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FAILURE OF HUMAN DEFENSE MECHANISMS
FAILURE OF HUMAN DEFENSE MECHANISMS
FAILURE OF HUMAN DEFENSE MECHANISMS
* Mechanisms of Failure* Evasion and subversion of the immune system by
pathogens* Immunodeficiencies
* Inherited (Primary)
* Acquired (Secondary)* Malnutrition* Drugs* Radiation* Pathogens
MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS
* Genetic variation (antigenic differences)* Numerous different surface antigens (serotypes /
serovars) without modification* Streptococcus pneumoniae
* 90 serotypes (capsular polysaccharides)
* Salmonella species
* 2,500 serotypes (cell wall polysaccharides)
* Rhinoviruses
* 100 serotypes (capsid proteins)
* Poliovirus
* 3 serotypes (capsid proteins)
MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS
* Genetic variation (antigenic differences)* Few different surface antigens with frequent modification
* Influenza viruses * Classification into “types” on nucleoprotein
* A, B and C
* Classification of Influenza A virus into “subtypes* Hemagglutinin (HA or H)
* Avian (16) and Human (3)
* Neuramindase (NA or N)
* Avian (9) and Human (2)
* Influenza A subtypes (H3N2, H1N1, H5N1)
MECHANISMS OF GENETIC CHANGE IN INFLUENZA A VIRUS
* Antigenic Drift* Point mutations in HA and NA genes
* No proofreading of replication
* Minor antigenic change resulting in new “strains”
* Antigenic Shift* Re-assortment of gene segments from avian and human viruses in
same host (swine or humans)
* Major antigenic change resulting in new “subtype” of Influenza A virus
MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS
* Establishment of a dormant state (latency) with reactivation
* Blocking of antigen processing and presentation* MHC I degradation
* Interference with proteasome
* Interference with TAP
* Interference with Tapasin
* Retention of MHC 1 in ER
* Interference with NKG2A receptor
* Inhibition of humoral immunity
MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS
* Characteristic of the Herpesviruses* Herpes simplex virus, type 1 (HSV-1)
* Herpes simplex virus, type 2 (HSV-2)
* Varicella-Zoster virus (VZV)
* Epstein-Barr virus (EBV)
* Cytomegalovirus (CMV)
* Human herpesvirus 6 (HHV-6)
* Human herpesvirus 7 (HHV-7)
* Human herpesvirus 8 (HHV-8)
HUMAN HERPES VIRUS 8 (HHV-8)
* One of seven oncogenic virusesOne of seven oncogenic viruses
* History of stealing human genesHistory of stealing human genes* IL-6, BCL-2, cyclin DIL-6, BCL-2, cyclin D
* Etiologic agentEtiologic agent* Kaposi’s sarcomaKaposi’s sarcoma* Multicentric Castleman’s DiseaseMulticentric Castleman’s Disease
* Non-malignant tumor in lymph nodesNon-malignant tumor in lymph nodes* Hyperproliferation of B cellsHyperproliferation of B cells
HUMAN HERPES VIRUS 8 (HHV-8)
* Target cell for latencyTarget cell for latency* B lymphocyteB lymphocyte
* Mechanism of latency (genes and proteins)Mechanism of latency (genes and proteins)* Cyclin DCyclin D* LANA (latency associated nuclear antigen)LANA (latency associated nuclear antigen)* K 13K 13
* Blocks Fas apotosis pathwayBlocks Fas apotosis pathway
* Target cell for Kaposi’s sarcomaTarget cell for Kaposi’s sarcoma* Spindle cellSpindle cell
MECHANISMS OF SUBVERSION OF THE IMMUNE SYSTEM
* Production of exotoxins (superantigens)* Staphylococcus aureus* Streptococcus pyogenes
* Staphylococcus aureus superantigens* Toxic shock syndrome toxin-1 (TSST-1)
* 75% of cases (99% M and 40% NM)
* Staphylococcal enterotoxin B (SEB)* 20% of cases
* Staphylococcal enterotoxin C (SEC)
