Pediatrics

Antibody Deficiency Syndromes: CVID, XLA, SAD, IgA deficiency

OVERVIEW: What every practitioner needs to know

Are you sure your patient has antibody deficiency? What are the typical findings for this disease?

More than two thirds of all immunodeficiency patients can't make antibody normally. Antibody deficiency patients experience more bacterial infections than normal people. Antibody deficiency increases the risk that a common infection (e.g., sinusitis) will be unusually severe, protracted or complicated. Infections in antibody deficiency patients may be poorly or incompletely responsive to antibiotics.

Antibody deficiency may be an element of a combined immunodeficiency. Any patient whose infection(s) are out of the range of normal should be evaluated for immunodeficiency.

When to think about primary immunodeficiency manifesting as antibody deficiency

The hallmark of antibody deficiency syndromes (humoral immunodeficiency) is bacterial infection. These patients get the same kinds of infections, usually with the same organisms, as normal people but the frequency and severity of infection and the risk of infectious complications is out of the range of normal. The most common presentations are recurrent sinusitis, recurrent otitis and bacterial chest infections such as bronchitis and pneumonia. Any unexpected or unexpectedly complicated infection raises a question of primary immunodeficiency.

When to think about antibody deficiency in a hospitalized patient

A patient may present with an antibody deficiency when hospitalized for an unexpected infection or when a bacterial infection follows an unexpectedly complicated course. Unexpected infections include a single episode of a vaccine preventable infection (H. flu, pneumococcal meningitis, H. flu epiglottitis, polio, diphtheria, or tetanus); bacterial endocarditis in the absence of pre-existing structural heart disease; brain, liver, or other deep tissue abscess without a history of superficial infection or a penetrating wound; sepsis without obvious predisposing factors; or enteroviral meningoencephalitis.

Antibody deficiency should also be considered when there is more than one episode of septic arthritis or osteomyelitis over a patient's lifetime, more than one episode of pneumonia within two years, superficial abscess severe enough to require hospitalization, and/or bacteremia.

Unexpectedly complicated infections occurring without apparent risk factors include pneumonia with a large pleural effusion or empyema without underlying disease, brain abscess or endophthalmitis complicating sinusitis, mastoiditis, and disseminated or multifocal abscesses without other predisposing disorders. Failure of appropriate antibiotic therapy, particularly if therapy has been guided by a positive culture, is also an indication for concern.

When to think about antibody deficiency in an outpatient

Antibody deficiency should be considered whenever the frequency of bacterial infections exceeds the clinician's expectations. Some frequencies that invoke concern are excessive otitis media, more than four episodes of sinusitis per year, more than two episodes of varicella (varicella vaccine failure occurs often enough so that a single episode of chicken pox in a vaccinated child does not merit an immunodeficiency work up) per year, more than one pneumonia in two years, and the need for intravenous antibiotics more than once in a lifetime.

Non-infectious presentations of immunodeficiency are seldom seen in children

Antibody deficiency associated with autoimmunity is common but occurs infrequently in pre-pubertal children. The presence of an autoimmune diathesis does not, by itself, mandate an evaluation for antibody deficiency but when a patient with idiopathic thrombocytopenic purpura, arthritis, or inflammatory bowel disease has unusual or recurrent infection there is a high likelihood of identifying an antibody production abnormality.

Although malignancy, in general, is often immunosuppressive, most malignancies are identified for reasons other than immunodeficiency. Lymphoid malignancy occasionally presents with infection but virtually always in adults. Multiple myeloma and chronic lymphocytic leukemia are associated with suppression of antibody formation and patients may experience significant infections prior to the diagnosis of malignancy but, again, these are malignancies of older adults.

Problems in diagnosed antibody deficiency patients

The major problems experienced by patients who carry a diagnosis of antibody deficiency is recurrent infection. Infection frequency and severity can be dramatically diminished by treatment with IgG replacement (gamma globulin) but the side effects may be problematic for as many as 25% of patients. Patients with Bruton's X-linked agammaglobulinemia have an increased risk of lymphoid malignancy that may develop during childhood/adolescence. Common variable immunodeficiency carries a risk of lymphoma and gastrointestinal malignancy but they usually present later in life.

What other disease/condition shares some of these symptoms?

