AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Panhypogammaglobulinemia is characterized by low levels of all immunoglobulins (ie, immunoglobulin G [IgG], immunoglobulin A [IgA], immunoglobulin M [IgM], immunoglobulin D [IgD], immunoglobulin E [IgE]). In 1952, panhypogammaglobulinemia was first described by Colonel Ogden Bruton while examining the electrophoresis pattern of a child's serum and noting the absence of gamma globulin. For the purpose of this section, patients with marked decreases (at least 2 standard deviations for the age-adjusted mean) in IgG levels are considered. All patients with X-linked agammaglobulinemia (ie, Bruton-type agammaglobulinemia, congenital agammaglobulinemia) and many patients with common variable immunodeficiency (CVI or CVID) meet these criteria. Other conditions that result in panhypogammaglobulinemia are also discussed.

Pathophysiology

An absence or loss in the production of all antibodies is caused by abnormalities in the development or function of plasma cells that develop from B lymphocytes. The genetic defect in X-linked agammaglobulinemia is due to mutations in the BTK gene (located on the long arm of the X chromosome at band Xq21.3 to Xq22), which codes for a tyrosine kinase (Bruton tyrosine kinase [Btk]) that is necessary for maturation of pre–B cells into B cells. Many distinct mutations of the BTK gene have been described.

Other rare causes of panhypogammaglobulinemia include mutations in the heavy mu gene, the immunoglobulin-alpha gene, the lambda-5 gene, the BLNK gene, the LRRC8 gene, and the ICOS gene. Panhypogammaglobulinemia can also occur as part of T- and B-cell–negative, severe combined immunodeficiency (SCID) syndromes such as recombinase-activating gene (RAG)-1 deficiency, RAG-2 deficiency, adenosine deaminase deficiency (ADA), and reticular dysgenesis.

The defect in CVID is variable. A few patients show lack of B-cell development similar to that found in X-linked agammaglobulinemia, but most have circulating B cells that either do not mature completely or mature into plasma cells that do not produce adequate amounts of immunoglobulin. Approximately 30% of patients have abnormalities in T-cell function.

Patients with panhypogammaglobulinemia, regardless of basis, share a predisposition to infections with encapsulated pathogenic bacterial organisms such as Streptococcus pneumoniae, meningococcus, and Haemophilus influenzae. Less often, infections develop from beta-hemolytic streptococci, Pseudomonas aeruginosa, and Staphylococcus aureus. Infections with these latter, more virulent organisms tend to occur in patients with architectural derangements such as bronchiectasis. Reports also exist of acute and chronic infection with Mycoplasma pneumoniae. Infections with more virulent organisms, such as S aureus and Pseudomonas species, tend to develop in patients with structural derangements due to bronchiectasis or sinus surgery.

Patients with X-linked agammaglobulinemia have an increased susceptibility to viral hepatitis, echovirus, and Coxsackievirus infections and may develop disseminated poliomyelitis and chronic enteroviral encephalitis. Patients with CVID have an increased incidence of tuberculosis, fungal infections, and Pneumocystis carinii infection.

The most common sites of infection are the upper and lower respiratory tract, and the most common conditions are otitis media, pharyngitis, sinusitis, bronchitis, and pneumonia. These patients are also predisposed to lymphadenitis, meningitis, septic arthritis, osteomyelitis, cellulitis, and infectious gastroenteritis. Common organisms causing infectious gastroenteritis include Giardia lamblia, Clostridium difficile, and Campylobacter, Salmonella, Shigella, Yersinia, and Cryptosporidium species.

Frequency

United States

Specific frequencies are not available.

International

X-linked agammaglobulinemia occurs at a rate of 5-10 cases per million population, and CVID occurs at approximately 10 cases per million population. In general clinical practice, CVID is the most common symptomatic primary antibody deficiency syndrome. It is much more common than X-linked agammaglobulinemia.

