Role of Phosphorylcholine-Specific Immunoglobulin M in Acute Upper Respiratory Tract Infections.

OBJECTIVES: The aim of this study was to clarify the role of serum phosphorylcholine (PC)-specific immunoglobulin M (IgM) as a natural antibody against infectious diseases. METHODS: The relationship between serum PC-specific IgM level and C-reactive protein level or white blood cell counts was examined in patients with severe upper respiratory tract infections (ie, acute epiglottitis and peritonsillar abscess). RESULTS: PC-specific IgM level was significantly negatively correlated with C-reactive protein level and white blood cell count. In addition, C-reactive protein level and white blood cell count was significantly lower in women than in men, whereas PC-specific IgM level was significantly higher in women. CONCLUSIONS: PC-specific IgM is suggested to have protective and suppressive effects against the progression of infectious and inflammatory reactions. Higher levels of PC-specific IgM in women might be one of the reasons why the incidence and severity of acute epiglottitis and peritonsillar abscess are lower in women.

[Antimicrobial immunity in patients with acute epiglottitis].

Fifty-three patients with catarrhal epiglottitis and 31 patients with epiglottic abscess aged 16-60 years were examined. It was determined that development of epiglottitis is tightly related to abnormalities in reactivity of phagocytic and humoral arms of immunity. Decreased affinity of produced antibodies, opsonizing properties of serum as well as phagocytic and biocide activity of neutrophils were revealed in patients. In patients with catarrhal and necrotic epiglottitis similar abnormalities of immunoreactivity were observed although in patientswith necrotic epiglottitis they were more pronounced.

Invasive epiglottic aspergillosis: A case report and literature review.

Invasive aspergillosis is a life-threatening infection in immunocompromised hosts and occurs most frequently in the lungs. Invasive laryngeal aspergillosis is extremely rare. Due to the potential progression of invasive aspergillosis, antifungal therapy must be started immediately in cases involving clinical suspicion of the disease. A 65-year-old male with agranulocytosis complained of sore throat and dysphagia. His epiglottis was covered with caseating granulomatous lesions and the tissue was easily disrupted. A histopathological examination showed an aggressive invasion of Aspergillus species and cartilage destruction. Therefore, we made a diagnosis of primary invasive epiglottic aspergillosis. The invasive aspergillosis resolved with antifungal therapy and an increase in neutrophils. It is therefore necessary to include invasive laryngeal aspergillosis in the differential diagnosis when encountering immunocompromised patients presenting with laryngeal granulomatous lesions and laryngitis-like symptoms.

Long term enhancement of the IgG2 antibody response to Haemophilus influenzae type b by breast-feeding.

SUBJECTS: Sets of sera were obtained from 30 children <6 years of age with invasive type b (Hib) infection and their mothers. Duration and mode of breast-feeding were monitored. Titers of IgG1, IgG2, IgA and IgM antibodies against Hib capsular polysaccharide were determined in sera taken during the acute illness and during early and late convalescence. RESULTS: Children 18 months or older with longer durations of exclusive breast-feeding (13 weeks or more; mean, 19.3 weeks) had higher Hib antibody concentrations of the IgG1, IgG2, IgA and IgM isotypes than those with a shorter duration of exclusive breast-feeding (<13 weeks; mean, 5.4 weeks). The difference was greatest for the IgG2 isotype. In regression analyses the association between the duration of exclusive breast-feeding and the anti-Hib IgG2 concentration was significant when breast-feeding, type of Hib infection, maternal Hib antibody titer and age were used as explanatory factors. In the group of 14 children <18 months of age no significant differences were noted. DISCUSSION: This study indicates the presence of a long lasting enhancing effect of breast-feeding on the antibody response to Hib in children, in particular on IgG2 Hib antibody production. This may result from the content in the milk of IFN-gamma and IFN-gamma-producing cells and possibly other factors, which can support IgG2 antibody production.

[Invasive infection with Haemophilus influenzae type b in spite of complete vaccination]. / Invasieve infectie met Haemophilus influenzae type b ondanks volledige vaccinatie.

Five patients, 4 boys and 1 girl aged 13-41 months, developed invasive Haemophilus influenzae type b (Hib) disease (2 epiglottitis, 3 meningitis) despite full (or at least 3 times) vaccination. At admission as well during convalescence, 3 out of 5 had IgG anti Hib antibody levels < or = 5 U/ml. Serum immunoglobulin levels, including IgG subclasses, as well as complement were normal in all cases. In 2 of the 3, booster vaccinations with Hib conjugate vaccine elicited adequate antibody titres. Since the incorporation of the conjugated Hib polysaccharide tetanus toxoid vaccine (HibTT) in the National Vaccination Programme in the Netherlands, the number of invasive infections caused by Hib has dropped significantly. Causes of Hib conjugate vaccine failures are mostly unknown. In about one-third of the cases serum immunoglobulin levels are deficient, most often IgG2 or IgM. Susceptibility to Hib infection is in part also genetically determined. In the follow-up of Hib vaccine failures, anti Hib antibody titres should be determined. Booster vaccinations may be necessary.