Antibody deficiencies are disorders of host defense. Other disorders of host defense that may present with similar clinical findings include combined immunodeficiency, complement deficiency, Job's or hyper IgE syndrome, cystic fibrosis, phagocytic cell defects, ciliary dysmotility syndrome, and ectodermal dysplasia.

Recurrent sinusitis, the most common infection in antibody deficiency patients, is more often caused by allergic or chronic non-allergic rhinitis than by immunodeficiency. Asthma may be mistaken for bronchitis or "wheezy pneumonia". Atopic dermatitis predisposes to staphylococcal skin infections and even superficial abscesses.

What caused this disease to develop at this time?

Patients are identified because of infection. Antibody deficient patients may present at any age and recognition of antibody deficiency depends on the occurrence of infection and the acuity of the clinician. Antibody deficiency syndromes are genetic disorders that predispose to infection. For a few of these disorders, Bruton's agammaglobulinemia, hyper IgM syndrome, and some common variable immunodeficiencies, the molecular defects are known, but for many forms of antibody deficiency, the exact defect has yet to be identified. At this time, a specific abnormal gene can be identified in more than 25% of antibody deficiency patients.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Measurement of serum protective immunoglobulin concentrations, IgA, IgG and IgM usually leads to the diagnosis.

Some patients have normal or near normal IgA, IgG and IgM serum concentrations but cannot produce protective antibody normally. Therefore, when an antibody deficiency is suspected, it is insufficient to only measure IgA, IgG and IgM. One should also test the patient's ability to make functional antibody when challenged by an antigen. This is commonly demonstrated by measuring the patient's antibody response to vaccination, most commonly with diphtheria and tetanus vaccine and pneumococcal polysaccharide vaccine, Pneumovax®.

Some clinicians also measure isohemagglutinins and the antibody response to Haemophilus influenza type b.

Would imaging studies be helpful? If so, which ones?

Imaging studies do not contribute to the diagnosis of antibody deficiency, but may be necessary to define the extent of a particular infection. For example, once the diagnosis of antibody deficiency is made via laboratory studies in a patient with a history of recurrent or severe chest infections, a high resolution CT chest scan should be performed to evaluate bronchiectasis. Sinus plain films can be used, though seldom are.

When there is chronic, complicated or severe sinus disease, a coronal CT scan of the paranasal sinuses may identify the need for surgical intervention.

Confirming the diagnosis

Although measurement of IgA, IgG, and IgM is the starting point for evaluation of humoral immunity, demonstrating that the patient produces functional antibody is crucial (see above).

If you are able to confirm that the patient has antibody deficiency, what treatment should be initiated?

If the diagnosis of antibody deficiency is made during hospitalization for acute infection, the patient should be treated immediately with IgG replacement, starting with intravenous gammaglobulin. (See Table I)

Table I.

IgG Replacement Methods
IGIV IGSC IGHy
Frequency Q3-4 wk daily to Q2wk Q2, 3, or 4wk
Needle Sticks/treatment 1 2-8 1-2
Infusion duration (hours) 2.25-5 1.25-2 1.5-3
Infusion Site Reactions none ~3-59% ~18%
Systemic Reactions ~15-25% ~3% ~8%
Healthcare Provider (HPC) or self-administered HPC to start the IV self-administered HPC or self-administered

If diagnosis is a result of an evaluation for recurrent infection in an outpatient, the most appropriate immediate treatment is determined by the specific diagnosis and the patient's infection history. Patients in whom the diagnosis of X-linked agammaglobulinemia, hyper IgM syndrome or a significant combined immunodeficiency (SCID, Wiskott-Aldrich syndrome) has been made should be treated with IgG replacement therapy as soon as possible.

Some patients with milder antibody production abnormalities may do well with carefully attention to nasal hygiene and prophylactic antibiotics.

Common variable immunodeficiency disease is actually a phenotypic waste basket of many genotypically different disorders in which antibody production ranges from absent to near normal. Where a particular patient falls in that spectrum determines the need for IgG therapy. Whenever a significant abnormality of antibody formation is identified, the primary treatment, however, is IgG replacement therapy. Appropriate treatment with immunoglobulin dramatically decreases infection frequency and severity; preventing hospitalization. For most patients, the need for IgG replacement will be lifelong.

