Immunodeficiency in an adult patient

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Immunodeficiency in an adult patient

• Golda Hudes, MD, PhD
• Division of Allergy Immunology

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Case 1
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C.R.

• Presentation June 2001
• 50 yo Hispanic female admitted to Montefiore
  Medical Center with chief complaints of cough,
  weakness, fever and chest pain
• PE remarkable for fever of 104oF, rales on lung
  auscultation and pulse oxymetry of 84

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C.R.

• WBC of 14,000
• CXR LLL infiltrate, RUL infiltrate and right
  side pleural effusion with pleural infiltrate
• Started on Tequin, later on Vancomycin after
  blood culture grew 4/4 Strep. pneumoniae

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Past medical history

• Pneumonia
• April 1997
• November 1997
• February 2000
• April 2000 (treated in walk-in clinic, returned
  one week later symptoms not resolved)
• Hospitalized 4/22/01-4/27/01
• June 2001 hospitalized

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Sinusitis

• 12/97 ENT clinic treated for acute sinusitis
• 6/98 ENT chronic sinusitis. Offered surgery
  refused
• 8/98 Medicine clinic- sinusitis, given Biaxin
• 9/98 ENT treated with Clindamycin. Nasal culture
  grew H. influenzae and M. morganii
• 1999 Neurology clinic for chronic headaches

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Sinusitis (cont.)

• 11/99 ENT otitis media
• 10/00 Medicine clinic sinusitis, given
  Clarithromycin
• 12/00 Scheduled for FESS
• 2/01 Medicine clinic sinusitis treated with
  Ampicillin then Augmentin
• 3/01 Otitis media

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Other Medical history

• History of diarrhea, colonic polyps. Colonoscopy
  consistent with inflammatory bowel disease
• Joint pain, weight loss and depression. Seen in
  Rheumatology clinic

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Social history

• Born in Dominican Republic
• No smoking history
• No history of alcohol or drug use
• No history of toxic exposure
• Healthy as a child and young adult
• No family history of chronic infections

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Radiography

• Sinus CTs
• 6/99 Pansinusitis with complete opacification of
  left maxillary sinus
• 6/99 Worsening pansinusitis
• 4/00 Pansinusitis
• 1/01 Pansinusitis with worsening frontal
  sinusitis and opacification of left mastoid
  aircells
• Chest CT
• - left lower lobe and right middle and lower
  lobes bronchiectasis.

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What diagnostic tests do you want to order?
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Pathology

• Nasal biopsy (bedside)
• Inflammation, focal metaplasia, hypertrophied
  mucosal glands, negative for fungus, negative for
  vasculitis

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Immunology testing

• HIV testing negative
• Anergy panel to PPD, mumps (normal)
• Antibody Titers
• measles IgG non-immune
• mumps IgG non-immune
• rubella IgG non-immune
• T cell counts and ratios normal (CD3, CD4 CD8)
• Low B cell count (CD19)

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Quantitative Immunoglobulins
IgG lt 33 (nl844-1912) IgA lt 6.67
(nl68-423) IgM 31.2 (nl 50-196) IgE lt 2
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IgG subclasses

• IgG1 lt65 (nl4559-8838)
• IgG2 lt70 (nl 1939-4926)
• IgG3 lt50 (nl184-949)
• IgG4 lt36 (nl104-671)

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Diagnosis
Common Variable Immunodeficiency
hypogammaglobulinemia with impaired specific
antibody production Presenting as chronic
sinusitis, frequent pneumonias, diarrhea and
arthralgias
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Common variable immunodeficiency

• Common variable immunodeficiency (CVID) is a
  heterogeneous group of disorders, the predominant
  manifestation of which is a generalized failure
  of antibody synthesis
• Affects 1 in 100,000 persons of European ancestry
• Most cases are sporadic, but familial cases have
  been reported
• Men women are equally affected
• Onset in the second or third decade of life
  (average age is 25 years)

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Mutations in CVID

• 162 patients with CVID screened (135 sporadic
  cases 27 familial cases) for TACI mutations
• TACI is a receptor for TNF family, which is
  expressed on B cells and promotes T cell
  independent responses isotype switching
• Homozygous and heterozygous mutations of TACI in
  13 cases
• Homozygous mutations - more severe cases
• Same mutations - different clinical phenotypes

Salzer et al. Nat Genet 2005 37(8) 829
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Clinical Manifestations

• Infections
• Gastrointestinal disease
• Autoimmunity
• Lymphoproliferative disorders
• Granulomatous disease
• Others

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C.R. Clinical Manifestations

