Juvenile idiopathic polyarticular arthritis and IgA deficiency in the 22q11 deletion syndrome.

Five patients with the 22q11 deletion syndrome (velocardiofacial syndrome) developed chronic inflammatory polyarticular arthritis. These new cases add to 8 previously reported and confirm the association. The arthritis in all cases was moderate to severe, but at least partially responsive to methotrexate and/or corticosteroids, and was clinically indistinguishable from juvenile idiopathic arthritis (JIA). Analysis of the total 13 patients indicates that 2 are rheumatoid factor positive, 6 are antinuclear antibody positive, 5 have subtle T cell deficiencies, and 6 have hypergammaglobulinemia. Of particular interest is the occurrence of IgA deficiency in 4 patients, including 2 from our own series. Although IgA deficiency is seen in both JIA (2-4%) and 22q11 deletion syndrome (2-4%), the prevalence of low IgA in this series (31%) is much greater than expected. This phenomenon and the true association of inflammatory arthritis and a chromosome deletion disorder provides further evidence of important genetic factors in the pathogenesis of JIA.

Cytokine and chemokine dysregulation in hyper-IgE syndrome.

Hyper-IgE syndrome is characterized by severe recurrent staphylococcal infections, eczema, bone abnormalities, and markedly elevated levels of immunoglobulin E (IgE). The genetic basis is not known and the central immunologic defect is largely undefined. Reduced neutrophil chemotaxis is often described, and variable T cell defects have been demonstrated in some patients. It has been hypothesized that hyper-IgE is associated with a Th1/Th2 imbalance. We wished to characterize cytokine and chemokine imbalances that might reflect the underlying disease process or reflect ongoing pathologic processes. Nine patients with hyper-IgE syndrome and six controls were studied. Radioimmunoassays, flow cytometry, and gene array analyses were performed to characterize cytokine and chemokine production. Hyper-IgE patients express more IL-12, while ENA-78, MCP-3, and eotaxin are markedly underexpressed. Underexpression of a set of chemokines could explain a number of features of hyper-IgE syndrome and may offer a new paradigm for the understanding of this disorder.

Unrelated umbilical cord stem cell transplantation for X-linked immunodeficiencies.

Banked unrelated umbilical cord blood matched at 5 of 6 human leukocyte antigen loci was used to reconstitute the immune system in 2 brothers with X-linked lymphoproliferative syndrome and 1 boy with X-linked hyperimmunoglobulin-M syndrome. Pretransplant cytoreduction and posttransplant graft-versus-host prophylaxis were given. Hematopoietic engraftment and correction of the genetic defects were documented by molecular techniques. Two years after transplantation, all 3 patients have normal immune systems. These reports support the wider use of banked partially matched cord blood for transplantation in primary immunodeficiencies.

Breast milk transmission of viral disease.

Breast milk transmission of maternal viral infection is well established for CMV and HIV-1. In the case of CMV, this usually does not pose a risk to the infant since serious disease is prevented by placentally transferred maternal antibody. However, in HIV infection, breast-feeding increases the risk of maternal-fetal transmission by about 25% with late breast-feeding (after six months of age) constituting a particular risk. In other maternal viral diseases, e.g., other herpes viruses, parvovirus, hepatitis A, B and C, and rubella, the virus is often demonstrated in the breast milk, but transmission is very rare. The highest risk is during an acute viral infection at the time of birth, since the breast milk has a high titer of virus, and a lack of antibody to neutralize the organism.

Passive immunity in prevention and treatment of infectious diseases.

Antibodies have been used for over a century in the prevention and treatment of infectious disease. They are used most commonly for the prevention of measles, hepatitis A, hepatitis B, tetanus, varicella, rabies, and vaccinia. Although their use in the treatment of bacterial infection has largely been supplanted by antibiotics, antibodies remain a critical component of the treatment of diptheria, tetanus, and botulism. High-dose intravenous immunoglobulin can be used to treat certain viral infections in immunocompromised patients (e.g., cytomegalovirus, parvovirus B19, and enterovirus infections). Antibodies may also be of value in toxic shock syndrome, Ebola virus, and refractory staphylococcal infections. Palivizumab, the first monoclonal antibody licensed (in 1998) for an infectious disease, can prevent respiratory syncytial virus infection in high-risk infants. The development and use of additional monoclonal antibodies to key epitopes of microbial pathogens may further define protective humoral responses and lead to new approaches for the prevention and treatment of infectious diseases.

Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.

PURPOSE: To provide recommendations for the use of immunosuppressive drugs in the treatment of patients with ocular inflammatory disorders. PARTICIPANTS: A 12-person panel of physicians with expertise in ophthalmologic, pediatric, and rheumatologic disease, in research, and in the use of immunosuppressive drugs in patient care. EVIDENCE: Published clinical study results. Recommendations were rated according to the quality and strength of available evidence. PROCESS: The panel was convened in September of 1999 and met regularly through May 2000. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although corticosteroids represent one of the mainstays in the management of patients with ocular inflammation, in many patients, the severity of the disease, the presence of corticosteroid side effects, or the requirement for doses of systemic corticosteroids highly likely to result in corticosteroid complications supports the rationale for immunosuppressive drugs (for example, antimetabolites, T-cell inhibitors, and alkylating agents) being used in the management of these patients. Because of the potential for side effects, treatment must be individualized and regular monitoring performed. With careful use of immunosuppressive drugs for treatment of ocular inflammatory disorders, many patients will benefit from them either with better control of the ocular inflammation or with a decrease in corticosteroid side effects.

Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine. Pediatric AIDS Clinical Trials Group 185 Team.

OBJECTIVE: To evaluate independent contributions of maternal factors to adverse pregnancy outcomes (APO) in HIV-infected women receiving antiretroviral therapy (ART). DESIGN: Risk factors for preterm birth (< 37 weeks gestation), low birth weight (LBW) (< 2500 g), and intrauterine growth retardation (IUGR) (birth weight < 10th percentile for gestational age) examined in 497 HIV-infected pregnant women enrolled in PACTG 185, a perinatal clinical trial. METHODS: HIV RNA copy number, culture titer, and CD4 lymphocyte counts were measured during pregnancy. Information collected included antenatal use of cigarettes, alcohol, illicit drugs; ART; obstetric history and complications. RESULTS: Eighty-six percent were minority race/ethnicity; 86% received antenatal monotherapy, predominantly zidovudine (ZDV), and 14% received combination antiretrovirals. Preterm birth occurred in 17%, LBW in 13%, IUGR in 6%. Risk of preterm birth was independently associated with prior preterm birth [odds ratio (OR) 3.34; P < 0.001], multiple gestation (OR, 6.02; P = 0.011), antenatal alcohol use (OR, 1.91; P = 0.038), and antenatal diagnosis of genital herpes (OR, 0.24; P = 0.022) or pre-eclampsia (OR, 6.36; P = 0.025). LBW was associated with antenatal diagnosis of genital herpes (OR, 0.08; P = 0.014) and pre-eclampsia (OR, 5.25; P = 0.049), and baseline HIV culture titer (OR, 1.41; P = 0.037). IUGR was associated with multiple gestation (OR, 8.20; P = 0.010), antenatal cigarette use (OR, 3.60; P = 0.008), and pre-eclampsia (OR, 12.90; P = 0.007). Maternal immune status and HIV RNA copy number were not associated with APO. CONCLUSIONS: Risk factors for APO in antiretroviral treated HIV-infected women are similar to those reported for uninfected women. These data suggest that provision of prenatal care and ART may reduce APO.

Complications according to mode of delivery among human immunodeficiency virus-infected women with CD4 lymphocyte counts of < or = 500/microL.

