Hospital Medicine

Common variable immunodeficiency (antibody deficiency)

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Common variable immunodeficiency (antibody deficiency)

I. What every physician needs to know.

Common variable immunodeficiency (CVID) is the most common antibody deficiency, and in many cases the etiology is unknown. In fact it is possible that further genetic testing will reveal that the entity currently termed CVID is actually a heterogeneous collection of antibody deficiency states. The age of onset and severity of manifestations can be varied, making this a disease of interest for both pediatricians and adults.

II. Diagnostic Confirmation: Are you sure your patient has common variable immunodeficiency?

CVID is defined by low or absent serum immunoglobulin (Ig) G levels combined with either a low IgA and/or low IgM level, without a known cause (malignancy, etc.) along with poor or absent antibody production. This can be determined by the absence of antibody response to a prior immunization or known disease exposure.

Secondary causes should be ruled out, such as lymphoid malignancy, thymoma, renal or gastrointestinal diseases, and side effects of anticonvulsants or rheumatologic agents.

While there are genetic tests available to confirm the diagnosis of CVID, many patients will not have one of the well-described mutations and yet still have the phenotype of CVID. This is still largely a clinical diagnosis.

A. History Part I: Pattern Recognition:

There are no clear guidelines on which patients should be tested for CVID. Because of the heterogeneous clinical presentations, the diagnosis is missed for a median of 6-8 years. Most patients are not diagnosed until they are adults between 20 and 40 years of age.

In the hospitalized setting, CVID should be suspected in otherwise healthy patients with recurrent pneumonia, unexplained bronchiectasis, chronic sinusitis, and or chronic diarrhea, especially if the patient has had multiple hospitalizations.

The one group that must be tested are individuals who have documented vaccinations to a particular disease who then develop the disease.

B. History Part 2: Prevalence:

CVID affects approximately 1:25,000 to 50,000 individuals. Males and females are equally affected.

C. History Part 3: Competing diagnoses that can mimic common variable immunodeficiency.

Hypogammaglobulinemia is the cardinal laboratory finding of CVID. However, other conditions can also have hypogammaglobulinemia as a feature. These include lymphoid malignancy, thymoma, medications (e.g., steroids, antiepileptics and immunosuppressives) and other systemic illnesses. Additionally, young children under the age of 4 years should not be diagnosed with CVID, as they may have other diseases such as transient hypogammaglobulinemia of infancy.

D. Physical Examination Findings.

There are no classic physical exam findings for CVID, but rather findings related to chronic sinopulmonary or gastrointestinal infections and other complications.

E. What diagnostic tests should be performed?

If there are symptoms suggestive of lymphoid malignancy such as fevers or night sweats, consider computed tomography (CT) chest/abdomen/pelvis to screen for lymphoma. Otherwise, routine testing is for diagnosis with serum immunoglobulins. A referral to an immunologist to assist with work-up of the vaccine response as well as replacement therapy should be considered.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Two key laboratory features must be confirmed to make a diagnosis of CVID.

First, measurement of quantitative serum immunoglobulins must show deficiency of two or more Ig subtypes (low IgG, IgA or IgM).

Second, there must be evidence of impaired functional antibody response. This can be determined by testing for antibodies to tetanus and diphtheria or other protein based vaccines or measuring isohemagglutinins. In CVID, these antibodies will be absent or below laboratory-defined protective levels.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

As stated previously, imaging should be directed by findings elicited by history and physical exam. For exam, CT of the chest, abdomen and pelvis may be indicated in a patient with fevers and night sweats. Patients with chronic lung findings such as cough and sputum production may benefit from CT of the chest to evaluate for bronchiectasis.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Genetic testing and flow-cytometric B-cell subset analysis are not warranted by the hospitalist.

III. Default Management.

A. Immediate management.

The immediate management concern for any hospitalized patient with CVID is aggressive treatment of any current infections. As these patients often suffer from chronic infections, attempts should be made to obtain a microbiologic diagnosis early while still aggressively empirically managing life-threatening infections.

