COMMON VARIABLE IMMUNODEFICIENCY

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COMMON VARIABLE IMMUNODEFICIENCY

• INTERNAL MEDICINE RESIDENTS 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 150,000 to 1200,000.
• 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 Haemophilus influenzae.
• 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 UTIs 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 Addisons, 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 Crohns 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-Hodgkins 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. Sxs 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 MMs
• 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, 40L)
• 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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SITES OF INFECTION IN 103 PATIENTS
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AUTOIMMUNE DISEASES AMONG 103 PATIENTS
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ASSOCIATED ILLNESSES IN 103 PATIENTS
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CAUSES OF HYPOGAMMAGLOBULINEMIA
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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.

63
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.