Selective IgG subclass deficiencies and antibody responses to pneumococcal capsular polysaccharide antigen in adult community-acquired pneumonia

We measured the serum concentrations of IgG subclasses in healthy subjects (n = 26) and in patients with community-acquired pneumonia (CAP) on admission (n = 38), at recovery (n = 21), and 9 months after admission (n = 19). Then, in 8 of the control subjects and 15 of the patients, we measured IgG subclasses and mean serum antibody concentrations of pneumococcal capsular polysaccharides before and 3 wk after immunization with a pneumococcal vaccine. Compared to the control subjects, the serum concentration of the IgG2 subclass was lower at admission in patients with CAP of bacterial or unknown cause (p less than 0.005). Concentrations of IgG subclasses in patients did not differ between admission and recovery, or between admission and 9 months later. After vaccination, in both control subjects and patients, there was an increase in the concentrations of IgG2 subclasses (p = 0.01) and antipneumococcal antibodies (p less than 10(-4)). We show that serum IgG2 concentration in patients with CAP of bacterial or unknown cause is lower than in healthy subjects and remains lower for several months. After immunization with a pneumococcal vaccine, the increase in serum concentrations of IgG subclasses and antipneumococcal antibodies in patients does not differ from those in control subjects.     

The course of cryptococcal capsular polysaccharide antigenemia/human cryptococcal polysaccharide elimination kinetics

The detection of cryptococcal polysaccharides in the serum is diagnostic of cryptococcosis in the absence of rheumatoid factor. The significance of the continued detection of this antigen in the serum during antifungal therapy is not known. Prolonged antigenemia might indicate ongoing active infection, delayed clearance of the polysaccharides from the blood, or continued release of the polysaccharide antigens from a reservoir of nonviable organisms. In seven cases the cryptococcosis with prolonged and high levels of cryptococcal polysaccharide antigenemia, the courses of antigenemia were determined. During the convalescent phase, the T 1/2's were approximately 48 hours for the antigen clearance in all the cases studied. The polysaccharide antigens recovered from the serum of one patient had molecular weights of greater than 200,000 daltons. In rabbits, a single intravenous injection of cryptococcal capsular polysaccharides showed a similarly slow clearance of the antigen with a T 1/2 of approximately 24 to 48 hours. These data suggest that adequately treated cases of cryptococcosis may have a predictable rate of antigen clearance from the serum during convalescence.     

Antibody to capsular polysaccharide of Streptococcus pneumoniae at the time of hospital admission for Pneumococcal pneumonia

IgG to capsular polysaccharide (CPS) of Streptococcus pneumoniae is thought to provide the greatest degree of protection against pneumococcal disease. Serum obtained at hospital admission from 14 (27%) of 51 patients with bacteremic pneumococcal pneumonia and 11 (37%) of 30 with nonbacteremic pneumococcal pneumonia contained IgG to CPS of the infecting serotype; these percentages are similar to the prevalence of IgG to CPS in a control population. However, when compared with antibody from healthy adults, this IgG had far less capacity to opsonize the infecting pneumococcal serotype for phagocytosis in vitro by normal human polymorphonuclear leukocytes or to protect mice against experimental challenge. Failure to opsonize correlated closely with failure to protect mice, and each of these parameters correlated well with poor avidity for CPS. Future vaccine studies may need to examine the functional capacity of antibodies as a surrogate for infection, in addition to measuring their concentration in serum.     

Pneumococcal pneumonia: epidemiology and clinical features.

