Howard M. Lederman

X-linked agammaglobulinemia : Report on a United States registry of 201 patients

Abstract: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in the gene for Bruton tyrosine kinase (BTK) that result in the deficient development of B lymphocytes and hypogammaglobulinemia. Because the disorder is uncommon, no single institution has had sufficient numbers of patients to develop a comprehensive clinical picture of the disorder. Accordingly, a national registry of United States residents with XLA was established in 1999 to provide an updated clinical view of the disorder in a large cohort of patients. A total of 201 patients were registered by 66 physicians. The estimated birth rate for the 10-year period of 1988-1997 was 1/379,000. Infection was the most common initial clinical presentation (85%), followed by a positive family history (41%) and neutropenia (11%). Although the average age of diagnosis was younger in patients with a positive family history (mean, 2.59 yr) than in patients with a negative family history (mean, 5.37 yr) (p < 0.001), only 34.5% of patients with a positive family history at the time of their birth were diagnosed before clinical symptoms developed-that is, based on family history alone. Seventy percent of patients had at least 1 episode of otitis, 62% at least 1 episode of pneumonia, 60% at least 1 episode of sinusitis, 23% at least 1 episode of chronic/recurrent diarrhea, 21% at least 1 episode of conjunctivitis, 18% at least 1 episode of pyoderma and/or cellulitis, 11% at least 1 episode of meningitis/encephalitis, 10% at least 1 episode of sepsis, 8% at least 1 episode of septic arthritis, 6% at least 1 episode of hepatitis, and 3% at least 1 episode of osteomyelitis. Fourteen of 201 (6.9%) patients were dead at the time they were entered in the Registry. However, in a prospective 4 1/4-year follow-up of living patients, only 3/80 (3.75%) patients died. Causes of death included disseminated enterovirus infection (n = 6), pulmonary insufficiency (n = 5), adenovirus infection (n = 1), sepsis (n = 1), acquired immunodeficiency disease syndrome (AIDS) (n = 1), myocarditis (n = 1), hepatitis (n = 2), and stem cell transplantation (n = 1). Abbreviations: BTK = Bruton tyrosine kinase, IVIG = intravenous immunoglobulin, XLA = X-linked agammaglobulinemia

X-linked agammaglobulinemia: An analysis of 96 patients

We have defined the clinical presentation and course of X-linked agammaglobulinemia (X-LA) by means of a multi-center retrospective survey of 96 patients. Infections were the most common presenting feature of patients with X-LA. The most frequent infections involved the upper respiratory tract (75%), lower respiratory tract (65%), gastrointestinal tract (35%), skin (28%), and central nervous system (16%). Clinical clues to the diagnosis of X-LA were the chronic or recurrent nature of infections, a family history of immunodeficiency, and infections at more than one anatomic location. Infections remained a significant problem after the diagnosis of X-LA was made and gamma-globulin prophylaxis had been instituted. One or more chronic infectious diseases occurred in 71% of patients. The respiratory tract was the most common site of disease, and the gastrointestinal tract was relatively spared. Patients died at a mean age of 17 years. The two major causes of death were chronic pulmonary disease with resultant cardiac failure, and disseminated viral infections which characteristically caused a dermatomyositis-like syndrome, hepatitis, pneumonitis, and meningoencephalitis.

Sarcoidosis and common variable immunodeficiency. Report of 8 cases and review of the literature.

The true incidence of sarcoidosis in common variable immunodeficiency (CVID) is unknown. We report here 8 cases of sarcoidosis among 80 patients with CVID followed in our clinics, along with 22 well-documented cases reported in the literature. Sarcoidosis, therefore, represents an important entity to consider among patients with CVID who exhibit clinical, radiographic, laboratory, and biopsy findings compatible with sarcoidosis. Conversely, the diagnosis of CVID should be considered in patients with sarcoidosis who do not exhibit the characteristic hypergammaglobulinemia and who have a history of recurrent infections. Although many features of sarcoidosis are similar in patients with CVID to those in patients with sarcoidosis alone, there are many important differences. Patients with CVID in whom sarcoidosis develops present with hypogammaglobulinemia rather than hypergammaglobulinemia and have a higher prevalence of recurrent infections, thrombocytopenia, and splenic involvement. Steroids, in most cases, appeared helpful in reducing adenopathy and splenomegaly, improving uveitis, lowering serum alkaline phosphatase, and reversing hematologic abnormalities. The underlying pathophysiology responsible for the association of these 2 disorders in the same patient remains obscure. However, as more patients are identified, it may be possible to gain a better understanding of the immunologic defect responsible for the dual presentation of these 2 relatively uncommon diseases.

Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen

ObjectivesTo ascertain if immunization results in the restoration of responses to recall antigens, in the development of responses to presumed neoantigens, and to identify the virologic and immunologic correlates of these responses in persons with HIV-1 infection. Design and settingOpen-label study carried out at three university-affiliated AIDS Clinical Trials Units in the United States. Subjects and methodsThirty-one subjects participating in AIDS Clinical Trials Group Protocol 375 who had received zidovudine, lamivudine, and ritonavir for at least 48 weeks. Subjects were immunized with tetanus toxoid (TT) at entry and with inactivated hepatitis A vaccine (hep A) and keyhole limpet hemocyanin (KLH) at entry and 6 weeks. The development of antibody, lymphocyte proliferative assay (LPA), and delayed-type hypersensitivity (DTH) responses after immunization were monitored. ResultsThe LPA and DTH responses to TT improved in 57 and 68% of participants, respectively; 73 and 65% developed enhanced LPA and DTH responses to KLH. Forty-eight percent of patients developed a four-fold increase in antibody concentration to tetanus. Seventy-three percent of patients without detectable hepatitis A antibodies at baseline developed antibodies after immunization. Eighty-three percent of patients experienced at least a four-fold rise in KLH antibody concentration. Immune activation and viral load predicted poor recall responses and the number of memory CD4+ T-cells predicted good responses to recall antigens. Naïve CD4+ T-cell numbers, decrease in viral load, increases in CD4+ and CD28+ cells, and decreases in immune activation were associated with responses to presumed neoantigens. ConclusionsMost HIV-infected patients treated with potent combination antiretrovirals develop responses to recall and presumed neoantigens after immunization. Functional immune restoration in response to immunization is related to control of viral replication, decreased immune activation as well as to both quantitative and qualitative restoration of circulating T- lymphocyte subpopulations.

Increased susceptibility to mycoplasma infection in patients with hypogammaglobulinemia

The incidence and morbidity of Mycoplasma infections were examined in a group of 23 patients with hypogammaglobulinemia. Among this group of patients, 18 had one or more episodes of acute respiratory illness during which Ureaplasma urealyticum, Mycoplasma orale, or Mycoplasma pneumoniae were isolated from sputum. Resolution only followed institution of specific antibiotic therapy and elimination of the Mycoplasma. In addition to respiratory illness, U. urealyticum was isolated from the urine of two patients with urinary tract infection and from an area of cellulitis in another patient. M. pneumoniae was isolated from the joint of a patient with arthritis. In six patients with chronic lung disease, Mycoplasma was frequently isolated and clinical improvement, albeit transient, coincided with negative Mycoplasma culture results. These findings emphasize the unique susceptibility to Mycoplasma infection in patients with hypogammaglobulinemia.

Consequences of the delayed diagnosis of ataxia-telangiectasia

Objectives. Ataxia-telangiectasia (AT) is a rare, autosomal recessive neurodegenerative disorder in which the diagnosis is obvious when ataxia and telangiectasia are both present. However, the diagnosis can be made upon the onset of ataxia and before the appearance of telangiectasia if confirmed by laboratory tests. Early diagnosis is important for genetic counseling, appropriate care, and avoidance of unnecessary tests. The purpose of this study is to identify factors responsible for delays in the diagnosis of AT. Design. The records of all patients seen at the Ataxia-Telangiectasia Clinical Center from July 1, 1995 to April 1, 1997 were reviewed to determine age of onset of gait abnormality, recognition of telangiectasia, and diagnosis. Results. In 48 patients with AT, who were the index cases in their respective families, the median age of diagnosis (78 months) occurred after the onset of gait abnormalities (15 months) and closely corresponded to the development of telangiectasia (72 months). In the majority of cases (34/48), telangiectasia appeared before the diagnosis was established. The most common misdiagnosis was cerebral palsy (29/48 cases). Twenty-one children (4 with AT) were born after the start of symptoms in the index case, but before the establishment of a diagnosis. Conclusions. The term AT, although a concise and memorable label for the disorder, is also a barrier to early diagnosis. We recommend the use of routine serum α-fetoprotein testing for all children with persistent ataxia.

Safety and Immunogenicity of Heptavalent Pneumococcal Vaccine Conjugated to CRM197 Among Infants With Sickle Cell Disease