Mortality/Morbidity

• Prior to availability of parenteral immunoglobulin infusions, morbidity and mortality rates were high. Most patients experienced early death due to recurrent pulmonary infections. Currently, earlier diagnosis, broad-spectrum antibiotics, and intravenous gammaglobulin infusions have decreased morbidity and mortality rates.
• For patients with X-linked agammaglobulinemia, chronic pulmonary disease due to bacterial pathogens and chronic enteroviral infections are still sources of significant morbidity. Arthritis (inflammatory with sterile effusions or with unusual organisms such as enteroviruses and Ureaplasma urealyticum) is relatively common. Up to 6% of patients may develop a lymphoreticular malignancy.
• Patients with CVID have the same susceptibility to chronic pulmonary disease as those with X-linked agammaglobulinemia. They also have a dramatic increase in susceptibility to autoimmunity, gastrointestinal pathology, and malignancy. Autoimmunity paradoxically occurs in approximately 20% of patients. The most frequent syndromes are hemolytic anemia, thrombocytopenia, pernicious anemia, and hypothyroidism. Almost any other autoimmune process can occur. Chronic gastroenteritis is more common in patients with CVID and is variably associated with a spruelike syndrome, nodular lymphoid hyperplasia, and nonspecific colitis. The incidence of gastrointestinal and lymphoid malignancies is 11-13% in the fifth to sixth decades of life. Distinguishing lymphoid malignancies from atypical reactive lymphoid hyperplasia, which is common in these patients, is important. Patients with granulomatous-lymphocytic lung disease have a shortened median survival (14 years v. 29 years).

Race

Race-based incidence data are not available.

Sex

• As an X-linked disease, patients with Bruton agammaglobulinemia are all male.
• CVID affects males and females in equal numbers.

Age

• X-linked agammaglobulinemia presents in infancy (ie, as early as 6 mo) once maternal IgG, which is placentally transferred, is catabolized. The half-life of IgG is approximately 21 days. Clinical diagnosis depends upon the presence of a significant infection, which may not occur immediately. Furthermore, with the use of antibiotics, appreciation of the immunologic defect may be delayed for several years.
• CVID does not usually present until the second or third decade of life. In a recent study, the mean age at onset of symptoms was 23 years for males and 28 years for females, although both younger (pediatric) and older (geriatric) patients can be affected. A substantial number of patients are sick as early as their first decade of life, even though they may finally be diagnosed as an adult. In the above-mentioned study, both males and females experienced an average 5- to 6-year delay between symptom onset and diagnosis.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Family history
• • In X-linked agammaglobulinemia, a family history of male children with recurrent infections or death in childhood due to infection may be present.

  • In CVID, family members may have similar suggestive histories, autoimmune diseases, or selective IgA deficiency.

• General
• • A history of recurrent or unusual infection initiates evaluation. Most commonly, these are in the upper and lower respiratory tract, but infection can occur in other systems.

  • Almost all patients with untreated or undertreated hypogammaglobulinemia report malaise and fatigue. Low-grade fever and occasional chills are also common.

  • Occasionally, patients with X-linked agammaglobulinemia have a history of failure to thrive.

• Head, ears, eyes, nose, and throat: Patients with panhypogammaglobulinemia typically have recurrent rhinosinusitis or bronchitis, which responds poorly to antibiotics. Patients seek treatment at short intervals and require frequent courses of antibiotics.
• Pulmonary
• • A chronic productive or nonproductive cough is common.

  • Recurrent pneumonia is common.

• Gastrointestinal tract: Gastrointestinal symptoms suggestive of colitis occur in a significant subset of patients with CVID.

Physical

• General: X-linked agammaglobulinemia can cause growth failure if accompanied by chronic recurrent infections.
• Head, ears, eyes, nose, and throat (common symptoms)
• • Nasal congestion

  • Purulent nasal discharge

  • Postnasal drip

  • Sinus pressure and tenderness suggestive of chronic sinusitis

• Pulmonary
• • If the patient has recurrent lower respiratory infections, rales or persistent rhonchi may be present.

  • Digital clubbing is unusual.

• Lymphatics
• • An important distinction between X-linked agammaglobulinemia and CVID is the absence of lymphoid tissue or detectable tonsils in Bruton agammaglobulinemia and the presence of normal or hyperplastic lymphoid tissue in CVID.

  • Patients with congenital hypogammaglobulinemia have an absence of lymph nodes in spite of recurrent sinopulmonary and other infections.

  • A patient with panhypogammaglobulinemia due to CVID may have an absence of lymph nodes, normal adenopathy, tender nodes of variable size, or diffuse adenopathy with splenomegaly.

• Musculoskeletal system: Arthralgias and frank arthritis can occur.
• Gastrointestinal system
• • These problems are generally benign.

