The syndrome of chronic mucocutaneous candidiasis with selective antibody deficiency.

BACKGROUND: Most patients with chronic mucocutaneous candidiasis (CMC) have a selective defect of cell-mediated immunity against Candida albicans (as demonstrated by cutaneous anergy and decreased lymphoproliferative responses to Candida antigen) and intact antibody responses. Many CMC patients also develop infections with other organisms, suggesting a more extensive immunologic defect. OBJECTIVES: The aim of this study was to describe a patient with CMC and selective antibody deficiency and identify eight similar previously reported patients. DATA SOURCES: Relevant articles in the English language derived from searching the MEDLINE database were used. RESULTS: We describe an 18-year-old male patient who was identified with CMC as an infant and later developed immunoglobulin (Ig)G2, IgG4, and IgA deficiency at age 12 associated with poor antibody responses to vaccine antigens. We have identified eight other previously reported CMC patients with selective antibody deficiencies and bacterial infections. IgG2 deficiency was present in all nine patients, and was associated with IgG4 deficiency in 8 patients and IgA deficiency in 3 patients. Six patients had poor or absent antibody responses to pneumococcal polysaccharide vaccine, and all nine patients developed severe recurrent lung infections. CONCLUSIONS: We suggest that these cases represent a distinct phenotype of CMC and should be studied for common histocompatibility leukocyte antigen types and molecular defects.     

The yellow nail syndrome. Light and electron microscopic aspects of the pleura

The yellow nail syndrome is a rare cause of recurrent pleural effusions. We studied a case of this entity, placing special emphasis on the microscopic and ultrastructural aspects of the pleural lymphatics. The patient had the classic symptoms of recurrent bilateral pleural effusions, yellow, dystrophic fingernails and toenails, and lower-limb edema. To control the pleural effusions, a left parietal pleurectomy was performed. Histologic study showed both pleura to be thickened with fibrosis and chronic inflammatory infiltration. The lymphatic capillaries in the visceral pleura were dilated. Electron microscopy confirmed the lymphatic nature of these capillaries. We believe that these ectatic lymphatic capillaries suggest a downstream obstruction to the lymph drainage.     

Systemic antibody deficiency in patients without serum immunoglobulin deficiency or with selective IgA deficiency.

Serum IgG tetanus toxoid antibody (IgGTTab) concentrations were measured in patients with chronic chest infections or recurrent acute chest infections following immunization and compared with results obtained in a group of 43 controls. Apart from selective IgA deficiency in some patients, all had normal or high serum immunoglobulins. Using an enzyme linked immunosorbent assay (ELISA) for IgG TTab, antibody was present following one immunization in all controls who had previously been immunized and following two immunizations in those not previously immunized. Ninety-seven and a half per cent of controls had a serum antibody concentration of greater than 4 micrograms/ml. Following the same immunization schedule, eight of 45 (18%) patients with chronic chest infections and three of 11 (27%) patients with recurrent acute infections had a serum IgG TTab of less than 4 micrograms/ml. The three patients with a low IgG TTab concentration and recurrent acute infections all had selective IgA deficiency. Two of these patients have benefited from injections of normal human immunoglobulin. It is suggested that systemic antibody deficiency as a cause of chronic or recurrent respiratory tract infections cannot be excluded by measuring serum immunoglobulin concentrations alone and that it is of value to measure antibody responses following immunization.     

Selective polysaccharide antibody deficiency in familial DiGeorge syndrome.

A family including three children with DiGeorge syndrome is described. One child died in the neonatal period from cardiac anomalies accompanying complete DiGeorge syndrome. The two surviving siblings shared a common set of pharyngeal pouch anomalies and immunodeficiency consistent with partial DiGeorge syndrome, and other morphologic anomalies characteristic of the velocardiofacial syndrome with which familial DiGeorge syndrome is associated (reviewed in reference 1). Both had normal karyotypes. Both presented with recurrent otitis media and sinopulmonary infections, CD4+ T cell lymphopenia, and defective DCH skin test responses to recall T cell antigens. Both had low serum IgM levels and IgG4 levels at the lower limits of normal. Immunization with bacterial polysaccharides resulted in impaired IgG antibody responses to the same set of antigens (H. influenzae polyribophosphate and S. pneumoniae capsular serotypes 9N and 14), while responses to protein antigens were intact. Both siblings were treated successfully with intravenous gamma globulin. The pattern of selective antibody deficiency in these patients with familial DiGeorge syndrome suggests a heritable lesion in certain regulatory antipolysaccharide CD4+ T cell subpopulations.     

Dopa-responsive dystonia: a syndrome of selective nigrostriatal dopaminergic deficiency.

