Abstract
Intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) are effective in the treatment of patients with primary antibody deficiency disorders (PAD). The purpose of this study was to evaluate Streptococcus pneumoniae (Spn) antibody titres to 14 serotypes in patients receiving IVIG compared to SCIG and to correlate Spn antibody levels to clinical outcome. The doses of immunoglobulin (Ig)G/kg/month were similar in both IVIG and SCIG groups. In 11 patients treated with IVIG, Spn antibody titres were ≥ 1·3 μg/ml to 99·4 ± 2·1% of the 14 serotypes at peak IVIG but decreased to 66·9 ± 19·8% at trough IVIG. Loss of Spn titres ≥ 1·3 μg/ml was most frequent for Spn serotypes 1, 4, 9V and 23. This correlated with lower Spn antibody titres to these serotypes at peak IVIG compared to the other serotypes. In 13 patients treated with SCIG, Spn antibody titres were protective to 58·2 ± 23·3% of the serotypes 3–5 days after infusion, similar to trough IVIG. Similarly, the Spn serotypes with the least protective percentages were the same as the ones observed in trough IVIG. There were no annualized serious bacterial infections (aSBI) in either group. However, there were significantly decreased annualized other infections (aOI) in the SCIG group compared to the IVIG-treated group, 0·8 ± 0·7 versus 2·2 ± 1·2 infections/patient/year (P = 0·004). Breakthrough aOI did not correlate with protective or higher serum Spn antibody titres.
Keywords: antibodies, B cell, immunodeficiency diseases
Introduction
Immunoglobulin (Ig)G antibody replacement therapy is a mainstay used in patients with primary antibody deficiency (PAD) to prevent recurrent and severe infections 1. IgG antibody replacement therapy is usually administered either as intravenous immunoglobulin (IVIG) every 3–4 weeks or as subcutaneous immunoglobulin (SCIG) weekly. The kinetics of IVIG and SCIG are very different. IVIG therapy is associated with high peak IgG levels and low trough IgG levels, whereas SCIG results in steady state IgG levels 1. Despite IVIG or SCIG therapies, patients continue to develop some sinopulmonary infections. Several studies have reported that higher doses of IgG antibody replacement therapy result in decreased infections with both IVIG 2–4 and SCIG 5 treatments. In addition, previous studies in PAD patients treated with IVIG have reported a wear-off effect of IVIG in the third week of therapy 1. As IgG antibody therapy provides protective antibody titres to bacteria, such as Streptococcus pneumoniae (Spn), we hypothesized that IgG anti-Spn antibody titres may decrease below protective titres at 3–4 weeks post -IVIG treatment, whereas IgG anti-Spn antibody titres would remain in protective steady state titres with SCIG treatment.
Methods
Patients
Patients with known primary immunodeficiency disorders (PIDD) 6 who were receiving either intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) were enrolled during 2014–15 from the Pediatric Allergy and Immunology Clinic at Cardinal Glennon Children’s Medical Center at Saint Louis University. Twenty-four subjects with PIDD were enrolled, which included X-linked agammaglobulinaemia (XLA, n = 6), common variable immunodeficiency (CVID, n = 9), specific antibody deficiency (SAD, n = 7) and persistent hypogammaglobulinaemia in patients with severe combined immunodeficiency following transplantation (SCID, n = 2). The patients with SAD had a severe classification based on antibody responses ≥ 1·3 μg/ml to ≤ 2 of 14 S. pneumoniae serotypes (Spn) 7. Patients in the IVIG group received either Gamunex 10% ® or Gammagard Liquid 10%® and patients in the SCIG group received Hizentra 20%®. The S. pneumoniae serotype-specific IgG concentrations were not measured in the IVIG preparations. The doses of IgG were similar in the IVIG group compared to the SCIG group: 668 ± 102 mg/kg/month versus 603 ± 181 mg/kg/month [P = not significant (n.s.)] (Table1). When converting from IVIG to SCIG, the SCIG dose was typically increased approximately 1·3-fold times the IVIG dose. Antibodies to Spn were considered normal if ≥ 1·3 μg/ml 7. Patients were between ages 6–18 years. We recorded data on serious bacterial infections (pneumonia, sepsis, meningitis, osteomyelitis and visceral abscess) (aSBI) and all other infections (otitis media, sinusitis, bronchitis, pharyngitis, skin infections) (aOI) expressed as infections/patient/year. The study was approved by the Saint Louis University Investigational Review Board. Study subjects received no compensation for their participation.
