Martin L. Lee

Common variable immunodeficiency disorders: division into distinct clinical phenotypes

The European Common Variable Immunodeficiency Disorders registry was started in 1996 to define distinct clinical phenotypes and determine overlap within individual patients. A total of 7 centers contributed patient data, resulting in the largest cohort yet reported. Patients (334), validated for the diagnosis, were followed for an average of 25.6 years (9461 patient-years). Data were used to define 5 distinct clinical phenotypes: no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy. A total of 83% of patients had only one of these phenotypes. Analysis of mortality showed a considerable reduction in the last 15 years and that different phenotypes were associated with different survival times. Types of complications and clinical phenotypes varied significantly between countries, indicating the need for large, international registries. Ages at onset of symptoms and diagnosis were shown to have a Gaussian distribution, but were not useful predictors of phenotype. The only clinical predictor was polyclonal lymphocytic infiltration, which was associated with a 5-fold increased risk of lymphoid malignancy. There was widespread variation in the levels of serum immunoglobulin isotypes as well as in the percentages and absolute numbers of B cells, confirming the heterogeneity of these conditions. Higher serum IgM and lower circulating CD8 proportions were found to be predictive markers for polyclonal lymphocytic infiltration and autoimmunity, respectively.

Appropriateness of the Decision to Transfer Nursing Facility Residents to the Hospital

OBJECTIVES: To develop and test a standardized instrument, the purpose of which is to assess (1) whether skilled nursing facilities (SNFs) transfer residents to emergency departments (ED) inappropriately, (2) whether residents are admitted to hospitals inappropriately, (3) and factors associated with inappropriate transfers.

Infection outcomes in patients with common variable immunodeficiency disorders: Relationship to immunoglobulin therapy over 22 years

BACKGROUND Common variable immunodeficiency disorders (CVIDs) are the most common forms of symptomatic primary antibody failure in adults and children. Replacement immunoglobulin is the standard treatment, although there are few consistent data on optimal dosages and target trough IgG levels required for infection prevention. OBJECTIVE To provide data to support the hypothesis that each patient requires an individual dose of therapeutic immunoglobulin to prevent breakthrough infections and that efficacious trough IgG levels vary between patients. METHODS Data, collected prospectively from a cohort of 90 patients with confirmed CVIDs from 1 center over a follow-up period of 22 years, was validated and analyzed. Immunoglobulin doses had been adjusted in accordance with infections rather than to achieve a particular trough IgG level. Doses to achieve infection-free periods were determined and resultant trough levels analyzed. A smaller group of patients with X-linked agammaglobulinemia was analyzed for comparison. RESULTS Patients with a CVID had a range of trough IgG levels that prevented breakthrough bacterial infections (5-17 g/L); viral and fungal infections were rare. Doses of replacement immunoglobulin to prevent breakthrough infections ranged from 0.2 to 1.2 g/kg/mo. Those with proven bronchiectasis or particular clinical phenotypes required higher replacement doses. Patients with X-linked agammaglobulinemia showed a similar range of IgG levels to stay infection-free (8-13 g/L). CONCLUSION These data offer guidance regarding optimal doses and target trough IgG levels in individual patients with CVIDs with or without bronchiectasis and for particular clinical phenotypes. The goal of replacement therapy should be to improve clinical outcome and not to reach a particular IgG trough level.

Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging

Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with β-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels. The effects of testosterone on physical function and outcomes important to patients have not, however, been studied. In older men, increased hematocrit and increased risk of prostate biopsy and detection of prostate events are the most frequent, testosterone-related adverse events. Concerns about long-term risks have restrained enthusiasm for testosterone use as anabolic therapy. Selective androgen-receptor modulators that are preferentially anabolic and that spare the prostate hold promise as anabolic therapies. We need more studies to determine whether testosterone or selective androgen-receptor modulators can induce meaningful improvements in physical function and patient-important outcomes in patients with physical dysfunction associated with chronic illness or aging.

Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome

Intravenous immunoglobulin improves many antibody-mediated autoimmune disorders, but its mode of action is unknown. We investigated its effects on muscle strength and on the serum titer of the calcium-channel autoantibodies that are likely to be pathogenic in the Lambert-Eaton myasthenic syndrome (LEMS). In a randomized, double-blind, placebo-controlled crossover trial, serial indices of limb, respiratory, and bulbar muscle strength and the serum titer of calcium-channel antibodies in nine patients were compared over an 8-week period, using the area-under-the-curve approach, following infusion on two consecutive days of immunoglobulin at 1 g/kg body weight/day (total dose 2.0 g/kg body weight) or placebo (equivalent volume of 0.3% albumin). Calcium-channel antibodies were measured by radioimmunoassay using125 I-omega-conotoxin MVIIC. Direct anti-idiotypic actions of immunoglobulin were tested in this assay. Immunoglobulin infusion was followed by significant improvements in the three strength measures (p = 0.017 to 0.038) associated with a significant decline in serum calcium-channel antibody titers (p = 0.028). Improvement peaked at 2 to 4 weeks and was declining by 8 weeks. Mean serum titers were unchanged at 1 week, however, and direct anti-idiotypic antibody neutralization by immunoglobulin was not demonstrable in vitro. We conclude that immunoglobulin causes a short-term improvement in muscle strength in LEMS that probably results from the induced reduction in calcium-channel autoantibodies. The reduction is not due to a direct neutralizing action of the immunoglobulin, but a delayed anti-idiotypic action cannot be excluded. Improvement following intravenous immunoglobulin in other autoantibody-mediated disorders may similarly be associated with decline in levels of pathogenic autoantibodies. NEUROLOGY 1996;47: 678-683

Successful reversal of spontaneous diabetes in dogs by intraperitoneal microencapsulated islets.

Long-term euglycemia by intraperitoneal transplantation of microencapsulated islets has not been described in the diabetic large animal model. In this study, we report the successful long-term reversal of diabetes by this method in spontaneous diabetic dogs. We have identified fundamental mechanism (s) associated with alginate-based microcapsule fibrosis, and have devised methods to ameliorate this problem. These include the use of purified alginate of low mannuronic acid content and cytokine suppression. Ten insulin-dependent, spontaneous diabetic dogs (insulin requirement 1–4 units/kg/day; absence of circulating C-peptide and diabetic K-values of 0.6±0.4) were entered into the study. Islets from mongrel donor pancreata were isolated and transplanted intraperitoneally either as free islet controls (n=3) or as microencapsulated islet allografts (n=7). In all seven encapsulated islet recipients, euglycemia was achieved within 24 hr (serum glucose falling from 304±117 to 116±72 mg/dl). IVGTT performed 14 days after islet transplant demonstrated normalization of K-values changing from a pretransplant level of 0.6±0.4 to 2.6±0.6. All animals receiving encapsulated islets remained euglycemic, free of the need for exogenous insulin, for a period of 63–172 days, with a median insulin-independence for 105 days. In contrast, recipients receiving free islets rejected their graft within seven days of implantation. In conclusion, this is the first report of long-term successful reversal of spontaneous diabetes in the large animal model by an intraperitoneal injection of encapsulated islets. The potential exists for this form of therapy to be explored in the treatment of type I diabetes in man.

Randomized Trial of Exclusive Human Milk versus Preterm Formula Diets in Extremely Premature Infants

OBJECTIVE To compare the duration of parenteral nutrition, growth, and morbidity in extremely premature infants fed exclusive diets of either bovine milk-based preterm formula (BOV) or donor human milk and human milk-based human milk fortifier (HUM), in a randomized trial of formula vs human milk. STUDY DESIGN Multicenter randomized controlled trial. The authors studied extremely preterm infants whose mothers did not provide their milk. Infants were fed either BOV or an exclusive human milk diet of pasteurized donor human milk and HUM. The major outcome was duration of parenteral nutrition. Secondary outcomes were growth, respiratory support, and necrotizing enterocolitis (NEC). RESULTS Birth weight (983 vs 996 g) and gestational age (27.5 vs 27.7 wk), in BOV and HUM, respectively, were similar. There was a significant difference in median parenteral nutrition days: 36 vs 27, in BOV vs HUM, respectively (P = .04). The incidence of NEC in BOV was 21% (5 cases) vs 3% in HUM (1 case), P = .08; surgical NEC was significantly higher in BOV (4 cases) than HUM (0 cases), P = .04. CONCLUSIONS In extremely preterm infants given exclusive diets of preterm formula vs human milk, there was a significantly greater duration of parenteral nutrition and higher rate of surgical NEC in infants receiving preterm formula. This trial supports the use of an exclusive human milk diet to nourish extremely preterm infants in the neonatal intensive care unit.