OBJECTIVE: We sought to describe rates of and risk factors for complications by delivery mode among human immunodeficiency virus-infected women with CD4 counts of < or = 500/microL. STUDY DESIGN: Complication rates were calculated by delivery mode, as follows: planned cesarean delivery performed without labor or rupture of membranes, other cesarean delivery performed after labor or rupture of membranes, or vaginal delivery. Risk factors were evaluated. RESULTS: Major complications in the planned cesarean delivery (n = 37), other cesarean delivery (n = 95), and vaginal delivery (n = 365) groups were amnionitis or endometritis (16%, 27%, and 7%, respectively), wound infection (5%, 8%, and <1%, respectively), and transfusion (8%, 6%, and 3%, respectively). Any peripartum infection occurred among 16 (18%) of those with a CD4 count of <200/microL and 43 (13%) with a CD4 count of > or =200/microL (P =.17). On multivariate analyses, factors associated with amnionitis-endometritis were cesarean delivery and African American race, and a factor associated with transfusion was third-trimester anemia. CONCLUSION: Endometritis and wound infection occurred more frequently among human immunodeficiency virus-infected women after cesarean than among women undergoing vaginal delivery; however, complication rates overall were within the range reported in human immunodeficiency virus-negative women. Measures to decrease complications in human immunodeficiency virus-infected women, such as greater use of prophylactic antibiotics, should be assessed.

Use of human immunodeficiency virus (HIV) human hyperimmune immunoglobulin in HIV type 1-infected children (Pediatric AIDS clinical trials group protocol 273).

The clinical, immunologic, and virologic effects and the pharmacokinetics of human immunodeficiency virus (HIV) human hyperimmune immunoglobulin (HIVIG) were assessed in 30 HIV-infected children aged 2-11 years. All had moderately advanced disease with an immune complex-dissociated (ICD) p24 antigen >70 pg/mL and were on stable antiviral therapy. Three groups of 10 children received 6 monthly infusions of 200, 400, or 800 mg/kg of HIVIG, and serial immunologic and virologic assays were performed. HIVIG doses as high as 800 mg/kg were safe and well tolerated. The half-life of HIVIG, determined by serial p24 antibody titers, was 13-16 days, the volume of distribution was 102-113 mL/kg, and clearance was 5.6-6.0 mL/kg/day. Plasma ICD p24 decreased during the infusions, but CD4 cell levels, plasma RNA copy number, cellular virus, immunoglobulin levels, and neutralizing antibody titers were minimally affected by the infusions. Clinical status did not change during the 6-month infusion and 3-month follow-up periods.

Immune thrombocytopenia after umbilical cord progenitor cell transplant: response to vincristine.

An 8-month-old male with X-linked lymphoproliferative disease underwent an unrelated, partially matched (with major mismatch at DR locus), cord blood stem cell transplant. Four months following the transplant, he developed immune thrombocytopenia with hemolytic anemia (Evans syndrome). He received multiple courses of intravenous immunoglobulin, anti-Rh D immunoglobulin, a pulse of high-dose corticosteroids and cyclosporine with some improvement of hemolytic anemia, but no improvement of the thrombocytopenia. Addition of vincristine, resulted in long-term resolution of thrombocytopenia and anemia. No major toxicity was observed during treatment. Vincristine should be considered as a treatment for refractory immune thrombocytopenia after hematopoietic stem cell transplantation.

Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team.

