Robert P. Nelson

Genetic Linkage of Hyper-IgE Syndrome to Chromosome 4

The hyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated levels of serum IgE. HIES is now recognized as a multisystem disorder, with nonimmunologic abnormalities of the dentition, bones, and connective tissue. HIES can be transmitted as an autosomal dominant trait with variable expressivity. Nineteen kindreds with multiple cases of HIES were scored for clinical and laboratory findings and were genotyped with polymorphic markers in a candidate region on human chromosome 4. Linkage analysis showed a maximum two-point LOD score of 3.61 at recombination fraction of 0 with marker D4S428. Multipoint analysis and simulation testing confirmed that the proximal 4q region contains a disease locus for HIES.

Serum IgE and human immunodeficiency virus (HIV) infection

Human immunodeficiency virus infection is characterized by a progressive depletion of helper T-lymphocytes and, like allergic diseases, is associated with altered T cell regulation. Total serum IgE was measured in 67 infected male subjects, 27 uninfected heterosexual male subjects, and 18 uninfected homosexual male subjects. The mean IgE level (132 IU/ml) of infected subjects with a helper T-lymphocyte number less than or equal to 200/mm3 was significantly greater than mean IgE levels of the uninfected heterosexual (38 IU/ml) and homosexual (35 IU/ml) groups. IgE levels were inversely related to both helper T cell and suppressor/cytotoxic T cell numbers but not to IgG or IgA levels. The increase in IgE was not a reflection of an increased prevalence of atopic disease (allergic asthma, allergic rhinitis, or atopic dermatitis) in the infected subjects. The elevation of IgE may be related to a difference among the groups in T cell production of IgE regulatory lymphokines.

A Phase I/II Study of the Protease Inhibitor Ritonavir in Children With Human Immunodeficiency Virus Infection

Background. Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human immunodeficiency virus (HIV) infection. In a phase I/II study, we assessed the safety, tolerability, and pharmacokinetic profile of the oral solution of ritonavir in HIV-infected children and studied the preliminary antiviral and clinical effects. Methods. HIV-infected children between 6 months and 18 years of age were eligible. Four dose levels of ritonavir oral solution (250, 300, 350, and 400 mg/m2 given every 12 hours) were evaluated in two age groups (≤2 years, >2 years). Ritonavir was administered alone for the first 12 weeks and then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks. Results. A total of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) were included in this analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in discontinuation of ritonavir in 7 children. Ritonavir was well absorbed at all dose levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cells counts increased by a median of 79 cells/mm3 after 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 to 2 log10 copies/mL within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/m2 for the 24-week period. Conclusions. The oral solution of ritonavir has potent antiretroviral activity as a single agent and is relatively well tolerated by children when administered alone or in combination with zidovudine or didanosine.

Elevated serum levels of IL‐8 in patients with HIV infection

Scrum levels of IL‐8 were determined in HIV‐infected individuals and the results were compared with those for HIV controls. The IL‐8 levels were measured by an ELISA with a MoAb and a polyclonal antibody to recombinant IL‐8. The means and 95% confidence intervals of IL‐8 in sera of 36 HIV‐infected individuals and 32 matched controls were 275 and 216 349 pg/ml, and 8 and 4 14 pg/ml, respectively, showing a 34‐fold increase in IL‐8 in the circulation of HIV‐infected individuals. This increase does not appear to be related to the disease state, infection or systemic medical agents. This finding suggests the possible involvement of IL‐8 in the pathogenesis of HIV‐induced disease.

Immunoreconstitution after ritonavir therapy in children with human immunodeficiency virus infection involves multiple lymphocyte lineages.