MECHANISMS OF SUBVERSION OF THE IMMUNE SYSTEM
* Streptococcus pyogenes superantigens* Streptococcus pyrogenic exotoxins A, B and C
* Exotoxins produced primarily from M types* 1 and 3
* Mechanism of action* Activation of 5 to 30% of T cells* Cytokine storm
TOXIC SHOCK SYNDROME (TSS)
* Staphylococcal TSS* First reported in 1978 followed by outbreak in 1980
* Clinical manifestations (acute onset)* Fever (>102 F), chills, headache* Hypotension (<90 mmHg)* Diffuse macular erythroderma rash* Myalgias* Nausea, vomiting and diarrhea * Cutaneous desquamation (palms and soles)
IMMUNODEFICIENCY DISEASES
* A group of diseases where one or more components of the immune system are either absent or defective
* Classification* Primary (Inherited)
* Gene defects may be autosomal or X-linked
* Secondary (Acquired)* Malnutrition, diseases, drugs, radiation, microorganisms
COMPONENTS OF THE IMMUNE SYSTEM AND CLINICAL PRESENTATION IN IMMUNODEFICIENCY DISEASES
* Humoral* Persons with history of recurrent infections with
encapsulated bacteria* Streptococcus pneumoniae
* Haemophilus influenzae
* Cellular (Cell mediated)* Persons with history of recurrent infections with
opportunistic pathogens* Pneumocystis jiroveci (carinii)
EVALUATION OF PATIENTS WITH IMMUNODEFICIENCY DISEASES
* Humoral* Measure antibody levels by nephelometry
* IgM* IgG + subclasses* IgA + subclasses
* Measure absolute number and percent of B cells by flow cytometry
* Cellular* Measure absolute numbers and percentages of T
lymphocytes by flow cytometry
PRIMARY IMMUNODEFICIENCY DISEASES
* WHO currently recognizes 100 primary immunodeficiency diseases* < 20 account for >90% of all cases
* General Classification* Primarily humoral deficiency* Primarily cellular deficiency * Combined humoral and cellular deficiency* Phagocyte dysfunction or deficiency* Complement deficiency* MHC deficiency
PRIMARY IMMUNODEFICIENCY DISEASES
* Prevalence of primary immunodeficiency diseases
* B cell (50 to 60%)* T cell (5 to 10%)* B and T cells (20%)* Phagocytes (10 to 15%)* Complement (2%)* NK (< 0.1%)
PRIMARY IMMUNODEFICIENCY DISEASES
* Most common primary immunodeficiency diseases
* B cell Selective IgA deficiency* T cell DiGeorge syndrome ZAP-70 deficiency* B and T cells SCID* Phagocytes Chronic granulomatous disease* Complement Immune complex disease* NK Viral infections and tumors
PRIMARY IMMUNODEFICIENCY DISEASES
* Gene defects * Autosomal recessive or dominant* X-linked
* Examples* CVID (autosomal dominant)* Selective IgA (autosomal dominant)* Hyper-IgM (autosomal recessive or X-linked)* Classic complement (autosomal recessive)
* First PID described in 1952* Bruton’s X-linked agammaglobulinemia
CASE STUDY – 13 YEAR OLD MALE
* Bone marrow transplantation (BMT) for SCIDBone marrow transplantation (BMT) for SCID* BM from sister was unmatchedBM from sister was unmatched
* 3 months later developed3 months later developed* FeverFever* Nausea, vomiting and diarrheaNausea, vomiting and diarrhea* Abdominal painAbdominal pain* Intestinal bleedingIntestinal bleeding
* Autopsy revealedAutopsy revealed* Hundreds of intraabdominal malignant tumorsHundreds of intraabdominal malignant tumors
CASE STUDY – DAVID P. VETTER
* Parents – David J and Carol AnnParents – David J and Carol Ann
* ChildrenChildren* Katherine (1968)Katherine (1968)* David J III (1970)David J III (1970)
* Died of SCID at 7 monthsDied of SCID at 7 months
* Advised of risk of another male childAdvised of risk of another male child