Table 1.
Characteristics of patients receiving intravenous immunoglobulin (IVIG) compared to subcutaneous immunoglobulin (SCIG).
| Characteristics | IVIG 11 | SCIG 13 | P |
|---|---|---|---|
| Age, years | 10·9 ± 6·1 | 13·7 ± 4·5 | n.s. |
| Male: female | 9: 2 | 13: 0 | n.s. |
| PIDD | n.s. | ||
| XLA | 2 | 4 | n.s. |
| CVID | 3 | 6 | |
| SCID post-transplantation | 1 | 1 | |
| SAD | 5 | 2 | |
| IgG, mg/dl* | 365 ± 217 | 312 ± 235 | n.s. |
| IgA, mg/dl* | 23 ± 29 | 50 ± 46 | n.s. |
| IgM, mg/dl* | 47 ± 23 | 41 ± 48 | n.s. |
| Spn, % protective serotypes | 5·9 ± 9·6% | 7·4 ± 9·7% | n.s. |
| IVIG or SCIG, mg/kg/month | 668 ± 102 | 603 ± 181 | n.s. |
| aSBI, infections/patient/year | 0 | 0 | n.s. |
| aOI, infections/patient/year | 2·2 ± 1·2 | 0·8 ± 0·7 | 0·004 |
PIDD = primary immunodeficiency disorder; XLA = X-linked agammaglobulinaemia; CVID = common variable immunodeficiency; SCID = severe combined immunodeficiency post-bone marrow transplantation without B cell engraftment; SAD = specific antibody deficiency; aSBI = annualized serious bacterial infections (pneumoniae, sepsis, meningitis, osteomyelitis, visceral abscess), infections/patient/year; aOI = annualized other infections (otitis media, sinusitis, bronchitis, pharyngitis, skin infections), infections/patient/year.
SAD patients included. Data presented as mean ± standard deviation or percentage (%). P-value was determined by t-test. A P-value ≤ 0·05 was considered significant.
Serum S. pneumoniae antibody titres
Serum samples to measure Spn antibody levels were collected prior to IVIG (trough) and 15–30 min from an opposite site post-IVIG (peak). In patients treated with SCIG weekly, serum samples were collected 3–5 days (range 1–6 days) following SCIG administration. Because pharmacokinetics of SCIG shows steady state levels, only one sample was obtained. In all samples, serum IgG levels and antibody titres to 14 S. pneumoniae serotypes (Spn serotypes 1, 3, 4, 6B, 7F, 9V, 11A, 12F, 14, 15B, 18C, 19F, 23F and 33F) were measured at trough levels of patients on IVIG and 3–5 days following SCIG administration.
Measurement of IgG anti-pneumococcal antibody levels by enzyme-linked immunosorbent assay (ELISA)
IgG anti-pneumococcal polysaccharide serotypes 1, 3, 4, 6B, 7F, 9V, 11A, 12F, 14, 15B, 18C, 19F, 23F and 33F were determined by a standardized, World Health Organization (WHO)-recommended ELISA method calibrated against the Food and Drug Administration (FDA) 89SF reference sample 8,9. Serum samples were pre-absorbed with pneumococcal C polysaccharide (CPS) and Ser 22F.
Statistical analysis
The data were expressed as percentage (%) of subjects, mean ± standard deviation (s.d.) for demographic data and immunological studies, and mean ± standard error (s.e.) for S. pneumoniae antibody titres. Student’s t-test was performed comparing IVIG versus SCIG groups. For percentages of patients, Fisher’s exact test for independence was used. P-values ≤ 0·05 were considered significant, using GraphPad InStat software package.
