FOM 6 Summary PDF

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Week 1 ________________________________________________________________________________________ 4 Biochemistry – Cancer Genetics ________________________________________________________________ 4 Immunology – Cancer ________________________________________________________________________ 5 Immunology – Autoimmunity __________________________________________________________________ 5 Histology – Blood Cells Review _________________________________________________________________ 6 Microbiology – Blood Parasites Part 1 – African Trypanosomes & Filarial Worms______________________ 7 Microbiology – Blood Parasites Pt 2 – Malaria ____________________________________________________ 7 Pathology – RBCs – Anemia ___________________________________________________________________ 8 Pathology – Hemostasis and Coagulopathies _____________________________________________________ 10 Pharmacology – Anti-Anemia _________________________________________________________________ 11 Microbiology – Mono / EBV / CMV ____________________________________________________________ 11 Pathology – Leukemia and Lymphoma (know markers) ___________________________________________ 12 Pathology – MPD / MPN / MDS _______________________________________________________________ 14 Immunology – Immunodeficiency Disorders _____________________________________________________ 15 Immunology – Transplantation ________________________________________________________________ 15 Immunology – HIV __________________________________________________________________________ 16 Pharmacology – HIV, AIDS, Anti-Retroviral (ARV = ART) ________________________________________ 17 Pathophysiology – HIV / AIDS ________________________________________________________________ 18 Pharmacology – Chemotherapy / Anti-Cancer Drugs _____________________________________________ 19 2. Week 2 _______________________________________________________________________________________ 22 Pathophysiology – Anemia ____________________________________________________________________ 22 Pathophysiology – Disorders of Primary Hemostasis ______________________________________________ 23 Pathophysiology – Disorders of Secondary Hemostasis ____________________________________________ 24 Pathophysiology – Leukemia, Lymphoma _______________________________________________________ 24 Pediatrics – Hematology______________________________________________________________________ 25 Pediatrics – Immunology _____________________________________________________________________ 26 Pediatrics – Oncology (review questions in slides) ________________________________________________ 27 PHS – Access to Health Care __________________________________________________________________ 28 PHS – Quality of Health ______________________________________________________________________ 28 PHS – Health Care Reform ___________________________________________________________________ 29 PHS – Conflict & Change in Health Care _______________________________________________________ 30 PHS – Social Medicine – Medical Ethics ________________________________________________________ 30 3. Week 3 _________________________________________________________________________________________ 31 Pathophysiology – POCUS MSK_______________________________________________________________ 31 Pathology – Bone, Soft Tissue, and Joint ________________________________________________________ 32 Pathology – Muscle __________________________________________________________________________ 34 Pathophysiology – Orthopedics (not highlighted = slide not starred) _________________________________ 35 Pathophysiology – Osteoarthritis / Crystal Arthritis ______________________________________________ 36 TOC Pathophysiology – Rheumatoid Arthritis and Sjogren’s ___________________________________________ 37 Pathophysiology – Seronegative Spondyloarthropathies, Fibromyalgia _______________________________ 38 Microbiology – Osteomyelitis and Septic Joint ___________________________________________________ 38 Pharmacology – Osteomyelitis and Septic Joint __________________________________________________ 39 Pathology – Osteomyelitis and Septic Joint ______________________________________________________ 40 Pathophysiology – Osteomyelitis and Septic Joint_________________________________________________ 40 Pathophysiology – Myopathies, SLE, Scleroderma ________________________________________________ 41 Pharmacology – Joint Disorders _______________________________________________________________ 42 Pharmacology – NSAIDs _____________________________________________________________________ 44 Pharmacology – Skeletal Muscle Relaxants ______________________________________________________ 45 4. Week 4 _________________________________________________________________________________________ 46 Geriatrics – Fall Assessment and Prevention _____________________________________________________ 46 Pediatrics – MSK Oncology ___________________________________________________________________ 47 Pediatrics – MSK Disorders___________________________________________________________________ 48 Pediatrics – Rheumatology ___________________________________________________________________ 49 Immunology – Pathologies / Hypersensitivities / Autoimmune Skin Diseases __________________________ 49 Pathophysiology – Eczema and Contact Dermatitis _______________________________________________ 50 Pathophysiology – Acne and Facial Lesions ______________________________________________________ 51 Pathology – Inflammatory Skin Disorders _______________________________________________________ 52 Pathophysiology – Papulosquamous (‘scaly bumps’) Disorders _____________________________________ 53 Pathology – Benign & Malignant Tumors _______________________________________________________ 53 Pathophysiology – Benign Nevi and Malignancy __________________________________________________ 54 Pathophysiology – Cutaneous Malignancies _____________________________________________________ 55 Microbiology – Wound / Skin Infections ________________________________________________________ 55 Pharmacology – Glucocorticoids _______________________________________________________________ 56 Pathophysiology – Skin Infections______________________________________________________________ 57 Geriatrics – Elder Abuse _____________________________________________________________________ 57 5. Weeks 5 / 6 ______________________________________________________________________________________ 58 Microbiology – Pediatric Infections ____________________________________________________________ 58 Pathophysiology – Superficial Fungal Infections__________________________________________________ 59 Pathophysiology – Yeast and Parasitic Diseases __________________________________________________ 59 Pharmacology – Dermatologic Pharm __________________________________________________________ 60 Pathophysiology – TEN, Steven Johnson Syndrome, Others ________________________________________ 61 Pathophysiology – Important Blistering Conditions _______________________________________________ 62 Emergency Medicine – Dermatology in EM _____________________________________________________ 62 DEI – Dermatologic Findings in Varying Skin Tones ______________________________________________ 63 6. CMR & OPP ____________________________________________________________________________________ 64 CMR – Motivational Interviewing & Pt Education _______________________________________________ 64 TOC CMR – MSK H&P __________________________________________________________________________ 64 CMR - UE Ortho Tests_______________________________________________________________________ 65 CMR - LE Ortho Tests _______________________________________________________________________ 66 CMR – Dermatome Image ____________________________________________________________________ 68 OPP – Upper Extremity Exam ________________________________________________________________ 68 OPP – Upper Extremity – Elbow ______________________________________________________________ 69 OPP – Upper Extremity – Shoulder ____________________________________________________________ 69 OPP – Upper Extremity – Hand & Wrist________________________________________________________ 70 OPP – LE Exam ____________________________________________________________________________ 70 OPP – LE Hip ______________________________________________________________________________ 71 OPP – Still’s Technique: HIP _________________________________________________________________ 71 OPP – LE Ankle ____________________________________________________________________________ 71 OPP – LE Foot _____________________________________________________________________________ 71 OPP – LE Knee _____________________________________________________________________________ 72 OPP – LE Integrated Case ____________________________________________________________________ 72 TOC 1. Week 1 Biochemistry – Cancer Genetics Cells proliferate via cell division and growth – contact inhibition = inhibited proliferation/growth of cells that are in contact with one another – attrition = loss of DNA from telomeric regions (higher cancer risk) – invasion = tumor cell capacity to disrupt basement membrane – metastasis = spread of cancer cells to other organs/tissues – clonal origin = originating from same cell; Genetic Basis of Cancer: Tumor Heterogeneity: primary tumor/metastases with a subpopulation of cells that lead to distinct genotypes and phenotypes and unique bio behaviors, Driver Mutations: driver gene (regulatory) mutations that promote cancer development (ex. TP53 gene mutation), Passenger Mutations: random & non-neoplastic mutations in cells with driver mutations that do not provide proliferative advantage but may help track mutagenesis via passenger genes, Proto-oncogene: normal regulatory genes that mutate to form oncogenes (ex. MYC) induce transformation = molecular basis of cancer, Tumor Suppressor Gene: regulates division, replication & proliferation – if mutated → LoF → uncontrollable cell growth → cancer –include Rb1, TP53, APC, VHL, BRCA1/BRCA2, MLH1/MSH2; Mutations can be caused by errors in cell cycle, exposure to mutagens, viral infection, or carcinogens – Frameshift: base insertion or deletion, Translocation: break & reattachment on different chromosomes (ex. BCR-ABL translocation), Transformation direct incorporation of exogeneous genetic material → genetic alteration, Oncogenic transformation = acquired genetic & epigenetic alterations affecting proliferation & survival; Epigenetics: reversible altered gene activity without change in DNA sequence due to environmental/lifestyle factors – alterations can be due to acetylation, methylation, etc – noncoding RNAs (ncRNAs) important for transcription & translation = miRNAs, snowRNAs, and snRNAs = oncomirs (contribute to oncogenesis); Apoptotic genes = Bad, Bax, Bim, Bak; Anti-apoptotic genes = Bcl-2, Bcl-xL, Mcl-1, Bcl-w, etc →  cancer cell survival & accumulation of mutations; Two-Hit Theory: cancer results from two ‘hits’ (mutations) – hereditary cancer syndrome = inherited germline + acquired/somatic (post-fertilization) = AD, recognizable pattern, early onset, must confirm w/genetic testing, Ex. Rb gene heterozygous for germline mutation and somatic mutation– sporadic cancer (most common) = no inheritance, both mutations are acquired = more common, later onset, & aging is risk factor; Higher risk for hereditary cancer if parent and/or sibling (1st deg relatives) have the cancer – incidence directly related to penetrance of mutation – familial cancer syndrome = occur in > 1 family member but without clear pattern (often due to mutations & penetrance), later ages, accumulation of changes due to multiple causes (genetic and epigenetic), rather than genetic testing pedigree analysis is recommended; Loss of Heterozygosity: LoF of dominant gene (etiology chromosomal changes, genetic or epigenetic) → homozygous due to loss of an allele (allelic imbalance) → selective growth advantage for tumorigenesis; Retinoblastoma Protein Mutation = phosphorylation of RB1 → degradation →  E2F activity → tumorigenesis – unilateral (unifocal) = dx age ~ 24 months, bilateral (multifocal) = dx age ~ 15 months – Sx: red pupil doesn’t reflect light, strabismus, redness, pain, poor vision, calcification, etc – Coats’ Disease (not retinoblastoma) = neovascular disease in unilateral eyes of young males, lacks calcification; Tumor Suppressor Gene LoF (sporadic cancer): TP53 mutation on chromosome 17 (Li-Fraumeni syndrome (dominant) = rare familial TP53 germline mutation) – metabolic reprogramming  ATP via switch to aerobic glycolysis (Warburg effect) → fast-growing cancer cells get the energy they need; Familial Adenomatous Polyposis: AD LoF of APC gene, high # of small colorectal polyps that will develop into early-onset colorectal cancer if untreated – Gardner syndrome = phenotypic variant involving intestinal polyps and osteomas of mandible & skull, epidermal cysts, fibromatosis, & development of extra teeth; Lynch Syndrome (HNPCC): AD LoF of DNA mismatch repair genes (MLH1, MSH2), much fewer polyps, onset = early adulthood → micro- and macro-satellites (small pieces of DNA that repeat & prone to mutations) → cancer – Muir-Torre Syndrome (sebaceous gland tumors) can be 1st sign of HNPCC; Von Hippel-Lindau disease: AD deletion of VHL gene (chromosome 3) → multi-system non-cancerous tumors – renal cell carcinoma = leading cause of death; Familial Ovarian / Breast Cancer results from BRCA mutation; Chronic Myelogenous Leukemia (CML): BCR (gene)-ABL1 (proto-oncogene) translocation = t(9;22) → formation of Philadelphia chromosome →  tyrosine kinase activity; Burkitt Lymphoma: MYC proto-oncogene t(8;14) [or t(8;22) or t(2;8)]; Telomerase adds guanine-rich sequences to prevent shortening → genomic stability – loss of telomerase = oncogenic Pediatric Cancer Syndrome: AR LoF DNA repair proteins – Heterozygotes more common & higher risk of malignancy Syndrome Inheritance Age Constitutional Mismatch AR; biallelic mismatch mutation or < 18 yr old Repair Syndrome (CMMRD) repair gene → multiorgan cancers Xeroderma pigmentosum AR < 2 yr old Ataxia-telangiectasia AR 1 – 4 yr old (toddlers have ataxic gait) Fanconi Syndrome AR or acquired FTT Bloom Syndrome AR mutation or BLM gene Dx ~ 23 yr & death < 30 yr old Bloom (become an adult lol) before you die TOC Immunology – Cancer Cancer is a disease that involves a complex, multi-step process of mutation formation (heterogeneous = constantly changing & evading host control) – lack antigenicity since cells are derived from host; Tumor Antigens: Tumor-Specific (TSA) = unique + rare and difficult to ID, Tumor-Associated not unique & often involves cells at different developmental stages [Ex. inappropriate expression of embryonic gene] & may involve overexpression of normal protein – Clinical Role: (1) Oncofetal antigens are normal during fetal development but abn when expressed later (a) carcinoembryonic antigen (CEA) found in colon cancers, alpha-fetoprotein (AFP) found in liver tumors & teratomas (germ cell tumor) or elevated in hepatitis or pregnancy (2) Overexpressed antigens = Her2 proto-oncogene within EGFR family and PSA – Viral Antigens → viral proteins expressed + presented w/MHC Class I & potentially induce abnormal regulation of cell (i.e. oncogenic virus or proto-oncogene mutation); Immunosurveillance: NK cells and T cells recognize altered expression & kill cancer cells but immunosuppression or tumor growth → Tregs can suppress immune response; Immune Effectors: (1) B Cells/Antibodies destroy cancer cells via C’ cascade activation (MAC → lysis) and/or ADCC (Fc-FcR binding → toxicity) (2) Macrophages (M) + Dendritic Cells (APCs) process & present tumor antigens to T cells, but may lead to release of Tregs → immune suppression (3) T Cells both CD4 (cytokines) & CD8 (cytotoxicity) cells respond (4) NK Cells recognize  MHC Class I (causes  CD8 activity) → Fc receptor induces ADCC; Tumor Detection: Radioimmunoassay, ELISA, or electrophoresis are useful for soluble antigens & Immunofluorescence for cell-surface antigens – PCR and monitoring cytokine levels can detect cancer genes & tumor antigens, respectively – ELISA: Ab with enzyme bound → binds to Ag → color change & intensity indicates presence and concentration – Immunofluorescence: involves Ab marker with specific fluorescent tags & Flow Cytometry: similarly uses tags for soluble antigens & plots relative concentrations (know how to read & interpret plot – CD4 to CD8 count should be 3:1 or 2:1 ratio); Immune Evasion: (1) Lack distinct antigen b/c tumor originates from self- tissue (2)  MHC Expression and/or deficient APC activity =  T cell activation (3) Lack of Co-Stim =  CD80/CD86 (B7) interaction w/CD28 [CD28-B7 interaction = 2nd signal → activates T cells] - CTLA-4 suppresses T cells by binding to B7 (no 2nd signal) (4) Inhibitory cytokines produced (i.e. IL-10 & TGF-) (5) Release tumor antigen decoys into blood and/or stimulate tolerance → block