The atopy patch test in the diagnostic workup of suspected food-related symptoms in children

BACKGROUND: There is an increasing need to develop test instruments that make oral food challenges superfluous. OBJECTIVE: We sought to study the utility of atopy patch tests (APTs) in the diagnostic workup of food allergy. METHODS: We investigated 437 children (median age, 13 months; 90% with atopic dermatitis) referred for evaluation of suspected food allergy. Specific serum IgE (sIgE) measurements, skin prick tests (SPTs), APTs, and controlled oral food challenges were performed. RESULTS: We analyzed 873 oral challenges with cow's milk, hen's egg, wheat, and/or soy. One thousand seven hundred single APTs were performed. As a single parameter, the APTs showed the best specificity compared with sIgE measurements, SPTs, or both. Combining the APT with either the SPT or sIgE measurement resulted in improved sensitivity and specificity. Decision points for sIgE measurement and for the SPT showed lower values when combined with a positive APT result. Correctly bypassing an oral food challenge with combined testing, including APTs, only between 0.5% and 7% (99% predicted probability) and between 6% and 14% (using 95% predicted probability) of children would fulfill the criteria for avoiding an oral food challenge. CONCLUSION: Although the predictive capacity of the APT is improved when combined with sIgE measurement or the SPT, oral food challenges become superfluous in only 0.5% to 14% of study patients. In addition, the APT is time consuming and demands a highly experienced test evaluator. CLINICAL IMPLICATIONS: For daily clinical practice, the APT adds only a small predictive value to the standard SPT and sIgE measurement in the diagnostic workup of suspected food-related symptoms in our study population.     

Panhypopituitarism in a child with common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) represents a group of heterogeneous, still undifferentiated, syndromes that are all characterized by defective antibody formation. It is often associated with autoimmune disease. METHODS: An African-American girl was diagnosed with CVID at age 3 years. She was seen during an adrenal crisis precipitated by pneumonia at the age of 8 years and 10 months. The diagnosis of panhypopituitarism was established soon after. RESULTS: Panhypopituitarism in this patient was believed to be the result of the autoimmune process known as lymphocytic hypophysitis. This hypothesis was suggested by the results of magnetic resonance imaging. CONCLUSIONS: Awareness of the possibility of this process in children or adults with CVID may lead to earlier diagnosis of panhypopituitarism. These patients also have failure to thrive, and earlier diagnosis may avoid a life-threatening event.     

Primary hepatic leiomyosarcoma in a child with the acquired immunodeficiency syndrome.

We report the first case of acquired immunodeficiency syndrome (AIDS)-related primary hepatic leiomyosarcoma in a 9-year-old girl. The pathologic diagnosis was made on a partial hepatectomy specimen and was confirmed by immunohistochemistry and electron microscopy. No human immunodeficiency virus-related nucleic acid was identified in tumor cells by in situ hybridization. Review of the AIDS-related literature reveals a rising incidence of tumors of smooth muscle origin in human immunodeficiency virus-infected patients. This case study details the eighth pediatric AIDS patient with a tumor of smooth muscle origin and represents the 20th and the youngest patient with primary hepatic leiomyosarcoma to be reported in the world literature.     

The immunologic basis of autoimmunization.

Autoimmunization is today so readily accepted as established fact that it is easy to forget its turbulent history. There was a time when a few stubborn physicians had to insist against informed opinion that autoimmune diseases really existed. The answer they received was, “… I'll never believe there is such a thing as an autoantibody.”¹ Now the tables are turned. Today immunochemists are presenting schemes that require the formation of autoantibodies during the normal immune response. ² Between these two extremes there is an evolution of thought that began with horror autotoxicus, ³ continued with the demonstration of experimental autoimmunization in laboratory animals, ⁴ entered the clinic with the realization that certain forms of hemolytic anemia were due to autoantibodies, ⁵ crystallized as a biologic problem with the advent of immunologic tolerance, ⁶ advanced into the rarefied theory of forbidden clones, ⁷ progressed immeasurably when spontaneous autoimmunity was found in the mouse, ⁸ and reached its present state of complexity with the discoveries of immunoglobulin receptors on lymphocytes, ⁹idiotypes, ¹⁰ and suppressor cells. ¹¹ Perhaps the most important advance was the realization, spontaneously arrived at by almost the entire immunologic community, that the production of autoantibodies can be understood only in the context of the general rules of antibody formation.     

