Common variable immunodeficiency
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COMMON VARIABLE IMMUNODEFICIENCY. INTERNAL MEDICINE RESIDENT’S GRAND ROUNDS MARCH 9, 1995 JAMES W. SCHNELL, MD. INTRODUCTION. First case of hypogammaglobulinemia was reported by Bruton in 1952. First case reports of common variable immunodeficiency in 1954.

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Common variable immunodeficiency l.jpg

COMMON VARIABLE IMMUNODEFICIENCY

INTERNAL MEDICINE RESIDENT’S GRAND ROUNDS

MARCH 9, 1995

JAMES W. SCHNELL, MD


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INTRODUCTION

  • First case of hypogammaglobulinemia was reported by Bruton in 1952.

  • First case reports of common variable immunodeficiency in 1954.

  • Term “common variable immunodeficiency” coined by WHO in 1971.


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INTRODUCTION

  • Common variable immunodeficiency is characterized by hypogammaglobulinemia and recurrent respiratory infections.

  • Normal numbers of circulating B cells which fail to produce adequate levels of antibodies.

  • Present with recurrent sinusitis, otitis media, bronchitis, and pneumonia.

  • Can develop bronchiectasis and cor pulmonale.


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INTRODUCTION

  • Also have defects in cell mediated immunity.

  • Can develop opportunistic infections.

  • Strong association with autoimmune diseases.

  • Increased risk of developing maligancies.


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EPIDEMIOLOGY

  • Estimated prevalence of 1:50,000 to 1:200,000.

  • Biphasic age of onset with peaks at 1-5 years and 16-20 years.

  • Not clinically apparent until 2nd or 3rd decades.


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GENETICS

  • CVID has classically been considered an acquired disorder.

  • Kindred studies suggest possible inheritence and genetic association with IgA deficiency.

  • High incidence of deletions of C4A or C2 alleles in MHC class III genes.

  • High incidence of neutral amino acids in HLA-DQB region of MHC class II genes.


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PATHOGENESIS

  • Hallmark of CVID is reduced IgG levels.

  • Early mitogen studies suggest a primary B cell defect.

  • B cell defect in immunoglobulin production is not absolute.

  • Most B cells have the ablility to secrete some immunoglobulin, if given the appropriate stimulus.


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PATHOGENESIS

  • Many patients also have T cell defects.

  • 30% of patients are cutaneously anergic.

  • 50% of patients have depressed lymphocyte transformation responses to T cell mitogens.


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PATHOGENESIS

  • T cell defects function decreases with age.

  • Two types of T cell defects identified.

    1. Increased CD8+ T cells.

    2. Depressed levels of T cell cytokines(IL2).

  • IL2 is an important T cell growth factor.


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CLINICAL FEATURES

  • INFECTIONS

  • AUTOIMMUNE DISEASES

  • GASTROINTESTINAL DISEASE

  • MALIGNANCIES

  • LYMPHOPROLIFERATIVE DISORDERS


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INFECTIONS

  • Clinical Hallmark is recurrent infections of the respiratory tract.

  • Encapsulated bacteria, Streptococcus pneumoniae and Haemophilusinfluenzae.

  • Can develop chronic sinusitis and bronchiectasis.

  • Bordetella pertussis in children.


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INFECTIONS

  • Cellulitis, urinary tract infections, septic arthritis and meningitis much less common than respiratory infections.

  • Ureaplasma UTI’s frequently occur.

  • Mycoplasma most commonly isolated organism in synovial fluid.

  • Meningitis rare in adults.


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INFECTIONS

  • Tolerate viral infections well with the exception of Herpes zoster.

  • Herpes zoster occurs in 20%.

  • Severe cases of Herpes simplex, CMV and Molluscum contagiosum reported.

  • Severe enteroviral encephalitis has been described.

  • Vaccinate with killed polio virus.


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AUTOIMMUNITY

  • 20 % of patients will develop autoimmune disease.

  • Hemolytic anemia and idiopathic thrombocytopenic purpura are the most common autoimmune disorders.

