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PRIMARY IMMUNODEFICIENCIES: Case Studies

PRIMARY IMMUNODEFICIENCIES: Case Studies. NIRAJ PATEL, MD, MS INFECTIOUS DISEASES AND IMMUNOLOGY. OUTLINE. Define primary immunodeficiency (PID) Identify history and physical exam findings of PID Clinical Cases to help!.

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PRIMARY IMMUNODEFICIENCIES: Case Studies

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  1. PRIMARY IMMUNODEFICIENCIES: Case Studies NIRAJ PATEL, MD, MS INFECTIOUS DISEASES AND IMMUNOLOGY

  2. OUTLINE • Define primary immunodeficiency (PID) • Identify history and physical exam findings of PID • Clinical Cases to help!

  3. Taken with permission from Shearer WT. J Allergy Clin Immunol 2005;116:263-266.

  4. DEFINITIONS • Immunodeficiency diseases • Result from absence or malfunction of components of immune system • Caused by genetic mutations (primary immunodeficiencies) • Caused by external factors (secondary immunodeficiencies)

  5. PRIMARY IMMUNODEFICIENCY • >130 genetically defined immunodeficiencies • Estimated general incidence 1:10,000 (except for IgA deficiency 1:500) • Serious immunodeficiencies 1:100,000 live births • X-linked, recessive, and dominant inheritance • 58% of cases diagnosed in children <15 years of age • 83% are males

  6. Risk Factor for Infection?

  7. Differential Diagnosis of Recurrent Infections • Anatomic Abnormalities • Foreign Bodies • Defects in mucus clearance • Atopic conditions • Secondary Immunodeficiencies • Primary Immunodeficiency

  8. SOME PHYSICAL SIGNS OF IMMUNODEFICIENCY • DYSMORFIC FACIES, HEART MURMUR • ORAL THRUSH • FAILURE TO THRIVE • ATYPICAL ATOPIC DERMATITIS/ ERYTHRODERMA • SMALL TONSILS • GINGIVAL DISEASE • ABSENCE OF PALPABLE LYMPH NODES • LYMPHADENOPATHY/ORGANOMEGALY • TELANGIECTASIAS

  9. (NOT the typical immunodeficient patient)

  10. Indications for Immunological Evaluation RED FLAG: FAMILY HISTORY

  11. Basic Immune Evaluation CBC with diff CELLULAR HUMORAL COMPLEMENT QUANTITATION T, B, NK cells IgG, IgA, IgM CH50 Antibody to diptheria, tetanus, pneumococcus DHST Lymphocyte proliferation FUNCTION OTHER HIV ELISA or HIV DNA PCR History dependent: DHR assay to assess for CGD; CXR, PTH level, and Ionized Calcium level for suspected DiGeorge

  12. Recurrent bacterial sinopulmonary infections sepsis, particularly with encapsulated organisms Unexplained bronchiectasis Chronic or recurrent gastroenteritis (often Giardia or enterovirus) Chronic enteroviral meningoencephalitis Arthritis X-linked agammaglobulinemia Common Variable Immunodeficiency Selective IgA deficiency Transient hypogammaglobulinemia Presentation of Antibody Defects

  13. Infection with catalase-positive organisms Soft tissue abscesses or lymphadenitis Chronic gingivitis and periodontal disease Delayed separation of the umbilical cord Chronic granulomatous disease Leukocyte adhesion deficiency Chediak-Higashi syndrome Presentation of Phagocyte Defects

  14. Recurrent, severe, or unusual viral infections Failure to thrive Infection with fungal pathogens Pneumocystis jirovecii, graft-versus-host disease Severe combined immunodeficiency Wiskott-Aldrich syndrome DiGeorge syndrome HyperIgE syndrome HyperIgM syndrome Ataxia Telangiectasia Presentation of Cellular Defects

  15. Abrupt onset of sepsis with encapsulated organisms Angioedema of the face hands, feet or GI tract Autoimmune manifestations Recurrent disseminated Neisserial infections C5-C9 terminal complement defiency C1 esterase inhibitor deficiency C2, C3, C4 deficiency Presentation of Complement Defects

  16. Case 1 • A 6 month-old male with chronic diarrhea and failure-to-thrive has a 2 day history of high fever, tachypnea, and cyanosis • A CXR shows a diffuse interstitial pattern and absent thymus. Silver stain on a bronchoscopy specimen reveals Pneumocystis jiroveci (PCP) • Laboratory analysis shows an IgG <200, IgA <6, and IgM <5

  17. Case 1 (cont) The most likely diagnosis is: A. chronic granulomatous disease B. X-linked severe combined immunodeficiency C. cystic fibrosis D. leukocyte adhesion deficiency E. complement deficiency