Pneumoccal pneumonia is a common illness; the highest incidence occurs at the extremes of age. The rate of pneumococcal bacteremic pneumonia is higher in blacks than in whites and 41 times higher in those with human immunodeficiency virus (HIV) infection than in individuals of the same age who are not HIV infected. Risk factors for pneumococcal pneumonia include dementia, seizure disorders, cigarette smoking, congestive heart failure, cerebrovascular disease, institutionalization, and chronic obstructive pulmonary disease. Outbreaks of pneumococcal pneumonia occur in situations of overcrowding such as in jails or in shelters for the homeless. Streptococcus pneumoniae is the most common cause of community acquired pneumonia requiring hospitalization, accounting for up to 50% of all such cases. The mortality rate from this infection varies considerably in reported studies ranging from 7% to 36%. Bacteremic pneumococcal pneumonia often has a complicated course. Respiratory failure, meningitis, pleural effusion, and empyema are the most common complications. The radiographic manifestations of pneumococcal pneumonia vary, but in general lobar consolidation is more likely to be associated with bacteremia. Cavitation is unusual.     

A model of high-affinity antibody binding to type III group B Streptococcus capsular polysaccharide.

We recently reported that the single repeating-unit pentasaccharide of type III group B Streptococcus (GBS) capsular polysaccharide is only weakly reactive with type III GBS antiserum. To further elucidate the relationship between antigen-chain length and antigenicity, tritiated oligosaccharides derived from type III capsular polysaccharide were used to generate detailed saturation binding curves with a fixed concentration of rabbit antiserum in a radioactive antigen-binding assay. A graded increase in affinity of antigen-antibody binding was seen as oligosaccharide size increased from 2.6 repeating units to 92 repeating units. These differences in affinity of antibody binding to oligosaccharides of different molecular size were confirmed by immunoprecipitation and competitive ELISA, two independent assays of antigen-antibody binding. Analysis of the saturation binding experiment indicated a difference of 300-fold in antibody-binding affinity for the largest versus the smallest tested oligosaccharides. Unexpectedly, the saturation binding values approached by the individual curves were inversely related to oligosaccharide chain length on a molar basis but equivalent on a weight basis. This observation is compatible with a model in which binding of an immunoglobulin molecule to an antigenic site on the polysaccharide facilitates subsequent binding of antibody to that antigen.     

Detection of capsular polysaccharide in serum for the diagnosis of pneumococcal pneumonia: clinical and experimental evaluation

To improve diagnostic options for pneumococcal pneumonia, an ELISA system was developed that can detect less than or equal to 6 ng/ml capsular polysaccharide in serum. The test was limited to 39 serotypes causing greater than 95% of pneumococcal infections. In clinical evaluation the test identified 14 of 15 cases (missing one serotype not included). No false-positive reaction occurred. However, the duration and level of antigenemia were variable (greater than or equal to 500-2.5 ng/ml) and seemed not to depend solely on the severity of infection. Therefore, the question of whether the extent of antigenemia was determined by a serotype-dependent variation in the elimination rates of polysaccharides was investigated. Clearance rates for 12 serotypes varied in rabbits and rats by a factor of greater than 250. This remarkable variability appeared to affect the extent of clinical antigenemia. Thus, only very sensitive systems can detect circulating antigen from rapidly cleared polysaccharide serotypes. Furthermore, the question arises whether slow polysaccharide clearance contributes to the virulence of some pneumococcal serotypes.     

Role of capsular polysaccharide and lipopolysaccharide of Klebsiella pneumoniae in experimental mice pneumonia model]

In this study, role of capsular polysaccharide (CPS) and lipopolysaccharide (LPS) of Klebsiella pneumoniae was investigated in experimental mice pneumonia model. Inoculation with K. pneumoniae mucoid strain DT-S into mice lung induced expansive, voluminous lethal pneumonia characterized with thickening of the alveolar septa caused by infiltration of inflammatory cell and packing of bacteria within alveolar spaces. On the other hand, mice lung inoculated with K. pneumoniae DT-X, which was non-mucoid mutant isolated from DT-S during natural passage, showed infiltration of inflammatory cell into alveolar spaces but there was no death of mice during the course of this pneumonia. Inoculation of CPS 100 micrograms of DT-S strain into mice lung induced lesser extent of accumulation of inflammatory cell than that of LPS 4 micrograms of this strain. Stimulation of alveolar and peritoneal macrophage with CPS, even at a concentration of 100 micrograms/ml, induced weaker Interleukin-1 (IL-1) activity than stimulation with LPS 4 micrograms/ml. These results suggest that since CPS of K. pneumoniae DT-S encapsulate bacteria including LPS, CPS may inhibit chemotaxis of inflammatory cell and IL-1 production of macrophage to be induced by LPS during course of pneumonia. It is speculated that existence of CPS have important role in modulating host response to bacterial LPS, and this effect of CPS may be related with difference of pathological findings of lung and lethality between K. pneumoniae DT-S and DT-X.     