Hib epiglottitis despite fully vaccinated status.

The introduction of an effective vaccine has markedly reduced the incidence of invasive Haemophilus influenzae type b (Hib) disease. However, vaccination failure can occur, and this report describes one such case in a previously healthy 4-year-old girl, who became severely unwell with Hib epiglottitis. She had received a full course of Hib vaccine administered via the buttocks. This site has been associated with reduced immunogenicity compared to vaccination by injection into the thigh or deltoid muscles. Current recommendations are to avoid gluteal injection for all vaccinations.

Interactive effect of genes associated with immunoglobulin allotypes and HLA specificities on susceptibility to Haemophilus influenzae disease.

Genes associated with immunoglobulin (Ig) allotype determinants are important in regulation of immune responses to bacterial polysaccharides. Furthermore, loci associated with Ig allotypes have been reported to interact with those associated with the major histocompatibility complex and affect susceptibility to certain diseases. In the present study we determined the frequencies of certain Gm phenotypes in patients with Haemophilus meningitis or epiglottitis and in controls. HLA-A, -B and -DR specificities had previously been determined in the majority of these subjects. Although no Ig phenotype was associated with increased or decreased relative risk of disease, the frequencies of several combinations of HLA specificities and Ig phenotypes were significantly different from those of controls. Thus, for subjects with the Gm phenotype (1, 3, 17; 23; 5, 13, 21), the risk of Haemophilus meningitis or epiglottitis was lower in individuals with HLA-B5 than in those without this specificity (odds ratio less than 0.1, P less than 0.004). In contrast, for subjects with the closely related Gm phenotype differing only by the absence of Gm(23), (1, 3, 17; ; 5, 13, 21), the risk of disease was higher in those with HLA-DR3 than in individuals who lacked DR3 (odds ratio = 11.0, P = 0.02). Although the present data require confirmation in an independent sample, they suggest that complex interactions between genes at two independent loci controlling HLA and Ig allotypes, respectively, may affect susceptibility to Haemophilus disease.

Antibodies to Haemophilus influenzae type b outer membrane proteins in children with epiglottitis or meningitis and in healthy controls.

The two most common manifestations of Haemophilus influenzae type b (Hib) infection in Western communities are meningitis and epiglottitis. The role of antibodies against outer membrane proteins (OMP) in the pathogenesis of these diseases was investigated by Western blotting (immunoblotting) with an OMP antigen prepared from a local Hib strain. Acute- and convalescent-phase serum samples from 25 children with epiglottitis and 20 with meningitis and single serum samples from 19 control children in the same age group were tested. Western blots were evaluated quantitatively by use of graphs generated from a densitometer. OMP antibody was detected in all sera from patients and controls. There was no significant difference between the mean antibody level in acute-phase sera from children with meningitis (336 +/- 143 arbitrary units) and those from children with epiglottitis (286 +/- 134 arbitrary units). However, the mean OMP antibody level in sera from healthy controls, with no known history of Hib disease, was significantly higher than that in sera from patients with Hib disease within 2 days of admission to the hospital (patients [n = 35], 282 +/- 144; controls [n = 19], 425 +/- 236; P = 0.007). The difference was due mainly to higher levels, in control sera, of antibody against four proteins, one of which is either P1 or a comigrating protein of 49 kDa. The finding of higher levels of OMP antibody in healthy controls suggests a protective role for antibodies directed against one or more OMP. This information could be exploited in future vaccine development.

Characterization of the serum antibody response to the capsular polysaccharide of Haemophilus influenzae type b in children with invasive infections.

The serum antibody response to the capsular polysaccharide of Haemophilus influenzae type b (Hib) was studied in 30 children aged 1 day-5 years with invasive Hib infections. From each child, serum was obtained 0-2 days, 5-11 days, 1 month, and 6-12 months after onset of symptoms. Total antibodies were determined with RIA and isotypes with ELISA. Only 2 children had antibody levels above the estimated protective level (0.15 microgram/mL) in the first serum sample. The antibody response was age dependent with wide individual variations. Children > or = 2 years had increases in IgG, IgM, and IgA antibodies with predominance of IgG. The initial IgG response was IgG1 and IgG2 with predominance of IgG1. In the last serum sample, IgG1 antibodies had decreased while IgG2 antibodies remained unchanged. Only 2 of 7 children < 1 year had a detectable antibody response. The correlation coefficient for total antibodies compared with the sum of IgG, IgM, and IgA was .88 (P < .0001) and for IgG compared with the sum of IgG1 and IgG2 was .97 (P < .0001).

