Fouad Madhi

Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort

Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sβ(0)), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 10(9)/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.

Chronic and acute anemia and extracranial internal carotid stenosis are risk factors for silent cerebral infarcts in sickle cell anemia

Early transcranial Doppler (TCD) screening of the Créteil sickle cell anemia (SCA)-newborn cohort, and rapid initiation of transfusion programs, resulted in successful prevention of overt strokes, but a high cumulative risk of silent cerebral infarcts (SCI) remained, suggesting that TCD screening does not identify all patients with SCA at risk for SCI. We hypothesized that episodes of hypoperfusion/hypoxia, as observed during acute chest syndromes or acute anemic events (AAE), and extracranial internal carotid artery (eICA) stenoses, detectable via submandibular Doppler sonography and cervical magnetic resonance angiography (MRA), could also be risk factors for SCI. This study includes 189 stroke-free patients with SCA from the Créteil newborn cohort (1992-2010) followed longitudinally by magnetic resonance imaging/MRA, including cervical MRA at the last assessment. All patients with abnormal TCD and/or intracranial stenoses were placed on a transfusion program. Mean follow-up was 9.9 years (range, 2.2-19.9 years; 1844 patient-years). Annual rates of clinical events were calculated. The cumulative risk for SCI was 39.1% (95% confidence interval [CI], 23.5%-54.7%) by age 18 years, with no plateau. We confirm that baseline hemoglobin level lower than 7 g/dL before age 3 years is a highly significant predictive risk factor for SCI (hazard ratio, 2.97; 95% CI, 1.43-6.17; P = .004). Furthermore, we show that AAE rate (odds ratio, 2.64 per unit increase; 95% CI, 1.09-6.38; P = .031) and isolated eICA stenosis (odds ratio, 3.19; 95% CI, 1.18-8.70; P = .023) are significant and independent risk factors for SCI.

Evaluation of a model for efficient screening of tuberculosis contact subjects.

RATIONALE Contact tracing is an important component of tuberculosis (TB) control programs. Standardization of contact investigation protocols can make them more efficient. OBJECTIVES To develop a model to select contact subjects for screening. METHODS We prospectively collected standardized data on 325 TB index cases and their 2,009 contacts. Factors that independently influenced the risk of TB infection were included in the model, which was then validated in a second prospective cohort of 88 cases of TB and their 618 contacts. MEASUREMENTS AND MAIN RESULTS A total of eight independent risk factors were identified (odds ratio; 95% confidence interval): age, with three subgroups: 6-14 years (3.6; 1.6-8.0); 15-29 years (3.7; 1.8-7.7); > or =30 years (4.1; 2.0-8.5); cavitation on the index cases chest radiograph (1.6; 1.1-2.2); an index case sputum smear with 100 or more acid-fast bacilli per field (1.8; 1.2-2.8); household contact at night (2.1; 1.3-3.2); first-degree family relationship with the index case (2.1; 1.3-3.3); active smoking by the contact (1.6; 1.1-2.4); free health care (2.0; 1.2-3.2); and birth in a country with TB incidence rate higher than 25 of 100,000 (2.2; 1.5-3.2). Predictive probabilities were chosen to ensure false-negative rates lower than estimated TB infection background. The number of contacts to be investigated was reduced by 26% while maintaining a false-negative rate of 8%. CONCLUSIONS This study provides a standardized contact screening model which reduces resources required without negatively affecting disease control.