OBJECTIVE To evaluate lymphocyte reconstitution after protease inhibitor therapy in children with human immunodeficiency virus (HIV) infection. STUDY DESIGN Forty-four HIV-infected children receiving ritonavir monotherapy followed by the addition of zidovudine and didanosine were evaluated during a phase I/II clinical trial. The cohort had a median age of 6.8 years and advanced disease (57% Centers for Disease Control and Prevention stage C, 73% immune stage 3) and was naive to protease inhibitor therapy. RESULTS After 4 weeks of therapy, there was a significant increase in CD4(+) and CD8(+) T cells. CD4(+) T cells continued to increase, whereas CD8(+) T cells returned to baseline by 24 weeks. Unexpectedly, there was a significant increase in B cells. Changes in CD4(+) T-cell subsets revealed an initial increase in CD4(+) CD45RO T cells followed by a sustained increase in CD4(+) CD45RA T cells. Children <6 years of age had the highest increase in all lymphocyte populations. Significant improvement in CD4(+) T-cell counts was observed even in those children whose viral burden returned to pre-therapy levels. CONCLUSIONS Early increases in lymphocytes after ritonavir therapy are a result of recirculation, as shown by increases in B cells and CD4(+) CD45RO and CD8(+) T cells. Children exhibited a high potential to reconstitute CD4(+) CD45RA T cells even with advanced disease and incomplete viral suppression.

A Phase I/II Study of the Protease Inhibitor Indinavir in Children With HIV Infection

Background. Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose. Methods. Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/m2, 350 mg/m2, and 500 mg/m2 per dose given orally every 8 h) were evaluated in 2 age groups (<12 years and ≥12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks. Results. Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median CD4 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/mm3, and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy. Conclusions. Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine.

Long-term Virologic and Immunologic Responses in Human Immunodeficiency Virus Type 1-Infected Children Treated with Indinavir, Zidovudine, and Lamivudine

Virologic and immunologic responses were examined for 33 human immunodeficiency virus (HIV)-infected children who participated for > or = 96 weeks in a phase 1/2 protocol of 16 weeks of indinavir monotherapy, followed by the addition of zidovudine and lamivudine. At week 96, a median increase of 199 CD4+ T cells/microL and a median decrease of 0.74 log(10) HIV RNA copies/mL were observed. The relationship between control of viral replication and CD4) T cell count was examined. Patients were categorized into 3 response groups on the basis of duration and extent of control of viral replication. Of 21 children with a transient decrease in virus load of > or = 0.7 log(10) HIV RNA copies/mL from baseline, 7 experienced sustained increases in CD4+, CD4+ CD45RA+, and CD4+ CD45RO+ T cell counts. CD4+ CD45RA+ (naive) T cells were the major contributor to CD4+ T cell expansion. Continued long-term immunologic benefit may be experienced by a subset of children, despite only transient virologic suppression.

Multicenter Crossover Comparison of the Safety and Efficacy of Intraglobin-F with Gamimune-N, Sandoglobulin, and Gammagard in Patients with Primary Immunodeficiency Diseases