  • Treat blood dyscrasias with high dose IV immunoglobulin.


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AUTOIMMUNITY

  • Arthritis is the 3rd most common autoimmune manifestation.

  • Clinically resembles rheumatoid arthritis.

  • Responds to IV immunoglobulin.


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AUTOIMMUNITY

  • Pernicious anemia occurs in 10 % of patients.

  • Younger age of onset than general public.

  • No detectable antiparietal cell antibodies.

  • Other disorders include: Addison’s, SLE, hepatitis, and thyroid disease.


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GASTROINTESTINAL

  • Diarrhea occurs in 60% of patients.

  • Giardiasis is the most common etiology.

  • Diagnosis often requires biopsy.

  • Treatment with metronidazole or qiunacrine.

  • Increase in more common bacterial enteric pathogens: Salmonella, Shigella, Campylobacter, Yersinia.


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GASTROINTESTINAL

  • Campylobacter fetus has been reported as a cause of diarrhea and septicemia.

  • Increase in Cryptosporidium.

  • Must consider Dysgonic Fermenter-3.

  • Grows on Cefperazone-Vancomycin agar plates.


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GASTROINTESTINAL

  • Malabsorption in the absence of infection occurs in 10% of patients.

  • Small bowel biopsy histologically resembles celiac sprue.

  • Treatment is supportive.


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GASTROINTESTINAL

  • Increased incidence of Crohn’s disease and ulcerative colitis.

  • 30%-50% will develop achlorhydria.

  • 13% will develop hepatitis, usually transfusion related.

  • 25% will develop cholelithiasis.

  • Nodular lymphoid hyperplasia and gastric carcinoma are common.


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MALIGNANCIES

  • Increased risk of gastric carcinoma and lymphoma.

  • Kinlin et al:

    - 7/220 pts with stomach CA.

    - 3/220 pts. with lymphoma.

    - 47 fold increase in stomach CA. - 30 fold increase in lymphoma.


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MALIGNANCIES

  • Cunningham-Rundles et al:

    - 7/98 pts with lymphoma (all females).

    - 1/98 pts with stomach CA.

    - 438 fold increase in lymphomas in

    females.

  • All lymphomas of the non-Hodgkin’s type.


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MALIGNANCIES

  • Defects in cell mediated immunity may contribute to increased lymphoma.

  • Most patients who develop malignancies have proliferative T cell defects.

  • Earlier onset of atrophic gastritis and achlorhydria may contribute it increased risk of stomach CA.


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LYMPHOPROLIFERATIVE

  • Benign lymphoproliferative disorders are common.

  • 30% will develop diffuse lymphadenopathy, splenomegaly or both.

  • Two histologic forms of adenopathy:

    1. Reactive lymphoid hyperplasia.

    2. Atypical lymphoid hyperplasia.


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LYMPHOPROLIFERATIVE

  • Atypical lymphoid hyperplasia resembles lymphoma and the two may be mistaken for each other.

  • Can be differentiated by immunohistochemical staining.


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LYMPHOPROLIFERATIVE

  • Nodular lymphoid hyperplasia is very common.

  • Discrete nodules in the submucosa of the GI tract consisting of B cells.

  • Usually found in the small intestine.

  • Often found in the presence of Giardiasis.

  • Not a premalignant lesion.


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OTHER FEATURES

  • Patients with CVID often develop granulomatous disease and a sarcoid-like condition.

  • Often develop cutaneous disease, an eczema-like condition is well described.

  • CD4+ lymphopenia/ “HIV negative AIDS.”


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DIAGNOSIS

  • Consider the diagnosis in any patient with recurrent infections of the respiratory tract.

  • Draw quantitative immunoglobulins.

    -Most patients have panhypoglobulinemia.

    -IgG is consistently low.

    -IgA and IgM may sometimes be normal.


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DIAGNOSIS

  • Confirm the diagnosis measuring pre and post immunization titers to protein and polysacharide antigens.