Clinical and immunologic analyses of 103 patients with common variable immunodeficiency

Common variable immunodeficiency (CVI) or hypogammaglobulinemia is a heterogeneous primary immunodeficiency disease in which B cells produce little or no antibody. Since the disease is relatively rare and the spectrum of associated illnesses is broad, patients are given care by a variety of specialists. Thus it has been difficult to determine the incidence of specific complications. In these studies we analyzed 103 consecutively referred CVI patients of age range 3–71 years (average, 29 years) who were followed for a period of 1–13 years (total of 750 patient years). The average serum IgG was 174.4 mg/dl for untreated patients and 301 mg/dl for patients treated with intramuscular immunoglobulin at the time of the first visit. The average IgA was 14.5, and the average IgM was 80.7, with no difference between or after immunoglobulin treatment. About one-half of the patients had T-cell dysfunction, but lymphocyte stimulation responses were inversely related to age, which implies worsened T-cell immunity with age. Serum IgG and IgA levels were found to be statistically associated (P=0.008), and serum IgG was related to lymphocyte stimulation with concanavalin A (P=0.01). By 1986, 79 patients were alive, 23 had died, and 1 could not be located. Recurrent bacterial illnesses were common to all patients, and 22% had developed chronic lung disease, 22% autoimmune disease, 15% cancer, 13% hepatitis, and 9% malabsorption. Autoimmune disease was more common in females, and cancer was more likely to develop in the fifth and sixth decades. In 11% of the group, other family members were found to be immunodeficient (hypogammaglobulinemic or IgA deficient). Nine patients died of respiratory insufficiency (with or without other complications), and seven patients died of cancer. These data provide valuable information about the immunologic abnormalities and the spectrum and frequency of illnesses associated with hypogammaglobulinemia.     

Anti-IgA antibodies in common variable immunodeficiency (CVID): diagnostic workup and therapeutic strategy

Common Variable Immunodeficiency (CVID) patients who are seropositive for anti-IgA antibodies have a predisposition for anaphylactoid reactions to intravenous immunoglobulin replacement therapy (IVIG). Among 88 CVID patients, we identified eight with IgG anti-IgA antibodies (9%). All eight completely lacked IgA (<0.0009 g/l). Five of them had a history of anaphylactoid reactions to IVIG. However, four of these five patients tolerated subcutaneous immunoglobulin replacement therapy (SCIG). To identify predisposing factors for anti-IgA antibodies and related anaphylactoid reactions, we analyzed the clinical and immunological phenotype of affected patients. All eight IgG anti-IgA-positive patients lacked IgA(+) B cells in peripheral blood. Moreover, CVID patients with retained class-switched CD27(pos) IgM(neg) IgD(neg) memory B cells (Freiburg classification group II) and total IgA deficiency seem to have an increased risk for developing anti-IgA antibodies. In seven of the eight patients, lymphoproliferation was observed (most prominently nodular lymphatic hyperplasia), two had granulomatous disease, and two showed autoimmune phenomena.     

Clinicians' reporting of suspected child abuse: A review of the empirical literature

Although psychologists are mandated by law to report suspected child abuse, large numbers of clinicians have been found to comply inconsistently with reporting laws. A variety of factors have been shown to influence clinicians' child abuse reporting. When placed within the context of a comprehensive decision-making model, these factors explain willingness to report suspected child abuse. Legal requirements, clinician characteristics, and situational dimensions have all been found to interact to influence child abuse reporting decisions. A review of the child abuse reporting literature suggests that practitioners may take effective action toward increasing compliance with mandatory reporting laws while minimizing potential disruption to treatment. Implications for public policy, practice, and suggestions for further research are offered.     

