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Keywords:

  • antibody deficiency;
  • immune globulin;
  • infection;
  • lung disease

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Serum immune globulins (Ig) treatment and lung disease
  5. Subsets of B cells and memory B cells and lung disease
  6. Conclusions
  7. Conflicts of interest
  8. References

Defects of antibody production are the most common of the primary immune defects of man. While these defects have been described in clinical terms for more than five decades, in most cases, the pathogenesis is still poorly understood. The most common clinically important of these is common variable immune deficiency. However there is no strict definition of this defect and the criteria for initiating immune globulin therapy are not standardized, leading to wide variation in treatment practices. In addition there has been no clear means to adequate assess progression of lung disease or elucidate the causes of progressive pulmonary inflammation found in some subjects. Moreover, there are still questions such as what are the best predictors of chronic lung disease and how can we prevent this disorder. Other complications such as autoimmunity, granulomatous disease, gastrointestinal inflation, are similarly poorly understood although treatment with various biological agents has been used with some success. A few bio-markers for assessing clinical and immunologic status have been proposed, and some have proved to be useful, but additional methods to gauge the benefits of therapy, predict outcomes, and harmonize treatment practices are needed. Aside from Ig replacement, additional means of prevention of lung disease may need consideration to reduce lung damage apart from prophylactic antibiotics. These might include using macrolides as anti-inflammatory agents, inhaled corticosteroids, bronchodilators, mucolytics or mechanical or rehabilitative respiratory methods.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Serum immune globulins (Ig) treatment and lung disease
  5. Subsets of B cells and memory B cells and lung disease
  6. Conclusions
  7. Conflicts of interest
  8. References

Replacement immune globulin therapy is the mainstay of treatment of subjects with insufficient production of immune globulins due to either genetic or secondary failure of B cell development. For subjects with congenital failure of antibody production, replacement immune globulin, given at punctual intervals, is the standard of care, and it has revolutionized the lives of these patients. While some congenital immune defects do not require the use of immune globulin, about 70% of the known defects lead to a lack of antibody and require antibody replacement. While many publications in the past 25 years have described the use of immunoglobulin in primary immune deficiency, additional questions remain about some of the most basic concepts of this therapy. Some of these are discussed here.

Serum immune globulins (Ig) treatment and lung disease

  1. Top of page
  2. Summary
  3. Introduction
  4. Serum immune globulins (Ig) treatment and lung disease
  5. Subsets of B cells and memory B cells and lung disease
  6. Conclusions
  7. Conflicts of interest
  8. References

Sufficient immune globulin replacement has been shown to reduce systemic bacterial infections significantly in subjects with primary immune defects. In a study in common variable immune deficiency (CVID), 42 of 50 consecutively referred subjects (84%) had at least one episode of pneumonia prior to starting treatment. After intravenous immune globulin was started, only 11 of the 50 (22%) had additional episodes of pneumonia, representing a clear reduction (P = 0·01) [1]. These data are similar to another report in CVID in which 62·9% of patients had had pneumonia prior to the recognition of immune deficiency, but only 20·5% had pneumonia after this diagnosis was made [2]. It was recognized quite early that Ig replacement in X-linked agammaglobulinaemia (XLA) and CVID also led to reduced hospitalizations [3,4]. Other studies have shown the benefits of Ig replacement in subjects with IgG subclass defects, resulting in fewer infections [5]. While systemic bacterial infections such as sepsis and meningitis are clearly more rare in patients who receive sufficient Ig treatment, some of the more common infections still remain a clinical problem, including sinusitis, bronchitis and an occasional instance of pneumonia. Of more concern is the progression of lung disease in some subjects who receive what is considered standard Ig replacement therapy. High-resolution computerized tomography showed that progression of lung disease can occur in subjects with at least 500 mg/dl serum IgG [6]. In addition, bronchial lavage samples of patients with bronchiectasis, fibrosis and/or emphysema revealed that both bacteria (mainly Haemophilus influenzae) and/or viruses [adenovirus, cytomegalovirus (CMV) or rhinovirus] may be present. No patient was ill at the time of this study, suggesting that subclinical infections might lead to ongoing pulmonary damage [7]. Reaffirming this concern, Quinti et al. noted that, for 224 subjects on standard Ig replacement, followed over a mean time of 11 years, 34·2% had a history of chronic lung disease at diagnosis [based on high-resolution hypocretin] but 46·3% had this diagnosis at follow-up. Furthermore, bronchiectasis was found in 56 patients at diagnosis, but in 65 at the most recent encounter [2,8].