The definition of selective IgA Deficiency is very specific: IgA is absent (<5mg/dL) IgG (and IgG subclasses) and IgM are normal and specific antibody production is normal. More than 50% of these patients do not have recurrent infection. IgG replacement should not be considered for patients with isolated IgA Deficiency. The question of IgG treatment for a Selective IgA Deficiency patient with specific antibody deficiency is complex and should be considered by an experienced immunologist.

Since the early 1980's the primary method of delivering IgG has been IV (IGIV). After the turn of the millennium an IgG product specifically developed for subcutaneous use (IGSC) was approved and the subcutaneous route has become increasingly popular.

In 2014 a new approach using human recombinant hyaluronidase to facilitate subcutaneous infusion by enhancing bulk fluid flow in the subcutaneous space and increasing systemic IgG absorption was reported. This modality appears to combine the advantages of IV and SC delivery.

What are the adverse effects associated with each treatment option?

There are two categories of adverse effects associated with IgG replacement therapy, systemic and local.

The major systemic side effects of gamma globulin therapy include thromboembolic events (MI, stroke, DVT - risk factors are high dose, rapid infusion, advanced age, previous MI, stroke or DVT); renal failure (risk factors are carbohydrate containing product, especially sucrose), rapid infusion, high dose, diabetes or pre-existing renal disease); and aseptic meningitis (risk factors are migraine headache and previous episodes of aseptic meningitis).

Major systemic side effects are rare in immunoglobulin recipients in general and particularly rare in primary immunodeficiency patients who tend to be younger and have fewer risk factors than other IgG recipients.

Anaphylactic and anaphylactoid reactions to immunoglobulin are very rare. To develop an anaphylactic reaction the patient must have no detectable IgA and have the ability to form IgE anti-IgA antibodies; a very uncommon combination. The mechanism of anaphylactoid reactions is poorly understood. Acutely, reactions should be managed with supportive care. Patients who have experienced severe reactions with one IGIV product may tolerate another product with little or no difficulty. Testing IgA deficient patients prior to IgG therapy is not possible as tests for IgE anti-IgA are no longer available. The use of IgG product with very low levels of contaminating IgA is rarely indicated.

Minor systemic side effects of immunoglobulin therapy are milder and less frequent with subcutaneous than intravenous gamma globulin and include headache (migraine), myalgias, malaise, fever, sinus tenderness, chest tightness, cough, diarrhea, rash. These minor side effects occur in about 15-25% of patients and can be quite problematic. Although patients intolerant of one IGIV preparation may tolerate another without difficulty, the frequency and severity of these minor systemic side effects is significantly less with IGSC than with IGIV. Mild systemic adverse events are about 50% less frequent with enzyme-facilitated subcutaneous IgG infusion than with IGIV but more common than with conventional IGSC.

Local adverse events do not occur with IV therapy but are common with subcutaneous administration. Erythema, induration, pruritis and pain occur in 3-59% of infusions.

What are the possible outcomes of antibody deficiency?

The prognosis for patients with antibody deficiency depends primarily on the specific diagnosis and the occurrence of comorbid conditions. Patients with CVID have been stratified into two groups; those with infections only and those with associated autoimmunity or malignancy. The long-term survival of those with infections only is almost the same as normals while those with significant comorbidities do not do as well. For both groups, the ability to prevent infection depends on the extent of tissue damage (chronic sinusitis, bronchiectasis) present at the time of diagnosis. In general, when treated appropriately, these patients lead normal lives.

The cornerstone of antibody deficiency treatment for most patients is IgG replacement. Although patients may experience adverse effects of this treatment as described, there are no long-term problems associated with immunoglobulin therapy.

What causes this disease and how frequent is it?

Antibody deficiency syndromes comprise the most common of the primary immunodeficiencies (PIDD) representing more than 50% of PIDD patients. The current estimate is that about 250,000 PIDD patients reside in the US; giving an incidence ratio of roughly 1:1000 to 1:1500. This estimate, however, is thought to represent only 30-50% of PIDD patients. If correct, the true incidence is significantly greater than 1:1000. Despite the wide-spread belief that PIDD is a pediatric disease, 50% of new diagnoses are made in patients over 18 years of age.

There are more than 300 PIDD genotypes that sort into a variety of overlapping clinical presentations. Patterns of inheritance include X-linked recessive (Bruton's X-linked agammaglobulinemia, Hyper IgM Syndrome), autosomal recessive (Bruton's-like agammaglobulinemia, some common variable immunodeficiencies) and autosomal dominant (Hyper IgE Syndrome) genotypes have been identified.