  18. 2004 ITE: Clinical findings associated with T-lymphocyte dysfunction Case 1: Answer • (B) X-linked SCID is the correct choice. Age of presentation coincides with waning maternal immunoglobulin (~4-6 months). FTT is usually present. ¾ of SCID cases are X-linked, and present with absent immunoglobulins, absent thymus, and opportunistic or frequent infections. • (A) CGD does occur mostly in males, but usually presents with granulomas and organisms such as Aspergillus fumigatus, Staphylococcus aureus, Serratia marscecens. (C) CF can present with FTT but not absent immunoglobulins or absent thymus. Bacterial pneumonia is typically present. (D) LAD is associated with delayed umbilical cord separation, recurrent staphylococcal infections, and normal immunoglobulins. (E) Patients with complement deficiency have normal immunoglobulins and a present thymus.

  19. SEVERE COMBINEDIMMUNODEFICIENCY (SCID) • Life threatening infections soon after birth • Wasting, failure-to-thrive • Absent thymus • No T cells, non functioning B cells • Treatment: transplantation

  20. Timeline of SCID 1950’s 1968 1970- present 2010 2012 SCID discovered 1st transplant in SCID infant from matched related donor Bone marrow transplantation with T-cell depletion Newborn screening approved for SCID North Carolina newborn screen begins

  21. http://www.theonion.com/content/node/27503

  22. Case 2 • A 14 month-old male presents to the emergency room with a 4 day history of fever and respiratory failure after visiting a construction site. • The temperature is 102°F, and physical exam is significant for severe retractions and laboratory shows hypoxemia and acidosis • Intubation followed by bronchoscopy reveals hyphae with dichotomous branching by fungal staining. Culture grows Aspergillus fumigatus.

  23. Aspergillus fumigatus

  24. Case 2 Which of the following is most likely to lead to the diagnosis? A. IgG, IgA, and IgM antibody levels B. neutrophil receptor profile C.nitroblue tetrazolium test or dihydrorhodamine assay D. chest X-ray evaluating for the presence of a thymus E. total complement or CH50

  25. 2003 ITE: Bacterial pathogens of CGD Case 2 (answer) • The correct choice is (C) nitroblue tetrazolium test or dihydrorhodamine assay. This is a “two-step” question, where one needs to know the patient’s diagnosis as well as the test associated with that diagnosis. • The infant in this scenario has chronic granulomatous disease (CGD). CGD occurs mostly in males (2/3, 66%) as X-linked, and in females (1/3, 33%) as autosommal recessive. The pathogens typically associated with CGD are Serratia marcescens, Aspergillus fumigatus, Staphylococcus aureus, Burkholderia cepacae,Nocardia and Chromobacterium violaceum. Invasive infection with any of these pathogens (except for staphylococcus aureus) is unusual and should raise a red flag about an underlying immune problem (although recurrent infections with staphylococcus aureus can be seen in other immunodeficiencies such as leukocyte adhesion defect and hyperIgE syndrome).

  26. Chronic granulomatous disease

  27. CHRONIC GRANULOMATOUS DISEASE • Skin, lymph node, lung infections • Aspergillus sp, Serratia marcescens, Staphylococcus aureus, Burkholderia Cepacia • Defective NADPH oxidase system: no intracellular killing/H2O2 • Diagnosis: NBT, DHR assays

  28. Case 3 • An 8 year-old female with a history of recurrent skin abscesses and bacteremia presents to the office with a 6 day history of enlarging perirectal abscess and fever. • Physical exam is significant for small for age (<5% for height and weight) and a 2x3 cm erythematous very tender nodule over the perirectal area that is devoid of pus. • A white blood cell count is 42,000 of which the majority are neutrophils.

  29. Case 3 (cont) Which of the following additional findings is most likely to be present? A. ocular telangiectasias B. history of delayed umbilical separation C. retained primary teeth D. heart murmur E. lack of enlarged lymph nodes

  30. 2004 ITE: Associated findings in leukocyte adhesion deficiency Case 3 (answer) • The correct choice is (B) delayed umbilical cord separation. This child has leukocyte adhesion defect (LAD). LAD is a disorder of phagocytes due to lack of a surface marker CD11/CD18 present on neutrophils. The immune response to an infection involves neutrophils in the blood stream binding to the endothelium via CD11/CD18, then extravasating to the tissue to assist at the site of infection. In LAD, neutrophils cannot get out of circulation, and hence ongoing inflammation and infection is the result. The bone marrow continues to receive signals to produce neutrophils as a result of the infection, explaining the extremely elevated high white blood cell count. • Since pus is made up of dead neutrophils, which are not present at the site of infection in LAD patients, the formation of abscesses are often devoid of pus. Abscesses are usually caused by Staphylococcus aureus, the most common etiologic agent in LAD.

