David Amrol, M.D.
Resident Grand Rounds
December 19, 2000

Introduction

Primary immunodeficiencies have traditionally been thought of as a pediatric problem and often go undiagnosed by internists. Several primary immunodeficiencies commonly present in adulthood. Common variable immunodeficiency (CVID), IgA deficiency, IgG subclass deficiency, and complement deficiencies all can present in adults with no childhood history of immunodeficiencies. With diseases such as CVID, the immune defect may develop later in life while in complement deficiencies the defect is present since birth but may not produce symptoms until adulthood.

Complement Deficiencies

Genetically determined deficiencies have been described for almost all components of the complement system. They result from a null allele with absent protein production. Early components of the complement pathway present as recurrent infections in children, as opposed to adults where they can present as infections or as autoimmune disorders. The terminal components C5, C6, C7, or C8 lead to recurring Neisseria infections. Recurring Meningococcal meningitis is a terminal complement disorder until proved otherwise.

The test of choice for complement screening is CH50, or total hemolytic complement assay. It gives the serial dilution at which patient's serum can lyse sheep red cells coated with antibody. A normal value is 150 to 250 units/ mL. If positive, further complement components may be tested. This test is only useful for the classical pathway. An alternative pathway assay is available but these disorders are often fatal in young children. Treatment consists of aggressive treatment of infections and possible prophylactic use of antibiotics, as well as immunization with meningococcal and pneumococcal vaccines.

Selective IgA Deficiency

About one in 700 Caucasians fail to produce normal levels of IgA. The majority is asymptomatic, but patients can present with respiratory, gastrointestinal, or urinary tract infections. In addition, there is an increase in diabetes mellitus type 1 and other endocrinopathies.

The diagnosis is made by confirming IgA levels two standard deviations below the mean with normal IgG levels. Treatment consists of antibiotic prophylaxis and management of infection. Ideally, antibiotics should only be used for short periods of time. IVIG is not indicated and actually contraindicated. Patients can have anti IgA antibodies leading to severe reactions. Rarely patients can have anti IgA IgE leading to anaphylaxis.

Immunoglobulin G Subclass Deficiency

Patients who have normal total IgG levels may lack one or more subclasses. Most patients are asymptomatic, but some have recurrent infections similar to CVID. IVIG therapy is only indicated in patients who posses a functional antibody deficiency. That is, they lack antibody response to prior vaccination. In fact some clinicians do not check subclasses at all, and only check response to vaccination. Up to 10% of the population will have absent IgG subclass 4.

Common Variable Immunodeficiency

Introduction

CVID consists of a heterogeneic group of disorders of humoral immune deficiency associated with infections, malignancies, and autoimmune diseases. There is a bimodal distribution with the major peak between 25 to 45 years and a second smaller peak from age five to 15. The pathogenesis is unknown with no known molecular defects. The incidence is 1:50,000 to 1:200,000 with most cases being sporadic. Patients have normal numbers of circulating immunoglobulin bearing B-lymphocytes but these cells fail to produce immunoglobulins. If these cells are cultured with appropriate stimulatory factors they will produce immunoglobulins, suggesting the disorder is actually a T-cell defect. There seems to be a relationship with selective IgA deficiency as many IgA deficient patients will progress to CVID.

Patients with CVID typically present with recurrent sinopulmonary bacterial infections (pneumonia, otitis media, and sinusitis) due to encapsulated bacteria, as well as enteroviral infections such as meningoencephalitis. Other disorders include asthma, chronic giardiasis, inflammatory bowel disease, lymphoproliferation, pernicious anemia, spruelike syndrome, gastrointestinal and lymphoid malignancy, and autoimmune and rheumatic disorders. There also appears to be a relationship between CVID and sarcoidosis, with both forming noncaseating granulomas.

Chronic complications include irreversible bronchiectasis, pulmonary fibrosis and sinus destruction due to repeated infections. The most common killer in adults is malignancies rather than infection.

Diagnosis

The diagnosis is made by identifying laboratory abnormalities in a patient greater than age two with characteristic clinical findings. The total serum IgG concentration is less than two standard deviations below the mean. There is a poor response to immunization with twofold or less increases in serum antibody titers. The diagnosis also rests on the absence of other identifiable molecular defects.