Qualitative change in antibody responses of human immunodeficiency virus-infected individuals to pneumococcal capsular polysaccharide vaccination associated with highly active antiretroviral therapy

Variable region gene family 3 (V(H)3) is the predominant immunoglobulin (Ig) gene family used in human antibodies to pneumococcal capsular polysaccharide (PPS). This study examined whether highly active antiretroviral therapy (HAART) restores the ability of human immunodeficiency virus (HIV)-infected individuals to generate a V(H)3-positive response to PPS. The IgM, IgG, and V(H)3 (represented by antibodies expressing the determinant recognized by the monoclonal antibody D12) responses to PPS were determined for first-time recipients of a 23-valent PPS vaccine, both receiving and not receiving HAART, and second-time vaccine recipients receiving HAART. The results showed that only the individuals receiving HAART manifested a V(H)3-(D12)-positive response to PPS, despite a similar IgG response in each group. There was also a negative correlation between HIV load and PPS response for the groups receiving HAART. These findings suggest that HAART may influence qualitative aspects of the PPS response by restoring expression of certain V(H)3 genes used in the normal PPS response.     

The unspecific antibody response to N. meningitidis group A capsular polysaccharide often seen in bacteraemic diseases

When studying acute and convalescent phase sera of patients with bacteraemic diseases, an unexpected rise of antibody activity (measured as binding of radioactive antigen) towards the capsular polysaccharide of Neisseria meningitidis group A (MenA) was observed in 59 out of 292 patients whose infection was caused by other organisms (other groups of N. meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Escherichia coli or Staphylococcus aureus). This non-specific reaction was not seen in non-bacteraemic diseases (Mycoplasma pneumonia, viral meningitis) or after immunization with H. influenzae type b capsular polysaccharide or Salmonella and cholera whole cell vaccines. The 'unspecific' anti-MenA antibodies were of all immunoglobulin classes A, G and M tested, and had lower avidity than did those in the specific response. They were clearly inhibitable by N-acetylmannosamine which inhibited the specific antibodies only marginally.     

Induction of increased antibody responses to pneumococcal type 19F polysaccharide by Klebsiella polysaccharide

The level of antibody to pneumococcal 19F polysaccharide (PS) was studied in the serum of mice inoculated with klebsiella K2 PS or pneumococcal 19F PS or both. The serum antibody levels and the IgM plaque-forming-cell (PFC) response after immunization were higher in mice given both K2 PS and 19F PS than in mice of a control group given 19F PS alone. This immune response was also higher than the sum of PFC production in mice given 19F PS or K2 PS separately. Thus, K2 PS produced the cross-reactive antibody to 19F PS and also enhanced the magnitude of the antibody response to 19F PS. This response appeared to be specific for the 19F PS. The resulting high levels of antibody to pneumococcal 19F persisted for eight weeks after the administration of K2 PS and 19F PS. Animals immunized with both type 3 PS and K2 PS did not show an increased antibody response to pneumococcal type 3 PS. Klebsiella K-O3 antigen also stimulated the immune response to 19F PS. Higher immunologic responses to 19F PS were also induced in nude mice injected with the cross-reacting K2 PS or K47 PS and 19F PS. The ability to stimulate an antibody response to 19F PS by administering both K2 PS and 19F PS could not be transferred with spleen cells obtained from mice given both K2 PS and 19F PS.     