Because of these concerns, some studies have addressed the question of the optimum dose of Ig to use in order to prevent ongoing lung damage. Roifman et al. demonstrated that 600 mg/kg was more effective than 200 mg/kg in preventing lung impairment [9], illustrating the benefit of the higher dose, but the lower dose used in this study would be generally be considered insufficient by current guidelines [10]. Eijkhout also showed that comparing adult patients first given 300 mg/kg/4 weeks and then 600 mg/kg, and children on 400 mg/kg/ 4 weeks then 800 mg/kg, the time-periods on higher doses were associated with a reduced number of infections: (3·5 versus 2·5 per patient; P = 0·004) and shorter infection duration (median, 33 days versus 21 days; P = 0·015). For the standard treatment patients the trough IgG level was 6·6 g/l ± 1·6, and for the higher-dose group it was 9·4 g/l ± 2·6; higher levels of antibody to relevant bacteria were also noted in the blood of those with higher serum IgG levels [11]. Taking a different tactic, another prospective study examined the evolution of lung damage in 24 newly diagnosed adults with CVID who received a dose of intravenous immunoglobulin (IVIG) treatment sufficient to maintain stable serum IgG trough levels of at least 600 mg/dl over 2 years. Ig treatment improved lung functions for some of those with initial lung disease; however, these subjects also required higher doses of IVIG to maintain serum levels of IgG over 600 mg/dl (P = 0·002), suggesting more rapid consumption of Ig due possibly to chronic bronchial inflammation, but this was unclear [12]. Even in this study, two patients had increased lung damage over the period of examination, thus it is difficult to attribute all the progression of lung disease to inadequate treatment with IVIG.

Examining this from another viewpoint, it would seem logical that very low initial serum IgG levels might be a predictor for developing pneumonia. This may be true; in a New York cohort of 105 CVID subjects a lower baseline serum IgG was an independent predictor of both previous pneumonia (P = 0·007) and severe infections (P = 0·001) [13]. On the other hand, the recent European Society for Immunodeficiencies (ESID) study of 334 subjects with CVID did not find an association between the serum IgG level and previous severe infections (including pneumonia) before diagnosis, even though 21% of subjects in the group, individuals who might be particularly susceptible to such infections, had a serum IgG of less than 150 mg/dl [14]. In addition, the initial level of serum IgG in the ESID study was not related to a higher incidence of mortality. In the New York cohort, however, a lower serum IgG level was not correlated with the development of chronic lung disease, known as a cause of significant morbidity in CVID [15]. While there are some differences in these studies, together these data suggest that the serum IgG is not the only important factor in protecting against long-term pulmonary damage in such patients. By extrapolation, therefore, increasing serum IgG levels by replacement to higher levels may not be the only factor that provides long-term lung protection. However, prophylactic antibiotics are used currently for some patients, most often for those with established lung disease. Whether this therapy should be initiated earlier, and in what patients, and in what regimen, has not been clarified.

