Key aspects for successful immunoglobulin therapy of primary immunodeficiencies

Abstract

Immunoglobulin (Ig) therapy is the mainstay for treatment in the majority of primary immune deficiencies. While B cell defects are the predominant conditions in man, other diseases in which T cell dysfunction is severe also require antibody replacement. In many medical practices the phenotypic overlap between immune deficiency and symptoms of asthma leads to both missed opportunities for diagnosing immune defects and inappropriate Ig treatment of asthmatic patients with normal B cell function. As steroid therapy can lower serum IgG levels, this finding alone is an insufficient indicator for Ig replacement. In the past 3 decades, there has a gradual increase in recommended and commonly used doses of parenteral immune globulin, often based on both IgG trough levels and clinical responses. Special attention to Ig doses is needed for growing children, in cases of weight loss or gain, pregnancy and for subjects in whom more rapid consumption of Ig is likely, including febrile patients or those with gastrointestinal or lung disease. While acute bacterial infections are much less common in Ig-treated subjects, a number of reports note continued evidence of inflammatory complications. Monitoring patients over time includes, at minimum, physical examination, blood counts and chemistry screening tests and IgG trough levels, at 6–12-month intervals. Other monitoring tools include spirometry and at wider intervals with those with lung disease, carbon monoxide diffusion capacity and chest computed tomography scans. With careful selection of patients and adequate therapy, an improved quality of life is possible.

Introduction

In the past 3 decades, replacement immune globulin (Ig) therapy has become the standard of care in patients with primary and secondary antibody defects [1–3]. While many studies have described this advance in medical care, the increasing number of patients on this therapy, and diversity of physicians in various specialities who care for them, suggests that practical guidelines for the use of Ig may be of use. The current paper outlines an approach to achieve successful therapy with Ig in patients with primary immune defects. This approach can be considered in five stages: a good evaluation at the beginning before starting therapy, deciding on the type, dose and location of treatment, working through the early stages of treatment, defining expectations and continued follow-up over time.

A good evaluation at the beginning

The majority of the primary immune defects lead to loss of antibody; this is not only the hallmark feature of the pure B cell defects, but also includes most of those with profound T cells defects (Fig. 1). While for patients with agammaglobulinaemia or otherwise very low serum Ig, severe combined immune deficiency or hyper-IgM syndromes can be considered as having no functional serum IgG antibody, other subjects with more modest degrees of immune deficiency, leading to hypogammaglobulinaemia or IgG subclass defects, can have varying degrees of retained antibody production [4]. This is especially true for subjects with modestly reduced serum IgG and normal or nearly normal IgA and IgM. For these patients, a thorough evaluation of immune function before deciding on Ig replacement is important. This is also true for subjects with a significant degree of reactive airway disease who have been given steroids; here the reduced serum IgG may not imply significant antibody deficiency and Ig therapy would probably not prove a useful therapy [5]. The loss of antibody is demonstrated commonly by lack of protective IgG responses to two or more protein vaccines such as tetanus or diphtheria toxoids, Haemophilus conjugate, measles, mumps and rubella vaccines, and also by lack of response to pneumococcal polysaccharide vaccines [6,7]. Other options for protein antigens include hepatitis A or B vaccines or varicella, either after vaccination or disease exposure. Examining blood for pertinent isohaemagglutinins can be used to test for (mainly) IgM anti-carbohydrate antibody production in older children and adults. Subjects who have retained antibody production in these studies are less likely to benefit by Ig therapy. If replacement Ig therapy is initiated without a compete evaluation and the use of this therapy is questioned later for insurance or other reasons, it must be stopped for about 5 months before such an evaluation can be performed.

Fig. 1.

Most of the primary immune defects are accompanied by loss of immunoglobulin (Ig) and antibody. For a representative patient population, these subjects, and their relative proportions, are indicated in black, while those subjects with immune defects not usually treated with Ig are shown in white.

