Abstracts of Staff Publications
aSpring 2001
Oligoclonal IgA response in the vascular wall in acute Kawasaki disease
Anne H. Rowley, Stanford T. Shulman, Benjamin T. Spike,
Carrie A. Mask, and Susan C. Baker
From the Departments of Pediatrics and Microbiology and Immunology,
Northwestern University Medical School, Children’s Memorial Hospital, Chicago, and the Department of Microbiology and Immunology,
Loyola University Stritch School of Medicine, Maywood, Illinois.
Journal of Immunology 2001;166:1334–1343
Copyright (c) 2001 by The American Association of Immunologists
Kawasaki disease (KD) is a potentially fatal acute vasculitis of childhood. Although KD is the leading cause of acquired heart disease in children in developed nations, its pathogenesis remains unknown. We previously reported the novel observation that IgA plasma cells infiltrate the vascular wall in acute KD. We have now examined the clonality of this IgA response in vascular tissue from 3 fatal cases of KD to determine whether it is oligoclonal, suggesting an antigen-driven process, or polyclonal, suggesting nonspecific B-cell activation or a response to a superantigen. We first sequenced VDJ junctions of 44 a genes isolated from a primary, unamplified KD vascular cDNA library. Five sets of clonally related a sequences were identified, comprising 34% (15/44) of the isolated a sequences. Furthermore, point mutations consistent with somatic mutation were detected in the related sequences. Next, using formalin-fixed coronary arteries from 2 additional fatal KD cases, we sequenced VDJ junctions of a genes isolated by RT-PCR, and a restricted pattern of CDR3 usage was observed in both. We conclude that the vascular IgA response in acute KD is oligoclonal. The identification of an oligoclonal IgA response in KD strongly suggests that the immune response to this important childhood illness is antigen-driven.
Serum vascular endothelial growth factor is elevated in cystic fibrosis and decreases with treatment of acute pulmonary exacerbation
S.A. McColley, V. Stellmach, S.R. Boas, M. Jain, and S.E. Crawford
From the Departments of Pediatrics, Pathology, and Internal Medicine, Northwestern University Medical School, Chicago, Illinois.
American Journal of Respiratory and Critical Care Medicine 2000; 161:1877–1880
Chronic bacterial infection and neutrophilic inflammation characterize cystic fibrosis (CF) pulmonary disease. In many disorders, inflammation and angiogenesis are codependent phenomena. We previously noted excessive angiogenesis in CF tissues and elevated vascular endothelial growth factor (VEGF) in random serum samples from CF subjects. To further explore this finding, we measured serum VEGF in 38 stable subjects with CF and in 25 subjects with other pulmonary diseases. Mean VEGF was elevated in both groups compared to reference values, but was higher in CF: 403 6 280 vs. 255 6 169 pg/ml, p= .02. VEGF was negatively correlated with FEV1 in CF, r = 20.51, p= .007. To assess the effect of airway infection on VEGF, 10 CF subjects were studied before and after intravenous antibiotic therapy for pulmonary exacerbation. VEGF levels decreased with antibiotic therapy, from 537 6 220 to 259 6 176 pg/ml, p= .001. We conclude that circulating VEGF is increased in subjects with CF and other inflammatory pulmonary disorders. In CF, VEGF elevation is related to airway infection. We speculate that increased circulating VEGF is related to chronic inflammation, which is robust in CF. Elevated circulating VEGF may result in tissue angiogenesis, furthering the progression of pulmonary disease.
Itraconazole pulse therapy for dermatophyte onychomycosis in children
Po-Han Huan and Amy S. Paller
From the Department of Dermatology, Chang Gung Memorial Hospital-Kaohsiung, Kaohsiung, Taiwan, and Departments of Pediatrics and Dermatology, Children’s Memorial Hospital, Northwestern University Medical School, Chicago, Illinois.