The safety and clinical efficacy of a liquid, β-propiolactone-stabilized intravenous γ-globulin, Intraglobin-F, was evaluated in a multicenter, double-blind study comparing Intraglobin-F to Gamimune-N, Sandoglobulin, or Gammagard. β-Propiolactone stabilizes the IgG molecule to decrease aggregate formation and is a potent virucidal agent that reduces the risk of viral transmission by intravenous γ-globulin (IVIG) preparations. Twenty-seven patients with primary immunodeficiency diseases were enrolled at three centers. Each patient received 6 months of therapy with either Intraglobin-F or the IVIG preparation that they had received during the preceding 3 months, then crossed over to the other preparation. Twenty-three patients completed the study. One patient withdrew because of an adverse event, generalized urticaria. A second patient withdrew because of fatigue and perceived decreased efficacy. Adverse reactions were comparable and occurred in 8.7% of the infusions of Intraglobin-F and 6% of the infusions with Sandoglobulin. None were severe or life-threatening. There was no discernible difference in efficacy between any of the products. The number of days when patients noted symptoms in their diaries was similar for Intraglobin-F and the comparison preparations, 4158 vs 4143. Similarly, there were no differences in the number of physician visits (33 vs 22), days missed from work or school (405 vs 404), days with fever (41 vs 47), or days of prophylactic antibiotics (675 vs 642). There was an increase in the number of days when antibiotics were given therapeutically (578 vs 451); most of the difference was attributable to one patient. There also was a difference in the number of days of hospitalization (21 vs 0), but 19 of the days were accounted for by two patients. When the patients were asked to score their feeling of well-being on a scale of 1 to 5, with 1 being entirely well, the mean score for the patients on Intraglobin-F was 1.86 (range, 1.0 to 3.0), compared to 1.85 (range, 1.0 to 3.2) for patients while on the comparison preparations. Trough IgG levels were slightly lower during the period when patients were treated with Intraglobin-F compared to the other products. There were no abnormalities in blood chemistries or hematologic parameters. Thus, Intraglobin-F is comparable to three of the marketed IVIG preparations in efficacy and safety, as well as patient acceptability, and offers the additional benefit of an extra virucidal step to reduce further the risk of transmitting viral infections.

Methyl inosine monophosphate: a potential immunotherapeutic for early human immunodeficiency virus (HIV) infection.

MIMP is a new thymomimetic purine under development for immunorestorative therapy. Lymphocytes were obtained from eight patients with acquired immunodeficiency disease (AIDS), eight with symptomatic pre-AIDS (ARC), and 22 normal controls and were stimulated in vitro with phytohemagglutinin (PHA). AIDS patients (mean CD4 counts of 40) showed PHA responses less than 10% of control while ARC patients (mean CD4 counts of 544) showed responses approximately 50% of the control responses. MIMP (0.1, 1, 10 and 100 micrograms/ml) progressively augmented the PHA responses in all these groups. The augmentation of the responses of the leukocytes of AIDS patients while statistically significant was minimal. The augmentation of the responses of ARC patients was significant and their maximal responses approached control levels. The effect of 1 micrograms/ml MIMP was comparable with that observed with indomethacin (10(-6) M) and interleukin-2 (IL2 - 4 units/ml) and was additive with each of these stimulants. In a parallel manner, MIMP restored the suppression of control lymphocytes induced by the immunosuppressive 17 amino acid fragment of the P41 peptide of HIV. In vivo experiments showed that MIMP significantly delayed death in a murine FLV AIDS model at a dose of 1 mg/kg by the oral or parenteral route. MIMP is under preclinical development for early HIV disease to forestall progression to AIDS by attenuating virus-induced immunosuppression.

Glucocorticosteroid treatment for cerebrospinal fluid eosinophilia in a patient with ventriculoperitonial shunt

BACKGROUND Cerebrospinal fluid (CSF) eosinophilia commonly occurs in patients with ventriculoperitoneal (VP) shunts and is associated with shunt complications such as obstruction or infection. Glucocorticosteroids (GCS) are effective in reducing eosinophilia and eosinophils in skin, nasal mucosa, and airway epithelium. Effects of GCS on CSF eosinophils has not been reported. OBJECTIVE To demonstrate glucocorticosteroid effects on the CSF eosinophil levels and to propose that GCS may be used as a therapeutic agent for CSF eosinophilia. RESULT A case report of a patient with congenital hydrocephalus and a VP shunt developed CSF eosinophilia associated with latex allergy and shunt malfunction. Daily treatment with 2 mg/kg of methylprednisolone was associated with reduced peripheral eosinophilia and slightly reduced CSF eosinophil counts. Pulse methylprednisolone, 15 mg/kg, was associated with complete reduction of CSF eosinophils and prolonged VP shunt survival. CONCLUSION Systemic glucocorticosteroids effectively reduce CSF eosinophils. Glucocorticosteroids may be beneficial for treatment of CSF eosinophilia associated with VP shunt malfunction.