  • Occasionally, a patient with CVID presents with splenomegaly.

Causes

• Congenital hypogammaglobulinemia is an X-linked condition due to a loss in function of the Bruton tyrosine kinase (BTK) gene, which is located on the mid portion of the X chromosome (Xp22). The product of this gene is a tyrosine kinase that is essential for B cell development and activation.
• The cause of CVID is unknown. This is a variable disorder that may have multiple etiologies. Mechanisms proposed to explain CVID include intrinsic B-cell defects, excessive T suppressor cell activity, deficient T cell helper function, cytokine deficiencies, and suboptimal T-cell and B-cell interactions. Commonly, IgA deficiency and autoimmune disease is present in family members, suggesting a possible autoimmune basis.
• In addition to Bruton agammaglobulinemia and CVID, other diseases are characterized, at least in part, by decreased immunoglobulin concentrations. Drugs can also cause hypogammaglobulinemia.
• • Genetic disorders - X-linked lymphoproliferative disease and hyper-IgM syndrome

  • Neoplastic disorders - Immunodeficiency with thymoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma

  • Disorders of excess catabolism or increased loss of immunoglobulins - Myotonic dystrophy, severe burns, nephrosis, severe malnutrition, thyrotoxicosis, and protein-losing gastroenteropathy

  • Disorders of decreased synthesis of immunoglobulin - Uremia and the effects of multiple drugs and toxins

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

The following are diseases with symptoms similar to those of panhypogammaglobulinemia:

Genetic disorders

X-linked hypogammaglobulinemia
Hyper-IgM syndrome

Neoplastic diseases

Immunodeficiency with thymoma
Chronic lymphocytic leukemia
Multiple myeloma

Unknown etiology

Common variable immunodeficiency (CVID)
Selective inability to form specific antibodies but with normal total immunoglobulin concentrations
IgG subclass deficiency

Excess catabolism or increased loss of immunoglobulins

Myotonic dystrophy
Nephrosis
Severe malnutrition
Thyrotoxicosis
Protein-losing gastroenteropathy

Decreased synthesis

Uremia

Drugs

Antimalarial agents
Captopril
Carbamazepine
Fenclofenac
Glucocorticoids
Gold salts
Immunosuppressive therapy
Penicillamine
Phenytoin
Sulfasalazine

The following diseases usually have immunoglobulin concentrations within the reference range but may present with recurrent infections. Patients with these conditions usually have a different pattern of infections compared to infections observed with primary hypogammaglobulinemia:

Asthma with relative hypogammaglobulinemia secondary to systemic corticosteroids
Bronchiolitis obliterans with organizing pneumonia
Chronic allergic or nonallergic rhinosinusitis
Cystic fibrosis
Ciliary dysmotility syndromes
Complement deficiency syndromes
Chronic obstructive pulmonary disease (COPD) with relative hypogammaglobulinemia secondary to adrenal corticosteroids
Hyperplastic rhinosinusitis
Interstitial lung diseases
Wegener granulomatosis

Other immunodeficiency diseases are as follows:

Acquired immunodeficiency syndrome (AIDS)
Severe combined immunodeficiency
Wiskott-Aldrich syndrome
Chronic granulomatous disease
Adhesion molecule deficiency
Specific granule deficiency
Hyper-IgE syndrome
Opsonin deficiency
Deficiency of terminal complement components
Duncan disease
Omenn disease
Restrictive airway disease
Autoimmune diseases (for patients with CVID), including hypothyroidism and idiopathic thrombocytopenia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Quantitative immunoglobulins
• • Quantitative immunoglobulins, specifically IgG, IgA, and IgM, are the most important in diagnosing panhypogammaglobulinemia.

  • For the pediatric patient, carefully compare these results to appropriate age-matched controls for the laboratory. IgD levels are generally not useful. IgE levels are useful when severe allergic rhinitis or the hyper-IgE syndrome is a possible diagnosis. IgG levels are typically less than 2 standard deviations below the mean for age-matched controls.

  • For the adult patient with X-linked agammaglobulinemia, ensure that IgG levels (in the absence of replacement therapy) are less than 200 mg/dL. A patient with CVID may have IgG concentrations in this range, but values closer to the lower limits of the reference range may be present. Occasionally, a patient with normal concentrations of immunoglobulins (usually in the lower part of the reference range) may be identified because of the lack of a specific antibody response to immunization.