Subsets of B cells and memory B cells and lung disease

  1. Top of page
  2. Summary
  3. Introduction
  4. Serum immune globulins (Ig) treatment and lung disease
  5. Subsets of B cells and memory B cells and lung disease
  6. Conclusions
  7. Conflicts of interest
  8. References

Mature B cells in humans bear the activation surface marker CD27; these can be subdivided further into IgM+ memory and switched memory B cells IgM–IgD. IgM memory B cells in murine systems, and possibly in humans, may play a role in the protection against encapsulated bacteria, as the absence of these cells is correlated with reduced or absent anti-polysaccharide IgM antibodies. Comparing the memory B cell phenotypes of 26 patients with CVID with recurrent bacterial pneumonias and bronchiectasis to 22 subjects who never had pneumonia and had no lung abnormalities, a previous study proposed that a lack of these IgM memory B cells was correlated with lung disease [16]. However, we did not verify this suggestion for a group of 105 CVID subjects, as none of the memory B cell subsets were correlated with the occurrence of pneumonia (55 with pneumonia and 50 without) or chronic lung disease (n = 27), including bronchiectasis, lymphoid interstitial infiltrates or significant lung impairment on pulmonary function testing. Another interesting B cell population in CVID is the CD21low population, which is expanded in autoimmunity and in some subjects with CVID. While an increase of these cells is associated with splenomegaly and autoimmune disease in CVID, these patients may have also a higher incidence of lower respiratory tract infections and chronic lung disease [17].

Re-examining the half-life of serum IgG

The half-life of serum IgG is viewed commonly as approximately 21 days with some differences between the IgG subclasses, IgG3 having a shorter half-life due to the increased length of the hinge region. This half-life is based on the pioneering work of Waldman et al. using radioiodinated serum IgG. However, it was recognized early from these studies [18] that for hypogammaglobulinaemic subjects, the half-life was, in some cases, longer than this interval. For example, for 26 of 28 subjects the serum IgG half-life was 30–70 days; for the other two subjects, the half-lives were 12 and 20 days. The median half-life was 38 days, with 3·9% of the intravascular pool catabolized per day. For normal subjects the IgG half-life was 22 days, with 6·8% of the IgG catabolized per day. These studies showed longer half-lives of serum IgG in most hypogammaglobulinaemic subjects compared to normal subjects, but the reasons for this have remained unclear. Based on studies in immune-deficient individuals, commercially available IgG concentrates in use have actually reported half-lives of 30–35 days [19–22]. Potentially, these differences might be due to the lower serum IgG levels and, in the hypogammaglobulinaemic subjects, lack of saturation of the neonatal Fc receptor for IgG (FcRn). The FcRn is a transport receptor which seems to play an essential role in IgG homeostasis, salvaging IgG from degradation. As the FcRn becomes saturated with serum IgG, the ability of this receptor to slow the catabolism of IgG is lost, resulting in shorter half-lives of IgG at higher serum IgG levels. The FcRn is present in a variety of cell types, including epithelial cells, vascular lining, macrophages and dendritic cells. It also controls the transport of IgG from mother to fetus [23,24]. Interestingly, the FcRn promoter contains a genetically determined number of variable number tandem repeats, which dictates the expression of the receptor. Greater expression of the FcRn leads to a greater ability to bind to polyvalent human IgG, potentially enhancing the IgG half-life [25]. While differences in the intrinsic serum levels of IgG between controls and patients in the original studies may have led to differences in half-lives, the original studies were performed using iodinated proteins; thus it is also probable that the iodination process interfered with the FcRn binding, leading to a reduced estimation of the half-life serum IgG in normal controls. When treating immune-deficient subjects with IG replacement, it is possible that in some subjects FcRn genetic differences might lead to longer half-lives of serum IgG. One example of such a subject is seen in Fig. 1. Although this patient's initial serum IgG was 68 mg/dl, after several years of replacement it is clear that he has a much reduced catabolism of IgG, and is infused with 400 mg/kg at intervals of 8 weeks.

image

Figure 1. A 54-year-old man with a history of sinusitis. His serum was immunoglobulin (Ig)G = 68, IgA < 7 and IgM < 4 mg/dl. He was started on 400 mg/kg of intravenous immunoglobulin (IVIG) and this dose has been continued. However, the level of serum IgG in the blood has been stable for longer than the expected half-life of infused IgG.