Clinical Uses of Intravenous Immunoglobulins

Immunoglobulins are an important component of host defense against infections. They also play a central role in immune regulation. A wide spectrum of human diseases is associated with decreased or abnormal regulation of immunoglobulin levels. Recently IV preparations of immunoglobulin have become available for clinical studies. There are already substantial data indicating a useful role for IV immunoglobulin in patients with primary hypogammaglobulinemia, neonates predisposed to group B streptococcal infections, individuals with ITP, children with Kawasaki disease, and bone marrow transplant patients predisposed to CMV infections. Promising data have been reported in burn patients and in individuals with CLL; these data require confirmation. Potential areas for future investigation include AIDS, autoimmune disorders, and viral disorders other than CMV.

High-resolution sonography versus EMG in the diagnosis of carpal tunnel syndrome

Background: Carpal tunnel syndrome (CTS) is a common entrapment neuropathy. Electrodiagnostic testing (EMG) is used to confirm the diagnosis. It is not known what the diagnostic accuracy of high-resolution sonography is in comparison to EMG. Objective: The aim of this study was to compare the diagnostic accuracy of both tests in CTS patients. Methods: A prospective cohort of 207 patients with possible CTS underwent high-resolution sonography and EMG. The diagnosis of CTS was based on clinical signs and symptoms. The cross-sectional area of the median nerve at the carpal tunnel inlet and at the distal one-third level of the forearm was assessed by an investigator, blinded to the clinical and EMG data. Normal sonographic values were obtained from 137 controls. All patients and 40 controls underwent a standardised nerve conduction study. The kappa coefficient was used to evaluate the relationship between sonography, EMG and clinical diagnosis. Results: The cross-sectional area at the distal one-third of the forearm was not significantly different between the controls and patients (p = 0.59), whereas the cross-sectional area at the carpal tunnel inlet was significantly increased in the patient group (p<0.0001). The kappa coefficient for EMG using the median-ulnar distal sensory latency difference versus clinical evaluation was 0.64 and, for sonography, this coefficient was 0.69; these were not statistically different (p = 0.37). Combining the two tests resulted in a kappa coefficient of 0.72, which was not significantly different from sonography alone (p = 0.73). Conclusion: In patients with a clinical diagnosis of CTS, the accuracy of sonography is similar to that for EMG. Sonography is probably preferable because it is painless, easily accessible and preferred by the patients.

Immune Responses and Antibody Decay after Immunization of Adolescents and Adults with an Acellular Pertussis Vaccine: The APERT Study

As part of a prospective acellular pertussis (ACP) vaccine efficacy trial, 5 serum samples were obtained, over an 18-month period, from 101 ACP-vaccine recipients and 99 control subjects, to assess ACP antibody response and decay. Immunoglobulin (Ig) G and IgA antibodies to pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae 2/3 (FIM) were measured by enzyme-linked immunosorbant assay, and titers of agglutinin were determined. Of the subjects, 16%-19% had preimmunization values of antibodies to PT that were above the assays limit of quantitation (LOQ); in contrast, 36%-63% of the subjects had preimmunization values of antibodies to FHA, PRN, or FIM that were above the LOQ. Substantial increases in titers of IgG and IgA antibodies to the 3 ACP antigens (PT, FHA, and PRN) were observed. Over the 18-months, the percent decay in IgG and IgA antibodies ranged from 56% to 73% and from 57% to 70%, respectively; the IgG antibody response and decay suggests that geometric mean titers likely remain above the LOQ for 2-9 years and above the threshold of detection for 4-13 years. These findings support the use of ACP booster immunizations for adolescents and adults, to provide sustained levels of antibody.