• IgG subclasses: These determinations are only useful for research purposes. Evaluating the ability of a patient to respond to immunization is much more germane to the question of immunodeficiency than determining IgG subclass levels.
• Response to immunization with common antigens such as tetanus, Haemophilus influenzae B (HIB), meningococcal polysaccharide, and pneumococcal polysaccharide
• • This is a measure of functional humoral immunity as opposed to the determination of quantitative immunoglobulins.

  • If the patient has recurrent infections and normal or low-normal IgG levels, exclude the inability to mount a specific immune response. Measure baseline antibody titers and then compare them with titers obtained 3-4 weeks after immunization with pneumococcal and tetanus toxoid vaccines. Ideally, the preimmunization and postimmunization titers are assayed simultaneously to exclude interassay variability. Standard pneumococcal and diphtheria or tetanus vaccines are usually used. The art of medicine comes into play because even healthy persons (no recurrent infections) do not respond normally to some antigens, particularly some of the polysaccharide antigens. Therefore, the cumulative evidence is what is important. To ensure that the patient is unable to respond, administer a second immunization.

• Isohemagglutinins
• • This is a measure of naturally occurring IgM class antibodies against blood group A and/or B antigens. They are present in all healthy persons except those of blood group AB.

  • The absence of isohemagglutinins where they are expected to occur is evidence of abnormal humoral immunity.

• Serum protein electrophoresis and urine protein electrophoresis (24-h collection) to rule out multiple myeloma
• • A patient with plasma cell tumors may have polyclonal hypogammaglobulinemia in conjunction with a monoclonal gammopathy; therefore, IgA or IgM myeloma may be associated with very low IgG levels.

  • A patient with IgG myeloma may show marked decreases in other immunoglobulins, including IgG (other than the monoclonal band). A patient with Bence Jones proteinuria (eg, production of free-light chains excreted in the urine) may have panhypogammaglobulinemia.

• Microbiology studies: Cultures of potentially infected body fluids allow for appropriate treatment and the consideration of alternative diagnoses. Most importantly, the patient may have both clinically common organisms and unusual organisms. The unusual organisms are often identified in routine cultures, but, occasionally, the microbiology laboratory needs to be informed that a specific organism is suspected or excluded. This is particularly true with gastroenteritis. Patients with CVID may have common pathogens such as Giardia and Salmonella species but may also have uncommon bacteria such as dysgonic fermenter 3, which requires special culture conditions.
• CBC with differential count: This is particularly useful in a patient with CVID because of the propensity to develop autoimmune hematologic abnormalities (eg, hemolytic anemia, thrombocytopenia) and pernicious anemia.
• Lymphocyte subsets: Some patients with CVID have substantial deficiencies of CD4 cells, which need identification. Patients with X-linked agammaglobulinemia and, occasionally, those with CVID have an absence of B cells (<2% CD19⁺ cells). A similar profile in male relatives strongly supports the diagnosis of X-linked agammaglobulinemia.
• T cell function: Because some individuals with CVID have altered cellular immunity, assessing T cell function in these patients is worthwhile. This can be easily achieved by delayed hypersensitivity skin testing with an appropriate panel of positive controls. Antigens commonly used are the mumps skin test antigen, candidal antigen, trichophytin, and tetanus toxoid. Testing with all 4 antigens is optimal because healthy individuals may not react to one or more of these antigens but always react to one of them. Testing may also be accomplished with in vitro lymphocyte thymidine incorporation assays.
• Consider evaluating vitamin B-12 levels in any patient with CVID and anemia, increased red cell distribution width (RDW), or neurologic symptoms.

• Demonstration of a mutation in the Bruton-type agammaglobulinemia gene: BTK, if available, confirms the diagnosis of X-linked agammaglobulinemia.

• Nitroblue tetrazolium (NBT) test: Conduct this test for a patient (including adults) with borderline immunoglobulin values in order to rule out chronic granulomatous disease.

• Sweat chloride test, screening for CF gene mutations, or both: Perform this test if the patient (child or adult) has borderline immunoglobulin values in order to rule out cystic fibrosis.

• Skin tests to specific allergens: Perform these tests in patients (including adults) with borderline immunoglobulin values in order to rule out allergic rhinosinusitis in patients with a history suggestive of allergic disease.