Dopa-responsive dystonia (DRD) is no longer a rare oddity. For the clinician, DRD poses a diagnostic challenge as its clinical presentation can be quite diverse. Marked and sustained response to L-dopa is the most crucial and absolute hallmark in confirming a diagnosis. Absence of degenerative nigral cell loss underlies the remarkable L-dopa response. The broadening spectrum of the clinical presentations, progress in molecular genetics with evidence of incomplete penetrance and phenotypic variability, biochemistry, utility of nuclear imaging in differential diagnosis, and treatment are discussed. I propose the concept of DRD as a syndrome, defined as selective nigrostriatal dopamine deficiency caused by genetic defects in dopamine synthesis without degenerative cell loss. I further propose the term DRD-plus, defined as inherited metabolic disorders which have symptomatic features of DRD, and those features not seen in DRD as well.     

Severe selective IgM deficiency.

Among the primary antibody deficiency syndromes, severe selective IgM deficiency (also previously known as type V dysgammaglobulinaemia) is rare, and the majority of previous reports have indicated a fatal outcome. Three adult patients who were found to have a persistently low serum IgM are described. This deficiency was not obviously related to their presenting illness; in two of the patients, who were investigated in detail, it appeared to be of no immediate consequence.     

Clinical and laboratory characteristics of 75 patients with specific polysaccharide antibody deficiency syndrome.

BACKGROUND: There are limited studies of large cohorts of patients with specific polysaccharide antibody deficiency (SPAD) syndrome. OBJECTIVE: To study the clinical and laboratory characteristics of patients with specific polysaccharide antibody deficiency syndrome. METHODS: We retrospectively studied 75 patients with total IgG levels of at least 500 mg/dL and fewer than 9 of 12 responses to vaccination with pneumococcal vaccine polyvalent. Exclusion criteria included an IgG level less than 500 mg/dL, established immunodeficiency syndrome, and secondary immunodeficiency. RESULTS: The most common clinical presentation was frequent infections (n = 69; 92%), including sinusitis (n = 53; 77%), pneumonia (n = 29; 42%), ear infections (n = 18; 26%), and bronchitis (n = 19; 28%). Other presentations were systemic infections (n = 5; 7%), autoimmune or rheumatic diseases (n = 6; 8%), and chronic diarrhea (n = 4; 5%). The median IgG2 level of patients with no response to pneumococcal vaccine polyvalent tended to be lower than that of patients with at least 1 response (150 vs 193 mg/dL, respectively; P = .06). There was no association between total IgG level (categorized as 500-600 or > or = 600 mg/dL) and frequency of infection (P = .43). Patients with fewer responses to pneumococcal vaccine polyvalent and a higher frequency of infections were more likely to receive intravenous immunoglobulin (IVIG) therapy (P = .01 and .003, respectively). Treatment with IVIG significantly reduced the number of infections (P < .001). CONCLUSION: Patients with no response to pneumococcal vaccine polyvalent tended to have lower IgG2 levels; those with fewer responses were more likely to receive IVIG therapy.     

The clinical syndrome of specific antibody deficiency in children

Specific antibody deficiency (SAD) is an immune deficiency which has been reported in adults and children with recurrent respiratory tract infections; however, the clinical features of SAD are not well described. This study evaluated formally the clinical syndrome of SAD, by comparing the clinical features of children with SAD and those of children with recurrent infection but normal immune function tests. SAD was defined as an adequate IgG antibody response to less than 50% of 12 pneumococcal serotypes tested following 23-valent unconjugated pneumococcal immunization. An adequate IgG antibody response was defined as a post-immunization titre of >or= 1.3 microg/ml or >or= four times the preimmunization value. Seventy-four children with recurrent infection were evaluated where immune deficiencies other than SAD had been excluded. Eleven (14.9%) of these children had SAD. Clinical features differed between the group with SAD and the group with normal antibody responses. A history of otitis media, particularly in association with chronic otorrhoea was associated with SAD [relative risk (RR) of SAD in those with chronic otorrhoea 4.64 (P = 0.02)]. SAD was associated with allergic disease, particularly allergic rhinitis [RR of SAD in those with allergic rhinitis 3.77 (P = 0.04)]. These two clinical associations of SAD were independent in this study [RR of chronic otorrhoea in those with allergic rhinitis 0.85 (P = 0.28)]. SAD was not an age-related phenomenon in this population. SAD has a distinct clinical phenotype, presenting as recurrent infection associated with chronic otorrhoea and/or allergic disease, and the condition should be sought in children with these features.     

Interferon deficiency syndrome.