BACKGROUND: Maternal, obstetrical, and infant-related factors associated with the risk of perinatal transmission of human immunodeficiency virus type 1 (HIV-1) were identified before the widespread use of zidovudine therapy in pregnant women. The risk factors for transmission when women and infants receive zidovudine are not well characterized. METHODS: We examined the effects of maternal, obstetrical, and infant-related characteristics and maternal virologic and immunologic variables on the risk of perinatal transmission of HIV-1 among 480 women and their infants, all of whom received zidovudine. The women and infants were participating in a phase 3 trial of passive immunoprophylaxis for the prevention of perinatal transmission. RESULTS: In univariate analyses, the risk of perinatal transmission was associated with each of the following: decreased maternal CD4+ lymphocyte counts at base line; decreased maternal HIV p24 antibody levels at base line and delivery; increased maternal HIV-1 titer at base line and delivery; increased maternal HIV-1 RNA levels at base line and delivery; and the presence of chorioamnionitis at delivery. In multivariate analyses, the only independent risk factor was the maternal HIV-1 RNA level at base line (odds ratio for transmission, 2.4 per log increase in the number of copies; 95 percent confidence interval, 1.2 to 4.7; P=0.02) and at delivery (odds ratio, 3.4; 95 percent confidence interval, 1.7 to 6.8; P=0.001). There was no perinatal transmission of HIV-1 among the 84 women who had HIV-1 levels below the limit of detection (500 copies per milliliter) at base line or the 107 women who had undetectable levels at delivery. CONCLUSIONS: Among pregnant women and their infants, all treated with zidovudine, the maternal plasma HIV-1 RNA level was the best predictor of the risk of perinatal transmission of HIV-1. Antiretroviral therapy that reduces the HIV-1 RNA level to below 500 copies per milliliter appears to minimize the risk of perinatal transmission as well as improve the health of the women.

Compound-heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis.

Homozygous type I plasminogen deficiency has been identified as a cause of ligneous conjunctivitis. In this study, 5 additional patients with ligneous conjunctivitis are examined. Three unrelated patients (1 boy, 1 elderly woman, and 1 man) had plasminogen antigen levels of less than 0.4, less than 0.4, and 2.4 mg/dL, respectively, but had plasminogen functional residual activity of 17%, 18%, and 17%, respectively. These subjects were compound-heterozygotes for different missense mutations in the plasminogen gene: Lys19 --> Glu/Arg513 --> His, Lys19 --> Glu/Arg216 --> His, and Lys19 --> Glu/Leu128 --> Pro, respectively. The other 2 patients, a 14-year-old boy and his 19-year-old sister, who both presented with a severe course of the disease, exhibited plasminogen antigen and functional activity levels below the detection limit (<0.4 mg/dL and <5%, respectively). These subjects were compound-heterozygotes for a deletion mutation (del Lys212) and a splice site mutation in intron Q (Ex17 + 1del-g) in the plasminogen gene. These findings show that certain compound-heterozygous mutations in the plasminogen gene may be associated with ligneous conjunctivitis. Our findings also suggest that the severity of clinical symptoms of ligneous conjunctivitis and its associated complications may depend on the amount of plasminogen functional residual activity.

Efficacy of zidovudine and human immunodeficiency virus (HIV) hyperimmune immunoglobulin for reducing perinatal HIV transmission from HIV-infected women with advanced disease: results of Pediatric AIDS Clinical Trials Group protocol 185.

Pediatric AIDS Clinical Trials Group protocol 185 evaluated whether zidovudine combined with human immunodeficiency virus (HIV) hyperimmune immunoglobulin (HIVIG) infusions administered monthly during pregnancy and to the neonate at birth would significantly lower perinatal HIV transmission compared with treatment with zidovudine and intravenous immunoglobulin (IVIG) without HIV antibody. Subjects had baseline CD4 cell counts /=200/microL) but not with time of zidovudine initiation (5.6% vs. 4.8% if started before vs. during pregnancy; P=. 75). The Kaplan-Meier transmission rate for HIVIG recipients was 4. 1% (95% confidence interval, 1.5%-6.7%) and for IVIG recipients was 6.0% (2.8%-9.1%) (P=.36). The unexpectedly low transmission confirmed that zidovudine prophylaxis is highly effective, even for women with advanced HIV disease and prior zidovudine therapy, although it limited the study's ability to address whether passive immunization diminishes perinatal transmission.

Syndromes associated with immunodeficiency.