• Antibody studies for miscellaneous conditions
• • A common error in caring for patients with panhypogammaglobulinemia is obtaining tests that depend on the patient's ability to mount a specific antibody response. Examples of such tests include screens for hepatitis, HIV, and Helicobacter pylori. In these cases, a negative test result has absolutely no value and a positive test result may indicate the level of antibodies in the intravenous immunoglobulin (IVIG) that was infused. For these reasons, such serologic tests can be misleading and are worthless in patients with hypogammaglobulinemia.

  • To evaluate a patient with panhypogammaglobulinemia for viral hepatitis or HIV, perform polymerase chain reaction (PCR) or RNA studies to confirm the presence of a viral genome.

Imaging Studies

• Chest radiographs
• • Obtain an anteroposterior (AP) and lateral chest radiograph as part of the typical evaluation of a patient with recurrent bronchitis or pneumonia.

  • A thymoma may be observed on lateral view.

• Coronal CT scan of the sinuses
• • This is essential for documenting and following chronic rhinosinusitis.

  • Findings may not be abnormal, but they usually show chronic mucosal thickening.

• Chest CT scan
• • Use a chest radiograph and thin-cut CT scan to look for bronchiectasis and other pulmonary conditions (eg, tumor, foreign body, interstitial lung disease).

  • This is also an excellent way to rule out a thymoma.

Other Tests

• Spirometry: If the patient is old enough to cooperate, spirometry provides a baseline measure of airway obstruction that can be followed. Premature deterioration in pulmonary function is a late sign of inadequate therapy.
• Spirometry after bronchodilator: This is useful to diagnose concomitant asthma.
• Complete pulmonary function tests (PFTs): Obtain complete PFTs at baseline and every 1-2 years thereafter.
• Shilling test (2 part): This may be necessary to establish the diagnosis of pernicious anemia.

Procedures

• Rarely, transbronchial, CT-guided, or open-lung biopsy is necessary to establish the microbial basis of a lung abscess or to evaluate other lesions.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Medical care includes correct diagnosis, removal or correction of secondary causes of hypogammaglobulinemia, identification and treatment of specific infections, identification and treatment of noninfectious complications, the administration of IVIG, and the judicious rotation of antibiotics. Administer prophylaxis for P carinii infection in patients with CVID and low levels of CD4 positive lymphocytes (<200/mm³).

• For treatment of infections such as bronchitis, sinusitis, pneumonia, and infectious gastroenteritis administer the highest dose of antibiotics safely used for an extended period. Remember that these patients still do not have adequate levels of secretory IgA, although serum IgG levels are reconstituted, and they are relatively immunosuppressed at mucosal surfaces.

• Adjunctive treatment of rhinosinusitis includes isotonic sodium chloride solution (eg, Ocean nasal spray), nasal lavage, and topical (nasal) corticosteroids.

• Reactive airway disease occurs frequently and is treated with bronchodilators and inhaled corticosteroids. Attention to underlying infection is mandatory.

• Gastroenteritis can be due to infectious or inflammatory processes. In addition, irritable bowel syndrome or dietary intolerances may be present. If present, infectious gastroenteritis must be treated aggressively. Chronic colitis is a significant problem for many patients. It is treated with appropriate anti-inflammatory drugs. Adjunctive use of antispasmodics is often helpful.

• Antibiotics for acute infections
• • Choose specific drugs based on clinical presentation. These patients should be administered broad antibiotic coverage until specific culture results are obtained. Endogenous immunity is compromised even with replacement IVIG. Therefore, higher antibiotic doses and longer courses of treatment are needed.

  • The discussion of specific drugs is beyond the scope of this article.

• Rotation of antibiotics as an adjunct to IVIG replacement
• • Occasionally, a patient with persistent bronchitis or rhinosinusitis, in spite of adequate replacement with IVIG, may benefit from the addition of rotating antibiotics. Do not use rotating antibiotics as a substitute for effective doses of IVIG.

  • The choice of antibiotics used may be limited by history of drug reactions or availability due to cost. A recommendation is to use 2 separate drugs, each for 10 days, followed by 10 days without an antibiotic.

  • Some patients may fare better with continued treatment with antibiotics. For an inexpensive regimen of rotating antibiotics, use 10 days of trimethoprim-sulfamethoxazole followed by 10 days of amoxicillin.

