acid derivatives in organic acid chromatography, confirmed by plasma salicylate levels at 580 mg/L, ultimately re-established the diagnosis. Further inquiry retrospectively highlighted the prolonged topical application in occlusion (3 days) of an extemporaneous preparation containing 23% salicylic acid on the scalp. The course after urine alkalinization was rapidly favorable without sequelae. COMMENT AND CONCLUSIONS: Salicylate intoxication is potentially lethal, particularly in infants under 12 months of age. The vast majority of these intoxications result from accidental ingestion. The present observation underscores the original and undescribed risk of intoxication due to a localized application to the scalp. In the presence of warning symptoms, salicylate poisoning should be investigated, including topical application of salicylic acid, even if localized. Careful attention should be paid to following the indications of use of this product in terms of concentration, characteristics of the infant, and exposed skin. The use of extended topical application of salicylic acid in concentrations greater than 3% should be avoided.

Nonbacterial purpura fulminans and severe autoimmune acquired protein S deficiency associated with human herpesvirus-6 active replication.

Nonbacterial purpura fulminans (PF) is rare, usually follows viral infection in young children, and is characterized by specific coagulation disorders, requiring specific therapy. Following a transient rash, a 2-year-old previously healthy girl developed PF without haemodynamic impairment. Laboratory data revealed disseminated intravascular coagulation and a severe transient protein S deficiency. Antiprotein S autoantibodies and active human herpesvirus-6 (HHV6) replication were demonstrated. Purpuric skin lesions spread very rapidly despite broad-spectrum antibiotics and right leg amputation. Plasmapheresis and intravenous immunoglobulins gave complete clinical recovery and normalization of protein S level within 10 days, with progressive clearance of antiprotein S autoantibodies. Transient severe protein S deficiencies have previously been reported in patients with nonbacterial PF, usually after varicella infection. This is the first documented case of PF after HHV6 infection.

Is intestinal transplantation the future of children with definitive intestinal insufficiency?

UNLABELLED: Intestinal transplantation (IT) is the newest and most difficult of organ transplantations. The first ever (1987) and the longest surviving (1989) IT were performed in our institution. However, IT still has to demonstrate its benefit to children on long-term parenteral nutrition (PN). We tried to clarify this aspect by looking back at our 13 years' experience. PATIENTS: From 1994 to December 2007, 74 IT were performed in 69 children, 39 with an isolated small bowel (IT), 35 combined with a liver transplant (LITx). The indications were: short bowel syndrome (n = 25), congenital mucosal diseases (n = 22), and motility disorders (n = 22). Median age at transplantation was 5 years (1 - 17 years). Follow-up was 1 to 12 years (median 5 years). RESULTS: Thirty-one children have a functioning graft (42 %), 15/39 IT, 16/35 LITx. They are at home without PN, with a good quality of life. One child is PN-dependent 1.5 years post IT. Post IT, 16 children were detransplanted: 12 early on (1 for mechanical complications, 11 because of resistant rejection; 3 less than 3 years, one 9 years post SBT (chronic rejection). In 2 noncompliant teenagers, PN was reintroduced (one was detransplanted later on). Several years post LITx, 2 children underwent bowel detransplantation due to an acute viral infection complicated with rejection. Twenty-two children died (32 %, 8 IT, 14 LITx), 18 early on from infectious or surgical complications, 4 more than 1 year post IT, 3 after retransplantation (1 in another unit). Bad prognostic factors are multiple previous surgeries, an older age (> 7 y), and chronic intestinal pseudo-obstruction. DISCUSSION: Complications post IT are frequent and life-threatening, especially early on: rejection (IT), infections (LITx). Later on, the rate of complications decreases but remains significant, especially in noncompliant patients. However we describe here a 13-year learning curve; the recent results are encouraging with regard to control of rejection and viral infections. CONCLUSION: Intestinal transplantation is indicated only in selected patients in whom long-term PN cannot be performed safely any more. In every child with intestinal insufficiency, the therapeutic strategy must be discussed early on in order to perform IT at the right time under optimal conditions. IT should evolve from being a "rescue" procedure to becoming a true therapeutic option.

Induced mild hypothermia reduces mortality during acute inflammation in rats.