Long-term treatment follow-up of children with sickle cell disease monitored with abnormal transcranial Doppler velocities

Stroke risk in sickle cell anemia (SCA), predicted by high transcranial Doppler (TCD) velocities, is prevented by transfusions. We present the long-term follow-up of SCA children from the Créteil newborn cohort (1992-2012) detected at risk by TCD and placed on chronic transfusions. Patients with normalized velocities and no stenosis were treated with hydroxyurea, known to decrease anemia and hemolytic rate. Trimestrial Doppler was performed and transfusions restarted immediately in the case of reversion to abnormal velocities. Patients with a genoidentical donor underwent transplant. Abnormal time-averaged maximum mean velocities (TAMMV) ≥200 cm/s were detected in 92 SCA children at a mean age of 3.7 years (range, 1.3-8.3 years). No stroke occurred posttransfusion after a mean follow-up of 6.1 years. Normalization of velocities (TAMMV < 170 cm/s) was observed in 83.5% of patients. Stenosis, present in 27.5% of patients, was associated with the risk of non-normalization (P< .001). Switch from transfusions to hydroxyurea was prescribed for 45 patients, with a mean follow-up of 3.4 years. Reversion, predicted by baseline reticulocyte count ≥400 × 10(9)/L (P< .001), occurred in 28.9% (13/45) patients at the mean age of 7.1 years (range, 4.3-9.5 years). Transplant, performed in 24 patients, allowed transfusions to be safely stopped in all patients and velocities to be normalized in 4 patients who still had abnormal velocities on transfusions. This long-term cohort study shows that transfusions can be stopped not only in transplanted patients but also in a subset of patients switched to hydroxyurea, provided trimestrial Doppler follow-up and immediate restart of transfusions in the case of reversion.

Neonatal Outcomes of Prenatally Diagnosed Congenital Pulmonary Malformations

BACKGROUND AND OBJECTIVE: Congenital pulmonary malformations (CPM) are mostly recognized on prenatal ultrasound scans. In a minority of cases, they may impair breathing at birth. The factors predictive of neonatal respiratory distress are not well defined, but an understanding of these factors is essential for decisions concerning the need for the delivery to take place in a tertiary care center. The aim of this study was to identify potential predictors of respiratory distress in neonates with CPM. METHODS: We selected cases of prenatal diagnosis of hyperechoic and/or cystic lung lesions from RespiRare, the French prospective multicenter registry for liveborn children with rare respiratory diseases (2008–2013). Prenatal parameters were correlated with neonatal respiratory outcome. RESULTS: Data were analyzed for 89 children, 22 (25%) of whom had abnormal breathing at birth. Severe respiratory distress, requiring oxygen supplementation or ventilatory support, was observed in 12 neonates (13%). Respiratory distress at birth was significantly associated with the following prenatal parameters: mediastinal shift (P = .0003), polyhydramnios (P = .05), ascites (P = .0005), maximum prenatal malformation area (P = .001), and maximum congenital pulmonary malformation volume ratio (CVR) (P = .001). Severe respiratory distress, requiring oxygen at birth, was best predicted by polyhydramnios, ascites, or a CVR >0.84. CONCLUSIONS: CVR >0.84, polyhydramnios, and ascites increased the risk of respiratory complications at birth in fetuses with CPM, and especially of severe respiratory distress, requiring oxygen supplementation or more intensive intervention. In such situations, the delivery should take place in a tertiary care center.

New Cases of Isolated Congenital Central Hypothyroidism Due to Homozygous Thyrotropin Beta Gene Mutations: A Pitfall to Neonatal Screening

BACKGROUND Congenital central hypothyroidism (CCH) is a rare condition that is often diagnosed in late childhood in countries where neonatal screening programs rely solely on detecting thyrotropin (TSH) elevation. TSHbeta gene mutation is one of the causes of CCH. We describe two cases of c.Q49X mutation and three cases of c.C105Vfs114X mutation in exon 3 of the TSH beta-subunit gene. SUMMARY We found two different TSHbeta gene mutations in two families. In one family, we identified a missense mutation in exon 3 leading to a premature stop at position 49 (c.Q49X) in the two affected twins. In the other family, the three affected siblings had a 313delT nucleotide deletion leading to a frame shift responsible for premature termination at codon 114 (c.C105Vfs114X); neonatal screening showed very low TSH levels in all three patients. The presence of inappropriately low TSH levels at birth in the three affected members of the second family raises questions about the value of the TSH level for CCH screening. CONCLUSIONS The marked phenotypic variability in patients with the c.Q49X mutation suggests modulation by interacting genes and/or differences in the genetic background. TSHbeta gene mutations should be suspected in neonates with inappropriately low TSH levels.