  • Unfortunately, many patients with hypogammaglobulinemia are colonized with organisms that do not respond to first-generation penicillins. In this case, broader-spectrum agents are substituted for the amoxicillin such as amoxicillin/clavulanate, clarithromycin, azithromycin, levofloxacin, and loracarbef. Ensure that the doses are at the highest safe levels for each agent based on the history, age, and clinical status of the patient. A discussion of each of these common antibiotics is beyond the scope of this article.

Surgical Care

• Surgical care includes the incision and drainage of cutaneous or pulmonary abscesses and biopsy of suspicious lymph nodes or other lesions suggestive of neoplasia.
• Avoid sinus surgery if possible.

Consultations

• Always involve a clinical immunologist experienced with the care of patients who are immunocompromised.
• Consult a gastroenterologist if the patient has chronic diarrhea.

Diet

No specific dietary restrictions are required. Unfortunately, patients with CVID and gastroenteritis and spruelike lesions rarely respond to a gluten-free diet. Some patients have specific dietary intolerances such as lactose intolerance.

Activity

• No absolute restrictions on activity exist.
• Some patients may experience significant fatigue, especially during the 5-7 days prior to each IVIG infusion. This is a relative indication of inadequate control of low-grade infections, which should lead to the consideration of increasing the IVIG dose, a 3- to 6-week course of suppressive antibiotics, or institution of rotating antibiotics. Moderate activity is recommended during periods of fatigue.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

First, identify and treat specific infections with appropriate antibiotics. When specific isolates are not identified, use broad-spectrum antibiotics (usually with coverage for Mycoplasma) at their highest safe doses for a long period (no less than 3 wk; 6 wk may be necessary). Timely infusion of IVIG is critical. Rotating antibiotics may be useful as an adjunct to IVIG but should not be used as a primary treatment. Finally, other medically appropriate adjunct therapies may be needed such as administration of oxygen to a patient with pneumonia or treatment of seizures in a patient with meningitis.

A sequential trial comparing IVIG versus intramuscular gammaglobulin (IMGG) was reported in 1984 by Cunningham-Rundles et al. They demonstrated a substantial reduction of acute illnesses (18 of 21 patients). The current standard of care calls for higher doses of IVIG (300-800 mg/kg/mo) compared with the dose (300 mg/kg q3wk) used in that study.

Drug Category: Immunoglobulins

Replacement IVIG is available from multiple manufacturers. IVIG that is depleted of IgA is the safest because patients with hypogammaglobulinemia may be able to produce sufficient IgE directed against IgA to result in an anaphylactic reaction. In addition, some patients with CVID possess circulating IgG antibodies directed against IgA. When IgA is infused into such patients, circulating IgG-IgA immune complexes may form and activate complement, triggering an anaphylactoid reaction.

Remember that IVIG therapy has an intrinsic limitation because only IgG is infused. Even with reference range levels of circulating IgG, the chance of an inadequate host defense remains at mucosal surfaces where normal host defense relies on secretory IgA. Instead of secretory IgA, the patient must rely on diffusion of IgG from the plasma into the mucosa.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• If a patient with hypogammaglobulinemia is hospitalized for a serious infection, obtain cultures (if possible) and begin empiric therapy.
• Consultations with a clinical immunologist, infectious disease specialist, and an internal medicine specialist are essential.
• Identification and aggressive treatment of the underlying infectious agents are critical; however, when a specific organism is not found, continue empiric therapy.

Further Outpatient Care

• Patients should be monitored at relatively short intervals (eg, monthly) if they continue to have productive bronchitis or other evidence of continued infection. Patients who are doing well may receive their replacement IVIG and be monitored less frequently.
• Prior to infusion of IVIG, obtain a CBC count with differential and check transaminase levels. Trough levels of IgG should be checked in patients who continue to have infections.

Complications

• Patients with agammaglobulinemia from any cause, even while receiving IVIG, are always at risk for severe infections and the development of life-threatening neoplasms.
• Serious complications of IVIG include risk of anaphylactoid reactions, viral hepatitis, and renal failure.
• • Anaphylactoid reactions: This is a rare complication. Administer IVIG that is depleted of IgA. Ensure that appropriate resuscitative equipment and trained personnel are available.