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Serum IgG levels and antibody

While there is no clear consensus about what minimum level of serum IgG is sufficient, nor is it established that the level of serum IgG is an adequate measure of circulating antibody. Most practitioners do not continue to measure serum antibody titres in subjects on immune globulin replacement, partly because the antibody pools are likely to contain sufficient levels of relevant antibodies, and repetitive antibody determinations would be an expensive undertaking. However, some earlier data on the amounts of antibody present in a group of immune globulin preparations, directed to selected pneumococcal serotypes, suggested that the dilution of standard doses of immune globulin into human blood might lead to an insufficient final titre [26] (Fig. 2). Examination of serum of patients with X-linked agammaglobulinaemia on standard replacement therapies shows that these levels are, in fact, highly variable. While the trough levels of IgG antibody to common viral vaccine antigens such as measles, mumps, rubella and varicella zoster were well within the range considered protective (Table 1), the levels of antibody to pneumococcal serotypes might be distinctly suboptimum at the same serum IgG trough values. For example, XLA subject 1, who had a trough serum IgG of 668 mg/dl, had protective levels of IgG to four of 14 serotypes; on the other hand, subject XLA 2 with a similar trough IgG of 694 mg/dl had protective levels to 10 of 14 serotypes. (Fig. 3) These subjects were given different Ig products, suggesting insufficient antibody in one preparation or an increased consumption of this anti-bacterial antibody in XLA1.

image

Figure 2. The levels of immunoglobulin (Ig)G antibody to five serotypes of pneumococcus in seven commercial intravenous immunoglobulin (IVIG) products (identified as A to G), based on the amount relative to the IgG given in µg. Redrawn from Mikolajczk et al.[26].

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Table 1.  Serum antibodies to viruses in serum of nine intravenous immunoglobulin (IVIG)-treated X-linked agammaglobulinaemia (XLA) subjects.*
PatientProductTrough IgG mg/dlMeasles > 0·7Mumps > 0·5Rubella > 10VZV > 0·9
  • *

    Serum was taken just before an infusion. All subjects were on continuous IVIG replacement. VZV: Varicella Zoster Virus; n.d.: not determined.

116681·440·94107·71·67
226681·370·8296·31·44
327581·160·8581·11·89
429872·151·3198·81·92
5212501·831·471·22·4
637301·941·1899·2n.d.
749521·41112·71·65
846941·581·21136·31·68
946531·71·21361·77
image

Figure 3. The serum of two unrelated males was tested with X-linked agammaglobulinaemia (XLA) on continuous intravenous immunoglobulin (IVIG) treatment, just before an infusion; the levels of antibody to 14 pneumococcal serotypes were quantified. These subjects had been given different IVIG products. Subject XLA 1 had a trough serum IgG of 668 mg/dl; XLA 2 had a trough serum IgG of 694 mg/dl. A minimum of 1·0 µg/ml for each serotype is considered protective.

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Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Serum immune globulins (Ig) treatment and lung disease
  5. Subsets of B cells and memory B cells and lung disease
  6. Conclusions
  7. Conflicts of interest
  8. References

While many observations over the past almost three decades have led to major insights into the treatment of subject with primary antibody defects, there are still areas that have not been settled and for which clear data are still needed. Among these are questions of what are the best predictors of chronic lung disease and how this complication can be prevented. As the serum IgG is not an infallible marker, how can we define what levels of antibody are satisfactory and protective? Is it important to establish anti-bacterial antibody levels in Ig solutions so that adequate protection can be better achieved? What else do we need to know about the biology of the serum IgG half-life? What are the useful biomarkers for subjects at risk for lung disease? Aside from Ig replacement, additional means of prevention of lung disease may need consideration to reduce lung damage. Aside from prophylactic antibiotics, these might include using macrolides as anti-inflammatory agents [27], inhaled corticosteroids [28], bronchodilators, mucolytics or mechanical or rehabilitative respiratory methods devised in other fields of pulmonary medicine [29].

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Serum immune globulins (Ig) treatment and lung disease
  5. Subsets of B cells and memory B cells and lung disease
  6. Conclusions
  7. Conflicts of interest
  8. References
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