Renuka Gera

Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: lessons learned from Pompe disease

Purpose:High sustained antibody titers complicate many disorders treated with a therapeutic protein, including those treated with enzyme replacement therapy, such as Pompe disease. Although enzyme replacement therapy with alglucosidase alfa (Myozyme) in Pompe disease has improved the prognosis of this otherwise lethal disorder, patients who develop high sustained antibody titers to alglucosidase alfa enter a prolonged phase of clinical decline resulting in death despite continued enzyme replacement therapy. Clinically effective immune-tolerance induction strategies have yet to be described in the setting of an entrenched immune response characterized by high sustained antibody titers, wherein antibody-producing plasma cells play an especially prominent role.Methods:We treated three patients with infantile Pompe disease experiencing marked clinical decline due to high sustained antibody titers. To target the plasma cell source of high sustained antibody titers, a regimen based on bortezomib (Velcade) was used in combination with rituximab, methotrexate, and intravenous immunoglobulin.Results:The treatment regimen was well tolerated, with no obvious side effects. Patient 1 had a 2,048-fold, and patients 2 and 3 each had a 64-fold, reduction in anti-alglucosidase alfa antibody titer, with concomitant sustained clinical improvement.Conclusion:The addition of bortezomib to immunomodulatory regimens is an effective and safe treatment strategy in infantile Pompe disease, with potentially broader clinical implications.Genet Med 2013:15(2):123–131

Penicillin-resistant Streptococcus mitis as a cause of septicemia with meningitis in febrile neutropenic children

PURPOSE The purpose of this report is to emphasize the importance of occurrence of Streptococcus mitis meningitis in febrile neutropenic children with hematopoietic malignancy. PATIENTS AND METHODS Symptoms of meningitis and sepsis (fever, headache, changes in mental status) were seen in three patients who were severely neutropenic and undergoing cytotoxic chemotherapy for CNS relapse of their underlying malignancy (acute lymphoblastic leukemia (ALL), n = 2; Burkitts lymphoma, n = 1). Chemotherapy had included cytosine arabinoside administered 7-14 days prior to presenting with sepsis and meningitis. All three patients had buccal mucositis or sinusitis. Blood cultures and CSF cultures showed S. mitis resistant to penicillin but sensitive to vancomycin. Vancomycin, at a dosage of 60 mg/kg/day to maximize CNS levels of antibiotic, was administered to all three children. RESULTS Two of the patients recovered from S. mitis meningitis; recovery was associated with an improvement in their peripheral granulocyte counts. One patient, who remained neutropenic, died despite being treated with both intravenous and intraventricular vancomycin. CONCLUSION Physicians caring for patients who are neutropenic and febrile need to be aware of the risk of meningitis occurring with S. mitis sepsis. Early treatment with high dosages of vancomycin (60 mg/kg/day) and an attempt to limit the duration of neutropenia are important factors in the outcome of such patients.

Student Evaluation Practices in Pediatric Clerkships: A Survey of the Medical Schools in the United States and Canada

Despite the curriculum changes during the past decade, there is paucity of information regarding the structure and evaluation processes in pediatric clerkships. Information regarding the educational components of the pediatric clerkship and student evaluation practices was obtained from the pediatric clerkship directors via a paper/electronic survey. Completed surveys were received from 97 US and Canadian medical schools and were analyzed. The average length of a clerkship was 7 weeks. Most clerkships required a 4-week ward, a 1-week newborn rotation, and a 2-week ambulatory rotation. Students were evaluated on each component of the clerkship in 93.5% of the programs. All programs evaluated student’s clinical performance and fund of knowledge; 85.6% evaluated student’s written record. Student’s clinical performance was evaluated by direct observation in 57% of the programs. Penalties for failing in clinical performance were harsher. In 56% of programs, a student failing in clinical performance failed the entire clerkship in contrast to 21.8% or 7% of the programs where a student failed the entire clerkship if they failed in the examination for the fund of knowledge or written record evaluation, respectively. The survey demonstrated a fair amount of consistency in clerkships across programs when compared with data obtained in 1981 and 1986. There was a noticeable increase in the well-baby nursery rotation; however, there was a decline in direct observation to assess physical examination or clinical performance.

Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses

BACKGROUND Enzyme replacement therapy (ERT) has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD), a rapidly progressive neuromuscular disorder. Yet marked interindividual variability in response to ERT, primarily attributable to the development of antibodies to ERT, remains an ongoing challenge. Immune tolerance to ongoing ERT has yet to be described in the setting of an entrenched immune response. METHODS Three infantile Pompe patients who developed high and sustained rhGAA IgG antibody titers (HSAT) and received a bortezomib-based immune tolerance induction (ITI) regimen were included in the study and were followed longitudinally to monitor the long-term safety and efficacy. A trial to taper the ITI protocol was attempted to monitor if true immune tolerance was achieved. RESULTS Bortezomib-based ITI protocol was safely tolerated and led to a significant decline in rhGAA antibody titers with concomitant sustained clinical improvement. Two of the 3 IPD patients were successfully weaned off all ITI protocol medications and continue to maintain low/no antibody titers. ITI protocol was significantly tapered in the third IPD patient. B cell recovery was observed in all 3 IPD patients. CONCLUSION This is the first report to our knowledge on successful induction of long-term immune tolerance in patients with IPD and HSAT refractory to agents such as cyclophosphamide, rituximab, and methotrexate, based on an approach using the proteasome inhibitor bortezomib. As immune responses limit the efficacy and cost-effectiveness of therapy for many conditions, proteasome inhibitors may have new therapeutic applications. FUNDING This research was supported by a grant from the Genzyme Corporation, a Sanofi Company (Cambridge, Massachusetts, USA), and in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network (RDCRN).

Central venous catheter infections in pediatric patients - in a community hospital

SummaryWe reviewed the records of 23 pediatric patients who had received at least one central venous catheter during a two-year period. Nine patients had acute lymphoblastic leukemia (ALL), nine had other hematologic/oncologic diagnoses, and five had cystic fibrosis. Twenty-nine of 65 febrile episodes in 16 patients were associated with a catheter-related infection. Twenty of 40 catheters were associated with an infection over a period of 7,229 catheter days. For every 1,000 catheter days, four episodes of infections were observed. The number of infections/1,000 catheter days, the average life of a catheter (℞ 180 days), and mean number of days elapsing before the first infection were not significantly different in the three diagnostic groups. Broviac catheters were used most often (24/40), followed by Quinton (9/40) and Port-a-Cath (7/40). Broviac catheters lasted twice as long (224 days, p<0.01) as Quinton and Porta-a-Cath. Grampositive cocci were isolated most frequently andStaphylococcus epidermidis was the most common pathogen. No consistent relationship between an absolute neutrophil count of <1,000/mm3 and infection with gram-positive cocci was seen. However, seven of eight episodes of gram-negative bacillary infections occurred in patients with an absolute neutrophil count of <1,000/m3 (p<0.005). Those patients who were not considered terminally ill responded well to antimicrobials. Catheter removal was necessary in only two instances.ZusammenfassungBei 23 pädiatrischen Patienten (neun Kindern mit akuter lymphoblastischer Leukämie, neun mit anderen malignen hämatologischen Erkrankungen oder Tumoren und fünf Kindern mit zystischer Fibrose) war im Zeitraum von zwei Jahren mindestens ein Zentralvenenkatheter gelegt worden. Die Krankengeschichten dieser Kinder wurden retrospektiv ausgewertet. Bei 16 Patienten traten insgesamt 65 Fieberepisoden auf, in 29 Fällen bestand eine Katheter-assoziierte Infektion. 20 von 40 Kathetern mit einer Gesamtverweildauer von 7229 Kathetertagen waren infiziert. Im Mittel kamen 4,0 Infektionen auf 1000 Kathetertage. In den drei Diagnosegruppen waren keine Unterschiede bezüglich der Anzahl der Infektionen/1000 Kathetertage, der durchschnittlichen Katheterverweildauer (etwa 180 Tage) oder der mittleren Anzahl von Tagen bis zum Auftreten der ersten Infektion festzustellen. Am häufigsten wurden Broviac-Katheter verwendet (24/40), es folgten Quinton-Katheter (9/40) und Port-a-Cath (7/40). Die Liegedauer der Broviac-Katheter war doppelt so lang (224 Tage) wie die der Quinton- oder Port-a-Cath-Modelle (p<0,01). Am häufigsten wurden grampositive Kokken aus den infizierten Kathetern isoliert, der häufigste Erreger warStaphylococcus aureus. Absolute Granulozytenzahlen unter 1000/mm3 standen nicht in Korrelation zur Infektionshäufigkeit mit grampositiven Kokken; jedoch waren sieben der acht Infektionen mit gramnegativen Stäbchen bei Patienten mit einer absoluten Granulozytenzahl von weniger als 1000/mm3 (p<0,005) aufgetreten. Patienten, die nicht im terminalen Krankheitsstadium waren, sprachen auf Antibiotika gut an. Nur in zwei Fällen mußte der Katheter entfernt werden.

Severe intrarenal fibrosis, infundibular stenosis, renal cysts, and persistent perilobar nephrogenic rests in a patient with Beckwith-Wiedemann syndrome 27 years after diffuse nephroblastomatosis and Wilms tumor: natural progression or a consequence of treatment?