Results
Patients
The demographics of the patients treated with either IVIG or SCIG are presented in Table1. IVIG- and SCIG-treated patients were similar in age, 10·9 ± 6·1 years versus 13·7 ± 4·5 years (P = n.s.) and male to female ratio, 9: 2 versus 13: 0 (P = n.s.). There were six patients with XLA, nine with CVID, seven with SAD and two with SCID (hypogammaglobulinaemia post-transplantation) in the study. The types of immunodeficiency were similar in the IVIG and SCIG groups. At diagnosis, serum IgG levels were similarly decreased in the IVIG and SCIG groups, 365 ± 217 mg/dl versus 312 ± 235 mg/dl (P = n.s.), respectively. In the hypogammaglobulinaemia subjects IgG levels were 192 ± 104 mg/dl (n = 6) in the IVIG group versus 242 ± 170 (n = 11) (P = n.s.) in the SCIG group. In SAD subjects, IgG levels were 574 ± 68 mg/dl (n = 5) and 698 ± 148 (n = 2) in IVIG- and SCIG-treated patients (P = n.s.). The percentages of protective S. pneumoniae serotypes pretreatment were decreased in both the IVIG and SCIG groups, 5·9 ± 9·6% versus 7·4 ± 9·7% (P = n.s.), respectively. There were no serious bacterial infections (aSBIs) in the study year in both the IVIG and SCIG groups. However, the incidence of other infections (aOIs) were significantly greater in the IVIG group compared to SCIG group, 2·2 ± 1·2 versus 0·8 ± 0·7 (P = 0·004).
S. pneumoniae antibody titres
The IVIG and SCIG doses were comparable in the IVIG group and SCIG group, 668 ± 102 mg/kg/month and 603 ± 181 mg/kg/month, respectively (Table1). Serum trough IgG levels in patients treated with IVIG were similar to serum IgG levels in patients treated with SCIG, 965 ± 278 versus 945 ± 237 mg/dl (P = n.s.) (Table2). Spn titres were protective to 99·4 ± 2·1% of serotypes at peak in patients receiving IVIG; however, they decreased significantly to 66·9 ± 19·8% (P = 0·0002) at trough (Table2). In patients receiving SCIG, Spn titres were protective to 58·2 ± 23·3%, not significantly different compared to trough levels in the IVIG group. When individual serotypes were examined comparing IVIG peak versus IVIG trough (Table2), there were significantly decreased protective titres to Spn serotypes 1 (90·9 versus 27·3%, P = 0·008), 4 (100 versus 18·2%, P = 0·0002), 9V (100 versus 9·1%, P = 0·0002), 18C (100 versus 54.5%, P = 0·035), and 23F (100 versus 36·4%, P = 0·004). We next examined the rate of Spn antibody decline in the IVIG-treated group from peak to trough levels (Fig. 1). IgG antibody to serotypes 33F and 15B had an increased decline compared to the decay of the other Spn serotypes. However, the rate of decay was comparable in all the Spn serotypes from IVIG peak to IVIG trough. This indicates that the IVIG preparations probably contained higher IgG antibody levels to Spn serotypes 33F, 15B, 14, 7F, 19F and lower to serotypes 9V, 4, 23F, 6B, and 18C (Fig. 1). There were no significant differences comparing the percentage of protective serotypes in the IVIG trough group versus the SCIG group. The decrease in S. pneumoniae antibody titres to individual Spn serotypes is shown in Fig. 2. All specific antibodies were increased significantly in the IVIG peak group compared to both IVIG trough and SCIG groups to all Spn serotypes (P <0·01, P <0·01); Spn antibody titres in the latter two groups were similar (P = n.s.). Examining the decreased percentages of protective Spn antibody titres to Spn serotypes 1, 4, 9V, 18C, and 23F in the IVIG trough, the peak IVIG antibody titres for these Spn serotypes were not as great in comparison to other Spn serotypes. This may account for loss of protective antibody titres to these serotypes.
Table 2.