  • Tetanus toxoid(protein) and Pneumococcal vaccine(polysacharide).

  • Fourfold rise in anti-tetanus titers at 4 wks is normal, a twofold increase in anti -Pneumococcal titers is normal.


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DIAGNOSIS

  • Treat only if unable to mount an adequate antibody response.

  • Diagnosis is often delayed for many years.


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DIFFERENTIAL

  • Consider other causes of hypogammaglobulinemia: primary immunodeficiency disorders, drugs, infection and malignancy.

  • Other conditions which predispose to infection: allergies, ciliary dysmotility, cystic fibrosis and complement deficiencies.


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DIFFERENTIAL

  • Chronic lymphocytic leukemia, multiple myeloma, lymphoma.

  • Nephrotic syndrome and protein losing enteropathy often result in selective loss of IgG.

  • Nephrotic syndrome is probably the most common cause of moderate hypogammaglobulinemia.


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IVIG

  • The primary form of treatment is IV immune globulin replacement.

  • Immunoglobulin therapy initiated shortly after the first patient was diagnosed in 1952 with hypogammaglobulinemia.

  • Markedly reduced the number and severity of infections.


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TREATMENT

  • INTRAVENOUS IMMUNOGLOBULIN.

  • ANTIBIOTICS.

  • MANAGEMENT OF NON-INFECTIOUS COMPLICATIONS.

  • EXPERIMENTAL.


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IVIG

  • Decision to treat should not be dependent on absolute antibody level but rather on functional antibody response.

  • IVIG dose 300-400mg/kg/month.

  • Follow trough levels and adjust dose to keep trough levels at 400-500mg/dl.


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IVIG

  • Cost $25,000-$45,000 per year.

  • IVIG tolerated well.

  • Early side effects include: back pain, abdominal pain, nausea and vomiting.

  • Late side effects include: fevers, chills, haedache and myalgias.

  • Aseptic meningitis due to IVIG has been described.


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IVIG

  • True anaphalactic reactions are rare, and usually occur in patients who have IgA antibodies.

  • Gammagard S/D contains very low concentrations of IgA and is tolerated well by these patients.

  • Subcutaneous immunoglobulin successfully used in Europe.


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IVIG

  • Newborns of women with CVID are at high risk for developing neonatal infections.

  • Current recommendations are for these women to receive frequent high doses of IVIG in the third trimester.

  • Recent data suggests high dose treatment in the first trimester.


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IVIG

  • Transmission of hepatitis B and C through IVIG have been reported.

  • Cold ethanol fractionation inactivates hepatitis B and HIV.

  • No cases of HIV transmission with IVIG reported.

  • Hepatitis C is enveloped and not inactivated, outbreaks reported.


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IVIG

  • 150 cases of hepatitis C transmission over recent 5 month period.

  • All comercially available forms of IVIG now undergoe further viral inctivation steps.


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ANTIBIOTICS

  • Patients with CVID may continue to have respiratory infections after IVIG.

  • Agents with activity against encapsulated organisms should be used.

  • Longer course recommended.

  • Prophylactic antibiotics with chronic lung disease.


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OTHERS

  • Spirometry.

  • Postural drainage for bronchiectasis.

  • Sinus surgery.

  • Bronchodilators.

  • Corticosteroids for autoimmune or granulomatous diseases.


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EXPERIMENTAL

  • Interleukin-2 infusion in vivo.

  • B cells in these patients secrete more IgG in vitro.

  • Increased T helper activity in vitro.

  • Clinical benefits remain to be proven.


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PROGNOSIS

  • Excellent if treatment is instituted early.

  • Poor if chronic lung disease has developed.

  • Pulmonary disease and malignancies remain the leading causes of mortality.


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CONCLUSION

  • CVID should be considered in any patient who presents with recurrent respiratory tract infections.

  • Easily screened for with Quantitative Ig.

  • The clinician should be aware the increased frequency of autoimmune diseases, gastrointestinal diseases and malignancies.

