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Immunodeficiency in an adult patient

Immunodeficiency in an adult patient. Golda Hudes, MD, PhD Division of Allergy & Immunology. Case #1. C.R. Presentation: June 2001 50 yo Hispanic female admitted to Montefiore Medical Center with chief complaints of cough, weakness, fever and chest pain

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Immunodeficiency in an adult patient

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  1. Immunodeficiency in an adult patient Golda Hudes, MD, PhD Division of Allergy & Immunology

  2. Case #1

  3. 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%

  4. 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

  5. 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

  6. 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

  7. 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

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

  9. 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

  10. 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.

  11. What diagnostic tests do you want to order?

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

  13. 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)

  14. Quantitative Immunoglobulins IgG < 33 (nl=844-1912) IgA < 6.67 (nl=68-423) IgM 31.2 (nl= 50-196) IgE < 2

  15. IgG subclasses • IgG1 <65 (nl=4559-8838) • IgG2 <70 (nl= 1939-4926) • IgG3 <50 (nl=184-949) • IgG4 <36 (nl=104-671)

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

  17. 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)

  18. Clinical Manifestations • Infections • Gastrointestinal disease • Autoimmunity • Lymphoproliferative disorders • Granulomatous disease • Others

  19. C.R.: Clinical Manifestations • Infections • Gastrointestinal disease • Autoimmunity

  20. 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 lambliaand Gram-negative rod DF3 (dysgonic fermenter-3) • Infections of skin, urinary tract, sceleton and CNS • Sepsis • Viral infections

  21. 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

  22. Diagnosis • Medical history • Family history • Physical examination • Laboratory evaluation

  23. 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

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

  25. Functional antibody responses • Isohemagglutinin titers (IgM) • Specific antibodies (pre & post immunization) • anti-diphtheria/tetanus antibodies • anti-pneumococcal polysaccharide antibodies • anti-hemophilus antibodies

  26. T cell function • Anergy panel • In vitro mitogen reactivity • In vitro specific antigen reactivity (Candida, tetanus, diphtheria)

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

  28. 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

  29. 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 patient’s 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; 98:196

  30. 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 • Patient’s 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; 98:196

  31. Case #2

  32. 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

  33. 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

  34. 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 (50%of normal)

  35. 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

  36. What diagnostic tests do you want to order?

  37. Quantitative Immunoglobulins IgG – 980 (nl=844-1912) IgA - 266 (nl=68-423) IgM – 482 (nl= 50-196) IgE - 108 (normal) Normal IgG subclasses

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

  39. 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

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

  41. Categorization of evidence and basis & strength of recommendation

  42. Uses of IVIG in primary & secondary immune deficiencies

  43. 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

  44. 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; 95:293 J.Lin et al., JACI 2006; 117:878-882

  45. 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

  46. 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 (p<0.001) • 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

  47. Reduced survival in CVID patients with granulomatous disease Bates et al. JACI 2004; 114: 415-421

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

  49. 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

  50. 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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