Paul Babyn

An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist

BACKGROUND Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)

Principles, techniques, and applications of T2*-based MR imaging and its special applications.

T2* relaxation refers to decay of transverse magnetization caused by a combination of spin-spin relaxation and magnetic field inhomogeneity. T2* relaxation is seen only with gradient-echo (GRE) imaging because transverse relaxation caused by magnetic field inhomogeneities is eliminated by the 180 degrees pulse at spin-echo imaging. T2* relaxation is one of the main determinants of image contrast with GRE sequences and forms the basis for many magnetic resonance (MR) applications, such as susceptibility-weighted (SW) imaging, perfusion MR imaging, and functional MR imaging. GRE sequences can be made predominantly T2* weighted by using a low flip angle, long echo time, and long repetition time. GRE sequences with T2*-based contrast are used to depict hemorrhage, calcification, and iron deposition in various tissues and lesions. SW imaging uses phase information in addition to T2*-based contrast to exploit the magnetic susceptibility differences of the blood and of iron and calcification in various tissues. Perfusion MR imaging exploits the signal intensity decrease that occurs with the passage of a high concentration of gadopentetate dimeglumine through the microvasculature. Change in oxygen saturation during specific tasks changes the local T2*, which leads to the blood oxygen level-dependent effect seen at functional MR imaging. The basics of T2* relaxation, T2*-weighted sequences, and their clinical applications are presented, followed by the principles, techniques, and clinical uses of four T2*-based applications, including SW imaging, perfusion MR imaging, functional MR imaging, and iron overload imaging.

Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study.

Summary.  Background: Prophylactic treatment for severe hemophilia A is likely to be more effective than treatment when bleeding occurs, however, prophylaxis is costly. We studied an inception cohort of 25 boys using a tailored prophylaxis approach to see if clotting factor use could be reduced with acceptable outcomes. Methods: Ten Canadian centers enrolled subjects in this 5‐year study. Children were followed every 3 months at a comprehensive care hemophilia clinic. They were initially treated with once‐weekly clotting factor; the frequency was escalated in a stepwise fashion if unacceptable bleeding occurred. Bleeding frequency, target joint development, physiotherapy and radiographic outcomes, as well as resource utilization, were determined prospectively. Results: The median follow‐up time was 4.1 years (total 96.9 person‐years). The median time to escalate to twice‐weekly therapy was 3.42 years (lower 95% confidence limit 2.05 years). Nine subjects developed target joints at a rate of 0.09 per person‐year. There was an average of 1.2 joint bleeds per person‐year. The cohort consumed on average 3656 IU kg−1year−1 of factor (F) VIII. Ten subjects required central venous catheters (three while on study); no complications of these devices were seen. One subject developed a transient FVIII inhibitor. End‐of‐study joint examination scores – both clinically and radiographically – were normal or near‐normal. Conclusions: Most boys with severe hemophilia A will probably have little bleeding and good joint function with tailored prophylaxis, while infusing less FVIII than usually required for traditional prophylaxis.

Steady-State MR Imaging Sequences: Physics, Classification, and Clinical Applications

Steady-state sequences are a class of rapid magnetic resonance (MR) imaging techniques based on fast gradient-echo acquisitions in which both longitudinal magnetization (LM) and transverse magnetization (TM) are kept constant. Both LM and TM reach a nonzero steady state through the use of a repetition time that is shorter than the T2 relaxation time of tissue. When TM is maintained as multiple radiofrequency excitation pulses are applied, two types of signal are formed once steady state is reached: preexcitation signal (S-) from echo reformation; and postexcitation signal (S+), which consists of free induction decay. Depending on the signal sampled and used to form an image, steady-state sequences can be classified as (a) postexcitation refocused (only S+ is sampled), (b) preexcitation refocused (only S- is sampled), and (c) fully refocused (both S+ and S- are sampled) sequences. All tissues with a reasonably long T2 relaxation time will show additional signals due to various refocused echo paths. Steady-state sequences have revolutionized cardiac imaging and have become the standard for anatomic functional cardiac imaging and for the assessment of myocardial viability because of their good signal-to-noise ratio and contrast-to-noise ratio and increased speed of acquisition. They are also useful in abdominal and fetal imaging and hold promise for interventional MR imaging. Because steady-state sequences are now commonly used in MR imaging, radiologists will benefit from understanding the underlying physics, classification, and clinical applications of these sequences.