* David P born on September 21, 1971David P born on September 21, 1971* Unmatched BMT on 12/21/83Unmatched BMT on 12/21/83* Died of SCID on 2/22/84Died of SCID on 2/22/84
SELECTIVE IgA DEFICIENCY
* Most common and mildest of PI
* Prevalence* 1 in 700 caucasians* 1 in 18,000 Japanese
* Majority of patients are asymptomatic
* Clinical presentation* Recurrent sinopulmonary and GI disease, allergy, autoimmunity
SELECTIVE IgA DEFICIENCY
* Incidence of allergy and asthma is increased* Food allergy* Asthma may be more severe* Allergic rhinitis
* Incidence of autoimmune disease is increased* Rheumatoid arthritis (RA)* Systemic lupus erythematosus (SLE)
* Mechanism is unclear* 30% of patients have Anti-IgA (IgG > IgM > IgE)
SELECTIVE IgA DEFICIENCY
* IgA deficiency significant risk factor for* Anaphylactic transfusion reactions
* Mechanism is unclear* Classic anaphylaxis involves IgE
* Anti-IgA, IgG most prevalent
* Definition* Deficiency (< 7 mg/dL)
* Severe deficiency (<0.05 mg/dL)
SELECTIVE IgG DEFICIENCY
* Selective IgG subclass deficiency * IgG2 in children* IgG3 in adults
* Combined deficiency relatively common* IgG2 with IgA* IgG1 and IgG3* IgG2 and IgG4
* Clinical presentation* Recurrent upper and lower respiratory tract infections
SELECTIVE IgG DEFICIENCY – CASE STUDY
* 9 year old male presented to family physician by his mother for evaluation of short stature and recurrent infections
* Past medical history* Recurrent URI and LRI with
* Streptococcus pneumoniae, Haemophilus influenzae, Influenza virus, Respiratory Syncytial Virus, Parainfluenza virus
* 2 to 3 each year since age 1
* Recurrent diarrhea since age 4
SELECTIVE IgG DEFICIENCY – CASE STUDY
* Laboratory results for total serum antibodies* IgG of 6.0 gm/L (5.4 to 16.1 gm/L)* IgA of 0.9 gm/L (0.7 to 2.5 gm/L)* IgM of 0.6 gm/L (0.5 to 1.8 gm/L)
* Laboratory results for IgG subclasses* IgG1 of 4.6 gm/L (3.6 to 7.3 gm/L)* IgG2 of 0.1 gm/L (1.4 to 4.5 gm/L)* IgG3 of 0.5 gm/L (0.3 to 1.1 gm/L)* IgG4 of 0.2 gm/L (0.1 to 1.0 gm/L)
CORRECTION OF GENETIC DEFECTS OF IMMUNE SYSTEM
* Many immunodeficiencies affect hematopoietic cells
* Correction of deficiency by transplantation of * Bone marrow (hematopoietic stem cells)
* Success depends on degree of HLA matching between donor and recipient
* Major complication graft-versus-host disease (GVHD)
* Somatic gene therapy* Functional copy of defective gene inserted into patients stem
cells
SECONDARY (ACQUIRED) IMMUNODEFICIENCY DISEASES
* Malnutrition
* Diseases* Diabetes, nephrotic syndrome, protein-losing enteropathy
* Drugs* Corticosteroids
* Hydrocortisone, methylprednisolone, prednisone
* Immunosuppressants* Azathioprine, tacrolimus, cyclosporine A
ACQUIRED IMMUNODEFICIENCY DISEASES
* Radiation
* Microorganisms* Human T-cell lymphotropic virus, type I (HTLV-I)* Mycobacterium leprae
* Lepromatous leprosy
* Cytomegalovirus (CMV)* Epstein-Barr virus (EBV)* Human immunodeficiency virus (HIV)
CASE STUDY –20 YEAR OLD MALE
* Presented to ER of Southeast Regional Medical Center in Lumberton, NC* Headache, fever, chills, AMS and nuchal rigidity
* Blood cultures collected, but lumbar puncture was unsuccessful
* Treated with single 2 gram dose of ceftriaxone
* Transferred to New Hanover Regional Medical Center in Wilmington, NC
CASE STUDY (20 M) –PHYSICAL EXAMINATION
* VITAL SIGNS* Temperature 100 F, PR 92, RR 20, BP 120/60
* HEENT AND NECK* Pupils equal, round and light reactive* Nuchal rigidity is positive
* LYMPH NODES* No lymphadenopathy
* ABDOMEN* Soft. No distention, tenderness, organomegaly