Pneumococcal pneumonia: a report of 100 cases

This paper reports 100 cases of etiologically proved pneumococcal pneumonia. It is shown that Gram's stain smear and culture of sputum are still useful in the diagnosis of the disease but are easily influenced by antibiotics. Whereas coagglutination, a newly developed procedure in detecting pneumococcal capsular antigens, is relatively independent to antibiotic therapy. Moreover, it is rapid, convenient and sensitive. Both Gram's stain smear and coagglutination may confirm early diagnosis and are valuable in the initial treatment of the disease. If unhospitalized patients with acute pneumonia are checked routinely with these methods and samples are collected before administration of antibiotics, etiological diagnosis of pneumococcal pneumonia will be confirmed in more cases. The data from 100 cases of pneumococcal pneumonia demonstrates that pneumococcal pneumonia remains the most common type of community-acquired pneumonias in this country. Its clinical manifestations have not changed greatly since 1950s but the age of the afflicted tents to be greater especially in those with underlying diseases. There are two common types of roentgenographic manifestations, i.e., lobar consolidation and bronchopneumonia, the former is still overwhelming in those under sixty and the later is more frequently seen in those over sixty. Penicillin G showed good clinical effects in treating pneumococcal pneumonia and all the 57 strains tested were sensitive in vitro. Therefore, penicillin G is still the drug of first choice in treating pneumococcal pneumonia.     

Pneumococcal bacteremia with pneumonia. Mortality in acquired immunodeficiency syndrome.

OBJECTIVE: To compare mortality due to bacteremic pneumococcal pneumonia in patients with acquired immunodeficiency syndrome (AIDS) vs (control) patients without human immunodeficiency virus (HIV) infection. Non-AIDS patients with HIV infection were incidentally tabulated as a separate group. DESIGN: A two-year retrospective study. SETTING: Inpatients of St. Clare's Hospital, a community hospital in New York City. PATIENTS: Forty-nine patients had 50 separate episodes with at least one positive blood culture for Streptococcus pneumoniae (all were penicillin-sensitive) and pneumonia on chest roentgenogram. Twenty-four patients had no HIV infection, 14 patients had AIDS, and 11 patients with 12 bacteremic episodes were HIV-positive without AIDS. INTERVENTIONS: Treatment for pneumonia was determined by the patient's individual physician. MEASUREMENTS AND MAIN RESULTS: AIDS patients with pneumonia had a mortality of 57.1 percent (8/14), which was significantly higher than the 25 percent (6/24) seen in patients without HIV infection (p less than 0.025, two-sample test for independent proportions). Septic shock, usually occurring within the first five days of hospitalization, was the primary cause of death, occurring in six of eight AIDS patients and six of six patients without HIV infection. If the mortality in the first five days of hospitalization was excluded, the mortality would drop to 33.3 percent in the AIDS population and 5.3 percent in patients without HIV infection. Eleven HIV-infected patients without AIDS survived 12 episodes of bacteremic pneumococcal pneumonia. CONCLUSIONS: Bacteremic pneumococcal pneumonia in the setting of AIDS has a survival rate of less than 50 percent with septic shock as the usual mode of death. This is the highest pneumococcal pneumonia mortality rate ever reported in a large subgroup of patients in the antibiotic era. On the other hand, HIV-infected patients without progression to AIDS have an excellent chance for survival. This may be related in part to young age, absence of many underlying diseases, and a better humoral immune system.     

Peptide mimicry of the meningococcal group C capsular polysaccharide.