Nonoperative management of pancreatic injuries in children

PURPOSE The safety and efficacy of nonoperative management of pancreatic contusions and transections was examined by reviewing the case histories of 35 consecutive children with pancreatic injuries treated over the past 10 years. METHODS/RESULTS Surgical exploration was performed for the management of associated injuries only. The diagnosis of pancreatic trauma was suspected in children with abdominal pain, tenderness, elevated serum amylase levels and findings consistent with pancreatic injury on abdominal ultrasound scan or computerized tomography (CT) examination. After children were diagnosed with pancreatic injury, enteral feedings were withheld and total parenteral nutrition administered until abdominal pain resolved and serum amylase levels and radiographic findings improved. Twenty-three children received diagnosis within 24 hours of injury, and in 12, the diagnosis was delayed 2 to 14 days. Hyperamylasemia was found in 27 of 35 children. Twenty-eight children sustaining pancreatic injuries were treated nonoperatively. Abdominal imaging in these children demonstrated pancreatic contusion in 14, transection in 11, and pseudocyst in three. Enteral feeding resumed an average of 15 days after injury. The average hospital stay was 21 days. Pseudocysts formed in 10 children (2 of 14 with contusion; 5 of 11 with transection; three children presented late, and the type of pancreatic injury could not be determined), whose average hospital stay was 25 days. All pseudocysts were successfully managed nonoperatively, although percutaneous aspiration or drainage was required in six children. Children underwent follow-up for an average of 10 months after injury (range, 1 to 144 months). Abdominal pain and radiological abnormalities resolved in all children before discharge from the clinic. CONCLUSIONS Nonoperative management of pancreatic contusion and transection diagnosed radiologically is effective and safe. Pseudocysts may form after pancreatic injury, and if large or symptomatic, can be managed successfully by percutaneous drainage.

Initial experience with FSE STIR whole-body MR imaging for staging lymphoma in children

Our objective was to compare fast spin-echo (FSE) short inversion time inversion recovery (STIR) whole-body MR imaging with standard procedures in staging children with lymphoma. Eight children (age range, 2–16 years) underwent multi-station FSE STIR whole-body MR at initial staging (n=5) or for restaging following completion of therapy (n=5). Whole-body MR and conventional staging procedures, including CT (n=10), gallium-67 scintigraphy (n=9), bone scintigraphy (n=3) and bone marrow biopsy (n=7) were retrospectively compared for detection of sites involved by lymphoma and for the assigned stage. FSE STIR whole-body MR detected more sites of possible lymphomatous involvement at initial staging (87/88) and at restaging (5/5) than did conventional imaging (74/88, 3/5). MR was more sensitive than conventional imaging in detecting bone marrow involvement at initial staging. Following treatment, however, residual and therapy-induced bone marrow signal abnormalities could not be differentiated from lymphomatous involvement. Detection of nodal and visceral involvement correlated well. Our results suggest that FSE STIR whole-body MR imaging is a sensitive technique for evaluating lymphomatous involvement of bone marrow as well as non-marrow sites. Larger prospective trials are needed to determine if FSE STIR whole-body MR can replace standard radiographic procedures for initial staging and contribute in the follow-up of lymphoma in children.

Pulmonary thromboembolism in children

Pulmonary thromboembolism (PTE) is uncommonly diagnosed in the pediatric patient, and indeed often only discovered on autopsy. The incidence of pediatric PTE depends upon the associated underlying disease, diagnostic tests used, and index of suspicion. Multiple risk factors can be found including: peripartum asphyxia, dyspnea, haemoptysis, chest pain, dehydration, septicemia, central venous lines (CVLs), trauma, surgery, ongoing hemolysis, vascular lesions, malignancy, renal disease, foreign bodies or, uncommonly, intracranial venous sinus thrombosis, burns, or nonbacterial thrombotic endocarditis. Other types of embolism can occur uncommonly in childhood and need to be recognized, as the required treatment will vary. These include pulmonary cytolytic thrombi, foreign bodies, tumor and septic emboli, and post-traumatic fat emboli. No single noninvasive test for pulmonary embolism is both sensitive and specific. A combination of diagnostic procedures must be used to identify suspect or confirmed cases of PTE. This article reviews the risk factors, clinical presentation and treatment of pulmonary embolism in children. It also highlights the current diagnostic tools and protocols used to evaluate pulmonary embolism in pediatric patients.