Immunological studies of patients receiving intravenous immunoglobulin (IVIG) compared to subcutaneous immunoglobulin (SCIG).
| Study | IVIG 11 Peak | IVIG 11 trough | SCIG 13 | P versus T | P P versus SCIG | T versus SCIG |
|---|---|---|---|---|---|---|
| IgG, mg/dl | 965 ± 278 | 945 ± 237 | n.s. | |||
| Spn, % protective serotypes | ||||||
| 99·4 ± 2·1 | 66·9 ± 19·8 | 58·2 ± 23·3 | 0·0005 | 0·0001 | n.s. | |
| Spn serotypes, % protective | ||||||
| 1 | 90·9 | 27·3 | 15·4 | 0·008 | 0·0006 | n.s. |
| 3 | 100 | 72·7 | 61·5 | n.s. | 0·040 | n.s. |
| 4 | 100 | 18·2 | 15·4 | 0·0002 | 0·0001 | n.s. |
| 6B | 100 | 63·6 | 46·2 | n.s. | 0·006 | n.s. |
| 7F | 100 | 90·9 | 84·6 | n.s. | n.s. | n.s. |
| 9V | 100 | 9·1 | 23·1 | 0·0002 | 0·0001 | n.s. |
| 11A | 100 | 90·9 | 61·5 | n.s. | 0·041 | n.s. |
| 12F | 90·9 | 81·8 | 61·5 | n.s. | n.s. | n.s. |
| 14 | 100 | 100 | 92·3 | n.s. | n.s. | n.s. |
| 15B | 100 | 100 | 100 | n.s. | n.s. | n.s. |
| 18C | 100 | 54·5 | 38·5 | 0·035 | 0·002 | n.s. |
| 19F | 100 | 90·9 | 92·3 | n.s. | n.s. | n.s. |
| 23F | 100 | 36·4 | 46·2 | 0·004 | 0·003 | n.s. |
| 33F | 100 | 100 | 100 | n.s. | n.s. | n.s. |
Spn = Streptococcus pneumoniae; P = IVIG peak level; T = IVIG trough level; SC = subcutaneous; n.s. = not significant. Data are presented as mean ± standard deviation or percentage (%). P-value was determined by t-test. For percentages of patients, Fisher’s exact test for independence was used. A P-value ≤ 0·05 was considered significant.
Figure 1.
Streptococcus pneumoniae (Spn) antibody titres to individual Spn serotypes in patients receiving intravenous immunoglobulin (IVIG) at peak and trough. The decay rate of antibody levels to individual Spn serotype was comparable.
Figure 2.
Streptococcus pneumoniae antibody titres in patients receiving intravenous immunoglobulin (IVIG) compared to subcutaneous immunoglobulin (SCIG). S. pneumoniae antibody titres were increased significantly at peak IVIG compared to trough IVIG, P < 0·01 (*) and to SCIG, P < 0·01 (#). S. pneumoniae antibody titres were comparable in patients receiving IVIG at trough compared to SCIG. Data expressed as mean ± standard error (s.e.). P-value was determined by t-test. A P-value ≤ 0·05 was considered significant.
Discussion
Previous studies have reported that in patients treated with IVIG trough IgG anti-Spn antibody titres are often below protective levels. We chose ≥ 1·3 μg/ml as the level of antibodies that is associated with immunocompetence as recommended by Orange et al. and a group of experts 5. These experts concluded that in many studies of patients with recurrent infections this antibody level coincides with a majority of anti-Spn antibodies being below this level. The concentration of antibodies associated with protection against invasive pneumococcal infections has been estimated to be much lower, as reported by Siber et al. 10. Pieretti and Cunningham-Rundles 11 reported trough IgG antibody titres to Streptococcus pneumoniae (Spn) in 21 patients with CVID (n = 13), XLA (n = 7) and HIGM (n = 1) receiving IVIG therapy. IgG trough levels were > 600 mg/dl in all patients. Eleven of 20 patients had protective IgG antibodies (IgG ≥ 1·3 μg/ml) to ≥ 50% of serotypes tested. However, none of the subjects had protective Spn titres to serotypes 4, 9N and 12F. In the study reported here, the most decreased Spn serotypes at trough were 1, 4, 9V, and 23F. This difference suggests that various IVIG products and lots may have very different antibody concentrations to different Spn serotypes. Lejtenyi and Mazer 12 examined 44 separate lots of IVIG provided by CSL Behring. They demonstrated considerable variability in the antibody levels to 14 different Spn serotypes in the 44 lots. Antibody levels were lowest to serotypes 4 and 12F. However, these authors concluded that the Spn IgG levels were high enough to confer protection to all serotypes. Takahashi et al. 13 compared five lots of four commercially available IVIG preparations in Japan and found comparatively low antibody titres to Spn serotypes 4, 7F and 9V, with none of the IVIG preparations containing the required Spn concentrations against serotypes 4 and 9V. Mikolajczyk et al. 14 analysed five lots each of seven commercial IVIG preparations and found that antibody levels to Spn serotypes 14 and 19F were several-fold higher than those to types 4, 6B and 9V. The results of these various studies measuring antibody titres to Spn serotypes in