Archives of Pediatric and Adolescent Medicine 2000;154:614–618
Background: Onychomycosis, or fungal infection of the nail, can occur in prepubertal children. However, its diagnosis is often missed or the condition is inappropriately treated with topical medication. Griseofulvin has been the therapy of choice, but even long-term treatment is associated with a poor cure rate and high rate of relapse. Trials with adult patients have shown that itraconazole pulse therapy for onychomycosis requires a shorter duration of total therapy than griseofulvin treatment and is rarely associated with adverse reactions, suggesting that it may be the treatment of choice for pediatric patients with onychomycosis.
Design: We retrospectively reviewed the courses of prepubertal patients with dermatophyte onychomycosis who initiated treatment with itraconazole pulse therapy between January 1995 and June 1998.
Setting: Urban and suburban pediatric dermatology clinics of a children’s hospital.
Patients: Seventeen prepubertal patients met the enrollment and follow-up criteria. These included fungal infection of the nail(s), documented by fungal culture and/or positive potassium hydroxide mounts of nail scrapings; at least 1 follow-up visit; and contact by telephone or clinic visit within 2 months prior to compilation of data. In 59% of patients, a relative living at the home had onychomycosis at the time of diagnosis.
Intervention: Patients were treated with daily to twice-daily pulses of itraconazole, administered for 1 week of each of 3 to 5 months.
Main Outcome Measures: Clinical cure after itraconazole therapy in patients with documented onychomycosis and clinical and mycologic relapse after initial cure. Fungal cultures were not repeated if clinical cure was noted.
Results: All but 1 patient responded fully to therapy, showing improvement within a few months and subsequent clearance (94% clinical cure rate). No patients experienced any clinical adverse reactions. No relapses occurred after clinical cure during a follow-up period of 1 to 4.25 years after initiation of therapy.
Conclusions: Itraconazole pulse therapy is effective and safe for the treatment of onychomycosis in children. The relapse rate in pediatric patients is lower than in adults, although the high frequency of onychomycosis in nonpediatric family members suggests that the recurrence risk is increased if other family members are not treated concomitantly.
Squaric acid immunotherapy for warts in children
Nanette B. Silverberg, Joseph K. Lim, Amy S. Paller,
and Anthony J. Mancini
From the Departments of Pediatrics and Dermatology, Children’s Memorial Hospital and Northwestern University Medical School, Chicago, Illinois.
Journal of the American Academy of Dermatology 2000;42:803–8
Background: Warts are a common pediatric skin infection caused by human papillomavirus (HPV). Spontaneous clearance of warts involves anti-HPV immunity, which may be enhanced by contact sensitizers. Squaric acid dibutylester (SADBE) is a nonmutagenic sensitizing agent useful for immunotherapy of alopecia areata.
Objective: We hypothesized that SADBE home application might be effective therapy for warts.
Methods: An open-label, retrospective study of 61 children with warts was performed. Sensitization with 2% SADBE on the forearm was followed with home application of 0.2% SADBE to warts 3 to 7 nights per week for at least 3 months.
Results: Complete clearing occurred in 34 patients (58%), with a mean duration of therapy of 7 weeks. Partial clearing occurred in 11 (18%), and no response in 14 (24%). Clearance correlated with plantar distribution, wart duration under 2 years (P,.05), and first-line therapy with SADBE. Mild side effects occurred in one third of patients, were limited most commonly to mild erythema at the site of sensitization, and necessitated discontinuation of therapy in only 2 patients.
Conclusion: SADBE topical immunotherapy is a safe, effective option for home therapy of warts in children.
Bullous systemic lupus erythematosus with autoantibodies recognizing multiple skin basement membrane components, bullous pemphigoid antigen 1, laminin-5, laminin-6, and type VII collagen
L.S. Chan, J.C. Lapiere, M. Chen, T. Traczyk, A.J. Mancini, A.S. Paller, D.T. Woodley, and M.P. Marinkovich
From the Veterans Affairs Chicago Health Care System, Department of Dermatology, Northwestern University Medical School, Chicago, Illinois.
