Study population
57 men (54%) and 49 women (46%) whose median age was 65 (21–85 years) could be interviewed at measuring time t0 and during the course of the treatment (t1 - t6). In the CG 55 men (55%) and 45 women (45%) with a median age of 66 (18–87 years) were questioned. The mean age in both groups was 63 years (p = .659). Characteristics of the patients and the control group are shown in Table 1.
Table 1
Characteristics of patients and control group
| Patients | Control Group | |
Age - median (range) - mean | 65 years (21–85) 63 years | 66 years (18–87) 63 years | p = .659 |
Sex - male - female | n = 57 (54%) n = 49 (46%) | n = 55 (55%) n = 45 (45%) | |
Indications for IgG substitution - primary IgG deficiency (PID) - secondary IgG deficiency (SID) | n = 29 (27%) n = 77 (73%) | |
Underlying disease (only patients with secondary IgG deficiency) - chronic lymphocytic leukemia - multiple myeloma - follicular lymphoma - other non-Hodgkin lymphomas - other malignant diseases | n = 27 (35%) n = 17 (22%) n = 5 (6%) n = 23 (30%) n = 5 (6%) |
The majority of patients (73%) was given IgG substitution due to a secondary antibody deficiency, 27% due to a PID. Patients with PID were statistically significantly younger than patients with SID (mean age 52 years vs. 66 years; p < .001). The sex distribution also differed. 72% of the patients with PID were female compared to 36% of the patients with SID.
Patients with secondary antibody deficiency received IgG substitution due to chronic lymphocytic leukemia (35%), multiple myeloma (22%), follicular lymphoma (6%), other non-Hodgkin lymphomas (30%) or other malignant diseases (6%). 58% of the patients with secondary antibody deficiency were not given immunosuppressive treatment. The most frequently used immunosuppressive treatments provided to the remaining patients were rituximab (19%), corticosteroids (18%) as well as immunomodulatory drugs (lenalidomide and pomalidomide with 8%). In the last 2 months, 95% of the patients had suffered from infections and 81% had suffered from infections requiring the use of antibiotics.
The median immunoglobulin values in the serum at time t0 amounted to 500 mg/dl for IgG (n = 88, without MM patients), 62 mg/dl for IgA (n = 87, without MM patients) and 26.5 mg/dl for IgM (n = 98, without patients suffering from Waldenström macroglobulinemia). Patients with PID had a median serum IgG of 600 mg/dl at t0 compared to 460 mg/dl in patients with SID (without MM patients).
The most frequently used dosages of IgG substitution were 30 g (40%), 10 g (38%) and 20 g (17%). The scheduled treatment intervals were 4 weeks in 80%, 3 weeks in 8% and 2 weeks in 6% of the cases. The mean IVIG dose infused per 4 weeks was 21 g (10 g − 70 g). Patients with PID had a mean dose of 19 g compared to 21 g in patients with SID.
Changes in the course of the IgG substitution
IgG levels
Under substitution, the median IgG value rose from 500 mg/dl (t0) to 772 mg/dl (t6) and was therefore at the lower end of the normal range. Patients with PID had an IgG of 600 mg/dl at t0 and of 815 mg/dl at t6. Patients suffering from SID (without MM patients) had a median IgG value of 460 mg/dl prior to substitution and an IgG value of 751 mg/dl at t6. Figure 1 depicts the development of IgG in serum for the whole cohort and both subgroups.
Infections
Patients reported in a period of 8 weeks 1.8 infections (mean values). These values fell continuously after the start of IgG substitution therapy, at t6 patients reported 0.7 infections in mean. A repeated measures ANOVA with a Greenhouse-Geisser correction determined that the mean number of infections showed a statistically significant difference between the measuring time points: F(4.4, 179.7) = 9.43, p < .001. Bonferroni-adjusted post-hoc analyses revealed significant differences (p < .001) in the mean number of infections between t0 and t2 (1.07, 95%-CI[0.48, 1.66]), t0 and t3 (1.12, 95%-CI[0.60, 1.64]), t0 and t4 (1.07, 95%-CI[0.53, 1.62]), t0 and t5 (1.12, 95%-CI[0.53, 1.71]) and t0 and t6 (0.98, 95%-CI[0.24, 1.71]). A mean difference in infections of 0.67 between t0 and t1 was not statistically significant. All post-hoc comparisons between measurement times t1 - t6, i.e. after the start of IgG substitution, were not significant.