  • Viral hepatitis: In early 1994, episodes of hepatitis C virus transmission were associated with administration of Gammagard. Although safeguards are in place to avoid a repetition of this contamination, this experience underscores the ongoing concern that any product prepared from human serum has the potential for transmission of infectious disease.

• Renal insufficiency: More than 100 cases of renal adverse events (ie, acute renal failure or insufficiency) were reported to the FDA between June 1985 and November 1998. Death was reported in 13 patients with renal adverse events after the administration of IVIG. These patients had severe underlying conditions (ie, cardiac insufficiency, pneumonia, systemic lupus erythematosus).
• Thromboembolism: Cases of stroke, transient ischemic attack (TIA), retinal artery infarction, and myocardial infarction following IVIG have been reported. Judicious use of IVIG in patients with underlying risk factors is recommended.
• Ensure that patients receiving IVIG therapy, especially high-risk patients with preexisting renal disease, diabetes mellitus, hypovolemia, sepsis, those receiving nephrotoxic agents, or elderly people, have their renal function checked and are euvolemic before IVIG therapy and at regular intervals thereafter (up to 7 d after administration). For more information, examine the advisory concerning this topic on the Medwatch Web site Food and Drug Administration.
• Many patients experience chills, myalgias, and arthralgias during infusion of IVIG. Some of these symptoms are related to the rate of infusion and others may be due to formation of immune complexes. Some patients develop an aseptic meningitis picture that can be disabling. Pretreatment with diphenhydramine, acetaminophen, and hydrocortisone (see Immune globulin, intravenous) can be helpful.

Prognosis

• Prognosis is guarded. The reported 20-year survival rate is 64-67% but may be increasing as care improves. Patients with CVID and granulomatous-lymphocytic lung disease have a worse prognosis; median survival is 14 years.
• Risk of chronic pulmonary disease that can evolve into life-threatening end-stage restrictive lung disease exists.
• Furthermore, the risk of neoplasia, especially in the patients with CVID, is high. Cunningham-Rundles et al (1999) estimate that females with CVID have a 438-fold increased likelihood of non-Hodgkin lymphoma compared to an age-adjusted expected incidence.
• Infectious processes are still a significant problem, although response to antibiotics appears vastly improved with IVIG treatment.
• Unfortunately, an increased prevalence of neoplastic diseases (eg, lymphoma, other cancers) is likely to limit longevity for a significant minority of these patients, particularly those with CVID.

Patient Education

• Advise the patient and parents about the condition, especially the likelihood of the relative lack of the usual signs and symptoms of serious infection. Provide the patient appropriate genetic counseling and access to prenatal counseling and diagnosis.
• The Immune Deficiency Foundation (1-800-296-4433) is an international agency dedicated to providing information for patients and physicians regarding this and other immunodeficiency diseases.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The patient must not be administered any live viral vaccines, including the following:
• • Attenuvax (measles)

  • Biavax (rubella and mumps)

  • Meruvax II (rubella)

  • MMR (measles-mumps-rubella)

  • MR VAX II (measles-rubella)

  • Mumpsvax (mumps)

  • RotaShield (rotavirus)

  • Varivax (varicella)

  • Attenuated polio vaccine

• However, the patient may be administered killed viral vaccines, especially when a T cell response is theoretically of value. The influenza vaccine is relatively safe and useful.
• Finally, purified antigen vaccines such as tetanus, diphtheria, H influenzae, and pneumococcal vaccines are of no use because patients are not able to mount an appropriate antibody response to these antigens.
• Complications of IVIG: Be aware of the risk of anaphylactoid reactions, viral hepatitis, renal failure, and thromboembolism.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Ballow M, O'Neil KM. Approach to the Patient with Recurrent Infections. In: Middleton E, et al, eds. Allergy: Principles & Practice. Vol 2. 6th ed. St. Louis, Mo:. Mosby, Inc;2003:1043-1072.
• Ballow M. Intravenous immunoglobulins: clinical experience and viral safety. J Am Pharm Assoc (Wash). May-Jun 2002;42(3):449-58; quiz 458-9. [Medline].
• Ballow M. Primary immunodeficiency disorders: antibody deficiency. J Allergy Clin Immunol. Apr 2002;109(4):581-91. [Medline].
• Bates CA, Ellison MC, Lynch DA, et al. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol. Aug 2004;114(2):415-21. [Medline].
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Article Last Updated: Feb 27, 2006