Sequence analysis of the variable regions of the heavy and light chains of the anti-idiotypic antibody 6F9, which mimics the meningococcal group C capsular polysaccharide (MCP), was performed. The immunogenic site on 6F9 responsible for inducing an anti-MCP antibody response was determined by means of sequence and computer model analysis of these data. Complementarity-determining region 3 (CDR3) was found to be unique in that the sequence tract YRY was exposed on the surface. A synthetic peptide spanning the CDR3 domain was synthesized and complexed to proteosomes (meningococcal group B outer membrane protein). Immunizations of BALB/c mice with the peptide-proteosome complex resulted in a significant anti-MCP antibody response. Immunized mice were protected against infection with a lethal dose of Neisseria meningitidis serogroup C.     

Kappa and lambda light chain composition of antibody to the capsular polysaccharide of Haemophilus influenzae type b

Concentrations of total immunoglobulins bearing kappa and lambda light chains were measured in the sera of 215 healthy white children aged 6 months to 10 years. Both kappa and lambda concentrations increased with age. However, the concentration of immunoglobulins bearing kappa light chains increased at a greater rate than those bearing lambda light chains (P = .01). Thus, the kappa:lambda ratio of the youngest children (6-24 months) was significantly lower than that of the oldest (25-130 months) (P = .0015). The relationship between the IgG antibody concentration and the light chain composition of the specific antibody directed to Haemophilus influenzae type b (Hib) polysaccharide was also assessed in 62 of 215 serum samples with detectable Hib antibody. The IgG Hib antibody concentration was strongly correlated with the kappa:lambda Hib antibody ratio (r = .60, P = .001), and this correlation was independent of age. Thus, light chain selection and response to polysaccharides may be regulated by common mechanisms that mature late in ontogeny.     

Antibody response against the type specific capsular polysaccharide in pneumococcal pneumonia measured by enzyme linked immunosorbent assay

The enzyme linked immunosorbent assay (ELISA) was used for estimation of the IgG and IgM antibody responses against 13 type specific pneumococcal capsular polysaccharides, individually and in a pool, in 52 patients with pneumococcal pneumonia and in 20 control patients with non-pneumococcal pneumonia or enterobacterial septicemia. By use of the isolated type 3 polysaccharide as antigen a greater than or equal to 50% increase in absorbance from acute to convalescence phase serum, equivalent to a doubling in antibody titer, was seen significantly more often in 22 patients with type 3 pneumococcal pneumonia than in the 20 control patients (for IgG 14 vs. 3, p less than 0.01; for IgM 14 vs. 4, p less than 0.01). However, for an acceptable degree of specificity to be obtained (less than or equal to 10% control patients positive) a doubling of the IgG or IgM absorbance values had to be demanded. With this criterium only half of the patients infected with pneumococcal types included in the antigen set up used, showed a type specific antibody response and only one third of all patients with pneumococcal pneumonia could be diagnosed by use of the 13 polysaccharides as a pool antigen.     

Pneumococcal polysaccharide vaccine in young adults and older bronchitics: determination of IgG responses by ELISA and the effect of adsorption of serum with non-type-specific cell wall polysaccharide

Available pneumococcal vaccines provide only limited protection for certain at-risk populations. Fifteen healthy young adults and 11 older chronic bronchitics received 23-valent pneumococcal vaccine. ELISA showed that IgG reactive with capsular polysaccharides from Streptococcus pneumoniae serotypes 3, 4, 8, 14, and 19F increased after vaccination. Bronchitics exhibited lesser responses for four of these serotypes, although differences between the groups were significant only for serotype 3. Adsorption of postvaccination sera with pneumococcal cell wall polysaccharide significantly reduced mean antibody levels in both groups and lowered the proportion of sera that demonstrated type-specific antibody responses. Reactive IgG was largely restricted to the IgG2 subclass. Pneumococcal vaccine may provide suboptimal protection of older adults because antibody responses to some capsular polysaccharides are lower in elderly bronchitics than in healthy young adults. A substantial proportion of measured antibody reflects IgG reactive with cell wall polysaccharides rather than with type-specific, capsular constituents, suggesting that antibody responses in subjects of all ages deserve reappraisal.