effective recognition (6) PD-1 binds to PD-1L → inhibits tumor infiltrating lymphocytes (TILs) Immunotherapy: (conventional therapy) surgery, radiation & chemo (passive therapy) mAb for TSA → ADCC and/or C’ activation – mAb therapy: (1) signal apoptosis (ex. Ab binding to Fas protein) (2) prevent angiogenesis to block blood supply to tumor (3) alter immune response – Monoclonal Antibodies (mAb): anti-CD20 ADCC & C’ activation against B cell- derived cancers, anti-TNF-  inflammatory response, anti-PD-1 stimulates TILs (prevents PD1-mediated suppression), SLAMF7 (killers SLAM) = anti-CD139 induce NK-mediated ADCC (perforin + granzyme) to kill myeloma cancer cells, anti-CD3 activate T-Regs & suppress effector T cells (prevent transplant rejection), anti-IL4  chain blocks Th1 activation to  inflammation, anti-CD25 ( chain of IL-2 receptor) prevents T cell activation, anti-CTLA-4 promotes 2nd signal activation– Active Immunotherapy: Adoptive Cell Transfer (a) Tumor Infiltrating Lymphocytes (TILs) isolated → in vitro stimulation w/IL-2 → injected into pt (b) Chimeric Antigen Receptor T Cells (CAR-T Cells) isolate T Cells → modify to combine specificity of Ab w/cytotoxic function, add TSA used to help recognize tumor cells, add CD28 added to improve signaling function→ cells back in pt (3) Bone Marrow Transplant for lymphoid tumors (4) Cytokines activate immune response (a) IL-2 enhances NK cell & CD8 functions → higher vascular permeability (risk of vasc leak syndrome) (2) IFN- & INF- enhances antigen presentation & cytotoxicity (5) Vaccination (ex. HPV vaccine for cervical cancer) introduces TSA to CD8+ cells to generate immune memory Immunology – Autoimmunity Tolerance = anergy = turning off/not expressing self-reactive cell – autoimmunity = failed tolerance or failed of Fas- mediated apoptosis – Central Tolerance = self-reactive cells destroyed within: (1) bone marrow (B cells) = receptor editing of light chain, apoptosis, & anergy (2) thymus (T cells) = positive & negative selection, peptide-MHC complex must be recognized & have just the right affinity to be positively selected (Goldilocks model) → cortical epi cells express MHC (positive selection) vs medullary epi cells express TSA (negative selection) – Peripheral Tolerance = anergy of self-reactive cells that escaped central tolerance, lack of CD28-B7 interaction (absent 2nd signal → apoptosis), CTLA-4 competes with CD28 & inhibits co-stim (prevents autoimmunity), Tregs mediate suppression – T-Regs: FoxP3 (transcription factor) → CD4, CD25 ( chain of IL-2), Th3 → anti-inflammatory cytokines = TGF-, IL-10 & IL-35; Autoimmunity not fully understood, could be due to release of sequestered antigens, loss of suppression, cross-reactive antigens (ex. post-strep Rheumatic fever), altered self-antigens d/t infection, “break” of tolerance; Other Factors: (1) Genetics – MHC genes = HLA- B8, B27, DR2, DR3, DQ8, DQ2 (2) Gender (3) Environment: Organ-Specific: (1) Hashimoto’s thyroiditis: often middle- aged women, autoantibodies (to TSH receptor) and Th1 cells → delayed type hypersensitivity & ADCC → impaired iodine uptake → hypothyroidism (2) Type I Diabetes: CTLs (CD8 cells) attack pancreatic islet  cells, can have Ab-mediated C’ lysis +/- ADCC Organ Non-Specific: (1) Systemic Lupus Erythematous (SLE): associated with  estrogen and/or failed X-inactivation – predominance: females of childbearing age (becomes milder in older age), urban residents, HLA-DR2 & HLA-DR3 (MHC genes) – African Americans & Mexican Hispanics have poorer renal prognosis & less likely to respond to TOC Rx – BUT 1-year mortality higher in men – Immunology = anti-nuclear antibodies (ANA), anti-dsDNA, and anti-Smith = autoantibodies to DNA, histones, RBCs, platelets, etc. (ANA (+) in almost all pts, but nonspecific) – Sx: fever, weakness, arthritis, malar rash, kidney dysfunction – type III hypersensitivity – immune defects = failed immune complex clearance, elevated IL-6 and IL-10, elevated TLR7 promote SLE, defective B cell tolerance (2) Multiple Sclerosis (MS): autoreactive T cells causing demyelination – predominance: females, ~ 25-30, tobacco smoking & childhood obesity can be risk factors, higher latitude, HLA-DQ6 & HLA-DRB1, EBV infection (3) Rheumatoid Arthritis (RA) rheumatoid factor (IgM binds to Fc region of IgG), anti-cyclic citrullinated peptide (CCP), immune complex, C’ activation – predominance: females, HLA- DR4 and HLA-DRB1, cigarette smoking & asbestos exposure – Sx: morning stiffness, osteopenia, bilateral synovial inflammation, fatigue, fibromyalgia, muscle weakness, aggravated by glucocorticoids – may cause lung disease, skin disease, cardiac disease, hematologic abn, or kidney disease; Therapy: (1) Anti-inflammatory: NSAIDs & steroids (2) General T Cell Suppression: Calcineurin inhibitor (cyclosporin; block IL-2 signaling by inhibiting transcription factors) & Src kinase inhibitor (Dasatnib) (3) Cytokine blockade: (a) block Ab: anti-TNF (Humira) or anti-IL-17 (Taltz) (b) receptor agonists: TNF-RA (Enbrel) (4) T Cell Functional Blockade: CTLA4-Ig (5) T Cell Ablation: anti-CD3 (Teplizumab; stimulates C’ activation & MAC) (6) B Cell Ablation: Anti-CD20 (Rituximab) (7) Immune System Ablation: chemo and autologous stem cell transplant (8) TReg Therapies: low dose IL-2 or CAR-Tregs Histology – Blood Cells Review Blood composed of RBC, WBC & Platelets – WBCs = mononuclear leukocytes [lymphocytes & monocytes] and granulocytes [neutrophils, eosinophils, basophils] – Normal RBC rules of 1/3 = central pallor that’s ~ 1/3 of total RBC size and ratio of 1 lymphocyte to 3 RBCs – RBC Variations: hypochromic (larger central pallor), hyperchromic (smaller central pallor d/t higher Hgb content), anisochromia (both types of chromia present), polychromasia (purplish stain), basophilic stippling, anisocytosis (variable size); Maturation: common origin (hemocytoblast) → Myeloid lineage: pronormoblast (RBCs), megakaryoblasts (platelets), myeloblast (basophil, neutrophil, eosinophil & monocytes) Lymphoid Lineage: lymphoblast (B, T, and NK cells) – Reticulocyte = purplish/blue erythrocyte precursor – RBC Abnormalities: Target Cell, Sickle Cell (aggregation of HbS → crescent), Spherocyte (small & spheroidal), Schistocytes (fragmented, helmet/triangle shape), “Tear Drop” Cell – Inclusions: Siderocyte (mature RBC w/iron often d/t hemolytic anemia or chemical poisoning), Sideroblast (nucleated RBC + siderotic (iron-deposits) granules in a ring), Howell-Jolly Bodies (nuclear remnants associated w/ hemolytic anemia, leukemia, or after splenectomy), Rouleaux formation (stacked cells), Heinz bodies (aggregated denatured Hgb d/t abn synthesis or breakdown), Basophilic stippling (granules in cytoplasm); RBCs: pronormoblast → Basophilic normoblast → → → orthochromatic normoblast (nucleated) → polychromatic erythrocyte (reticulocyte) → erythrocyte; Platelets: blasts = less cytoplasm & larger, coarse nuclei → megakaryocyte = abundant cytoplasm & multi- lobed nuclei → thrombocytes (mature) = small, purple, no nucleus; Neutrophils: myeloblasts (immature) = round singular nucleus w/fine chromatin (granularity) + blue cytoplasm → mature form = multi-lobed (< 5) nucleus w/clumped chromatin and pink cytoplasm; Lymphocytes: immature blast = large cells w/prominent nucleoli, fine chromatin → mature = coarse/ clumped chromatin, smaller, can see more cytoplasm; Plasma cell (mature B cells): blast = larger cells, prominent nuclei, non-granular chromatin→ mature = eccentric nucleus (clock -face chromatin), blue cytoplasm, perinuclear clearing (hof region); Bone Marrow: trabecular bone, fat cells, fibrovascular tissue (pale), and hematopoietic cells; Lymph Node: Subcortical = capsule & subcapsular sinus, Cortical = marginal zone → lymphoid follicle with mantle zone and germinal center; Spleen: capsule, red pulp, white pulp (lymphocytes, purple tint), central artery; Bone: periosteum → compact bone → trabecula → marrow (hematopoietic) – also visualize woven bone (immature), osteoblasts, & lamellar bone; Skeletal muscle: visualize muscle fibers, I band (light), A band (dark), nuclei, & striations TOC Microbiology – Blood Parasites Part 1 – African Trypanosomes & Filarial Worms Filarial Worms: nematodes (round), separate sexes (dioecious), mosquito & biting fly vectors, tropical distribution – life cycle = juvenile parasite injected into blood via vector → maturation & infect lymphatics, subQ tissue & eye → larvae released into peripheral blood/lymph Disease Pathogen(s) Distribution & Cycle Sx / Dx / Tx Lymphatic Wuchereria Tropical South