Ultrasonographic and clinical predictors of intussusception

OBJECTIVE The objective of this study was to determine the positive and negative clinical predictors of intussusception and the correlation of ultrasonography and air enema in establishing this diagnosis. STUDY DESIGN This was a prospective descriptive cohort study. SETTING This study was performed in a tertiary care pediatric emergency department. PARTICIPANTS Eighty-eight of 245 candidates were assessed for clinical predictors of intussusception. All 245 cases were examined for correlation between ultrasonography and air enema. INTERVENTIONS A questionnaire, ultrasonography, and air enema were used. RESULTS Thirty-five of the 88 patients assessed for clinical predictors were positive for intussusception. Significant positive predictors were right upper quadrant abdominal mass (positive predictive value [PPV] 94%), gross blood in stool (PPV 80%), blood on rectal examination (PPV 78%), the triad of intermittent abdominal pain, vomiting, and right upper quadrant abdominal mass (PPV 93%, p = 0.0001), and the triad with occult or gross blood per rectum (PPV 100%, p = not significant). Significant negative predictors were a combination of > or = 3 of 10 clinically significant negative features (negative predictive value 77%, p = 0.035). Of the total 245 cases, intussusception (as confirmed by doughnut, target, or pseudokidney sign) was ruled out by ultrasonography in 97.4%. Alternate ultrasound findings comprised 27% of negative cases. CONCLUSIONS Excellent positive predictors of intussusception were identified prospectively. Although no reliable negative predictors were found, patients at low risk may be screened by ultrasonography.

Evaluation of the Utility of Radiography in Acute Bronchiolitis

Objectives To determine the proportion of radiographs inconsistent with bronchiolitis in children with typical presentation of bronchiolitis and to compare rates of intended antibiotic therapy before radiography versus those given antibiotics after radiography. Study design We conducted a prospective cohort study in a pediatric emergency department of 265 infants aged 2 to 23 months with radiographs showing either airway disease only (simple bronchiolitis), airway and airspace disease (complex bronchiolitis), and inconsistent diagnoses (eg, lobar consolidation). Results The rate of inconsistent radiographs was 2 of 265 cases (0.75%; 95% CI 0-1.8). A total of 246 children (92.8%) had simple radiographs, and 17 radiographs (6.9%) were complex. To identify 1 inconsistent and 1 complex radiograph requires imaging 133 and 15 children, respectively. Of 148 infants with oxygen saturation >92% and a respiratory disease assessment score <10 of 17 points, 143 (96.6%) had a simple radiograph, compared with 102 of 117 infants (87.2%) with higher scores or lower saturation (odds ratio, 3.9; 95% CI, 1.3-14.3). Seven infants (2.6%) were identified for antibiotics pre-radiography; 39 infants (14.7%) received antibiotics post-radiography (95% CI, 8-16). Conclusions Infants with typical bronchiolitis do not need imaging because it is almost always consistent with bronchiolitis. Risk of airspace disease appears particularly low in children with saturation higher than 92% and mild to moderate distress.

Compatible scales for progressive and additive MRI assessments of haemophilic arthropathy

Summary.  The international MRI expert subgroup of the International Prophylaxis Study Group (IPSG) has developed a consensus for magnetic resonance imaging (MRI) scales for assessment of haemophilic arthropathy. A MRI scoring scheme including a 10 step progressive scale and a 20 step additive scale with identical definitions of mutual steps is presented. Using the progressive scale, effusion/haemarthrosis can correspond to progressive scores of 1, 2, or 3, and synovial hypertrophy and/or haemosiderin deposition to 4, 5, or 6. The progressive score can be 7 or 8 if there are subchondral cysts and/or surface erosions, and it is 9 or 10 if there is loss of cartilage. Using the additive scale, synovial hypertrophy contributes 1–3 points to the additive score and haemosiderin deposition contributes 1 point. For osteochondral changes, 16 statements are evaluated as to whether they are true or false, and each true statement contributes 1 point to the additive score. The use of these two compatible scales for progressive and additive MRI assessments can facilitate international comparison of data and enhance the accumulation of experience on MRI scoring of haemophilic arthropathy.