Angioimmunoblastic lymphadenopathy in a child with unusual clinical and immunologic features

We report a case of angioimmunoblastic lymphadenopathy in a child followed for 13 years. Unusual features include prolonged course, cold urticaria, nonthrombocytopenic purpura, poor wound healing, transfusion reactions, and possible neurologic involvement with cerebritis and epileptic seizures. The patient's serum contained a monoclonal cryoglobulin, immunoglobulin G, kappa light chain type, that activated the classic complement pathway in vitro and mediated passive transfer of the cold urticaria. The patient responded well to corticosteroids and has been in clinical remission for 8 years without specific treatment. There is immunologic evidence of persistent residual disease activity. This case illustrates the remarkable diversity of clinical and immunologic features and the variable prognosis of this disorder.     

A patient with severe black fly (Simuliidae) hypersensitivity referred for evaluation of suspected immunodeficiency.

BACKGROUND: Biting flies of the Diptera order and specifically the black fly (Simuliidae family) can be rare causes of severe hypersensitivity reactions. OBJECTIVE: To describe a patient referred for evaluation of immunodeficiency whose clinical course is explained by severe Simuliidae hypersensitivity. METHODS: The patient's immune system was investigated using standard laboratory evaluations. Hypersensitivity to Simuliidae was pursued because of historical features of her presentation and was specifically examined by skin prick and intradermal testing with whole body extract. RESULTS: The patient's history was notable for recurrent and severe seasonal episodes of presumed cellulitis after black fly bites that responded poorly to intravenous antibiotics. One episode was followed by acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome) and another by minimal change nephrotic syndrome. The results of immunologic investigations were unremarkable, but cutaneous hypersensitivity to Simuliidae was demonstrated with a 6.5-mm wheel and 35-mm flare reaction to intradermal injection of only 0.0005 microg of whole body extract. CONCLUSION: Similar to Hymenoptera, Simuliidae can rarely result in extreme hypersensitivity and should be considered in appropriate cases. This patient illustrates how severe reactions toinsect bites can be misdiagnosed.     

Primary immunodeficiency state in a child with the pulmonary hypertension syndrome

A girl aged 2 years and 10 months repeatedly suffered viral (thrice) and bacterial (colitis, salmonellosis, pneumonia 6 times) infections. At an age of 2 years primary pulmonary hypertension was diagnosed. Diagnostic catheterization was performed to exclude a congenital heart disease. The death occurred during the catheterization. An increase of beta-lymphocytes and plasma cells, a reduction of the T-lymphocyte zone were detected in the immunocompetent system during postmortem histological examination. The pathology diagnosis: primary immunodeficiency with a predominant suppression of cell-mediated immunity; hyperplasia of the lymph nodes with their plasmacytization; pneumosclerosis of all lobes of both lungs (a syndrome of primary pulmonary hypertension clinically); hypertrophy of the muscles of both atria and right ventricle, dilation of the heart cavities; acute heart insufficiency.     

The discovery of immunologic tolerance

The phenomenon of tolerance can be said to have begun with the seminal observations in 1945 by R. D. Owen that cattle dizygotic twins display red cell chimerism—mosaicism as he called it—in adult life. Owen interpreted this extraordinary finding in terms of the much earlier discovery by F. R. Lillie that the placentae of cattle dizygotic twins undergo anastomosis early in fetal life, and he speculated that this would have permitted blood cells and their precursors to move from one twin to the other. Owen's discovery came out of the blue and it was ignored by immunologists until F. M. Burnet and F. Fenner highlighted it four years later in their influential monograph The Production of Antibodies, in which they predicted the existence of tolerance as a general phenomenon and developed their notion of “self-markers” to explain why the body does not react against self. Though it was Medawar's group that showed conclusively in 1953 that tolerance can be experimentally induced in fetal mice and in chick embryos, their entry into this field came from a totally different direction, an attempt to distinguish between mono- and dizygotic cattle twins by the exchange of skin grafts. This led to the seemingly paradoxic result that grafts exchanged between dizygotic twins were accepted (1951) and it was not until their cattle experiments had been virtually completed that they became aware of Owen's earlier discovery. Following the work of Billingham, Brent, and Medawar, and of Hasek, tolerance became incorporated into general immunologic theory and it helped to explain the fact that mammals do not normally suffer from injurious autoimmune manifestations. Ray Owen's discovery therefore has a secure place in the history of immunology.     