• Infections
• Gastrointestinal disease
• Autoimmunity

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Infections

• Respiratory tract sinusitis, otitis media,
  bronchitis pneumonia
• Streptococcus pneumoniae, Haemophilus influenzae,
  Staphyloccocus aureus
• Bordetella pertussis, Mycoplasma hominis,
  Pneumocystis carinii
• Gastrointestinal infections with Salmonella,
  Shigella, Yersenia, Campylobacter, Giardia
  lamblia and Gram-negative rod DF3 (dysgonic
  fermenter-3)
• Infections of skin, urinary tract, sceleton and
  CNS
• Sepsis
• Viral infections

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Gastrointestinal disease

• Diarrhea (60 of untreated patients)
• Infections
• Lactose intolerance
• Idiopathic malabsorption (10 of patients)
• Atrophic gastritis with achlorhydria
• Nodular lymphoid hyperplasia
• Hepatosplenomegaly
• Increased incidence of UC and Crohn disease
• Increased incidence of gastric carcinoma

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Diagnosis

• Medical history
• Family history
• Physical examination
• Laboratory evaluation

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History

• 8 or more ear infections in one year
• 2 or more sinus infections in one year
• 2 or more pneumonias in a year
• 2 or more months on antibiotics with little
  effect
• Family history of immune deficiency

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Laboratory evaluation

• Quantitative immunoglobulins (IgG, IgA IgM) and
  IgG subclasses
• T B cell subset determination
• Functional antibody responses
• T cell function

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Functional antibody responses

• Isohemagglutinin titers (IgM)
• Specific antibodies (pre post immunization)
• anti-diphtheria/tetanus antibodies
• anti-pneumococcal polysaccharide antibodies
• anti-hemophilus antibodies

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T cell function

• Anergy panel
• In vitro mitogen reactivity
• In vitro specific antigen reactivity (Candida,
  tetanus, diphtheria)

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Treatment

• Replacement therapy (IVIG)
• Antimicrobials
• Corticosteroids for autoimmune or granulomatous
  complications
• Supportive care (pulmonary hygiene measures)
• Experimental (IL-2, TNF-a antagonists)

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CR treatment/follow-up

• Received 1st dose of IVIG July 2001
• Initially received 30 grams every 3 weeks
• Patient symptoms have improved markedly although
  had some occasional nasal congestion, cough and
  asthma-like symptoms
• IgG trough level was in 800s range
• After almost 3 years of IVIG therapy, treatment
  was inadvertently interrupted for two months
  because of a problem with her medical insurance

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CR follow-up

• On re-initiating IVIG-infusions after the
  interruption, an infusion nurse noticed that the
  left radial pulse was absent and that she was
  unable to detect the patients blood pressure on
  the left arm.
• On questioning, the patient reported a one-month
  history of left arm pain, weakness, and numbness
  with minimal physical activity.
• On physical examination, she was found to have a
  blood pressure difference between her arms, an
  absent left radial pulse, and a left subclavian
  bruit.

E.Jerschow et al., Ann Allery Asthma Immunol
2007 98196
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CR follow-up

• Takayasu arteritis was suspected
• The dose of IVIG was increased to 45 g every 3
  weeks. Patient improved after her second
  infusion, regaining a weak radial pulse and
  maintaining a blood pressure around 110-120/60 in
  the left arm
• Patients state of health deteriorated again
  after ten months of continuous therapy with high
  dose of IVIG. Her symptoms worsened again and
  were not helped by high doses of prednisone
• Takayasu arteritis was confirmed by angiography.
  1g/kg IVIG dose (55g) every 3 weeks was used.
  Patient regained her pulse and blood pressure in
  her left arm and currently is doing well on that
  dose

E.Jerschow et al., Ann Allery Asthma Immunol
2007 98196
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Case 2
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H.K.

• Presentation September 2005
• 70 yo white male referred for evaluation of
  difficult to treat chronic rhinosinisitis
• Chief complaints productive cough,
  sneezing,postnasal drip, nasal congestion of many
  years duration. Worse for last 5 years. Requires
  antibiotics almost every month

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H.K.

• Past medical history
• COPD
• Multiple pulmonary nodules (stable CT) refused
  open lung biopsy
• CAD, PAF
• DM, Hyperlipidemia
• Carpal tunnel syndrome
• Glaucoma, optic neuritis, requiring intraocular
  steroid injections
• Chronic angioedema urticaria, controlled on
  Atarax
• PCN allergy

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H.K.

• Social history
• 40 pack/year smoking history quit 8 years ago
• Works as CPA, active life style
• No history of alcohol or drug use
• No history of toxic exposure
• No family history of chronic infections
• PE
• Enlarged crasted nasal turbinates with yellow
  discharge
• PF - 290 (50of normal)

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H.K.