  31. Case 3 (answer) • Ocular telangiectasias (choice A) are usually seen with ataxia telangiectasia which usually presents with recurrent sinopulmonary infections. Retained primary teeth are seen with hyperIgE syndrome. Although staphylococcus aureus and recurrent abscesses are usually associated with hyperIgE syndrome, other features are lacking in this scenario such as eczema, coarse facial features, and pneumonia/pneumatoceles. A heart murmur (choice D) is usually seen with DiGeorge syndrome, and lack of enlarged lymph nodes (choice E) is typically seen in B cell defects such as X-linked agammaglobulinemia (recurrent sinopulmonary infections presenting less than one year of age).

  32. LEUKOCYTE ADHESION DEFICIENCY • Delayed umbilical stump separation • Gingivostomatitis, skin infections • Very high WBC • Autosommal recessive inheritance • Absent CD11/CD18 beta integrin expression

  33. = CD11/CD18

  34. LEUKOCYTE ADHESION DEFICIENCY Gingivitis Omphalitis

  35. Cold And Flu Prevention Tips • Sneezing into a handkerchief just redirects germs back at you. Always sneeze outward so as to shoot germs as far across the room as possible. • Pack your sinus cavities with Vicks Vap-O-Rub to fully mentholate your respiratory system. • Sometimes, a severe respiratory infection will cause the lungs to fill with fluid. If this occurs, flush your lungs repeatedly with boiling hot water to clear them. A hose down your windpipe will help get around the gag reflex. • To prevent infections, have sick people cough into your food. This light "inoculative" dose of germs will boost your body's defenses against a full-blown infection later. www.theonion.com

  36. Case 4 • A 2 year old male presents to the office with a 2 week history of bruising and recurrent sinusitis since age 4 months. A maternal uncle died at 2 months of age from bacterial sepsis. • On physical exam, he has scattered petechiae, purulent rhinorrhea, and patches of dry skin with excoriations over the face and trunk which he scratches frequently.

  37. Case 4 The most likely diagnosis is: A. hyperIgE syndrome B. leukocyte adhesion defect C. severe combined immunodeficiency D. Wiskott-Aldrich syndrome E. x-linked agammaglobulinemia

  38. Case 4 (answer) 2002 ITE: Cause of immune deficiency, thrombocytopenia, and eczema 2002 ITE: Recognition of Wiskott-Aldrich syndrome 2005 ITE: Recognition of findings associated with Wiskott-Aldrich syndrome • The correct choice is (D), Wiskott-Aldrich syndrome (WAS). WAS is characterized by the triad of immune deficiency, thrombocytopenia, and eczema. The patches of dry pruritic skin suggest eczema, and petechiae and bruising suggest a platelet disorder (in this case, the child has thrombocytopenia). Wiskott-Aldrich syndrome is an X-linked disorder, explaining the maternal uncle’s early death from infection. The defect is in the Wiskott-Aldrich syndrome protein, or WASP.

  39. Case 4 (cont) • HyperIgE syndrome (A) is an autosommal dominant mutation, and is characterized by recurrent staphylococcal and candida infections. Leukocyte adhesion deficiency (B) is an autosommal recessive and is not usually associated with bruising or petechiae. Severe combined immunodeficiency (C) usually presents within the first year of life, and is characterized by life threatening infections and opportunistic organisms. Although X-linked agammaglobulinemia (E) is characterized by X-linked inheritance, they do not usually have thrombocytopenia or eczema.

  40. WISKOTT-ALDRICH SYNDROME • X-linked inheritance • TRIAD: eczema, thrombocytopenia, recurrent sinopulmonary infections • Defect in wiskott-aldrich syndrome protein (WASP) gene • Autoimmune disease: hemolytic anemia, ITP, IBD, nephritis