A27-year-old woman presented with back and abdominal pain. She was diagnosed in infancy with Beckwith-Wiedemann syndrome and bilateral multifocal perilobar nephrogenic rests that progressed to diffuse nephroblastomatosis with neoplastic nephroblastomatous rests at 14 months of age and subsequently to a right Wilms tumor at 5 years of age. Computed tomography of the abdomen during the current admission showed multiple obstructed calices. Ureteroscopic inspection of the left kidney revealed severe intrarenal scarring with multiple infundibular stenosis, hydrocalices, and nephrocalcinosis. Renal biopsy showed sclerotic glomeruli with calcification and scarring and persistent subcapsular nodular renal blastema. Electrocautery incision and balloon dilatation provided temporary pain relief. After discharge, the patient has had two or three episodes of recurrent pain associated with new areas of infundibular stenoses and renal cysts. Bilateral nephrectomy and renal transplantation is being considered for management of progressive disease and relief of intractable pain. The potential causes of progressive and severe intrarenal fibrosis, infundibular stenosis and nephrocalcinosis, and renal cysts in this patient may include abnormal renal development secondary to Beckwith-Wiedemann syndrome itself, radiation or chemotherapy damage, or a combination.

Pediatric transfusion therapy: practical considerations.

Over the past decade, safety of blood has increased tremendously because of better donor screening as well as testing of the units for transmissible diseases. Component therapy has allowed more effective and economic use of blood. Whole blood is rarely used; instead, packed red cells, platelets, and fresh frozen plasma (FFP) are the most common components used. These products are further refined using irradiation and microaggregate filters and in the case of FFP, viral inactivation. Irradiation prevents transfusion-associated graft versus host disease, whereas microaggregate filters remove leukocytes, decreasing the rates of alloimmunization, febrile nonhemolytic (FNH) reactions, and cytomegalovirus (CMV) transmission. Autologous donation in older children probably provides the safest blood as far as transmissible diseases are concerned. More families request a directed donation and solicit physician help in deciding as well as making arrangements for autologous and/or directed donations.Transfusions of blood and blood components in children are often challenging and require a knowledge of physiologic changes in hemoglobin and blood volumes during different ages. The unique needs of neonates, immunocompromised patients, and patients with congenital hemolytic anemia (sickle cell, thalassemia) mandate that the pediatrician have an appropriate knowledge of transfusion volumes and choice of blood product as well as indications for transfusion.

Polyfungal systemic infections in pediatric oncology patients

Three cases of two fungal agents causing simultaneous systemic infection in immunocompromised pediatric patients are presented and the literature is reviewed. All three patients had several underlying factors that predispose to systemic fungal infections. A species of candida was identified initially as an etiologic agent in all of the three patients causing subcutaneous abscesses, urinary tract infections, fungemia, catheter exit site infection, or pneumonia. However, a few days later blood cultures grew aspergillus species in two of the three patients; in the third patient aspergillus was identified on microscopic examination of the spleen. All three patients had an associated bacteremia with either Staphylococcus aureus or S. epidermidis requiring vancomycin therapy. Presence of aspergillus infection required treatment with amphotericin. Difficulties in making a definitive diagnosis of systemic fungal disease may explain paucity of reports in the literature with simultaneous polyfungal systemic infection.

Nondisclosure of human immunodeficiency virus and hepatitis C virus coinfection in a patient with hemophilia: Medical and ethical considerations

This article discusses a medical and ethical dilemma: whether to disclose a positive HIV (human immunodeficiency virus)/HCV (hepatitis C virus) coinfection to an adolescent boy without symptoms with hemophilia despite the objections of his parents. An actual case history is presented and the dilemma faced by the medical team is discussed. Numerous family conferences, all excluding the patient, held during the last 5 years discussed the medical teams obligation for full disclosure, the emerging autonomy of the patient, and the potential for medical disaster (e.g., HIV transmission) if full disclosure were not permitted. Despite this, the family did not agree to allow disclosure. The patient and parents assured us of his sexual inactivity. Legal opinion was sought from the university counsel. The dilemmas are multiple. Is there a convincing argument to insist on disclosure of these facts to this patient, particularly when there is ambiguity regarding the appropriateness of HIV and HCV treatment? Does the ethical argument that he is at potential risk for transmitting HIV/HCV outweigh the rights of the family? What are the rights of the rest of the family? What are the rights of the minor? Is it our ethical responsibility to disclose a probably fatal diagnosis?

Disabilities in adolescents with cancer

Advances in medical treatment have resulted in improved survival in adolescents and children with cancer and ironically increased the number of adolescent survivors of cancer, who have disabilities resulting from their treatment. Long-term cancer survivorship for most cancers is defined as continuous remission at five years from diagnosis. Despite the low risk of relapse beyond five years, cancer continues to remain a major cause of mortality and morbidity in children and adolescents. In addition to a constant threat of relapse, long-term cancer survivors suffer from disabling late complications. Adolescents and children with cancer fall into this category. Although the literature evaluating the impact of cancer on the growth and development of adolescents is plentiful, the magnitude of impairment and disability caused by cancer has not been completely realized. This discussion considers some of these