Asia, Africa, & Sx = Asymptomatic or inflammatory response Filariasis bancrofti Americas; mosquitos deposit larvae in → acute fever & inguinal lymphadenopathy wound → maturation → lymphatics → → thickened skin +  risk of infection [previously Brugia malayi lymphedema + microfilariae enter (chronic; lymphedema) → peripheral elephantiasis] blood stream (only active at night) swelling (ex. scrotum, vulva); Dx = nighttime blood smear or serology; Tx = Diethylcarbamazine (DEC) Loiasis Loa loa Central & West Africa; Fly vector Sx = asymptomatic (endemic residents) or [motile eye (Chrysops spp)→ larvae in wound → Calabar swelling (nodules in skin/eye), itching, worm] maturation & live in SubQ tissue → hives, muscle pain microfilariae enter lymph → lungs → Dx = remove worm or daytime blood smear Adult pathogen bloodstream (only active in day) & Tx = DEC lives 17 yr lives in eye Onchoceriasis Onchocerca Africa & Middle East; Black Fly vector Sx = itching, skin rashes, lesions on cornea, volvulus → larvae → maturation in SubQ tissue skin damage (pigmentation, loss of elasticity, (River → microfilariae into SubQ tissue → thinning) Blindness) Adult pathogen migration through tissue + damages eye Dx = skin snip lives 10-15 yr (does not live in eye); Tx = Ivermectin every 6 months African Trypanosomiasis: “African sleeping sickness,” protozoa, can be chronic (Trypanosoma brucei gambiense; years) or acute (Trypanosoma brucei rhodesiense; weeks) – vector = Tsetse fly (Glossina) – life cycle = fly injects parasite → Hemolymphatic Stage invades lymph & chancre at bite wound → trypomastigotes into bloodstream → lymph → early Winterbottom’s sign (posterior cervical LAD), fever, HA, fatigue, joint pain→ Meningioencephalatic Stage invades CSF → HA, confusion, personality changes, stiff neck, seizures, loss of consciousness, coma → late perivascular cuffing – Dx blood smear or CSF smear – Tx early Pentamidine, Melarsoprol, Suramin Microbiology – Blood Parasites Pt 2 – Malaria Malaria disproportionately affects tropical & subtropical regions of Africa → infants comprise 80% of all malarial deaths – rare local US transmissions are possible, but most incidences of malaria for US residents results from travel; Species: Plasmodium falciparum (primary, causes severe disease; hotspot in sub-Saharan Africa), Plasmodium vivax (relapsing episodes; more common in South America & Asia), Plasmodium ovale (has dormant stage; spotty distribution), and other plasmodium species; Vector: female Anopheles mosquito; Life Cycle: Injection → Hepatic Cycle: sporozoites enter liver cell & asexually reproduce [vivax & ovale can enter hypnozoite form = dormant] → 10-15 days later merozoites released from liver into RBCs → Erythrocytic Cycle: trophozoite (feeding, ring trophs) → schizont (asexual reproduction) → merozoites (progeny that invades cells or forms gametocytes) → fever follows merozoite release; Relapse of vivax & ovale hypnozoites in 3-5 yr, Recrudescence (return of Sx) within months of 1º falciparum infection if Tx is inadequate/ineffective; Ring Trophozoite (1st stage) within RBCs actively feed & must be Dx with blood smear – P. vivax cells are abnormally large TOC & Schuffner’s dots found in mature schizonts – P. ovale often oval shaped & more pronounced Schuffner’s dots – P. falciparum normal size with multiple ring trophs, elongate gametocyte; Clinical Features: high risk if no prior exposure or left endemic area long time ago & lost immunity, low risk older children & adults in endemic area – falciparum incubates for 7 days to 1 month – vivax incubates for up to 2 weeks & may relapse within 3 yrs – uncomplicated: asymptomatic → myalgia, malaise, HA, backache → cytokine response = fever ‘paroxysms’ (cold stage → hot stage → sweating stage) + tachycardia, anemia, abd discomfort, splenomegaly [maybe febrile seizures in children] – complicated (multi-organ failure, usually falciparum infection, ~ 20% mortality) uncomplicated Sx w/additional acidosis, hypoglycemia, severe anemia, renal impairment [blackwater fever: hemolysis, hemoglobinuria & acute renal failure → dark urine d/t Hgb presence], jaundice, ARDS, DIC, shock, hyper parasitemia → (maybe) cerebral malaria = encephalopathy = impaired consciousness, delirium, seizures; Diagnostics: (1) Microscopy → (a) Thick Blood Smears: to ID malaria presence (b) Thin Blood Smears: to Dx species b/c able to better visualize features like rings & gametocyte shape – both are stained with Giemsa or Wright Stain: (2) Serology = Indirect Fluorescent Ab to test for prior infection, species-specific, but cross rxn is likely (3) PCR = species- specific & ID drug-resistant genes (4) Rapid Dx POC helps ID Antigens specific to various species, but strains w/evolving mutations are not detected; Antimalarial Drugs can be used prophylactically, to tx clinical sx, to eradicate parasite from pt, & kill gametes to reduce human-to-vector transmission; Four Classes (1) Quinoline (2) Artemisinin (3) Antifolate (3) Abx – for life-threatening malaria use Quinidine or Artesunate – combo therapies prevent resistance Quinoline: [erythrocytic stage] Hydroxychloroquine, Quinidine, (others below) – MOA = accumulate in parasite food vacuole → form complex with heme to prevent crystallization → inhibits heme polymerase → accumulation of cytotoxic-free heme; malaria-endemic regions are chloroquine-resistant Chloroquine – falciparum resistance via PfCRT gene mutation– still Tx for other species USE: malaria and RED LIP (RA, Extraintestinal amoebiasis, Discoid Lupus Erythematosus, Lepra rxn, Infectious mono, Photogenic rxn) – safe for pregnancy & young children SEs: pruritus, retinopathy (esp dark-skinned pts), rare: impaired hearing, psychosis, bleached hair, G6PD deficiency → hemolysis, long-term: ototoxicity, myopathy, retinopathy, peripheral neuropathy Contraindicated: psoriasis, retinal abn, myopathy, hepatic/neuro/heme disorders, antacids Amodiaquine for strains resistant to chloroquine; Piperaquine has longest half life Quinine kills vivax and ovale gametes, SEs: Cinchonism (tinnitus, flushing, vision disturbance, etc) Mefloquine for resistant strains & prophylaxis, SEs: potential neuro & psych toxicity, thrombocytopenia, etc Primaquine & Tafenoquine [8-aminoquinolones] target hypnozoite (prevents relapse)stage & is gametocidal, used as prophylaxis, contraindicated if G6PD deficient (oxidative stress → hemolysis; must screen) Atovaquone targets schizonts & prophylaxis – MOA: disrupts mitochondrial electron transport Lumefantrine-Artemether (Coartem; fixed dose) 1st line for uncomplicated falciparum Pyronaridine-Artesunate combo to tx falciparum, SEs: eosinophilia & transaminitis Artemisinin: targets blood schizonts, drug endoperoxide bridge cleaved (iron catalysis) → produces free radicals Water-soluble: Artesunate, Dihydroartemisinin; Lipid-soluble: Artemether; Artemisinin-based Combo Therapy (ACT) improves efficacy & prevents resistance, to Tx falciparum – Ex of ACT = Dihydroartemisinin-piperaquine SEs: non-specific, or neutropenia, anemia, hemolysis [often delayed by ~ 2 weeks], elevated liver enzymes, allergy Antifolate: inhibit enzymes involved in folate metabolism, parasites confer resistance via mutations of DHF reductase and dihydropteroate synthase Pyrimethamine (erythrocytic forms), Proguanil (both forms), Sulfadoxine – often used in combo therapy [ex. Fansidar = Pyrimethamine-Sulfadoxine or atovaquone-proguanil combo] – safe for pregnancy SEs: non-specific GI sx, rash, itching – Proguanil: mouth ulcers & alopecia, Fansidar: Stevens-Johnson syndrome Abx: Clindamycin & Azithromycin, inhibit protein synthesis in apicoplast (plasmodial organelle) of parasites, must be used in combo d/t slow action Tetracycline and Doxycycline (erythrocytic forms only) Severe Malaria Tx: 3 doses IV Artesunate (0, 12, 24 hr) → assess parasite density 4+ hr after 3rd dose – density: < 1% = oral medications (ex. Coartem) if tolerated or continue IV daily for 6 more days, > 1% = continue IV artesunate daily for 6 more days and oral regimen after completion of IV; Consider prophylaxis for High-Risk Groups = travelers returning to endemic home regions, pregnant pts, & military personnel; Blood Disorders that confer resistance: (1) Sickle Cell Anemia: carriers of the trait have lower hospital admission & less severe/complicated malaria (2) Duffy Blood Groups: RBCs w/o Duffy antigens resist vivax infection less common in Africa (3) Thalassemia: altered globin chain synthesis (4) G6PD (5) Heme oxygenase polymorphism Pathology – RBCs – Anemia General Approach to Anemia: High RC = survival defect → hemolytic or hemorrhagic OR Low/NL RC = production defect → [normocytic] chronic disease or [microcytic] = Fe Def or [macrocytic] = B12 def TOC Anemia can be caused by hemorrhage, hemolysis, or bone marrow problem; Measuring Iron Review: serum Fe, TIBC (transferrin in blood → low iron = high TIBC), % saturation (denotes amount of transferrin bound by Fe, normal ~ 33%), serum ferritin (Fe storage capacity in M & liver); Hgb = heme (iron + protoporphyrin) + globin; Microcytic Anemia: results from  Hgb production → “extra” divisions to maintain Hgb concentration → smaller RBCs (1) Iron-Deficient Anemia: d/t chronic blood loss, dietary intake, demands during pregnancy & infancy, disease etiologies (celiac disease or post-gastrectomy) → iron depleted, but initially normocytic RBC production → microcytic-hypochromic → Dx: high TIBC & FEP (free erythrocyte protoporphyrin) + low ferritin (2) Anemia of Chronic Disease (ACD): most common anemia, often in hospitalized pts & w/chronic systemic inflammation (long-standing SLE), Dx: high FEP, high hepcidin (downregulated EPO & Fe-laden macrophages), high ferritin, low TIBC (3) Sideroblastic Anemia: ringed Sideroblast (Fe-laden mitochondria), congenital ALAS (forms protoporphyrin) defect or acquired d/t alcohol, lead, isoniazid (Vit B6 def) → iron-overloaded state (low TIBC, high ferritin, serum Fe & % sat) (4) Thalassemia: inherited  in synthesis of - or -globin chains → anemia (less RBC production & survival), tissue hypoxia, RBC hemolysis, heterozygote-protection against P. falciparum (a) -Thalassemia = gene deletion, less severe → 4 - genes (2 pairs) on chromosome 16 → 4 genes deleted = newborns w/ 4 (Hb Barts) → hydrops fetalis or 3 genes deleted = 4 (HbH) in adults & older children (b) -thalassemia = gene mutations → 3  genes on chromosome 11, 0 = absent globin synthesis, + = reduced globin synthesis, often splicing mutations, both smears = microcytic, hypochromic target cells– minor = 0/ or +/ = asymptomatic = doesn’t req transfusion, Dx with Hb electrophoresis = HbA2 vs major = 0/0 = severe = tetramer aggregation, damaged RBCs, extravascular hemolysis = erythroid hyperplasia → (a) abn hematopoiesis → crewcut skull + chipmunk facies (b) extramedullary → hepatosplenomegaly & LAD (c) risk of aplastic crisis w/ parvovirus → smear = nucleated RBC, Tx  major regular transfusions (may lead to 2º hemochromatosis) Macrocytic Anemia: Pancytopenia (megaloblasts, metamyelocytes, megakaryocytes) → both types have elevated serum homocysteine (a) Vit B12 Deficiency: rare, takes years to develop, generally loss/destruction of parietal cells [ex. pernicious anemia = autoimmune parietal cell destruction (anti-IF or anti-parietal cell) , chronic atrophic gastritis] → intrinsic factor deficiency → leukopenia, hyper-segmented neutrophils (>5 lobes), Sx: glossitis, pallor, fatigue, subacute spinal cord degeneration (B12 def →  MMA in myelin of spinal cord & urine + abn FAs) – PBS findings =  marrow cellularity, ineffective erythropoiesis [giant metamyelocytes & erythroid blasts], elevated LDH d/t hemolysis (b) Folic Acid Deficiency: faster onset, d/t poor absorption (celiac disease or phenytoin) or metabolism (ex. methotrexate) , no neuro sx b/c  MMA, Formininoglutamic A (FlGlu) in urine– must address B12 1st d/t neuro sx Normocytic Anemia:  RBC production/survival – production defect will have low reticulocyte count (RC) vs  destruction will have high RC & can be immune-mediated → Classify based on RC: corrected count >3% indicates peripheral destruction (hemolytic anemia)vs < 3% indicates poor BM response & underproduction of erythrocytes [Defective Fe utilization, Defective stem cell, marrow replacement by fibrosis, low EPO (renal cause)] Hemolytic Anemias → RC > 3% → (1) Extravascular Hemolysis → hyperbilirubinemia, jaundice, splenomegaly, bilirubin-rich gallstones,  risk of cholelithiasis →examples: (a) hereditary spherocytosis (aplastic crisis w/parvo B19) = RDW & MCHC, hyperchromic spherocytes, Howell-Jolly bodies,  osmotic fragility in hypotonic soln. (b) sickle cell anemia: recessive mutation (HbF is protective), hypoxia → HbS polymerization → needle-like cells → RBC Membrane damage [erythroid hyperplasia → crewcut Xray & aplastic crisis] + vaso-occlusive [hand-foot syndrome in bones, acute chest syndrome worsens w/PNA, splenic infarcts → infections] → hyperbilirubinemia & reticulocytosis, (+) metabisulfite (in disease & trait), sickle & target cells (only in disease) – sickle cell trait ( 20% blasts abrupt onset hematopoiesis suppressed → fatigue (anemia), bleeding (thrombocytopenia), infection (neutropenia) + LAD + hepatosplenomegaly + bone pain– high WBC count (1) Acute Myeloid Leukemia (AML): common in older adults – General Findings: (+)MPO, (-)TdT → Auer rods (MPO aggregates) – Classifications: M0 = minimal differentiation, M1 = no maturation = (+)CD34 & CD33, M2 = maturation, M3 = promyelocytic (APL) = MLL translocation → PML-RARA gene fusion = t(15;17)→ risk for DIC & Tx w/ATRA – M5 = monocytic = infiltrate skin & gums + (-)MPO, M7 = megakaryoblastic, (-)MPO, & associated w/Down syndrome ( 100,000 – good prognosis if between 2 – 10 yr, low WBC, hyperdiploid – B-ALL (children): poor prognosis w/ t(9;22) = Philadelphia (Ph) chromosome, smear shows larger cells w/ lacy chromatin & fine white spaces, Flow-Cyto (+) markers = CD20, TdT, CD19, and CD10 – T-ALL (adolescents): Flow Cyto (+) for TdT, CD 1a, CD2 → CD8 (and more) and (-) for CD10, smear shows nuclear indentation, thymic mass Chronic Leukemia: mature circulating lymphocyte proliferation → high WBC count, older adults (1) Chronic Lymphoid Leukemia (CLL): most common leukemia, (+) CD5 (T Cell marker) & CD20, CD19, CD23 – Smear  mature lymphocytes, smudge cells, basket cells & spherocytes – can progress to lymphoma if spreads beyond BM – associated w/ Trisomy 12, BCL2 overexpression– generalized LAD = small lymphocytic lymphoma (SLL) – Complications: hypogammaglobulinemia (#1 cause of death in CLL), autoimmune hemolytic anemia, transforms to diffuse large B cell lymphoma (DLBCL) = Richter transformation = LAD + splenomegaly TOC Leukemoid Rxn (below): benign rxn to sepsis, L shift & high WBC count, smear = bilobed neutrophils, myelocytes w/granules & bands (2) Hairy Cell Leukemia: indolent, middle-aged males, pancytopenia, splenomegaly without LAD, (+) TRAP, (+) B cell markers (CD19, CD20, IgG) (3) Adult T-Cell Leukemia/Lymphoma (ATLL): HTLV-1 (Japan, Caribbean, S America, Africa) → neoplastic prolif of CD4+, viral etiology, transmitted via bodily fluids, sx = skin rash, LAD + hepatosplenomegaly, lytic bone lesions (different from multiple myeloma) w/ hypercalcemia → cloverleaf cells – aggressive & fatal (4) Mycosis Fungoides: cutaneous CD4 prolif – rash → plaque → Pautrier micro abscess = aggregates of neoplastic cells in epidermis→ Sezary syndrome (spread to blood) = exfoliative erythroderma (skin lesions)+ leukemia & Smear = cerebriform nuclei + CD4 cells (unique to Sezary syndrome) Lymphadenopathy (LAD): enlarged lymph nodes are painful in acute infection vs painless in chronic inflammation, metastatic cancer, or lymphoma – (1) Acute Lymphadenitis: swollen, gray-red, large germinal centers w/mitotic figures (2) Chronic Lymphadenitis: follicular hyperplasia (ex. RA, toxoplasmosis, HIV), paracortical hyperplasia (ex. EBV) or sinus histiocytosis (ex. cancer) (3) Cat Scratch Disease: B. hensleae, regresses within 2-4 mo, painful regional adenopathy, granulomas w/central necrosis & neutrophils (nodal changes); Reactive Lymphocyte: smear = kissing borders Lymphoma: neoplastic lymphoid proliferation in lymph node or extranodal tissue (1) Non-Hodgkin’s Lymphoma (NHL): 60%, lymphoid cells, painless lymphadenopathy, later in life, includes leukemic phase, noncontiguous, multiple peripheral lymph nodes & extranodal, Waldeyer ring + mesenteric nodes; all are CD20+ (a) Small Cell: [Follicular Lymphoma] BCL2 translocation [t(14;18)]→ overexpressed BCL2 → absent tingible body M, monoclonality involves spleen (white areas), BM & liver, smear = mostly small cleaved (Butt) cells → Richter Transformation [Mantle Cell Lymphoma] uncommon, poor prognosis, Cyclin D1-mediated progression from G1 to S phase transition & detect IgM/IgD, CD5(+), and  cyclin D1, smear = indentation [Marginal Zone Lymphoma] expand marginal zone d/t chronic inflammation (ex. Hashimoto’s, Sjogren or H. pylori, chronic gastritis), untreated → MALToma at mucosal sites – regresses w/H. pylori eradication (b) Intermediate Cell: [Burkitt Lymphoma] jaw