Archives of Dermatology 1999;135(5):569–73
Background: Bullous systemic lupus erythematosus (SLE) is a generalized subepidermal blistering skin eruption in patients suffering from SLE. Type VII collagen was initially identified as the target antigen.
Observations: We studied an unusual patient who had bullous systemic lupus erythematosus (SLE). The patient fulfilled the criterion of SLE with an antinuclear antibody titer of 1:5120. Immunopathological testing revealed in vivo deposition of all IgG subclasses, secretory IgA1, and both light chains at the patient’s skin basement membrane. The in vivo-bound IgG and IgA were localized at the hemidesmosomes and lamina densa. The patient’s IgG and IgA circulating autoantibodies labeled both the epidermal roof and the dermal floor of salt-split skin and recognized the hemidesmosomal protein BP230, as well as the full-length native form and the recombinant noncollagenous domain 1 of type VII collagen (anchoring fibril). In addition, the patient’s IgG autoantibodies recognized the anchoring filament proteins laminin-5 and laminin-6 (alpha3 chain and gamma2 chain).
Conclusions: We conclude that patients with bullous SLE may have autoantibodies to multiple basement membrane components critical for epidermal-dermal junctional adhesion. Possible pathogenic mechanisms in this patient’s clinical diseases include provocation of organ-specific disease (bullous disease) by systemic autoimmunity (lupus) and the “epitope spreading” immune phenomenon.
Masses of the salivary gland region in children
Brandon G. Bentz, C. Anthony Hughes, Jeffrey P. Lüdemann,
and John Maddalozzo
From the Division of Otolaryngology-Head and Neck Surgery, Northwestern University Medical School, Chicago, Illinois.
Archives of Otolaryngology and Head and Neck Surgery 2000; 126(12):
1435–1439.
Background: Noninflammatory masses of the salivary gland region in children are extremely rare. Therefore, very few published individual and institution-based experiences exist.
Design: Retrospective chart review from 1990 through 1997.
Setting: University-based children’s hospital.
Patients: Patients 18 years of age or younger with a tumor in the salivary gland region were included. Masses of infectious origin were excluded. Hemangiomas and lymphangiomas were tallied for relative incidences only.
Results: We found 324 consecutive cases of salivary gland masses: 192 hemangiomas (59.2%), 89 lymphangiomas (27.5%), and 43 (13.3%) solid masses. No significant difference was found between the age at presentation of the patients with benign solid tumors and the patients with malignant solid tumors (mean 6 SEM age, 7.2 6 0.7 years). Sixty-one percent of the masses were found in the parotid region; 18% were localized to the submandibular gland region; and the remaining 21% were located in the minor salivary gland site. The most common benign perisalivary masses were
pilomatrixomas (20.9%), followed by pleomorphic adenomas (11.6%). The most common malignant masses were mucoepidermoid carcinomas (9.3%), followed by rhabdomyosarcomas (7.0%). Treatment was individualized to the disease. Twenty-two patients had adequate data for follow-up analysis (mean 6 SEM follow-up, 30.0 6 8.4 months). Four patients (18.2%) experienced recurrent or residual disease and were alive with disease at last follow-up, and 100% of our population demonstrated disease-specific survival at last follow-up.
Conclusion: Vascular lesions outnumber solid tumors of the salivary gland region. The most common salivary tumors were pleomorphic adenomas, followed by mucoepidermoid carcinomas. Although certain solid salivary masses may demonstrate locally aggressive behavior, the overall prognosis is favorable.
Complications associated with the Sistrunk procedure
John Maddalozzo, T.K. Venkatesaan, and Pankaj Gupta
From the Division of Pediatric Otolaryngology, Northwestern University, Rush-Presbyterian-St Luke’s Medical Center, Chicago, Illlinois.
The Laryngoscope 2001;111(1): 119–123
Objective: To assess the type and rate of complications in the postoperative period of pediatric patients undergoing the Sistrunk procedure.