Activation of the interferon (IFN) system is an early defence mechanism against viral infections. The virus stimulates production of IFN by nucleated cells including the peripheral blood mononuclear cells (PBMC), and this IFN in turn activates several IFN-dependent immune mechanisms including the induction of an anti-viral state in cells, which prevents or retards further intracellular viral replication. In an ongoing study of 1,500 individuals of all ages and with various illnesses, we found 15 cases (representing 5% of patients with acute viral disease) in whom the IFN system response during an acute viral illness was absent or grossly deficient. There was no detectable IFN in the blood, PBMC did not produce IFN-alpha and IFN-gamma or produced minimal amounts of one of them in vitro following appropriate stimulation, and the patients' PBMC were not in an anti-viral state. These patients had severe progressive or fulminant viral disease, often ending fatally. IFN therapy appears to be beneficial in these cases, as it rapidly induced a cellular antiviral state in most cases, stimulated in vitro IFN-alpha and IFN-gamma production by PBMC, and led to rapid recovery in seven of the nine patients who received treatment for at least 3 days. In our opinion IFN replacement therapy should be commenced as early as possible in such cases, and before irreversible cell and organ damage occur.     

Intravenous immunoglobulin therapy for antibody deficiency.

Twenty patients with antibody deficiency were treated at random with either intramuscular immune serum globulin (ISG) or intravenous modified immune serum globulin (M-ISG). Fourteen patients received of 259 M-ISG infusions during 242 months of treatment. Catastrophic vasomotor reactions were not observed. A single dose of 150 mg/kilo M-ISG increased serum IgG values a mean 248 mg%. Intravenous M-ISG therapy was effective in reducing the incidence of acute infections. Subjects receiving M-ISG developed 0.103 acute infections per month of treatment. Patients injected with ISG had 0.295 acute infections per month of treatment. Seven subjects had separate courses of both intravenous M-ISG and intramuscular ISG. Acute infections per month of treatment for M-ISG and ISG were 0.104 and 0.406, respectively.     

Secondary antibody deficiency

Secondary antibody deficiencies are defined by a quantitative or qualitative decrease in antibodies that occur most commonly as a consequence of renal or gastrointestinal immunoglobulin loss, hematological malignancies and corticosteroid, immunosuppressive or anticonvulsant medications. Patients with hematological malignancies or requiring immunosuppressive medications are known to be at increased risk of infection, but few studies directly address this relationship in the context of antibody deficiency. Immunoglobulin replacement therapy has been shown to be effective in reducing infections in primary and some secondary antibody deficiencies. The commonly encountered causes of secondary antibody deficiencies and their association with infection-related morbidity and mortality are discussed. Recommendations are made for screening and clinical management of those at risk.     

The acquired immune deficiency syndrome.

Liposomes prepared with human LS174T colon tumour cell membranes induce specific primary xenogeneic immune responses in BALB/c splenocytes in vitro. Characterization of the adjuvant role of these liposomes was accomplished by determining the effect on immune induction of several modifications on the liposomal carrier. The results showed that the carrier effect of liposomes was mediated primarily by tumour antigens exposed on the outer surface. Trypsin treatment of the liposomes eliminated 95% of the surface protein and significantly (P less than 0.05) reduced the ability of liposomes to induce cytotoxic splenocytes. The generation of cytolytic activity with liposomes was dose-dependent, with a 10 micrograms protein threshold and a maximal response at 100 micrograms. 'Rigid' liposomes were shown to be significantly (P less than 0.05) more efficacious than fluid liposomes in inducing cytotoxicity. In addition, the data indicate that the xenogeneic cell-mediated immunity exhibits identical classes of effector cells as found in murine-murine reactions. Lymphocytes bearing the THY-1, Lyt-1 and Lyt-2 surface markers were necessary for immune induction. The role of Lyt-123 subpopulation was suggested by the inability to achieve normal cytolytic levels by reconstitution with Lyt-1 plus Lyt-2 cells. Adherent cells were, as expected, necessary for the generation of primary immunity. Indeed, the interaction of I-A+ adherent cells with liposomes for at least 8 h was required to generate subsequent maximal T cell cytotoxic activity. The phenotype of the cytotoxic effector cell was Thy-1+, Lyt-2+, and I-Ad-. If this were an allo-or syngeneic, and not a xenogeneic system, this study would be of less interest. However, when coupled with the known molecular homologies between murine and human lymphocyte antigens, these results suggest that the concept of cross species major histocompatibility complex (MHC) restriction is tenable. Thus the liposome is not only an effective antigen carrier, but also a functional adjuvant for in vitro induced cell-mediated immunity.