mass (endemic to Africa, HIV-associated), sporadic abdominal mass, curable in children, associated w/EBV → starry sky (apoptosis), overexpressed c-MYC transcription factor, IgM, CD10, BCL6 (c) Large Cell: [Diffuse Large B Cell Lymphoma (DLBCL)] high-grade often arising from low-grade lymphoma, pts > 50 yo, enlarged lymph node or extranodal mass (diffuse growth),  BCL2/BCL6/MYC, (+) for CD19, IgM +/- IgG, fleshy tumor & smear large cells, pale/purple cytoplasm, huge nucleoli, abn mitotic nucleic (darker clumps) (2) Hodgkin’s Lymphoma: Reed-Sternberg (RS) cells (‘owl-eyed nuclei), young adults, ‘B Sx’ (fatigue, night sweats, fever), localized cervical/mediastinal/para-aortic nodes & rarely spreads to liver/spleen, no leukemic phase, CD15(+) and CD30(+), CD45(-), RS cells secrete cytokines → (maybe) fibrosis, can be associated w/EBV – stages: I = single region/ organ, II = 2+ nodes on same side, III = both sides of diaphragm, IV = disseminated sites – risk of developing 2º cancer later in life [Nodular Sclerosis] most common [Lymphocyte-rich] best prognosis [Mixed cellularity]  IL-5 [Lymphocyte depleted] HIV – Dx w/ RS cell detection TOC Pathology – MPD / MPN / MDS Myeloproliferative Disorders/Neoplasia (MPD/MPN): late adulthood, proliferation of mature myeloid cells caused by activated tyrosine kinase mutations [BCR-ABL fusion gene, JAK2 kinase mutation, MPL (myeloproliferative leukemia gene) mutations] → high WBC + hypercellular bone marrow → late spent phase (marrow fibrosis + peripheral cytopenia) → extramedullary hematopoiesis – complications = hyperuricemia/gout, and transformation to acute leukemia (1) Chronic Myeloid Leukemia (CML) = older adults, BCR-ABL mutation [t(9;22) = Philadelphia (Ph) chromosome], Sx: abd fullness (enlarged spleen), anemia, ‘B Sx’– Progression: accelerated phase (blast count < 20%) → ALL/AML = L shift blast crisis (abrupt rise in count > 20%) – CML Findings: thrombocytosis, low blast count (< 10%), hypercellular marrow (megakaryocytes), hematopoiesis within spleen, low leukocyte alkaline phosphatase (LAP),  basophils, high WBC, hepatomegaly, splenomegaly Leukemoid Rxn = similar findings, but elevated LAP & without basophils, Ph chromosome, hepatosplenomegaly (2) Polycythemia = elevated RBCs, WBCs, and platelets – Relative polycythemia d/t dehydration →  plasma volume or absolute polycythemia d/t  RBC mass = 1º (PV) low EPO, normal SaO2 or 2º (reactive) high altitude (low SaO2) or renal lesions → high EPO Polycythemia Vera (PV): indolent,  production of all cell lines d/t JAK2 mutation,  risk of venous thrombosis/ infarctions → CVA or MI –  basophils → histamine release → pruritis – rapid cell turnover → gout – late spent phase (myelofibrosis & hepatosplenomegaly), smear = overlapping RBCs (Rouleaux) & clusters of RBC precursors – labs: Hct (RBC mass) and Hgb, normal SaO2, leukocytosis (PMNs, eosinophils, basophils), large abn platelets + elevated count,  serum uric acid, low EPO levels, aneuploidy, hypercellularity; (3) Essential Thrombocythemia = JAK2 & MPL mutations, indolent proliferation of mature myeloid cells & giant platelets ( megakaryocytes) with normal RBC count, without hyperuricemia or progression to marrow fibrosis or acute leukemia (4) Primary Myelofibrosis = JAK2 & MPL mutations, often presents in older patients w/weakness, fatigue, anemia & abd discomfort [extramedullary hematopoiesis → LAD & hepatosplenomegaly] – smear = poikilocytoses = leukoerythroblastic (tear-drop RBCs, nucleated RBCs, and immature granulocytes) & abn megakaryocytes →  PDGF → fibrosis – high risk of infection, thrombosis & bleeding – Labs: leukoerythroblastic rxn, < 5% blasts, tear-drop RBCs, no Ph chromosome, BM exhibits panhyperplasia → myelofibrosis & osteosclerosis Myelodysplastic Syndromes (MDS): clonal stem cell disorders → ineffective hematopoiesis → peripheral blood cytopenia – > 60yr man w/hepatosplenomegaly– can be idiopathic (1º) or drug/radiation toxicity (2º, t-MDS) – poor prognosis ( risk of developing AML) = t-MDS,  blasts & TP53 mutations → BM Smear = nucleated RBCs & dysplastic megakaryocytes, ringed Sideroblast – Peripheral Smear Pseudo-Pelger-Huet (‘dumbbell nuclei’ & coarse chromatin clumping)– lead to Monoclonal Gammopathies (plasma cell neoplasm produce M protein & Ig light chain) → (1) Multiple myeloma (MM; most common 1º BM malignancy) = elderly pts,  IL-6 → myeloma cell proliferation – Findings: lytic bone lesions w/hypercalcemia (bone pain & spontaneous fractures d/t RANK-mediated osteoclast activity), high M protein on SPEP,  risk of infections, Bence Jones Protein (myeloma kidney = light chain protein casts in urine), amyloidosis (renal/cardiac problem; green birefringence), chromosome 14 translocation [IgH fusion onto oncogenes (ex. Cyclin D1 or D3)]– Dx: immunofixation (elevated serum Ig light chain & M protein) – Smear = pancytopenia & Rouleaux formation, BM exhibits monoclonal (-globulin pattern) plasma cell proliferation [ > 10% clonality] & CD138+ (2) Monoclonal gammopathy of undetermined significance (MGUS) does not show signs of MM, large M protein component in blood, common in adults, can become symptomatic or transform to MM (3) Waldenstrom’s Macroglobulinemia: CD20+ lymphoma found in adults d/t acquired MYD88 mutation and high levels of IgM, hyperviscosity syndrome (visual & neuro sx, cryoglobulinemia may cause Raynaud’s), maybe hepatosplenomegaly, generalized LAD, anemia, potential autoimmune hemolysis by cold agglutinins (IgM) – Smear shows plasma cells w/Dutcher bodies (intranuclear inclusions) – Tx: plasmapheresis & chemo (4) Plasmacytoma: solitary mass of monoclonal plasma cells, Dx: BM exhibits monoclonal plasma cell proliferation [< 5% clonality], absent signs of myeloma, hypercalcemia, renal failure & low M protein TOC Immunology – Immunodeficiency Disorders 1º (Congenital) Immunodeficiencies: inherited defects → deficiencies in lymphoid/myeloid (stem cells), mature T/B cells– newborns/infants w/1º disorder have higher risk of bacterial (within 3-6 mo post-delivery) or viral (1st month) infections & fatal transfusion-associated graft-vs-host disease, want to avoid live viral or bacterial vaccines Lymphoid Deficiencies: (1) Combined → both B & T cells = high early fatality or only T cell (still combined since T cells induce B cell activation) = overall  in Ig levels → increased intracellular microbe infection (a) Severe Combined Immunodeficiency (SCID), defect in T cell (lymphoid) → low circulating lymphocytes → severe recurrent infections (initially usually fungal or viral), normal myeloid & erythroid cells – Tx: bone marrow transplant (BMT; prevent graft-vs- host disease (GvHD) w/cyclosporine) – type of deficiencies: (i) X-linked (most common) → SCID =  chain (defective IL-2 signaling, Tx w/BMT) or Wiskott-Aldrich Syndrome (WAS): X-linked defect in actin filament formation, disease severity  w/age, gradual loss of T and B cell function (high IgA and IgE, low IgM), fatal often d/t encapsulated bacterial infection or lymphoid cancer and/or hemorrhage (low platelets) (ii) Autosomal JAK-3 mutation→ failed transcription of T and NK cells, RAG mutation→ lack of T & B cells, Adenosine Deaminase (ADA) mutation → pulm/neuro abn d/t problems w/ DNA synthesis (b) T Cell Defect: (i) DiGeorge Syndrome = thymic aplasia/hypoplasia d/t defective fetal development, Tx w/in utero thymic graft or thymus transplant (ii) Bare Lymphocyte Syndrome = MHC deficiency, Type II (more severe; no activation) exhibits low CD4 + agammaglobulinemia + respiratory/GI infections, Type I (TAP gene defect = no CD8 transport) generally no Sx (2) B Cell Defect: recurrent encapsulated bacterial infections (a) X-linked (Bruton) hypogammaglobulinemia = defect BTK gene (unable to rearrange light chain) → severe B cell deficiency affecting all Ig → recurrent bacterial infections, low survival past teenage yr, Tx IVIG (b) X-linked Hyper-IgM Immunodeficiency = defective class switching (high IgM levels) = defective CD40L (aka CD154) on T cells → failed 2nd signal → selective Ig deficiency – IgA deficiency is most common = asymptomatic or recurrent respiratory/GU infections, unrelated to genes encoding Ig Myeloid Deficiencies: problem w/phagocytosis → bacterial infections – Chronic Granulomatous Disease (CGD): more often X-linked, low NADPH oxidase activity → low H2O2 and ROS → defective oxidative burst in phagocytic cells, (-) Nitroblue tetrazolium dye reduction test – newer tests include DNA sequencing phagocyte oxidase (phox) genes or dihydrorhodamine 123 test (normally converts to fluorescent rhodamine) – Causes: bacterial & fungal infections (low APC activity) → excessive inflammation = gingivitis, swollen LN, opportunistic infections – Tx recombinant IFN- Complement (C’) Pathway: 3 pathways [classical(antigen-ab), MBL (lectin) + alternative (microbial cell wall)] converge at C3 → C5 → C5b6789 → MAC – Functions: C3a & C5a = anaphylatoxins (degranulation & extravasation → inflammation), C3b & C4b = opsonization (bind microbes and C’ receptors to  recognition & destruction), MAC = lysis, phagocytic cells= remove immune complexes – Deficiencies: (1) alternate/MBL defect →  infections (2) classical defect →  encapsulated bacterial infections (3) C3 defect → recurrent & severe pyogenic infections + immune complex-mediated disease (4) MAC defect (C5b6789)→  Neisseria infection (5) Cascade defects → excess immune-complexes → lupus-like Sx (a) Decay Accelerating Factor (DAF) and CD59 important for C3 convertase detachment from cell membrane → DAF deficiency = C’ complex accumulation,  MAC (lysis; esp RBCs) → paroxysmal nocturnal hemoglobinuria (PNH) → hemolytic anemia 2º (Acquired) Immunodeficiencies: HIV/AIDS, cancer, iatrogens, aging (1) HIV/AIDS: infects CD4 T cells via gp120 binding → lack of Th function → low CD4 count → opportunistic infections (ex. P. jiroveci or Kaposi Sarcoma), AIDS dx made when CD4 counts < 200 (2) lymphoid cancer: expansion of single clone of T or B cell = non-Hodgkin’s lymphoma & various leukemias (3) cancer therapy (iatrogenic) causes immunosuppression b/c bone marrow sensitive to Tx (4) organ transplant or autoimmune disease (iatrogenic)→ use of immunosuppressive drugs (5) splenectomy → more bacterial infections d/t loss of filtration & phagocytic cells – CD4 to CD8 count (2:1 – 3:1); Therapy: (1) Passive Supplementation → IV immune globulin (IVIG) = lifetime supplementation of missing component or cytokines (ex. CSF) boost immune response or enzymes (ex. ADA) (2) Bone Marrow Transplant (BMT) replaces stem cells, is ineffective in DiGeorge b/c defect is not in BM (3) Genetic Engineering ADA gene Immunology – Transplantation Autograft: pt’s tissue transferred from one site to another, Isograft: tissue transfer from an identical twin, Allograft: tissue from a genetically distinct individual of the same species, Xenograft: tissue transferred between different species – Recognition of graft = immunological response mediated by MHC & effector response driven by T and B cells – Alloreactivity: recognition of foreign MHC molecules (alloantigen) as antigenic – T Cells are strong effectors in graft rejection → CD4 has stronger influence, but CD8 plays a role as well (removal of only CD8 does not improve timeline of graft rejection); Graft Rejection via immune specificity & memory → 1st set rxn takes 1-2 wk to recognize alloantigen & mount immune response (1º immune response) → 2nd set rxn takes 3-6 days if same graft tissue is put on pt (2º/memory immune response) – Effectors: (1) Th1 Cells (major) = delayed type hypersensitivity (DTH, inflammatory) + CD8+ (cytotoxicity via alloantigen recognition) + cytokines (IL-2 induces T cell prolif & activates CD8+, IFN- recruits M,  TOC MHC expression, TNF- is directly cytotoxic) – inhibiting CD4 will prevent DTH (2) ADCC releases toxic components that kill graft cells – Types of Rejection: (1) Acute (2-4 wk post-transplant), Type IV hypersensitivity (host-cell mediated), quick progression upon initiation, due to differences in classical MHC genes (MHC I encoded by HLA – A/B/C, MHC II encoded by HLA – DP/DQ/DR) (2) Hyperacute (within min/hr of transplant) Type II Hypersensitivity (cytotoxic), d/t pre- existing Ab activating C’ pathway &/or NK cells → (a) blood type mismatch (b) repeated blood transfusions may expose pt to alloantigen (c) many pregnancies → fetus exposes paternal alloantigen to pregnant individual (d) previous graft (3) Chronic (months to yr) Type III (immune complex) and Type IV hypersensitivity = different minor histocompatibility antigens or non-MHC genes, cannot be Tx w/immunosuppressants, widespread graft rejection once induced – Blood Groups: Type AB = universal recipient, Type O = universal donor (4) Graft vs. Host Disease (GvHD) Type IV hypersensitivity (donor-cell mediated) has similar immune principles as alloreactivity, but graft rejects host, Ex. = BM transplants → donor BM cells reject host cells → skin/liver/GI Sx (prevent by removing donor CD8+ cells)  Transplant Success via: (1) Matching: blood type, MHC (class II matching most important), and minor histocompatibility antigens (mediated by NK cells; only a problem if significant # of differences) – > 35,000 HLA genes make it difficult to find exact matches, but higher # of locus matches = higher survival – HLA -A, -B, and -DR typically checked – MHC matching as strict for liver or heart transplants (2) Immunosuppression: (a) Steroids (prednisone) general  inflammation (b) Fungal Metabolites (cyclosporine) block IL-2 and IL-2R transcription to prevent T cell activation (c) Antibodies → anti-CD3 or anti-CD25 (IL-2R  chain, inhibits IL-2 action) or (maybe) CTLA-Ig (inhibits 2nd signal to cause anergy) Immunology – HIV Preferentially infects + destroys CD4+ cells →  IL-2, IFN-, IL-17 → loss of CMI &  risk of opportunistic infection – Cytokine functions: IL-2: viability of CD4 & CD8, IFN-: enhances CD8 function and activates M (ROI & antimicrobial activity), IL-17 (mucosal immunity) mediates control of intracellular and intracellular infections, IL-4 & IL-5 induce B cell class switching, polarizing cytokines = IL-12 (Th1), IL-10 (Th2), IL-23 (Th17); HIV belongs to Retrovirus group & Lentivirus subgroup (“slow” infections w/long incubation period), primary transmission is sexual contact or transfer of infected blood – HIV-1 found worldwide, HIV-2 primarily in West Africa – Initial Infection (genital tract) in Langerhans’ cells (DCs that line mucosa) – Genome: Gag (core proteins, p24 is most important), Pol (RT, integrase & protease), Env (gp120 & gp41) – protease breaks gp160 into gp120 & gp41 – Infection: gp120 binds to CD4 → interacts with CXCR4 (CD4 cells) or CCR5 (M + DCs)→ gp41 binds & mediates fusion with host cell membrane → reverse transcriptase (RT) makes copy of genome → integrase imbeds viral genome into host DNA → viral mRNA transcription → translated into viral protein → protease cleaves viral precursor proteins to create mature (infectious) virions; HIV strains that bind to CXCR4 = T-cell-Tropic strains vs bind to CCR5 = M-tropic strains (also DCs); Cytokine shift from Th1 → Th2 (significant  IL- 2 / IFN- +  IL-4 )  goes from IL-12 activating Th1 to form IL-2 & IFN- ➔ IL-10 activating Th2 to form IL-4 & IL-5 action → B cell growth & differentiation, Ab production (ineffective b/c HIV antigen is intracellular & Ab attacks circulating Ag) = Th2 Imbalance; CCL2 (monocyte chemoattractant protein-1 = MCP-1) produced by monocytes & M influences innate and adaptive immunity – attracts leukocytes to sites of trauma, infection, ischemia, etc and binds to CCR2 → polarizes Th0 →  Th2 action– HIV-1-infected cell dispersal → impairment of BBB → neuro AIDS, HIV encephalitis, and HIV- associated dementia; Impaired IL-17 → impaired neutrophil functions → loss of mucosal immunity in GI tract →  infections by normal flora; Impaired IL-2 & IFN- →  CD8 activation →  apoptosis & lysis of infected cells → AIDS; Stages: Primary Infection → Acute syndrome (2-4 wk post-infection), Sx of infectious mono + maculopapular rash (spares palms/soles/face), viremia (highly infectious), transient leukopenia→ Immune response to HIV → less viremia  CD8 → ~ 4 wk post-infection = Ab formation against p24 (seroconversion) – delayed Ab formation can result in false negative serology (perform PCR assay of viral RNA) → viral set point (viral load that remains constant for years) can be estimated w/viral RNA assay of pt’s plasma→ clinical Latency (can last 7-11 yr & asymptomatic), viral replication in lymph nodes (virus is not latent, still infectious), potential AIDS-related complex (ARC) syndrome (fever, fatigue, weight loss, LAD)→ loss of CD4+ cells → AIDS dx is made if CD4 counts < 200 and/or  frequency / severity of opportunistic infection; Opportunistic pathogen: (1) P. jirovecii → PNA (most common) (2) Viral Infections = disseminated herpes (simplex or zoster), CMV (3) Fungal infections = thrush d/t C. albicans, cryptococcal meningitis, & disseminated histoplasmosis (3) Protozoal infections = toxoplasmosis & cryptosporidiosis (4) M. tb (5) disseminated bacterial infections → M. avium-intracellulare; Dx: (1) ELISA for