Design: A retrospective review of patients with a diagnosis of thyroglossal duct cyst who had not had corrective surgery previously. An attempt to standardize the study was made as follows: All patients had surgery under the direction of one surgeon, using the Sistrunk procedure with minor modifications from its original description. Complications were divided into major and minor categories.
Methods: Charts were reviewed for age, sex, preoperative assessment, and postoperative follow-up. Complications were recorded. A postoperative telephone survey was conducted.
Results: A minor complication rate of 29% was observed. There were no recurrences or major complications.
Conclusions: The Sistrunk procedure remains the operation of choice for removal of the thyroglossal duct cyst. When the surgery is properly performed, with attention to key surgical landmarks, the risk of major complication is minimal. Complications that do occur are minor and wound-related.
The economic impact of intermittent high-dose intravenous versus oral corticosteroid treatment of juvenile dermatomyositis
Marisa S. Klein-Gitelman, Teresa Waters, and Lauren M. Pachman
From the Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois, and The Institute of Public Health Services Research and Policy Studies, Northwestern University, Chicago, Illinois.
Journal of the American College of Rheumatology 2000; 360–368
Copyright (c) 2000 by the American College of Rheumatology
Objective: To perform a cost-identification and cost-effectiveness analysis comparing oral corticosteroids (OCS) with high-dose intermittent intravenous corticosteroid (IVCS) regimens in the treatment of juvenile dermatomyositis (JDM).
Methods: Children previously diagnosed and treated for JDM (without myositis-specific or myositis-associated autoantibodies) at a single medical center by a single provider were identified. Two treatment protocols were compared: OCS and IVCS. Data on initial disease severity, time to remission, resource use, and costs generated were collected from patient records. Incremental cost-effectiveness ratios (ICE) were constructed.
Results: Patients treated with IVCS achieved median remission 2 years earlier at median increased cost of $13,736. The ICE ratio comparing IVCS to OCS is $6,868 per year of disease avoided.
Conclusion: This study suggests that, although IVCS treatments are costly, they are cost-effective.
Decreased levels of CD54 (ICAM-1)-positive lymphocytes in the peripheral blood in untreated patients with active juvenile dermatomyositis
Maurice R. G. Gorman, Laura Bianchi, David Zaas, Virginia Corrochano, and Laura Pachman
From the Departments of Immunology/Rheumatology and Pediatrics, Children’s Memorial Hospital, Northwestern University Medical School, Chicago, Illinois.
Clinical and Diagnostic Laboratory Immunology 2000; 7:693–697
Copyright (c) 2000 by the American Society for Microbiology
Significant abnormalities are observed in the peripheral blood of juvenile dermatomyositis (JDM) patients with active disease. In this study, we confirm that there is a significant increase in the relative percentage of B lymphocytes in the peripheral blood of a group of untreated children with newly diagnosed active JDM compared to healthy children (P<0.0001). In order to investigate if properties intrinsic to B cells contributed to their relative increase in JDM, the percentage of B cells expressing activation markers (CD23, CD25, CD54, and CD69) was measured and compared to pediatric controls. Compared to healthy children less than 10 years of age (not significantly different from the JDM group), the JDM patients had an increase in the proportion of lymphocytes expressing CD19 (B cells; P<0.0017) and decreases in the percentage of lymphocytes that were CD3– CD16+ and/or CD56+ (NK cells; P=0.01) and CD3+ CD8+ (T suppressor/cytotoxic cells; P=0.02). There were no significant differences in any of the B-cell activation markers assessed. Of note, the percentage of CD54+ non-B lymphocytes (i.e., T cells and NK cells expressing CD54) was significantly lower in the JDM patients (25%±5%) than in the “age-related” healthy control group (43%±4%; P=0.013). These results suggest the following for untreated children with active JDM: (i) the increase in the percentage of peripheral blood B cells is not due to intrinsic B-cell activation, and (ii) CD54/ICAM-1+ non-B cells, CD8+ T cells, and NK cells are being removed from circulation and may be participating in the pathophysiology of the disease.