Acute cervical lymphadenitis and infections of the retropharyngeal and parapharyngeal spaces in children

BackgroundAcute cervical adenitis can evolve into suppurative cervical lymphadenitis and may sometimes be associated with infection of the retropharyngeal and parapharyngeal spaces (i.e., retropharyngeal and poststyloid parapharyngeal abscesses). This study aimed to describe the clinical presentation of acute cervical lymphadenitis and infections of the retropharyngeal and parapharyngeal spaces in children and examine the management of these conditions.MethodsThis was a retrospective study including children from 3 months to 18 years old who were hospitalized in the Pediatric Department of the Centre-Intercommunal-de-Créteil between January 2003 and May 2010. Selected cases were based on the diagnosis of acute cervical lymphadenitis, suppurative cervical lymphadenitis, or infections of the retropharyngeal or parapharyngeal spaces. Case history, clinical signs, laboratory tests, imaging, treatment and clinical course were collected from patient charts.ResultsWe included 75 children (54 males [72%]); 62 (83%) were < 6 years old. Diagnoses were acute cervical lymphadenitis in 43 patients (57%), suppurative cervical lymphadenitis in 13 (17%), retropharyngeal or poststyloid parapharyngeal abscess in 18 (24%) and cervical necrotizing fasciitis in 1 (1%). In total, 72 patients (96%) presented fever and 34 (45%) had torticollis. Suppurative cervical lymphadenitis or abscesses of the retropharyngeal or poststyloid parapharyngeal spaces was significantly higher for children with than without torticollis (52.9% vs. 4.8%, p < 0.001). In all, 21 patients among the 44 > 3 years old (48%) underwent a rapid antigen detection test (RADT) for group A beta-hemolytic Streptococcus pyogenes; results for 10 were positive (48%). Contrast-enhanced CT scan of the neck in children with torticollis (n = 31) demonstrated an abscess in 21 (68%). Fine-needle aspiration was performed in 8 patients (11%) and 8 (11%) required surgical drainage. Bacteriology was positive in 8 patients (11%), with a predominance of Staphylococcus aureus and S. pyogenes. All patients received intravenous antibiotics and the outcome was favorable regardless of surgery. Recurrence was observed in only 1 case among the 34 patients with a follow-up visit after discharge.ConclusionOur data suggest that presentation with cervical lymphadenitis associated with fever and torticollis requires evaluation by contrast-enhanced CT scan. Furthermore, abscess drainage should be restricted to the most severely affected patients who do not respond to antibiotic therapy.

Leukocytosis is a risk factor for lung function deterioration in children with sickle cell disease

BACKGROUND The decline in lung volumes associated with sickle cell disease (SCD) may begin in childhood. Risk factors for early restrictive lung disease may include SCD severity markers such as leukocytosis. OBJECTIVE We examined the relationship between early alteration of lung function and extra-pulmonary markers of SCD severity. METHODS We analyzed pulmonary function test results for 184 SCD children (mean age 12.6 y) enrolled in a pediatric cohort. MAIN RESULTS Total lung capacity (TLC) and vital capacity (VC) were not associated with a history of acute chest syndrome. Lower TLC values were significantly associated with three independent factors: older age, previous acute episodes of anemia <6 g/dl, and higher baseline white blood cell counts. Only the baseline WBC count and age were independent risk factors for lower VC. Relative risks to have a TLC or a VC lower than the mediane value in our population were significantly associated to the baseline leukocytosis (per 10(9) G/L), after adjustment on age, sex, genotype, baseline Hb, and treatment (RR (95% CI) =1.16 (1.04-1.29) p<0.009, and 1.17 (1.06-1.29) p<0.002, respectively). The obstructive pattern, defined by FEV1/FVC ratio, was not significantly associated to biological parameters. CONCLUSIONS Hemolysis and leukocytosis were independent risk factors for an early decline in lung volumes in this pediatric SCD cohort.