Therapy

The cornerstone of therapy for CVID is IVIG replacement therapy. IgG was first used by Dr. Bruton in 1952 as an intramuscular dose, but found it was hard to give large volumes via this technique. Subsequently, it has been used as an IV preparation in the US since 1981. IVIG is made by pooling plasma from thousands of donors and precipitating immunoglobulins with cold ethanol. Additional viral inactivation steps have been used since the early 1990s when a Hepatitis C outbreak occurred. It is more than 99 percent IgG. Many preparations are IgA depleted to avoid reactions in sensitized patients. It contains antibodies against a variety of viral and bacterial infectious organisms as well as those derived from immunizations. The half-life ranges from 15 to 30 days.

Numerous dosing guidelines have been employed for IVIG with varying doses and intervals of administration. Generally, the serum trough of IgG is kept above 500 mg/dL in adults. Patients are usually dosed with 300mg/kg every three weeks or 400mg/kg every four weeks. There have been several studies of IVIG in CVID demonstrating efficacy, but there are few controlled trials comparing doses of IVIG. The few trials available reveal conflicting results.

Patients with CVID do not respond to vaccines. Live vaccines should not be used in patients with humoral deficiencies. Patients should follow routine immunization schedules for killed or subunit vaccines. Patients who receive IVIG usually have protective titers of antibodies via passive immunization.

Some patients receiving IVIG continue to develop recurrent infections and may benefit from periodic antibiotic chemoprophylaxis. Regimens used include amoxicillin 500mg per day in one or divided doses or trimethoprim-sulfamethoxazole 160mg per day as one or divided doses. Unfortunately, there are no controlled studies of the benefit of antibiotic prophylaxis in patients receiving IVIG. Acute infections must be treated aggressively with broad-spectrum antibiotics for longer than typical courses.

Evidence

Early studies were mostly aimed at children with x-linked aggamaglobulinemia, and this data was then extrapolated to CVID. One of the first studies comparing IVIG with intramuscular IgG was published in 1984 by Cunningham-Rundles et al. Twenty-one patients (nineteen of which had CVID) were treated with 300mg/kg/3 weeks for one year and these prospective results were compared with the retrospective results of the prior year when they were on intramuscular therapy. Over one year there were 834 sick days in the twenty one patients in the IM group, while only 258 days sick in the same group on IV therapy. There was significantly more improvement during the second six months over the first six months suggesting a gradual reduction in inflammation over time. After this study, IVIG became almost universal as the preparation of choice for IgG replacement.

Another study published in 1987 by Roifman et al compared 200mg/kg/month with 600mg/kg/month in a cross over fashion. Twelve patients (ten with CVID) with chronic lung disease as defined by symptoms and pulmonary function tests took six months of each therapy in a random fashion. The authors concluded that a serum level of 500 mg/dL was instrumental in preventing infection. In twelve patients with serum IgG levels less than 500 mg/dL there were 31 minor infections and 16 major infections over six months, compared to just twelve minor and three major infections in patients with levels greater than 500mg/dL. In addition, lung function as measured by FVC and FEV1 improved from 10-50% with the higher dose therapy over six months. All patients in the high dose group achieved the desired level of serum IgG while none of the patients in the low dose group achieved serum IgG levels of 500 mg/dL. This is an important study in that it quantified desirable serum IgG levels and this value is still used today to determine appropriate IVIG dosing.

In 1996 Pruzanski et al published a study comparing three doses of IVIG in adults with CVID. Twenty-one adults were enrolled in a double blind cross over study. Patients were randomized to 200, 400, or 600 mg/kg/month for a period of six months before starting a new dose regimen. The major outcome was again clinical infections. The highest number of infection free months occurred in the 400mg/kg/month dose, but no differences were clinically significant.

This is the only blinded cross over study using different doses of IVIG. There was a trend toward improvement in the 400mg/kg/month dose, and this possibly would have been significant if the study had been larger. There appeared to be no improvement in increasing from 400 to 600 mg/kg/month.

In Europe, there is a movement towards giving IgG subcutaneously. It can be given at home weekly providing decreased cost and excellent serum IgG concentrations. Gardulf et al followed 165 patients with immunoglobulin deficiencies in Scandinavia for 5 months to 9 years. Side effects were documented on patient questionnaires. They noted that mean serum IgG levels increased from 3.0 to 6.2 g/L compared to IM therapy and 4.9 to 7.3 g/L compared to IV therapy. The incidence of adverse reactions was less than 1% in those receiving SC therapy versus 5% for IM therapy and 14% for IV therapy. Cost was also a major factor, with home SC therapy costing $3,100 while traditional IV therapy cost $13,200. Unfortunately, infection end points and doses of SC IgG were not given.