Neurophysiologic and immunologic abnormalities associated with feline immunodeficiency virus molecular clone FIV-PPR DNA inoculation

Although direct feline immunodeficiency virus (FIV) proviral DNA inoculation has been shown to be infectious in cats, long-term studies to assess the pathogenic nature of DNA inoculation are lacking. We have recently reported that direct feline leukemia virus (FeLV) DNA inoculation resulted in infection and the development of FeLV-related disease end points with similar temporal expression and virulence to that of cats infected with whole virus. We show in this study that pFIV-PPR DNA inoculation resulted in infection of cats and the development of FIV-related immunologic and neurologic abnormalities. Infected cats demonstrated progressive loss of CD4+ lymphocytes resulting in decreased CD4:CD8 ratios. Neurologic dysfunction was demonstrated by increased bilateral frontal lobe slow-wave activity. Prolongation of the visual evoked potential peak latency onset response pattern also supported a similar progression of abnormal cortical response. Furthermore, histopathologic examination revealed lesions attributed to FIV infection in lymph node, thymus, brain, and lung. Finally, nested polymerase chain reaction detected FIV provirus in brain, bone marrow, mesenteric lymph node, thymus, spleen, tonsil, and liver. These results confirm that FIV DNA inoculation is an efficient model for study of the pathogenic nature of molecular clones in vivo and offers the opportunity to measure temporal genomic stability of a homogeneous challenge material.     

Unusual clinical and immunologic manifestations of transplacentally acquired maternal T cells in severe combined immunodeficiency

The persistence of transplacentally transferred maternal T cells is common in infants with severe combined immunodeficiency (SCID), occurring in more than half of patients with SCID undergoing transplantation at our institution. These T cells respond poorly to mitogens in vitro but can cause cutaneous graft-versus-host disease; however, other effects of these cells are unknown. We describe 2 infants with SCID who had unusual problems associated with transplacentally transferred maternal T cells. Patient 1 was a 5-month-old girl with Janus kinase 3-deficient SCID who had 4% circulating CD3(+) T cells but no lymphocyte proliferative response to mitogens. Although the number of T cells increased after 2 nonchemoablated, T cell-depleted, haploidentical, paternal bone marrow transplantations, T-cell function failed to develop, and she became pancytopenic. Restriction fragment length polymorphism studies of flow cytometry-sorted blood T cells revealed all to be of maternal origin. A subsequent nonchemoablated, T cell-depleted maternal transplantation resulted in normal T-cell function and marrow recovery. Patient 2 was a 9-month-old girl with IL-7Ralpha-deficient SCID who presented with autoimmune pancytopenia. She had 8% blood T cells (all CD45RO(+)) but no response to mitogens. High-resolution HLA sequence-specific priming typing detected both maternal haplotypes, indicating the presence of maternal cells. Her pancytopenia resolved after treatment with rituximab and was thought to be due to host B-cell activation by transplacentally acquired maternal T cells. Persistent transplacentally acquired maternal T cells in infants with SCID can mediate immunologic functions despite failing to respond to mitogens in vitro. We present evidence that these cells can cause allograft rejection and immune cytopenias.     

Lymph node examination. What is an adequate workup?

Lymph node examination has traditionally been difficult to perform satisfactorily. Both pathologists and clinicians often lack confidence in the resulting diagnosis, and repeated biopsy or routine requests for consultative opinion may follow. Artifactual distortion of lymph nodes during removal and processing are partially responsible for these unsatisfactory circumstances. More recently, a developing awareness of the inherent complexity of lymphoproliferative diseases and the availability of more sophisticated studies have further compounded these traditional problems. This article describes the specific methods recommended to allow community pathologists to scale lymph node examination to the diagnostic difficulty of the disease present. In particular, simple and inexpensive procedures allow tissue samples to be saved for immunologic phenotyping and electron microscopy while routine histopathologic sections are being evaluated.