B. Physical Examination Tips to Guide Management.

The incidence of malignancy, in particular lymphoma, occurs in up to 15% of patients. It is important to examine the lymph system thoroughly and pursue any findings of lymphadenopathy aggressively.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

N/A

D. Long-term management.

The mainstay of therapy is the provision of Ig, either intravenously or subcutaneously to prevent morbidity and mortality from recurrent infections. This needs to be arranged in conjunction with a specialist, if possible, to determine the correct dose and form of Ig to administer.

E. Common Pitfalls and Side-Effects of Management

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IV. Management with Co-Morbidities

F. Malignancy

These patients are at higher risk for malignancy and a low threshold of suspicion should be maintained.

G. Autoimmunity

Approximately 25% of patients develop autoimmune disease. The most common manifestations are immune thrombocytopenic purpura (ITP), autoimmune haemolytic anemia, or both (Evans syndrome). It is important to monitor complete blood counts on an annual basis or as symptoms warrant.

H. Primary Lung Disease (COPD, Asthma, ILD)

Many of these patients will have bronchiectasis and will benefit from good pulmonary hygiene during their stay. Pulmonary consultation, if available, is recommended for patients with lung findings. Based on an evaluation of risks and benefits, prophylactic long-term antibiotics may be considered for these patients.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Sign-out should emphasize that this patient is immunosuppressed and merits a careful evaluation should there be any unexpected change in status or even a mild temperature elevation.

B. Anticipated Length of Stay.

N/A

C. When is the Patient Ready for Discharge?

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D. Arranging for Clinic Follow-up

See below.

1. When should clinic follow up be arranged and with whom?

These patients are usually managed long-term by an allergist/immunologist. For patients with other manifestations, appropriate referrals should be made. For example, patients with bronchiectasis should be followed by a pulmonologist, and patients with autoimmune manifestations should be followed by a rheumatologist.

As with any hospitalized patient, clear communication with the primary care doctor regarding the diagnosis and key issues to be aware of, such as the decreased or absent response to routine vaccinations and the increased risk of malignancy, is essential to the safe discharge of the patient.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

N/A

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

N/A

E. Placement Considerations.

If long-term monthly intravenous therapy is planned, the patient may opt for port-a-cath placement. Risks and benefits should be discussed with the patient.

F. Prognosis and Patient Counseling.

The prognosis is generally good in the absence of comorbid conditions, particularly bronchiectasis, autoimmune disorders or malignancy.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

The patient is unlikely to respond to routine recommended vaccinations (in fact, failure to respond to pneumococcal vaccination is occasionally used as a test for the presence of CVID). Live vaccines should not be given. However, since influenza is unlikely to be represented in the replacement-immunoglobulin, annual vaccination with inactivated influenza vaccine is recommended.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

The mainstay of therapy is routine administration of intravenous immunoglobulin (IVIG). Prior to travel, patients can be given specific Ig preparations (e.g., against hepatitis A or hepatitis B). Consultation with an allergist or infectious disease specialist is recommended.

VII. What's the evidence?

Cunningham-Rundles, C. "How I treat common variable immune deficiency". Blood.. vol. 116. 2010. pp. 7-15.

(This review is the latest from the pre-eminent researcher of CVID and offers clear management advice on CVID.)

Quinti, I, Agostini, C, Tabolli, S, Brunetti, G, Cinetto, F, Pecoraro, A, Spadaro, G. "Malignancies are the major cause of death in patients with adult onset common variable immunodeficiency". Blood.. vol. 120. 2012. pp. 1953-4.

(This article covers the complications related to malignancy in a thorough manner.)

Park, MA, Li, JT, Hagan, JB, Maddox, DE, Abraham, RS. "Common variable immunodeficiency: a new look at an old disease". Lancet.. vol. 372. 2008. pp. 489-502.

(A very thorough review article covering diagnosis, management and an in-depth look at pathophysiology and the immunologic aberrancy of the disease.)

Resnick, ES, Cunningham-Rundles, C. "The many faces of the clinical picture of common variable immune deficiency". Curr Opin Allergy Clin Immunol.. vol. 12. 2012. pp. 595-601.

(This article emphasizes how and why CVID can be difficult to diagnosis and pitfalls that physicians can encounter.)
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