Objectives. To determine the immunogenicity and safety of heptavalent pneumococcal polysaccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) conjugated to CRM197 (7-valent conjugate pneumococcal vaccine [7VPnC]) among infants with sickle cell disease (SCD) and a comparison group of infants without SCD (non-SCD). Design. Two cohorts of infants were enrolled and received open-label doses of 7VPnC vaccine; infants enrolled before 2 months of age received 7VPnC vaccine at 2, 4, and 6 months of age followed by 23-valent pneumococcal polysaccharide vaccine (PS-23) at 24 months of age for those infants with SCD (schedule A), and infants enrolled between 2 and 12 months of age received 7VPnC at 12 months of age followed by PS-23 at 24 months of age for infants with SCD (schedule B). Safety data were collected for 3 days after each dose of vaccine. Antibody concentrations were measured to each of the 7VPnC serotypes by enzyme-linked immunosorbent assay before each vaccine dose and 1 month after the last 7VPnC dose and the PS-23 vaccine dose. Results. Forty-five infants (34 SCD and 11 non-SCD) were vaccinated according to schedule A and 16 infants (13 SCD and 3 non-SCD) according to schedule B. The 7VPnC vaccine was highly immunogenic for all serotypes among infants with and without SCD who received 3 doses of vaccine according to schedule A: depending on serotype, 89% to 100% achieved antibody concentrations above .15 μg/mL and 56% to 100% achieved antibody concentrations above 1.0 μg/mL. Among infants immunized according to schedule B, a single dose of 7VPnC vaccine resulted in antibody concentrations above .15 μg/mL in 53% to 92% by serotype and above 1.0 μg/mL in 31% to 71% by serotype. A single dose of PS-23 resulted in dramatic increases in the antibody concentrations to all serotypes regardless of 1- or 3-dose priming. There was no difference in the reactogenicity of the 7VPnC vaccine between those with and without SCD. There were no serious reactions to the 7VPnC or PS-23 vaccines, even among those with high antibody concentrations before immunization. Conclusions. Infants with SCD respond to 7VPnC vaccine with antibody concentrations that are at least as high as infants without SCD. Infants immunized with 7VPnC vaccine at 2, 4, and 6 months of age developed antibody concentrations in the same range as those achieved among infants without SCD enrolled in a large trial that demonstrated vaccine efficacy against invasive disease. Significant rises were seen in antibody concentrations to all 7VPnC serotypes after the PS-23 booster in children receiving schedule A or B.

Incomplete Immune Reconstitution after Initiation of Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus–Infected Patients with Severe CD4+ Cell Depletion

Immune function was observed for 144 weeks in 643 human immunodeficiency virus (HIV)-infected subjects who (1) had nadir CD4+ cell counts of <50 cells/mm3, followed by a sustained increase to > or =100 cells/mm3 after the initiation of HAART, and (2) were enrolled in a randomized trial of continued azithromycin prophylaxis versus withdrawal for prevention of Mycobacterium avium complex disease. The median CD4+ cell count was 226 cells/mm3 at entry and 358 cells/mm3 at week 144. Anergy (80.2% of patients) and lack of lymphoproliferative response to tetanus toxoid (TT; 73%) after immunization and impaired antibody responses after receipt of hepatitis A (54%) and TT (86%) vaccines were considered to be evidence of impaired immune reconstitution. Receipt of azithromycin did not have an effect on CD4+ cell count but was associated with higher rates of delayed-type hypersensitivity responses to TT (25% of subjects who received azithromycin vs. 15% of those who did not; P=.009) and mumps skin test antigen (29% vs. 17%; P=.001). Although the subjects had only partial responses to immune function testing, the rate of opportunistic infections was very low, and none of the tests was predictive of risk.

Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia

OBJECTIVES To determine whether patients with ataxia-telangiectasia exhibit oropharyngeal dysphagia with concomitant aspiration and to examine the relationships among swallowing function, age, and nutritional status. STUDY DESIGN Seventy patients (mean age, 10.7 years; range, 1.8 to 30 years) had feeding/swallowing and nutritional evaluations. Fifty-one patients, in whom there were concerns about swallowing safety, were examined with a standardized videofluoroscopic swallow study. RESULTS Fourteen of the 51 patients (27%) with histories suggestive of dysphagia demonstrated aspiration. Of these, silent aspiration (aspiration without a cough) occurred in 10 (71%) patients. Aspirators were significantly older than non-aspirators (mean age, 16.9 vs 10.8 years; P =.002). Advancing age was the strongest factor associated with aspiration during continuous drinking (P =.01). In patients with ataxia-telangiectasia, weight and weight/height were abnormally low at all ages and most compromised in older patients. Patients who aspirated had significantly lower mean weight (P <.002) and weight/height z scores (P <.001) than did patients who did not aspirate. CONCLUSIONS Oropharyngeal dysphagia is common and appears to be progressive in patients with ataxia-telangiectasia. Older patients also have a higher incidence of poorer nutritional status. The relationship between dysphagia and nutritional status deserves further investigation.

Cryptosporidiosis Stimulates an Inflammatory Intestinal Response in Malnourished Haitian Children

The mechanisms by which Cryptosporidium parvum cause persistent diarrhea and increased morbidity and mortality are poorly understood. Three groups of Haitian children <18 months old were studied: case patients, children with diarrhea not due to Cryptosporidium, and healthy control subjects. Compared with both control groups, children with acute cryptosporidiosis were more malnourished (including measures of stunting [P=.03] and general malnutrition [P=.01]), vitamin A deficient (P=.04), and less often breast-fed (P=.04). Markers of a proinflammatory immune response, interleukin (IL)-8 and tumor necrosis factor-alpha receptor I, were significantly elevated in the case population (P=.02 and P<.01, respectively), as was fecal lactoferrin (P=.01) and the T helper (Th)-2 cytokine IL-13 (P=.03). The counterregulatory cytokine IL-10 was exclusively elevated in the case population (P<.01). A Th1 cytokine response to infection was not detected. This triple cohort study demonstrates that malnourished children with acute cryptosporidiosis mount inflammatory, Th-2, and counterregulatory intestinal immune responses.