Recurrent acute epiglottitis in adults: defective antibody response.

BACKGROUND: Recurrent acute epiglottitis is uncommon in adults. In the medical literature, very little is known about the immune status of this population. OBJECTIVE: To evaluate the immune system of a group of four adult patients with recurrent acute epiglottitis, in what represents the largest series ever reported. METHODS: The clinical course of these episodes was carefully evaluated and a basic immune deficiency work-up was carried out for each patient. RESULTS: All four patients displayed clinical and laboratory evidence of impaired humoral immunity. One patient was splenectomized. Another patient had a below normal immunoglobulin G level. At the time of their first evaluation, none of our patients had specific antibodies against Haemophilus influenzae and one had a subnormal Streptococcus pneumoniae immunoglobulin G level for a majority of serotypes. After specific vaccination, two patients had persistent abnormalities in their response to one or more polysaccharides or conjugate-polysaccharide antigens. In the other two, the transient abnormalities were corrected by immunization. CONCLUSIONS: When recurrent acute epiglottitis occurs in adults, it is important to investigate the immune system because a quantitative or a specific antibody deficiency could be found. It also follows that these patients will be successfully treated either by immunization or antibody replacement.

Acute epiglottitis--aetiology, epidemiology and outcome in a population before large-scale Haemophilus influenzae type b vaccination.

Over a period of 18 years 219 consecutive cases of acute epiglottitis were diagnosed and subsequently investigated in order to elucidate the aetiology, epidemiology and outcome of this disease in a well-defined population in Sweden before general vaccination against Haemophilus influenzae type b infection was introduced. Compared with the results from other parts of the industrialized world, high incidence rates were found in both children (14/100,000/year) and adults (2.3/100,000/year). The annual trend showed a significant decline in incidence among children, whereas in adults it remained unchanged. In cases where the aetiological agent could be determined, infection with H. influenzae type b was the main cause of disease in all age groups. However, in adults 27% (6/22) had a disease caused by micro-organisms other than H. influenzae type b that were verified with a blood culture. Sixty-eight per cent had a negative blood culture. The mortality rate was 0.5% (1/219) and 6% (13/219) developed a significant complication of the disease.

Development of serum antibodies of the immunoglobulin G class and subclasses against the capsular polysaccharide of Haemophilus influenzae type b in children and adults with invasive infections.

The development of total immunoglobulin G (IgG) antibodies and antibodies of the four IgG subclasses in serum against Haemophilus influenzae type b capsular polysaccharide (CPS) was studied in 24 children and 11 adults with invasive Haemophilus influenzae type b infections, by using an enzyme-linked immunosorbent assay. None of the 8 children aged 10 months or younger had increases in the IgG class or in any of the IgG subclasses. In contrast, 14 of 16 children between 10 months and 6 years of age and 10 of 11 adults had significant increases in total IgG, IgG1, or IgG2 antibodies in various combinations, but none of them had increases in IgG3 or IgG4 antibodies. The increases in IgG1 and IgG2 antibodies in the children were of similar magnitudes. Of 11 adult patients, 9 had significant increases in IgG2 antibodies, while only 4 had increases in IgG1 antibodies. In conclusion, this study shows that children younger than approximately 1 year have no IgG response to H. influenzae type b CPS, while individuals above this age have a mixed IgG1 and IgG2 response.

Serum and salivary antibody responses to non-capsular Haemophilus influenzae antigens in children with meningitis and epiglottitis.

Serum IgG, IgA and IgM antibody and salivary IgA antibody concentrations to non-capsular Haemophilus influenzae antigens were measured in 13 children with H. influenzae type b meningitis and in 15 children with epiglottitis. Most had detectable serum IgG and IgM antibody at presentation but significantly fewer patients with meningitis had serum IgA antibody at presentation (P less than 0.05). Serum antibody concentrations had risen significantly by 3 weeks after presentation in patients with epiglottitis only. Convalescent serum IgG antibody concentrations against these antigens were higher in younger children with epiglottitis. Salivary IgA antibody to H. influenzae was detectable at presentation in all children with epiglottitis and in 12 of 13 with meningitis. Salivary antibody concentrations did not differ significantly between the two patient groups at presentation, although patients with meningitis had higher salivary IgA antibody concentrations than 10 children of similar age with bronchiolitis (P less than 0.02). There was no association between the presence of salivary antibody and low concentrations of convalescent serum antibody. The rise in convalescent serum antibody concentrations to non-capsular H. influenzae antigens only in children with epiglottitis is similar to findings for antibody to capsular polysaccharide. However, this rise was greater for IgG in younger patients, and the low titre of convalescent serum antibody in patients with meningitis was not associated with higher titres of IgA antibody in secretions as described by others for polysaccharide antibody. These findings suggest that the poor serum antibody response to these antigens in patients with meningitis is independent of age and is not due to mucosal induction of systemic tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Differing antibody responses to Haemophilus influenzae type b after meningitis or epiglottitis.