BACKGROUND: Hypothermia has been proposed as a therapeutic possibility in brain trauma, cardiac arrest and hemorrhagic shock. Experimental studies have shown that hypothermia may act by modulating the inflammatory response during endotoxemia. This study was carried out to test whether hypothermia could protect rats from endotoxemic insult. METHODS: After general anesthesia and oro-tracheal intubation, Sprague-Dawley rats were randomly assigned to either a hypothermic group or normothermic group. In each group, rats received intraperitoneal lipopolysaccharide (LPS) (10 or 20 mg/kg). Blood samples were taken prior to and 2 h after LPS injection to measure blood gases, liver enzymes, muscular enzymes, tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) plasma levels. After 2 h of hypothermia, the rats were extubated and brought back to their cages. The mortality rate was observed for 7 days following endotoxemia. In a second set of experiments, hypothermia was induced 1 h after endotoxemia (10 mg/kg of intraperitoneal LPS) and the mortality rate was observed for the following 7 days. RESULTS: The survival rate was significantly increased in the hypothermic group relative to the normothermic group, regardless of LPS dose. This increased survival rate was also observed when hypothermia was induced 1 h after endotoxemia. In the hypothermic group, IL-10 and the DeltaIL-10/DeltaTNF-alpha ratio were significantly increased relative to those in the normothermic group. CONCLUSION: Induced mild hypothermia reduces mortality during endotoxemia in rats. The modulation of the inflammatory response, with an increase in anti-inflammatory cytokines, may be involved in this protective effect.

Factors influencing outcome after intestinal transplantation in children.

We evaluated 131 patients (6 months-14 years) who experienced 21 deaths before listing, 11 continuing on the waiting list, 38 well on home parenteral nutrition, 6 off parenteral nutrition and 59 transplanted (20 girls) aged 2.5 to 15 years, (18 >7 years). They received cadaveric isolated intestine (ITx, n = 31) or liver-small bowel (LITx, n = 32), including right colon (n = 43; 23 LITx) for short bowel (n = 19), enteropathy (n = 20), Hirschsprung (n = 14), or pseudo-obstruction (n = 6). Treatment included tacrolimus, steroids, azathioprine, or interleukin-2 blockers. After 6 months to 10.5 years, the patient and graft survivals were 75% and 54%. Sixteen patients (10 LITx) died within 3 months from surgery (n = 3), bacterial (n = 5) or fungal (n = 6) sepsis, or posttransplant lymphoproliferative disorder (n = 2). Rejection occurred in 27 patients, including 10 steroid-resistant episodes requiring antilymphoglobulins. The grafts were removed due to uncontrolled rejection in seven ITx recipients. Surgical complications were observed in 38 recipients (25 LSBTx) within 2 months, including bacterial (n = 22) or fungal (n = 11) sepsis, cytomegalovirus disease (n=12), adenovirus (n = 11), or posttransplant lymphoproliferative disorder (n = 12). Forty-two children (19 LSBTx) are alive. Weaning from parenteral nutrition was achieved after 42 days (median). Factors related to death or graft loss were pre-Tx surgery (P < .01), pseudo-obstruction (P < .01), age over 7 years (P < .03), fungal sepsis (P < .03), steroid resistant rejection (P < .05), hospitalized versus home patient (P < .01), and retransplantation (P < .05). Colon transplant did not affect the outcome. Interleukin-2 blockers improved isolated ITx (P < .05). Early referral and close monitoring of intestinal failure and related disorders are mandatory to achieve successful ITx.

Gorlin syndrome presenting as prenatal chylothorax in a girl.

Gorlin syndrome (GS), also known as nevoid basal cell carcinoma syndrome, is a rare autosomal dominant condition with an estimated prevalence of 1:57 000. GS is associated with congenital malformations and predisposition to neoplasms. The main features observed in patients with GS are basal cell carcinomas, odontogenic keratocysts, skeletal anomalies including scoliosis and bifid ribs, palmar and plantar epidermal cysts, facial dysmorphism, and cerebral falx calcification. More than 100 other clinical manifestations have also been described in the literature including ovarian fibroma, enlarged cerebral ventricles, and lymphatic as well as chylous mesenteric cysts. The Patched (PTCH) gene is responsible for GS when mutated. Here, we report on a prenatal diagnosis of GS in a girl with a chylothorax, a previously unreported feature in GS. We discuss the clinical features observed in this family and we comment on the molecular studies that allowed us to describe a previously unreported Patched gene mutation.