In a 2000 study by Chapel et al in Europe, 40 patients were treated with equal doses of IVIG and SCIG in a crossover fashion for one year of each therapy. Patients were treated with 100 mg/kg SC each week or 200 mg/kg SC every two weeks. No differences were found in efficacy or adverse reaction rates, but there was a trend for fewer sick days and higher serum trough levels in the SC group. Low mercury IM preparations were used which are cheaper, but not currently available in the US.

Adverse Effects

IVIG can be associated with significant adverse effects. The most common symptoms include flushing, chest tightness, nausea, and chills. These side effects increase with increasing rate of infusion, and initial doses should be given very slowly (10-40cc/hr). Effects that are more serious include aseptic meningitis, hemolysis, neutropenia, renal toxicity, thromboembolic events, or rarely anaphylaxis. Hepatitis C transmission occurred in the early 1990s prior to screening, but currently no known pathogens are transmitted. Those preparations known to transmit Hepatitis C were pulled from the market and replaced with solvent detergent preparations to inactivate viruses. In all the mentioned studies, moderately severe side effects were in the two to five percent ranges with no life threatening side effects. Over 10% of patients will have minor transfusion reactions such as chills, flushing, and backache.

Cost is also an issue for patients. At Wake Forest Baptist Medical Center PolyGam and GammaGard are the two most commonly used preparations. These each cost the hospital 57$/gram and the patient charge is roughly double. This means that an average adult male may spend up to $3,000 per month for IVIG.

Conclusion

Primary immunodeficiencies will be encountered by almost all internists, with the most clinically significant being CVID. It is important to recognize recurrent sinopulmonary infections and to screen for immunodeficiency when appropriate. There is significant data supporting the use of IVIG in patients with CVID and recurrent infections, but the ideal dose is still not known. It seems wise for clinicians to start with a dose of 300-400mg/kg/month and then tailor the dose to the severity of infections your patient faces. The major goals of treatment are to minimize infectious episodes, preserve lung function, and increase quality of life for patients. We can slow or halt lung deterioration in these patients subjected to repeated pulmonary infections. As new studies show, SCIG is at least as effective as IVIG and far more cost efficient. We can look forward to seeing this therapy become more widely used in the US.

In addition to the obvious humoral effects of IVIG, there are probably yet undefined benefits of IVIG therapy. IVIG may reduce immune activity and alter the number of T cells and T cell subsets. These effects offer usefulness in diseases such as idiopathic thrombocytopenia purpura, demyelinating diseases, Myasthenia and other illnesses. Presumably, it also has an effect on the autoimmune and lymphoproliferative aspects of CVID, but this needs to be further studied.

There are new hopes for treating CVID in the future with modalities such as human interleukins, but these treatments still have to be further investigated. Rump et al show promise with IL-2 therapy after 6 months of therapy, but other authors have not found significant improvement. More well constructed clinical trials are needed to further define the role of IVIG in CVID as well as to uncover new therapies.

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References

Chapel H, Spickett g, Ericson W, et al. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol 20: 94-99, 2000.

Cunningham-Rundles C, Siegal F, Smithwick E, et al. Efficacy of intravenous immunoglobulin in primary humoral immunodeficency disease. Annals of Internal Med 101:435-439.

Eisenstein E, Sneller M. Common variable immunodeficiency: diagnosis and management. Annals of Allergy 73:285-291 1994.

Gardulf A, Anderson V, Bjorkander J, et al. Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet 345: 365-369, 1995.

Pruzanski W, Sussman G, Dorian W, et al. Relationship of the dose of intravenous gammaglobulin to the prevention of infections in adults with common variable immunodeficiency. Inflammation 20: 353-359, 1996.

Rump J, Jahreis A, Schlesier M, et al. A double blind, placebo controlled, crossover therapy study with natural human IL-2 in combination with regular intravenous gammaglobulin infusions in 10 patients with common variable immunodeficiencies. Clin Exp Immunol 110:167-173 1997.

Sicherer S, Winkelstein J. Primary immunodeficiency diseases in adults. JAMA 279: 58-61.

Roifman C, Levison H, Gelfand E. High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet May 1987 1075-1077.