Increased Humoral Immune Response Against C. Diff Toxins Linked to Mild Disease

Findings from a new study showed an association between high serum immunoglobulin G (IgG) and immunoglobulin A (IgA) levels and milder cases of Clostridium difficile (C. difficile).

Specifically, this association was modulated by the two serum antibodies targeting of both toxins A (TcdA) and B (TcdB), which play an essential role in the pathogenesis of the disease.

Investigators from Tel Aviv University and Tel Aviv Sourasky Medican Center conducted a case-control study to determine the risk factors of C. difficile infection (CDI) and evaluate the link between humoral immune response and CDI severity.

Thus, their analysis consisted of a total of 50 patients with CDI, 62% of whom were female. This represented a subset of 140 total CDI patients who were enrolled in their study.

They categorized CDI patients according to severity—severe disease was defined as leukocytosis with a white blood cell count of ≥15,000 cells/μL, decreased blood albumin (<30 g/L) or a rise in serum creatinine level ≥1.5 times the premorbid level. Any patient who did not fulfill any of these requirements were considered to have a mild case.

Additionally, they analyzed 52 patient controls who were not suffering from diarrhea, where 56% were female. In total, they had enrolled 140 controls.

Both CDI patients and controls were matched by age, sex, hospitalization ward (medical or surgical), and number of hospitalization stays. 

The mean age between the CDI and control groups were 79.2% years and 82.7%, respectively.

The investigators collected stool specimens from the both groups to test for C. difficile. Blood samples were also collected, and the levels of serum IgG and IgA antibodies against TcdA and TcDB were measured.

Overall, they found that patients with CDI presented with higher geometric mean titers (GMT) values of serum IgG antibody against TcdA when compared with the control group (20.1 EU vs 11.6 EU, respectively; P = .0001).

The GMT values of serum IgG against TcdB were also higher for the CDI group than for the control (18.0 EU vs 12.0 EU, respectively; P = .04).

They also noted that similar trends were observed for IgA antibodies, but the differences were not statistically significant.

In terms of associations for C. diff severity, they found that GMT values of serum IgA against TcdB was significantly higher among CDI patients with mild disease as compared with patients with severe disease (9.2 EU vs 4.9 EU, respectively; P = .023).

Similar but non-statistically significant trends were noted found for IgA and IgG levels against TcdA, as well as for IgG against TcdB.

“Limiting the analysis to sera that were collected at days 7–14 following the diagnosis of C. difficile showed significantly higher IgG levels against TcdA and TcdB in patients with mild CDI compared to patients with severe CDI,” they wrote.

Furthermore, they found significant correlations between serum IgG levels and TcdA and TcdB (Spearman’s r = 0.31). Other strong correlations included IgA levels against TcdA and TcDB (r = 0.53) and IgG and IgA levels against TcdB (r = 0.43).

Although there remains great uncertainty behind the mechanism that can explain the protective effect of serum IgA and IgG antibodies against C. diff toxins, the investigators nonetheless suggested implications for the findings.

“Based on the current evidence from observational studies and our new findings, the concept of presenting antigens that can prime or boost the immune system towards the production of antitoxin circulating antibodies seems a sensible approach for developing preventive and therapeutic vaccines and technologies for CDI,” the team wrote.

The study, "Enhanced Humoral Immune Responses against Toxin A and B of Clostridium difficile is Associated with a Milder Disease Manifestation," was publshed online in Journal of Clinical Medicine.