For those antibody deficiencies for which a molecular diagnosis is possible, conclusive genetic diagnosis enables the clinician to focus the attention of the parent or patient on the risk for developing autoimmune disease or malignancy. Whole exome and next-generation DNA sequencing have become less costly and the prices are likely to continue to fall.

How do these pathogens/genes/exposures cause the disease?

The most common organisms infecting antibody deficiency patients are Streptococcus pneumoniae, H. influenza and Moraxella catarrhalis causing respiratory tract infection (otitis, sinusitis, bronchitis, pneumonia).

Because antibody deficiency patients commonly experience frequent and prolonged antibiotic exposure, they become colonized or infected with Pseudomonas or other gram negative rods or with fungus. Frequent antibiotic exposure in antibody deficiency patients increases the risk of resistant organisms. Penicillin resistant pneumococci, beta-lactamase-producing H. influenza and M. catarrhalis, and methicillin resistant Staphylococcus aureus infections are common.

Other clinical manifestations that might help with diagnosis and management

Patients with primary immunodeficiency are predisposed to autoimmune diatheses and malignancy.

What complications might you expect from the disease or treatment of the disease?

Infections, and particularly recurrent infections, may cause tissue damage predisposing to additional infections. Bronchiectasis is a prime example. Bronchiectasis adds a structural disorder of host defense (i.e., damaged or absent cilia and bronchial wall dilatation that collects pus) to the underlying antibody production disorder. Sometimes, it is impossible to clear pus from bronchiectatic lung and recurrent exacerbations are a major problem. Exacerbations of bronchiectasis may destroy additional lung tissue leading to progressive pulmonary failure and death. This was a common cause of death in PID prior to the availability of IGIV.

Parallel to bronchiectasis is chronic sinusitis although the consequences are usually less severe. Sinus mucus membranes, damaged by recurrent infection, don't function normally to clear particulates including bacteria. Sinus surgery can contribute to this problem as well. Sinus surgery in PIDD patients should be considered very carefully.

Antibody deficiency patients with acute osteomyelitis may develop chronic osteomyelitis requiring indefinite antibiotic treatment. Appropriately aggressive surgical, antibiotic and IgG treatment is crucial in this setting. Consideration should be given to maintaining a higher than routine IgG serum concentration when treating osteomyelitis.

Are additional laboratory studies available; even some that are not widely available?

How can antibody deficiency be prevented?

Although primary antibody immunodeficiency cannot be prevented, the frequency of recurrent infections can be decreased by the use of prophylactic IgG replacement therapy and aggressive antibiotic treatment (for specific infections as well as prophylactically in some cases).

Genetic counseling can be provided to many patients with antibody deficiency syndromes for which the pattern of inheritance is known.

What is the Evidence?

Bonilla, FA, Khan, DA, Ballas, ZK. "Practice parameter for the diagnosis and management of primary immunodeficiency". J Allergy Clin Immunol.. vol. 136. 2015. pp. 1186-1205.e78.

(Comprehensive review of primary immunodeficiency.)

Cunningham-Rundles, C.. "Key aspects for successful immunoglobulin therapy of primary immunodeficiencies". Clin Exp Immunol.. vol. 164. 2011. pp. 16-9.

(Practical guidance for the treatment of antibody deficiency patients using IgG replacement.)

Wasserman, RL.. "Progress in Gammaglobulin Therapy for Immunodeficiency: From Subcutaneous to Intravenous Infusions and Back Again". J Clin Immunol.. vol. 32. 2012. pp. 1153-64.

(Discusses both IGIV and IGSC therapy including adverse reactions.)

Lucas, M, Lee, M, Lortan, J. "Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years". J Allergy Clin Immunol. vol. 125. 2010. pp. 1354-60.

(This article provides a basis for decisions regarding IgG dose and infusion interval.)

Orange, JS, Grossman, WJ, Navickis, RJ, Wilkes, MM.. "Impact of trough IgG on pneumonia incidence in primary immunodeficiency: A meta-analysis of clinical studies". Clin Immunol. vol. 137. 2010. pp. 21-30.

(A very important paper demonstrating the crucial relationship between IgG dose and the development of pneumonia.)
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