patients receiving IgG replacement therapy, including ours, suggests that the variations in antibody concentrations may be due to different donor pools used in the preparation of IVIG products. We observed that Spn antibodies in patients treated with SCIG were not different from those observed in patients receiving IVIG at the end of the infusion interval. Abghari et al. 15 compared Spn titres in 13 patients with PIDD treated with either IVIG or SCIG after at least 1 year of treatment. In contrast to our findings, they noted that more protective Spn titres were achieved (≥ 1.4 μg/ml) while on SCIG. This study also found that neither IVIG nor SCIG achieved therapeutic levels of Spn antibodies against pneumococcal serotypes 4 and 9N. In our study we observed that only patients treated with SCIG did not achieve therapeutic levels against serotype 23F. We anticipated that Spn antibody titres may be greater in patients treated with SCIG compared to trough levels of IVIG-treated patients. However, the finding of protective Spn antibody titres were similar in patients treated with SCIG compared to IVIG trough levels. Interestingly, the most frequent non-protective levels were to the same, namely Spn 1, 4, 9V and 23F in IVIG- and in SCIG-treated patients. This probably reflects lower titres to these Spn serotypes in the general population and plasma donors. There did not appear to be significant differences in rate of decay of the individual IgG Spn serotypes in the IVIG-treated patients.
In our study and in other reported studies, the most common Spn antibody levels noted to be decreased in the IVIG preparations were 4 and 9V, which are included among the serotypes causing the majority of disease in PIDD patients, along with serotypes 6B, 14 and 19F 14. Clinically, we observed no serious bacterial infections in either IVIG- or SCIG-treated groups; however, despite the Spn antibody titre findings, patients treated with SCIG had significantly decreased infections compared to patients treated with IVIG, having similar Spn antibody concentrations. In our patients treated for respiratory infections, as in patients in most other IgG treatment studies, cultures from respiratory sites such as sinuses, middle ear or the bronchial tree are not obtained routinely. Thus we do not know what proportions of infections were caused by S. pneumoniae or by other respiratory pathogens including viruses. SAD does not predispose exclusively to pneumococcal infections. These are abnormalities that are evidence of deficiency of antibody production that is likely to extend to other bacterial and viral antigens that are not currently tested. Our results coincide with a recent observation by Vathani et al. 16, in which they could not correlate Spn antibody titres to infectious rates. Therefore, the presence of Spn antibodies in different IVIG and SCIG products may not correlate closely with antibodies against other infectious agents responsible for other infections in PAD patients on IgG replacement therapy. In this context it is not clear why, in our study, patients on SCIG have fewer infections than patients on IVIG, although the trough IgG levels are similar. This reduction of infections is a small addition to the advantages of tolerability and home treatment possibilities offered by SCIG.
In summary, in our study both IVIG and SCIG provide protective S. pneumoniae antibody titres that were comparable at trough levels of IVIG and steady state of SCIG-treated patients. The low IgG anti-Spn antibody titres against Spn serotypes 1, 4, 9V and 23F at trough in IVIG and in SCIG patients are, again, due probably to reduced titres in the IVIG and SCIG preparations.
Acknowledgments
The authors wish to thank the patients who participated in this study. The authors appreciate Hanh Rimmer, M.T. who performed the ELISA Streptococcus pneumoniae antibody determinations.
Author contributions
A.P.K. designed the study, enrolled the subjects, analysed the data and contributed to writing the manuscript. L.E.L. performed measurement of S. pneumoniae antibody titres and contributed to writing the manuscript. R.U.S. performed measurement of S. pneumoniae antibody titres and contributed to writing the manuscript. C.C. contributed to writing the manuscript. J.R. contributed to writing the manuscript.
Funding
Funding for the study was a grant received from CSL Behring.
Disclosure
None.
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