Lemierre syndrome with meningo-encephalitis, severe cerebral artery stenosis, and focal neurological symptoms.

Figure 4. Carotid artery and anterior cerebral artery involvement in an 5-year-old girl with acute right otomastoiditis and neurologic symptoms. A, 3D TOF MRA coronal view. B, Follow-up coronal 3D TOF MRA image obtained 3 months later shows complete recovery of these arteries. A 5-year-old girl presented with otitis-derived meningoencephalitis. The diagnosis was based on clinical symptoms: purulent otorrhea, meningeal syndrome, convulsions, alteration in consciousness, apnea, secondary enuresis, right cerebellar syndrome; no hemodynamic or respiratory failure, along with biological signs (blood: severe inflammatory syndrome; cerebrospinal fluid: neutrophilia, high protein level) and severe electroencephalographic abnormalities (diffuse bihemispheric slow delta waveforms [Figure 1; available at www.jpeds.com]). She was admitted to the Intensive Care Unit. Blood culture grew Fusobacterium necrophorum, suggesting Lemierre syndrome. Rare but of increasing incidence, Lemierre syndrome is a head and neck–initiated septicemia caused by an anaerobic germ that induces septic thrombophlebitis of the faciocervical veins complicated by septic metastasis, with an overall 10% mortality. It typically involves a F necrophorum tonsillitis, septicemia, thrombosis of the internal jugular vein, and lung dissemination. The primary infection site usually is otitis media in young children. Neuroimaging revealed segmental right internal jugular vein thrombosis (not shown) as well as cavernous sinus thrombophlebitis (Figures 2 and 3; available at www.jpeds. com). An exceptionally severe stenosis with parietal thickening of the right anterior cerebral artery and the right internal carotid artery was demonstrated (Figures 2 and 4, A). The cerebral and cerebellar parenchyma were normal. Metastatic sites included the spleen (disseminated nodules), left talus (scintigraphic hyperintensity), cerebrospinal fluid, brain, and possibly the lung (persistent cough). Hemostatic and immunological explorations were normal. Neurological infection and inflammation are rare to exceptional features in Lemierre syndrome. Meningitis occurs in 1%. Convulsions have been reported in 2 patients. Reported focal neurological signs following ischemia, abscess, or inflammation are hemiparesis, aphasia, and Horner syndrome. Arteritis can lead not only to embolism but also to complete occlusion. In addition to antibiotic therapy, anticoagulation is debated but strongly recommended by the American College of Chest Physicians. Our patient initially received amoxicillin, metronidazole, and low-molecular-weight heparin. The electroencephalogram was normal after 2 weeks; she was discharged on amoxicillin and vitamin K antagonist after 1 month, when the daily 39 C fever, abundant ear discharge, and cough finally receded, and neurological examination and imaging normalized completely after 3 months only (Figure 4, B). n

Pneumococcal Meningitis Vaccine Breakthroughs and Failures After Routine 7-Valent and 13-Valent Pneumococcal Conjugate Vaccination in Children in France.

We collected cases of pneumococcal meningitis vaccine breakthrough (VBT) and vaccine failure (VF) from 2003 to 2013 after the implementation of pneumococcal conjugate vaccines (PCVs) in France. VBT accounted for 3.2% of the cases (PCV7 era: 24 of 943, PCV13 era: 15 of 290) and VF 0.6% (PCV7 era: 6 of 943, PCV13 era: 2 of 290). VBT and VF are rare and occur in most cases in children younger than 2 years. The serotype 19F was the most frequent cause even after the introduction of PCV13.