* EXTREMITIES* Bilateral upper and lower clubbing
* NEUROLOGIC* Babinski is negative and Kernig is positive
CASE STUDY –20 YEAR OLD MALE
* Past medical history* Recurrent infections (age 10)
* Sinusitis* Pneumococcal pneumonia and bacteremia
* Specimens collected for culture at NHRMC* Blood, CSF and ear drainage
* Treatment at NHRMC* Ceftriaxone (2 grams IV q12) and vancomycin (1 gram IV
q12)
CASE STUDY (20 M) – COMPREHENSIVE METABOLIC PANEL (CMP)
Patient Reference* Glucose 172 72 - 112 mg/dL* BUN 7 7 - 18 mg/dL* Creatinine 0.7 0.5 - 1.2 mg/dL* Sodium 139 136 - 146 mmol/L* Potassium 3.8 3.7 - 5.2 mmol/L* Chloride 106 98 - 108 mmol/L* Calcium 8.3 8.5 - 10.5 mg/dL* Total Protein 4.8 6.1 - 8.0 mg/dL* Albumin 2.6 3.5 - 4.8 g/dL* Bilirubin (T) 0.6 0.0 - 1.0 mg/dL* AST 7 15 - 37 U/L* ALT 22 19 - 55 U/L* Alk Phos 63 50 - 136 U/L
CASE STUDY (20 M) –CBC WITH DIFF
Patient Reference* WBC 19.8 4.8 - 10.8 K/uL* RBC 4.2 4.9 - 6.1 M/uL* Platelets 278 145 - 400 K/uL* HGB 11.5 14.0 - 18.0 g/dL* HCT 33.6 40 - 52 %* Neutrophils 85 40 - 74 %* Lymphocytes 7 15 - 47 %* Monocytes 7 0 - 12 %* Eosinophils 0 0 - 6 %* Basophils 0 0 - 2 %
CASE STUDY (20 M) –URINE DRUG SCREEN
* PCP Negative* Benzodiazepine Negative* Cocaine Negative* Amphetamine Negative* THC Negative* Opiates Negative* Barbiturates Negative* Methadone Negative* Tricyclic Antidepressants Negative
CASE STUDY (20 M) – COAGGULATION/HEMATOLOGY
Patient Reference* PT 16.6 10.7 - 13.5 seconds* INR 1.93 0.86 - 1.34 seconds* PTT 42.8 25 - 38 seconds
* Fibrinogen 711 160 - 440 mg/dL* Haptoglobin 425 43 - 212 mg/dL* Sed rate 60 0 - 15 mm/hr
CASE STUDY (20 M) – CEREBROSPINAL FLUID
* Glucose 0 40 - 70 mg/dL* Protein 314 15 - 45 mg/dL* Lactic acid 17.6 < 2.8 mmol/L* WBC 568 uL* RBC 373 uL* Neutrophils 73 %* Lymphocytes 11 %* Monocytes 16 %* VDRL Negative Negative
CASE STUDY (20 M) – MICROBIAL ANTIGENS (CSF)
* Haemophulus influenzae, type B Negative* Streptococcus pneumoniae Negative* Streptococcus agalactiae (GBS) Negative* Neisseria meningitidis (C, W135) Negative* Neisseria meningitidis (A, Y) Negative* Neisseria meningitidis (B)/ E.coli Negative
* Cryptococcus neoformans Negative
CASE STUDY (20 M) –CULTURE AND SMEAR (CSF)
* Routine* 2 to 6 WBC/HPF* No organisms seen on gram stained smear
* Acid-fast bacilli* No acid fast bacilli (AFB) seen on fluorochrome stained
smear
* Fungus* No fungal elements seen on PAS stained smear
CASE STUDY (20 M) –CBC WITH DIFF (DAY 2)
Patient Reference* WBC 14.5 4.8 - 10.8 K/uL* RBC 3.73 4.6 - 6.1 M/uL* Platelets 302 145 - 400 K/uL* HGB 10.0 14.0 - 18.0 g/dL* HCT 30.0 40.0 - 52.0 %* Neutrophils 76 40 - 74 %* Lymphocytes 16 15 - 47 %* Monocytes 8 0 - 12 %* Eosinophils 0 0 - 6 %* Basophils 0 0 - 2 %
CASE STUDY (20 M) –CMP (DAY 2)
Patient Reference
* Glucose 129 72 - 112 mg/dL
* Protein(T) 5.2 6.1 - 8.0 g/dL
* Albumin 2.3 3.5 - 4.8 g/dL
* AST 2.0 15 - 37 U/L
All other analytes within reference ranges
CASE STUDY (20 M) –CSF STUDIES (DAY 3)
Patient Reference* Glucose 34 40 - 70 mg/dL* Protein 100 15 - 45 mg/dL* WBC 576 uL* RBC 14 uL* Neutrophils 42 %* Lymphocytes 28 %* Monocytes 30 %
* Bacterial antigens Negative Negative
CASE STUDY (20 M) – CSF CULTURE AND SMEAR (DAY 3)
* Routine* 0 to 1 WBC/HPF* No organisms seen on gram stained smear
* Acid-fast bacilli* No acid fast bacilli seen on fluorochrome stained smear
* Fungus* No fungal elements seen on PAS stained smear
CASE STUDY (20 M) – MOLECULAR MICROBIOLOGY (DAY 3)
* Cerebrospinal fluid (CSF) by PCR
* HSV-1 and HSV-2 DNA Negative
* Enterovirus RNA Negative