• Laboratory data
• Normal Chem 20
• Mild eosiniphilia, the rest of CBC - normal
• Normal ESR, negative ANCA, ANA
• Positive RAST to shrimp, clam peanut
• T cell counts and ratios normal (CD3, CD4 CD8)
• Skin test
• Positive to dust mite roach

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What diagnostic tests do you want to order?
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Quantitative Immunoglobulins

• IgG 980 (nl844-1912)
• IgA - 266 (nl68-423)
• IgM 482 (nl 50-196)
• IgE - 108 (normal)
• Normal IgG subclasses

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SPEP

• 9/05 - 2 faint monoclonal proteins
• IFE IgG-k and IgM monoclonal spikes
• Seen by hematologist no stigmata of a plasma
  cell dyscrasia

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Antibody titers

• Immune to tetanus
• Not immune to pneumococcal antibody 12 serotype
  panel
• Vaccinated with Pneumovac in November, 2005
• December 2005 - not immune to pneumococcal
  antibody 10 serotype panel

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Diagnosis

• Common Variable Immunodeficiency -
  normogammaglobulinemia with impaired specific
  antibody production
• Presenting as chronic sinusitis, pulmonary
  nodules and paraproteinemia

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Categorization of evidence and basis strength
of recommendation
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Uses of IVIG in primary secondary immune
deficiencies
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H.K. treatment/follow-up

• Environmental control
• Sinus rinse, steam inhalations and intranasal
  Flonase
• Significant improvement since January 2006 had
  only one course of oral antibiotics
• No IVIG treatment at this point

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Granulomatous disease

• Noncaseating granulomas infiltrating liver, lung,
  lymph nodes, bone marrow and skin (10)
• Higher frequency of T cell abnormalities
• Associated with specific TNF lymphotoxin-a gene
  polymorphism
• High levels of TNF-a in patients with
  granulomatous disease
• Rule out mycobacterial fungal infections
• No treatment necessary (occasionally-
  corticosteroids)
• Severe cases can be unresponsive to steroids
• Both anti- TNF-a monoclonal antibodies and TNF-a
  receptor blocker are reported to cause
  improvement of granulomatous disease

A.Thatayaticom et al., Ann Allery Asthma
Immunol 2005 95293 J.Lin et al., JACI 2006
117878-882
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Pulmonary disease in CVID

• Purpose define outcomes of patients with
  different types of lung disease
• Retrospective analysis 69 patients with CVID
• Diffuse interstitial lung disease is common (25)
• GLILD - 2/3 patients with ILD

Bates et al. JACI 2004 114 415-421
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Pulmonary disease in CVID

• Patients were divided into 4 different groups
• Group I no pulmonary disease
• Group II bronchoectasis, asthma
• Group IIIA GLILD granulomatous disease, LIP,
  lymphoid hyperplasia, follicular bronchiolitis
• Group IIIB other ILD (BOOP)
• Median survival GLILD - 13.7 years, all other
  groups - 28.8 years (plt0.001)
• Mortality for patients with granuloma in any
  organ 10.9 years. Causes of death lymphoma,
  progressive lung or liver disease

Bates et al. JACI 2004 114 415-421
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Reduced survival in CVID patients with
granulomatous disease
Bates et al. JACI 2004 114 415-421
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Lymphoproliferative disorders

• Malignant lymphomas (30-fold increase compared
  with general population 400-fold increase in
  women)
• Benign lymphoproliferative disorders
• Rare cases of intestinal lymphomas

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Autoimmunity

• 22 of patients
• Autoimmune hematologic disorders (hemolytic,
  Coomb positive anemia ITP pernicious anemia
  neutropenia)
• Autoimmune neurologic diseases (Gullain-Barre
  syndrome)
• Autoimmune endocrinopathies (thyroid disease,
  Addison disease, diabetes mellitus)
• Chronic active hepatitis biliary cirrhosis
• RA, SLE, polymyositis, Sicca syndrome, arthritis
• Alopecia totalis

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Prognosis

• The 20-year survival rate after diagnosis is 64
  for males and 67 for females vs. 92 and 94 in
  general population
• Malignancies (most commonly - lymphoma) and
  chronic pulmonary disease are major causes of
  mortality
• IVIG has greatly reduced complications and
  improved quality of life for patients

Cunningham-Rundles Bodian, Clinical Immunology
1999, 92 (1)34-48
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Summary

• Antibody deficiency represents the most common
  type of primary immunodeficiency in humans
• Affected patients are prone to recurrent
  bacterial infections and variety of systemic
  conditions
• Management includes IVIG replacement along with
  vigorous treatment of infections and other
  complications

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Questions