  41. http://images.google.com/imgres?imgurl=http://img.medscape.com/pi/emed/ckb/allergy_immunology/134823-1337464-137015-1697681tn.jpg&imgrefurl=http://emedicine.medscape.com/article/137015-overview&usg=__f8UkiG-KUdlLpZyFcFpDdH_vxSE=&h=200&w=132&sz=16&hl=en&start=32&itbs=1&tbnid=WCIQRcoh8ndxMM:&tbnh=104&tbnw=69&prev=/images%3Fq%3Dwiskott-aldrich%2Bsyndrome%26start%3D18%26hl%3Den%26sa%3DN%26gbv%3D2%26ndsp%3D18%26tbs%3Disch:1http://images.google.com/imgres?imgurl=http://img.medscape.com/pi/emed/ckb/allergy_immunology/134823-1337464-137015-1697681tn.jpg&imgrefurl=http://emedicine.medscape.com/article/137015-overview&usg=__f8UkiG-KUdlLpZyFcFpDdH_vxSE=&h=200&w=132&sz=16&hl=en&start=32&itbs=1&tbnid=WCIQRcoh8ndxMM:&tbnh=104&tbnw=69&prev=/images%3Fq%3Dwiskott-aldrich%2Bsyndrome%26start%3D18%26hl%3Den%26sa%3DN%26gbv%3D2%26ndsp%3D18%26tbs%3Disch:1

  42. http://images.google.com/imgres?imgurl=http://mmserver.cjp.com/images/image/0144065.jpg&imgrefurl=http://image.bloodline.net/stories/storyReader%24774&usg=__zeQNuvJPRE38eP3Pzm4A5elZAJk=&h=400&w=600&sz=33&hl=en&start=13&um=1&itbs=1&tbnid=TL2nNZg4PBdOpM:&tbnh=90&tbnw=135&prev=/images%3Fq%3Dnormal%2Bplatelets%26um%3D1%26hl%3Den%26safe%3Dactive%26tbs%3Disch:1http://images.google.com/imgres?imgurl=http://mmserver.cjp.com/images/image/0144065.jpg&imgrefurl=http://image.bloodline.net/stories/storyReader%24774&usg=__zeQNuvJPRE38eP3Pzm4A5elZAJk=&h=400&w=600&sz=33&hl=en&start=13&um=1&itbs=1&tbnid=TL2nNZg4PBdOpM:&tbnh=90&tbnw=135&prev=/images%3Fq%3Dnormal%2Bplatelets%26um%3D1%26hl%3Den%26safe%3Dactive%26tbs%3Disch:1 http://web-apps.sun.ac.za/menu/Health/dept/patologie/Hematologie/wa.jpg NORMAL SMALL, FEW PLATELETS

  43. Case 5 • A 16 year old girl presents to the office with a 2 week history of nonbloody diarrhea after swimming in a fresh water lake. Upon further questioning, she has a history of recurrent pneumonia and sinusitis. • Laboratory evaluation shows IgG, IgM, and IgA which are all below the normal range.

  44. Case 5 (cont) Infection with which pathogen is most likely to be present? A. Giardia lamblia B. Rotavirus C. Entameoba histolytica D. Shigella E. salmonella

  45. Case 5 (answer) 2002 ITE: Etiology of diarrhea in B-cell immunodeficient host 2005 ITE: Clinical findings associated with deficient antibody production • The correct choice is (A), Giardia lamblia. The child in this case has a history that is consistent with common variable immunodeficiency (CVID). CVID is associated with recurrent sinopulmonary infections, bronchiectasis, and low immunoglobulins. As with other B cell deficiencies, infection with enteric pathogens, particularly giardia and enterovirus are frequent. Infection with the others listed can occur in patients with CVID or other B cell immunodeficiencies, but are less common. Rotavirus infection in the first year of life is associated with severe combined immunodeficiency.

  46. COMMON VARIABLE IMMUNODEFICIENCY (CVID) • Onset 15-35 years: low IgG, IgA, IgM • Pneumonia, bronchiectasis, sinusitis, gastrointestinal infections • Cellular immunity weakens • Associated autoimmunity, malignancy • Treatment: IVIG

  47. Case 6 • A 1 year old male with Wiskott-Aldrich syndrome and a history of multiple hospitalizations for recurrent sinopulmonary infections presents to your office for a 12 month well child visit. • Vital signs are stable, and physical exam is remarkable for eczema and petechiae. The patient is on bactrim and fluconazole for prophylaxis, and a recent lymphocyte enumeration shows a CD3 T cell count of 100 (normal >500).

  48. Case 6 (cont) Which of the following routine immunizations should be held? A. DTaP B. IPV C. Prevnar D. MMR E. HiB

  49. Case 6 (answer) 2002 ITE: Immunizations in immunocompromised children 2004 ITE: Contraindications for administering measles-mumps-rubella vaccine 2005 ITE: Guidelines for administering measles-mumps-rubella vaccine • The correct choice is (D), MMR. Wiskott-Aldrich syndrome is primarily a T cell disorder characterized by thrombocytopenia, eczema and recurrent sinopulmonary infections. The child in this scenario has severely depleted T cells (CD3+) and should not receive live viral vaccines, such as MMR. All of the other vaccines listed as answer choices are killed vaccines and would be acceptable to administer.

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