Deciding on the type, dose and location of treatment

A number of Ig products are available and deciding which one to use, and in what dose and what treatment location, are the next points to consider. In most cases, Ig is prescribed by brand name and not on a generic basis. In addition, as the product chosen initially is used for years, knowledge of the differences between products can be important. Numerous resources list the Ig concentrations, salt, sugar, IgA content and other components present; based on these considerations, the most suitable choices can be made. Treatment has been achieved by either intravenous (i.v.) or subcutaneous (s.c.) routes of Ig, usually in doses of 300–600 mg/kg body weight per month [8]. This dose is divided usually into once or twice a week, or every 2 weeks (for s.c.) or every 3 or 4 weeks (i.v.). In earlier studies the lower doses were most common, but the trend over the past 3 decades has been to use larger doses [9]. For one large group of subjects followed at one centre, the mean doses of intravenous immunoglobulin (IVIG) prescribed to prevent infections were 510 mg/kg/month in the 1980s; 580 mg/kg/month in the 1990s; and 570 mg/kg/month in the 2000s. The outcome of the steady increase in doses has led predictably to higher trough levels, as reported by Lucas et al. [10]. While early studies attempted to deliver doses that led to 500 mg/dl as an appropriate minimum trough target, higher targets, approaching the mid-range of normal serum IgG concentrations (700–800 mg/dl) have been sought more recently. These differing schedules for Ig replacement have been outlined [9,11]. Adequate Ig replacement leads to a marked decrease in the number of infections, to the point that bacterial meningitis or bacteraemia are rare, and episodes of pneumonia greatly diminished and generally noted only in those with poor trough values or chronic lung damage. Higher trough levels to prevent pneumonia are also supported by meta-analysis: the incidence of pneumonia associated with 500 mg/dl trough levels was fivefold that with 1000 mg/dl [9]. However, what is less clear is whether the more currently used doses of Ig have led to even fewer infections, aside from pneumonia. In the past 2 decades, data collected by Lucas et al. [12] did not demonstrate any significant further reduction in the low infection rates for subjects given more Ig in these years. This indicates that the therapeutic objective might be achieved in many patients without the highest doses, although it is likely that some patients require these higher doses. The latter possibility is suggested from data on subjects with chronic lung disease, malabsorption or X-linked agammaglobulinaemia (XLA), for which there is evidence suggesting that higher doses might be preferable. In addition, it is not clear that Ig therapy protects fully against intracellular organisms such as viruses; this would lead to a ‘background’ level of infections that might not be eliminated readily by any dose of Ig. To examine this, Kainulainen et al. [13] found that during a 12-month period, 10 adult common variable immunodeficiency (CVID) and two XLA patients had 65 episodes of acute respiratory tract infections while on 400–600 mg/kg/month of Ig. The 11 spouses of these patients had 12 acute episodes (P < 0·001). Respiratory tract viruses were found in sputum in 54% of infections, and rhinovirus was the most common virus found. In more than half of patients, the rhinoviral polymerase chain reaction (PCR) results remained positive for more than 2 months. Whether even higher doses might have altered these findings is an interesting question.

The choice of location for therapy is best defined with the convenience and safety of the patients in mind. In the United States, approximately 80% of immunologists reported to the Immune Deficiency Foundation that at least some of their patients receive their IVIG infusions in a hospital out-patient setting. In the same group, 66·2% of physicians had patients treated at home by a home infusion service. About 20% of these practitioners permitted self-infused IVIG in the home. In the United States, as elsewhere, the increasing use of s.c.-delivered Ig has also proved satisfactory, providing similar doses of Ig with similar efficacy rates as for intravenous delivery. This appears to approach 33% use for immune-deficient patients in the United States at this time.

Working through the early stages of treatment

In the early phases of treatment, the objective is to make the therapy as easy as possible. This includes starting with doses that are not likely to lead to reactions, and that will introduce the patient to this form of therapy in a way is both reassuring and efficient. It is our practice to use half the intended dose given i.v. for the first time, to achieve both objectives. Premedication for the i.v. route can be given, but is usually not required. The choice of treatment location is best decided based on convenience to the patient, as is the choice of the i.v. or s.c. route. Both supply excellent protection against infections. Having chosen one method does not exclude the other; for example, for those who travel or are away at school, the s.c. route might be used on a temporarily basis, even if the i.v. route is their main method when at home.

Defining expectations

For patients, the main expectation is that they will not have serious infections, be in the hospital, miss work or school due to illness. For the most part, data from trials on all licensed products will satisfy these expectations. Patients sometimes expect that Ig therapy will stop all infections immediately, but for many reasons this is not a realistic expectation. For those with structural lung damage such as bronchiectasis or those with bronchospasm, the risk of respiratory tract infections will continue, although these episodes are likely to be milder and not lead to hospitalizations. Viral infections as noted above or infections with current influenza strains will still occur. Most subjects with loss of IgG antibodies will also lack IgA, leaving mucosal surfaces less protected. In most studies of efficacy, episodes of sinusitis and nasopharyngitis continue to occur in a significant proportion, suggesting that this area is less well treated by increasing serum IgG levels [8,14,15]. Potentially for the same reasons, replacing Ig in the serum also does not seem to ameliorate gastrointestinal complaints such as diarrhoea or inflammatory bowel disease.

Continued follow-up

With growing confidence in the benefits of Ig therapy among physicians of all specialities, the increasing use of home therapy and the general mobility of patients, there is a tendency in some cases to allow long lapses between physician visits. In the United States there does not seem to be a consensus about how often a patient should see the physician who is ordering the Ig therapy. This leads to alterations in the optimal plan established, incorrect procedures being initiated, improper doses for patients who have gained weight and lack of surveillance for intercurrent problems that may have emerged. Determining trough levels and blood screening at least once a year for stable patients, and more often for those with complications, is medically important. Physicians in other specialities who see patients on Ig replacement not infrequently order antibody-based tests that lead to incorrect conclusions; the most common findings that cause concern are antibodies to hepatitis B, Epstein–Barr virus or cytomegalovirus and Coomb's test or anti-thyroid antibodies, among others [16]. Because these antibodies are found commonly in polyclonal Ig, mistaken diagnoses can occur. With continued contact with the physician ordering the Ig therapy, these errors can be avoided. Routines to monitor subjects with chronic lung disease have been controversial; there is no current consensus. High-resolution computed tomography (HRCT) of the lungs at baseline and to monitor therapy at 3–4-year intervals would be reasonable.

Conclusions

Immunoglobulin therapy provides the mainstay of all treatment protocols for the majority of subjects with primary immune deficiency. However, adherence to basic principles of evaluation, prescribing and ongoing care and attention by physicians familiar with this treatment are required to derive the most benefit from this therapy.

Disclosure

This paper is part of a supplement supported by an unrestricted grant from Grifols. The author received payment for the preparation of this article and attendance at the symposium in which it was presented.