* Borrelia burgdorferi DNA Negative
CASE STUDY (20 M) – MICROBIOLOGY AT NHRMC (DAY 3)
* Ear drainage growth* Pseudomonas aeruginosa
* Blood cultures * Negative at day 3 and day 5
* Cerebrospinal fluid cultures* Negative
CASE STUDY (20 M) –BLOOD CULTURES (SRMC-DAY 3)
* Streptococcus pneumoniae
* Penicillin G Resistant* Ceftriaxone Resistant* Azithromycin Resistant* Trim/Sulfa Resistant* Chloramphenicol Susceptible* Moxifloxacin Susceptible* Tetracycline Susceptible* Vancomycin Susceptible
CASE STUDY (20 M) - IMMUNOLOGY (DAY 3)
* Consultation between infectious disease and clinical microbiology* Monospot test
* RPR
* Antinuclear antibody (ANA)
* Complement (T)
* HIV-1/2 antibody
* Serum protein electrophoresis (SPE)
CASE STUDY (20 M) - IMMUNOLOGY (DAY 3)
* Monospot test Negative
* RPR Negative
* Antinuclear antibody (ANA) Negative
* Complement (T) 48 U/mL [31 – 66 U/mL]
* HIV-1/2 antibody Invalid
* Serum protein electrophoresis Severe hypogammaglobulinemia
PRINCIPLES OF HIV-1/2 ANTIBODY TEST
* Lateral flow immunochromatographic procedure
* Antigens and antibody immobilized onto nitrocellulose membrane in T and C zones
* Test (T) Zone * Synthetic peptides from HIV envelope region
* Control (C) Zone* Goat anti-human IgG
* Developer solution * Facilitates flow of specimen onto test strip* Rehydrates protein-A gold colorimetric reagent
CASE STUDY (20 M) – IMMUNOLOGY (DAY 4)
Patient Reference
* Immunoglobulin A (IgA) < 15.0 81 - 463 mg/dL
* Immunoglobulin G (IgG) < 60.0 694 - 1618 mg/dL
* Immunoglobulin M (IgM) < 5.0 48 - 271 mg/dL
CASE STUDY (20 M) – DIFFERENTIAL DIAGNOSIS
* Bruton’s X-linked agammaglobulinemia (XLA)
* Common variable immunodeficiency (CVID)
* Severe combined immunodeficiency (SCID)
* Omenn syndrome (OS)
CASE STUDY (20 M) - MOLECULAR PATHOLOGY (FLOW CYTOMETRY)
Patient Reference
* CD3+/CD5+ 79% 52 – 84%
* CD4 lymphocytes 45% 30 – 61%
* CD8 lymphocytes 30% 12 – 42%
* CD19+/CD20+ 18% 5 – 25%
* CD3-/CD56+ 3% 5 – 30%
CASE STUDY (20 M) –FLOW CYTOMETRY
Percent Cells/uL Reference* Lymphs (CD45) 1540 1000 - 4800
* T-Lymphs (CD3) 1175 690 – 2540
* % T-Lymphs 76 55 – 84 (CD3/CD45)
* T-Helper lymphs 687 410 – 1590 (CD3+CD4)
* %T-Helper lymphs 45 31 – 60 (CD3+CD4/CD45)
CASE STUDY (20 M) – CLINICAL MANIFESTATION (DAY 5)
* Herpetiform vesicles on erythematous base* Side of head
* Lower lip
* External ear
* CN V3 herpes zoster reactivation
CASE STUDY (20 M) – DISCHARGE DIAGNOSES (DAY 5)
* Pneumococcal meningitis with bacteremia
* Pseudomonas aeruginosa otitis externa
* Common variable immunodeficiency (CVID)
* CN V3 herpes zoster reactivation
COMMON VARIABLE IMMUNODEFICIENCY (CVID)
* Most prevalent primary immunodeficiency
* Heterogeneous group of immunologic disorders
* Unknown etiology
* Characterized by marked deficiency of* IgG and IgA* IgM and T-cell dysfunction* Generalized lymphadenopathy and splenomegaly
CVID – PATHOPHYSIOLOGY
* Number of mechanisms for defective antibody production
* B-cell defects* Differentiation of B-cells into plasma cells
* T-cell defects* Low level expression of CD40 ligand
CVID – EPIDEMIOLOGY
* Prevalence of 1 case in 10,000 to 50,000 population
* Female to male ratio of 1
* All races
* Age at diagnosis* 1 to 5 years* 16 to 20 years* 21 years and greater (60%)
CVID – COMPLICATIONS AND RISKS
* Recurrent infections* Upper and lower respiratory tract
* Streptococcus pneumoniae and Haemophilus influenzae* Herpes labialis (HSV)* Herpes zoster (VCV)
* Autoimmune diseases (RA, AHA, ATP)
* Malignancy * Non-Hodgkin’s lymphoma* Malignant lymphoma