Two common forms of invasive disease due to Haemophilus influenzae type b (Hib) are epiglottitis and meningitis. It is not known why some children develop epiglottitis and others meningitis. To examine the hypothesis that epiglottitis occurs in children who may have been previously exposed to Hib, and who would therefore exhibit a more vigorous antibody response in convalescence, we measured levels of antibody to Hib capsule in 92 children. Geometric mean convalescent-phase IgG, IgA, IgM and total antibody levels were significantly higher in 45 children with epiglottitis than in 47 with meningitis, even after adjustment for age differences (mean total antibody, 95% confidence intervals: meningitis 0.38, 0.34-0.43; epiglottitis: 2.25, 2.0-2.54 micrograms/ml). However, contrary to previous reports, a poor antibody response was only observed in a minority of children with meningitis; the antibody response of the majority was indistinguishable from that observed in children with epiglottitis.

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure.

AIMS: To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. METHODS: Unmatched case-control study in the UK and Eire 1992-2001 and Victoria, Australia 1988-1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. RESULTS: Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 microg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 microg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 microg/ml (2.78 to 5.15); unvaccinated GMC 1.48 microg/ml (0.90 to 2.21); p = 0.003). CONCLUSIONS: Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune mechanisms in conferring protection remain unclear.

Serum antibody response to capsular polysaccharide, outer membrane, and lipooligosaccharide in children with invasive Haemophilus influenzae type b infections.

Serum antibodies against capsular polysaccharide (CPS), outer membrane (OM), and lipooligosaccharide (LOS) from Haemophilus influenzae type b were measured by enzyme-linked immunosorbent assay in acute- and convalescent-phase sera from 21 children between 3 months and 4 years of age with invasive H. influenzae type b infections. As expected, the levels of anti-CPS antibodies in the acute-phase serum samples were low or not detectable, as were the levels of antibodies against LOS. In contrast, all children had detectable antibodies against the OM in the acute-phase serum sample, indicating that they are of little or no importance for protection. An antibody response to CPS was noted in 13 of the 21 patients, mainly in the older children. An antibody response to the OM was seen in 16 patients, with no evident relation to age. The antibody response to the OM preparation, which consisted of proteins and LOS, was probably directed mainly against the OM proteins, since only six children showed a response, usually of low magnitude, of antibodies to LOS.

Host and bacterial factors associated with Haemophilus influenzae type b disease in Minnesota children vaccinated with type b polysaccharide vaccine.

Host and bacterial factors were evaluated among 86 Minnesota children with Haemophilus influenzae type b disease detected by active surveillance after introduction of type b polysaccharide vaccine in the state. Children were 2-6 y of age. Thirty-three (38%) had been vaccinated. There was no significant difference between the frequency of low serum concentrations of IgM, IgA, IgG, or IgG2 in the vaccinated and nonvaccinated subjects (13% vs. 8%, P = .5). The presence of the Gm immunoglobulin allotype phenotype (1,3,17;23;5,13,21), previously associated with a lower relative risk of vaccine failure in children from other states, was associated with a fourfold decrease in the relative risk of vaccine failure in Minnesota (P less than .07). Haemophilus isolates from 58 of the children were available for clonal characterization by multilocus electrophoresis and outer membrane protein subtyping. There were no significant differences between the clone distribution of the strains causing disease in vaccinated and nonvaccinated patients, and nearly all disease-producing clones in Minnesota also are known to cause disease in other areas of the country. Thus, vaccine failure in Minnesota is infrequently associated with hypogammaglobulinemia or with infection by unusual clones of a H. influenzae type b. Also, the Gm phenotype associated with protection against vaccine failure in other areas of the USA appears to be protective in Minnesota.

Histocompatibility leukocyte antigen and erythrocyte MNSs specificities in patients with meningitis or epiglottitis due to Haemophilus influenzae type b.

The frequencies of erythrocyte MNSs antigens and certain histocompatibility leukocyte antigen (HLA) specificities (HLA-A, HLA-B, and HLA-DR) were determined in white patients with meningitis or epiglottitis due to Haemophilus influenzae type b and in controls. The frequency of the erythrocyte MNSs genotype was significantly lower among patients with meningitis than among those with epiglottitis (P = 0.03); this observation confirms a trend observed previously. However, the frequencies of the HLA specificities did not differ significantly in the three groups studied; this result fails to confirm previous reports of disease associations with several HLA-A and HLA-B specificities. Although susceptibility to different clinical manifestations of haemophilus disease may be influenced by genetic factors, our studies indicate that the major loci conferring susceptibility are not in linkage disequilibrium with specificities in the major histocompatibility complex.