520 likes | 712 Vues
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
E N D
Immunodeficiency in an adult patient Golda Hudes, MD, PhD Division of Allergy & Immunology
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%
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
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
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
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
Other Medical history • History of diarrhea, colonic polyps. Colonoscopy consistent with inflammatory bowel disease • Joint pain, weight loss and depression. Seen in Rheumatology clinic
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
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.
Pathology Nasal biopsy (bedside) Inflammation, focal metaplasia, hypertrophied mucosal glands, negative for fungus, negative for vasculitis
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)
Quantitative Immunoglobulins IgG < 33 (nl=844-1912) IgA < 6.67 (nl=68-423) IgM 31.2 (nl= 50-196) IgE < 2
IgG subclasses • IgG1 <65 (nl=4559-8838) • IgG2 <70 (nl= 1939-4926) • IgG3 <50 (nl=184-949) • IgG4 <36 (nl=104-671)
Diagnosis Common Variable Immunodeficiency – hypogammaglobulinemia with impaired specific antibody production Presenting as chronic sinusitis, frequent pneumonias, diarrhea and arthralgias
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)
Clinical Manifestations • Infections • Gastrointestinal disease • Autoimmunity • Lymphoproliferative disorders • Granulomatous disease • Others
C.R.: Clinical Manifestations • Infections • Gastrointestinal disease • Autoimmunity
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
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
Diagnosis • Medical history • Family history • Physical examination • Laboratory evaluation
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
Laboratory evaluation • Quantitative immunoglobulins (IgG, IgA & IgM) and IgG subclasses • T & B cell subset determination • Functional antibody responses • T cell function
Functional antibody responses • Isohemagglutinin titers (IgM) • Specific antibodies (pre & post immunization) • anti-diphtheria/tetanus antibodies • anti-pneumococcal polysaccharide antibodies • anti-hemophilus antibodies
T cell function • Anergy panel • In vitro mitogen reactivity • In vitro specific antigen reactivity (Candida, tetanus, diphtheria)
Treatment: • Replacement therapy (IVIG) • Antimicrobials • Corticosteroids for autoimmune or granulomatous complications • Supportive care (pulmonary hygiene measures) • Experimental (IL-2, TNF-a antagonists)
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
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
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
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
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
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)
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
Quantitative Immunoglobulins IgG – 980 (nl=844-1912) IgA - 266 (nl=68-423) IgM – 482 (nl= 50-196) IgE - 108 (normal) Normal IgG subclasses
SPEP: 9/05 - 2 faint monoclonal proteins IFE: IgG-k and IgM monoclonal spikes Seen by hematologist: no stigmata of a plasma cell dyscrasia
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
Diagnosis Common Variable Immunodeficiency - normogammaglobulinemia with impaired specific antibody production Presenting as chronic sinusitis, pulmonary nodules and paraproteinemia
Categorization of evidence and basis & strength of recommendation
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
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
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
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
Reduced survival in CVID patients with granulomatous disease Bates et al. JACI 2004; 114: 415-421
Lymphoproliferative disorders • Malignant lymphomas (30-fold increase compared with general population & 400-fold increase in women) • Benign lymphoproliferative disorders • Rare cases of intestinal lymphomas
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
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