Infections requiring antibiotics
In a period of 8 weeks patients reported a mean number of 1.3 infections requiring the use of antibiotics. The number of infections requiring antibiotics fell continuously after the start of IgG substitution therapy, too. At t6 0.3 infections requiring antibiotic treatment per patient were reported for an 8 week period. A repeated measures ANOVA revealed statistical significance between the measuring time points: F(6, 198) = 9.64, p < .001. Bonferroni-adjusted post-hoc analyses revealed significant differences in the mean number of infections requiring antibiotics between t0 and t1 (0.65, p = .002, 95%-CI[0.08, 1.22]), t0 and t2 (0.77, p = .002, 95%-CI[0.19, 1.34]), t0 and t3 (0.85, p < .001, 95%-CI[0.33, 1.38]), t0 and t4 (0.94, p < .001, 95%-CI[0.39, 1.50]), t0 and t5 (1.00, p < .001, 95%-CI[0.39, 1.61]) and t0 and t6 (0.94, p < .001, 95%-CI[0.35, 1.53]). The same pattern can be seen for infections requiring antibiotics as for infections in general: all post hoc comparisons between measurement times t1 - t6, i.e. after the start of IgG substitution, fail to reach statistical significance.
Infections and infections requiring antibiotics - subgroups
Patients with PID reported more infections than patients with SID. In both groups a substantial decrease in the number of infections could be observed after initiation of IgG substitution.
Patients with PID had 2.3 infections in an 8 weeks time period. The mean values developed as follows: 1.2 (t1), 1.6 (t2), 0.9 (t3), 0.8 (t4), 1.2 (t5) and 1.1 (t6).
Patients with SID had a mean number of 1.6 infections before substitution. The mean values developed as follows: 1.0 (t1), 0.8 (t2), 0.6 (t3), 0.6 (t4), 0.4 (t5) and 0.6 (t6).
A similar pattern can be seen for infections requiring antibiotics. Patients with PID had more infections requiring antibiotics and in both groups the number of infections decreased.
Patients with PID had 1.4 infections requiring antibiotics in an 8 weeks time period. The mean values developed as follows: 0.6 (t1), 0.6 (t2), 0.5 (t3), 0.4 (t4), 0.5 (t5) and 0.3 (t6).
Patients with SID had a mean number of 1.2 infections requiring antibiotics. The mean values developed as follows: 0.7 (t1), 0.5 (t2), 0.4 (t3), 0.3 (t4), 0.2 (t5) and 0.3 (t6).
Infections and infections requiring antibiotics – Comparison between patients and healthy control group (CG)
As far as the number of infections or infections requiring the use of antibiotics is concerned, there were substantial differences between CG and patients prior to the start of IgG substitution (t0) and during the course of substitution (t1 - t6). The mean number of infections was 1.8 (t0) and 0.7 (t6) in patients versus 0.2 in the CG. The number of Infections requiring the use of antibiotics decreased during the course of the replacement therapy in the patient group (1.3 (t0) and 0.3(t6)) but remained above the level of 0.1 in the control group.
Figure 2: Frequencies of infections and of infections requiring antibiotics (mean values) in the course of the replacement therapy (t0 - t6)
Health status
Patients' health status according to the EQ-5D-5L scale improved continuously in the course of the substitution therapy. At t0 a value of 57 was observed, at t6 of 68. A repeated measures ANOVA with a Greenhouse-Geisser correction showed a statistically significant difference between the measuring time points: F(4.4, 240.3) = 7.95, p < .001. Bonferroni-adjusted post-hoc analyses revealed significant differences in the mean health status values between t0 and t1 (9.64, p = .003, 95%-CI[2.17, 17.12]), t0 and t2 (12.61, p < .001, 95%-CI[4.47, 20.74]), t0 and t4 (9.34, p = .015, 95%-CI[1.05, 17.63]), t0 and t5 (11.93, p < .001, 95%-CI[4.10, 19.76]) and t0 and t6 (10.86, p = .006, 95%-CI[1.90, 19.82]). A mean difference in health status of 8.95 between t0 and t3 was not statistically significant. The further post-hoc analyzes between the measurement times t1 - t6, i.e. after the start of the IgG substitution, were not statistically significant with regard to health status.
Patients with primary and patients with secondary IgG immunodeficiencies had quite comparable values in health status. The biggest difference of 4 points could be observed at t0. The health status of all patients remained slightly inferior in comparison to a healthy control group: 68 (t6) compared to 73 in the CG.
Figure 3: Health status (mean values) in the course of the replacement therapy (t0 - t6)