  • Early diagnosis and treatment with IVIG significantly reduces morbidity and mortality.


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CASE REPORT

HPI: W.C was a previously healthy 48yowm who presented to NCBH with a 6 mo c/o of weakness, fatigue, anorexia, diarrhea, and a 40lbs weight loss. Sx’s began after drinking contaminated water in FL. Intermittent nausea, vomiting and diarrhea. No hematochezia, hemetemesis but possibly melena. Also reported a 3 wk c/o productive cough, fevers and chills.


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CASE REPORT

PMH: None. Recently involved in a MVA in mount Airy, NC. Was started on Lodine, Trazadone, and cyclobenzaprine.

SH: Recently moved to NC from New Mexico. No ETOH, Tobacco or homosexual activity. Divorced but living with girlfriend.

FH: Mother died age 59 stomach CA, father died age 60 with liver CA.


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CASE REPORT

PE: T 102.4 P 104 BP 110/60 RR 20

GEN: Cachectic, pale WM in NAD

HEENT: Pale MM’s

NECK: Supple, no adenopathy

LUNGS: Decreased BS and rales right base

CVS: RRR with II/VI SEM

ABD: Soft, NT, +BS. no masses.

RECTAL: Heme- , no masses.


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CASE REPORT

LABS: WBC: 1,800 (50% s, 40%L)

Hb: 4.8 MCV 107

Plt: 74,000

Na: 131 K: 3.2 LDH: 742

Prot: 4.0 Alb: 2.9 Chol: 80

CXR: RLL infiltrate


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CASE REPORT

IMPRESSION: Pneumonia and pancytopenia due to malignancy vs. B12 deficiency vs. myelopthisic process.


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CASE REPORT

WORK UP:

  • Vitamin B12 80 L (210-705)

  • HIV - Nonreactive

  • Bone marrow biopsy - B12 deficiency

  • Colonoscopy - Normal

  • Chest CT - Pneumonia, no adenopathy

  • EGD - Submucosal nodules


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CASE REPORT

  • Quantitative immunoglobulins:

    IgA 3 L (70-350)

    IgG 408 L (700-1700)

    IgM 14 L (70-210)

  • Gastric Ph - Achlorhydria


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CASE REPORT

DISCHARGE DIAGNOSIS

1. Common variable immunodeficiency

2. Pneumonia

3. Giardiasis

4. Atrophic gastritis + pernicious anemia

5. Nodular lymphoid hyperplasia


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CASE REPORT

FOLLOW UP: The patient was referred for immunologic evaluation and the diagnosis of CVID was confirmed by documenting inappropriately low post immunization antibody titers to tetanus toxoid and pneumococcus vaccine. The patient was started on IVIG 400mg/kg/month and IM B12. He has not had any further pulmonary or gastrointestinal infections and his anemia has resolved.






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GRANULOMAS

  • Granulomatous disease often occurs.

  • Can develop sarcoidosis.

  • Sarcoid can be severe and fatal.

  • Responds to steroids.


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CUTANEOUS

  • Infections.

  • Pyoderma gangrenosum, dermatitis herpetiformis, alopecia, conjunctivitis and Stevens-Johnson.

  • Eczema in 10%.

  • Severe plaques. Lack IgE.

  • Unresponsive to steroids. Treat with IVIG.


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CD4+ LYMPHOPENIA

  • Common variable immunodeficiency can be mistaken for AIDS.

  • Differential diagnosis for “HIV NEGATIVE AIDS.”


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INTRODUCTION

  • Also have defects in cell mediated immunity.

  • Develop opportunistic infections.

  • Strong association with autoimmune diseases.

  • Increased risk of developing malignancies.


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GASTROINTESTINAL

  • Diarrhea occurs in 60% of patients.

  • Giardiasis is the most common etiology.

  • Diagnosis often requires biopsy.

  • Treatment with metronidazole or quinacrine.

  • Increase in more common bacterial enteric pathogens: Salmonella, Shigella, Campylobacter, Yersinia.


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