Immunodeficiency often has a genetic basis. Immune defects are the predominant manifestation in primary immunodeficiency disorders, and immune defects may also be associated with a number of other recognizable syndromes. There are 45 recognized primary immunodeficiency disorders, but immunodeficiency has been reported in 105 other syndromes. Abnormalities associated with these syndromes include growth deficiency (19 syndromes with disproportionate or proportionate short stature); specific organ system dysfunction (39 with gastrointestinal, dermatologic, or neurologic abnormalities); inborn errors of metabolism (17); miscellaneous anomalies (17); and chromosome anomalies (13). In most of these disorders, immunodeficiency is present in only a portion of the patients. However, in 49 syndromes, immunodeficiency is present in the vast majority. We review the clinical manifestations of each syndrome and delineate the associated immune defects. For most, the underlying mechanism linking the immune defect and other anomalies is unclear. Recognition of these conditions involving both the immune and other organ systems may facilitate accurate diagnosis and management, as well as yield information regarding genes critical for the development of the involved systems.

Effect of interleukin (IL)-12 and IL-15 on activated natural killer (ANK) and antibody-dependent cellular cytotoxicity (ADCC) in HIV infection.

The ability of IL-12 and IL-15 to enhance natural killer (NK) activity and antibody-dependent cellular cytotoxicity (ADCC) of mononuclear cells (MNCs) from HIV+ children and their mothers was investigated. MNCs from HIV+ patients were deficient in NK and ADCC activity compared to control MNCs against several target cells. Overnight incubation with IL-15 or IL-12 augmented NK activity of MNCs from both patients and controls, and the combination of IL-12 and IL-15 resulted in the greatest enhancement. ADCC in HIV+ patients against gp120-coated CEM.NKR cells or chicken erythrocytes could also be enhanced by IL-2 or IL-15 in overnight cultures. Culturing MNCs with either IL-2 or IL-15 for 1 week increased the NK activity in patients to levels of controls treated with these cytokines. However, the response to the combination of IL-12 and IL-15 was less than that to IL-15 alone in 1-week cultures. Culturing MNCs with IL-2 and IL-15 for 1 week also increased the percentage of CD16+/CD56+ cells in both patients and controls. Thus, IL-15 can restore the deficient NK activity in patients and may be a candidate for immunomodulative therapy in HIV+ patients.

High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome.

BACKGROUND: High dose intravenous immunoglobulin (IVIG) has immunoregulatory and anti-inflammatory properties that might benefit illnesses with exaggerated IgE responses including atopic dermatitis and hyper-IgE immunodeficiency syndrome. OBJECTIVE: To determine if high-dose IVIG would be of benefit to patients with severe atopic dermatitis and/or hyper-IgE syndrome using serial clinical, pulmonary, and laboratory studies for evaluation. METHODS: This was an open label study in which we gave patients with hyper-IgE syndrome (n = 1) or severe atopic dermatitis (n = 9) IVIG as a 10% solution (Venoglobulin I-Alpha Therapeutic Corporation, Los Angeles, CA) at a dose of 2 g/kg every 30 days for seven infusions. RESULTS: Therapy was completed in nine of the ten patients. Skin disease improved slightly in six patients, remained unchanged in two patients, and worsened slightly in one patient. The average daily prednisone dosage was 6.8 mg/day prior to treatment and 5.1 mg/day during IVIG therapy (P = .1250). The three patients with abnormal pulmonary function showed very mild improvement of pulmonary function during treatment, but returned to baseline during follow-up. Flow cytometric studies showed no consistent pattern of change. IgA and IgM levels were unchanged. The mean serum IgE levels went from 3221+/-2454 IU/mL (SD) before IVIG to 2944+/-2491 IU/mL (P = .4609) during IVIG and then to 2321+/-2229 IU/mL (P = .1484) during the 6-month follow-up period. In vitro IgE production of peripheral blood mononuclear cells (PBMC) following IL-4 and anti-CD40 stimulation before IVIG was 6.6+/-3.1 ng/mL (SD) and 4.3+/-3.1 ng/mL (P = .1641) after six IVIG treatments. There were no significant trends in lymphocyte proliferative responses to PHA (phytohemaglutinin), Candida, tetanus, and anti-CD3 monoclonal antibody. Radioallergosorbent (RAST) testing showed no clear changes from positivity to negativity. CONCLUSION: We conclude that IVIG was of no clear clinical benefit in these nine patients and did not significantly decrease IgE levels, IgE synthesis, or other measures of immunologic function.