HIV Ab [plate coated w/potential Ag → specific Ab binds (1º Ab) → washing to remove unbound molecule → 2º Ab added likely w/enzyme attached (ex. ALP) → washing to remove unbound Ab → colorless substrate added & interacts with 2º Ab → color rxn = (+) result – Pros for ELISA: sensitive, reproducible, minimal reagents, provides quanti- & qualitative data, greater scope, can be automated, no radiation hazard – But ELISA may have false (+), so (2) Western Blot (immunoblot) provides definitive Dx: separates based on molecular weight → viral proteins (gp41 and p24) on gel transferred to nitrocellulose or nylon sheet via electric current → probe w/1º Ab → radiolabeled or enzyme-linked 2º Ab → visualize position w/ELISA rxn (3) Oraquick HIV = at-home oral swab (4) Useful in Early Infection (a) 4th Generation HIV Test = combo test that detects Ab against HIV-1, HIV-2, & p24 (5) PCR of plasma= sensitive & specific, useful for pts TOC who may not have detectable Ab + determines viral load (6) FACS staining → Flow Cytometry can quantify CD4 count; Tx lifelong antiretroviral therapy (ART) Pharmacology – HIV, AIDS, Anti-Retroviral (ARV = ART) Capsid Inhibitors: Lenacapavir [adjunctive therapy for adults w/non-responsive HIV-1] MOA: directly binds to capsid protein to interfere w/viral replication at nuclear import & capsid assembly stages SEs: nausea & injection site pain Interactions: substrate of P-gp, UGT1A1 & CYP3A Attachment Inhibitors: Fostemsavir (prodrug → temsavir) – CYP3A4 substrate, so contraindicated with CYP3A inducers MOA: inhibits gp120 (envelope glycoprotein) SEs: nausea, elevated ALT / AST, immune reconstitution inflammatory response (IRIS), prolonged QTc Entry Inhibitors Maraviroc – CYP3A4 & P-gp substrate – contraindicated with severe renal impairment MOA: CCR5 (co-receptor) antagonist → HIV unable to enter cell – prevents co-receptor tropism for HIV-1 SEs: systemic allergic rxn → hepatotoxic, URI, serum aminotransferase elevation, MI risk Enfuvirtide [adjunctive therapy for adults w/non-responsive HIV-1] – useful for resistant strains MOA: binds to HR1 (heptad repeat) on gp41 & inhibits fusion of HIV-1 w/CD4 cell membrane to prevent entry SEs: nodules/cysts at injection site (prevent w/ site rotation), diarrhea/nausea, fatigue, insomnia Ibalizumab [req loading dose] MOA: binds to CCR5 or CXCR4 → prevents gp120 interaction w/co-receptor → prevents viral entry w/o suppressing immune function or depleting CD4 count SEs:  serum Cr RT Inhibitors: nucleoside RT inhibitors (NRTIs) or non-nucleoside RT inhibitors (NNRTIs) NRTIs MOA: riboside analogs lacking 3’-OH → phosphorylated into triphosphate analog to activate → prevents 3’-5’ phosphodiester bond → terminates DNA chain elongation [inhibition of new virions] – renal elimination for all except zidovudine (ZDV; hepatic) & abacavir (ABC; alcohol dehydrogenase) – TDF & TAF = Tenofovir salts (pro-drugs), TAF metabolized in M & lymphocytes by Cathepsin A (milder renal/bone toxicity) General SEs: (mitochondrial toxicity) peripheral neuropathy, pancreatitis, lipoatrophy [often if ZDV given with other NRTIs], hepatic steatosis; (rare, FATAL) lactic acidosis or hepatomegaly ZDV other SEs: HAs, malaise, skeletal muscle myopathy, bone marrow suppression (neutropenia, anemia) Lamivudine: used in pregnancy, with HBV co-infection → HBV exacerbation with Tx interruption Emtricitabine: used in pregnancy; other SEs = hyperpigmentation, HAs, insomnia, diarrhea Tenofovir (combo with other ARVs) other SEs: GI disturbances, proximal renal tubulopathy + bone mineral density loss (TDF), HBV exacerbation if therapy stopped, Tenofovir alafenamide (TAF) milder toxicity than tenofovir disoproxil fumarate (TDF) – interactions w/P-gp inducers & inhibitors ABC other SEs: GI or neuro Sx, (most serious) hypersensitivity syndrome [higher risk if HLA-B*5701 allele mutation] and avoid alcohol use d/t metabolism via alc dehydrogenase (interaction causes  [ABC] in plasma) NNRTIs MOA: binds adjacent to catalytic site → conformation change without phosphorylation of drug, only against HIV-1; should never be used as monotherapy, metabolized by CYP3A4 (ineffective if pt taking CYP inducer), hepatic elimination Doravirine (most tolerated): HA, nausea, vomiting Efavirenz: CYP autoinducer → can’t combo w/protease inhibitor (substrate) – CNS SEs = vivid dreams, impaired concentration, insomnia, dizziness – CV SEs = prolonged QTc Nevirapine: CYP autoinducer → can’t combo w/protease inhibitor; SEs = rash worsened by steroids, Stevens- Johnson + toxic epidermal necrolysis, hepatotoxicity Etravirine SEs: rash, dyslipidemia, AST/ALT elevation with HepB or HepC co-infection Rilpivirine: used in pregnancy, req acidic environment for absorption (take 10 hr after PPI or 4 hr before); SEs = rash & depression, dose-dependent risk of QTc prolongation Integrase Strand Transfer Inhibitors (INSTIs): (-gravir) MOA: inhibits integrase for both strains and resistant strains Raltegravir + Dolutegravir + Bictegravir metabolized by UGT1A1 (low risk of adverse drug interaction) Raltegravir has high non-compliance d/t high pill burden, SEs = insomnia/HA/dizzy + Cr kinase elevation Dolutegravir SEs:  serum lipase, hyperglycemia, beware of hypersensitivity rxn + hepatotoxicity + fetal neural tube defect Bictegravir SEs: acute HBV exacerbation if co-infected (screen for HBV), nausea, diarrhea, HA – often given w/tenofovir & emtricitabine Elvitegravir CYP3A4 substrate → Cobicistat prevents rapid metabolism, 4-drug combo, SEs = nausea, diarrhea TOC Cabotegravir: long-acting used for PrEP, co-formulated w/Rilpivirine, SEs = injection site pain,  serum Cr phosphokinase, beware of depression, hepatotoxicity, & hypersensitivity rxn Protease Inhibitors (PIs) MOA (-navir): reversible inhibition HIV aspartyl protease →  formation of RT, protease, integrase, structural proteins  prevent maturation of new virion, high selectivity prevents inhibition of human PI – all metabolized by CYP3A4 & are P-gp efflux pump substrates = drug-drug interactions General SEs: GI disturbance, hyperglycemia (insulin resistance, avoid use in DM-2 pts) , dyslipidemia (ritonavir- based regimen), paresthesia Darunavir SEs: elevated serum cholesterol, triglycerides, & glucose Atazanavir competitive UGT inhibitor, bile excretion, needs acidic environment for absorption (take 10 hr after PPI or 4 hr before) – SEs: cholecystitis, cholelithiasis, cholestasis, hyperbilirubinemia (UGT1A1 inhibition) Fosamprenavir: prodrug → amprenavir (not recommended as initial ART) – SEs: diarrhea, rash, nausea, HAs, (Peds) vomit & neutropenia, (beware) sulfa allergy, lipid elevation, elevated serum glucose, transaminase elevation Tipranavir: “salvage” regimen in multi-drug resistant strains (rare use) – SEs: hepatotoxic, intracranial hemorrhage PK Enhancers (No ARV activity, just adjunctive therapy) Ritonavir – used w/ Darunavir, Atazanavir, Fosamprenavir – SEs = skin rash, dyslipidemia, hypertriglyceridemia, GI Sx, prolonged QTc, CNS effects Cobicistat – potent CYP3A4 inhibitor + can inhibit active tubular secretion of Cr –  activity of any CYP3A4 substrates – SEs: dyslipidemia Pathophysiology – HIV / AIDS Initial Infection (founder virus) of DCs in mucosal lining (Langerhans) = CCR5 co-receptor instead of CXCR4 (CCR5-tropic HIV)→ rapid increase HIV replication → inflammatory cytokines & chemokines; Acute Infection: 2-6 wk post-infection, non-specific clinical Sx (fever, LAD, maculopapular rash, pharyngitis) – pathogenesis: rapid multiplication & spread through body + CD4 cell destruction + high viremia (highly infectious) – starting Tx at this stage = good prognosis; Eclipse phase = undetectable infection for ~ 10 days after onset → Seroconversion (~ 23-25 day window) = anti-HIV Ab formation; Diagnostics: RNA PCR test detects HIV < 10 day post-exposure, Ag-Ab assays detect HIV~ 2-3 wk post-exposure, Ab assays detect HIV ~ 4 wk post-exposure – cannot r/o HIV until (-) result persists 12 wk past exposure – Testing algorithm improves acute HIV detection = Ag/Ab immunoassay (+) → Differentiation Assay (detects HIV-1, HIV-2, both, or none) → if none detected perform HIV-1 NAT (PCR) → (+) HIV-1 NAT = acute HIV-1 infection; Chronic HIV Infection: untreated acute infection → CD4 < 200 or recurrent opportunistic infections = AIDS; Screen: (1) One Time: anyone 15-65 w/o prior screening or getting Tx for TB or other STI (2) Annual: high-risk sexual behavior or IV drug users (3) Others: occupational exposure, correctional facility, pregnancy; Prior to ART: Gather baseline CD4 count, viral load, LFTs, chemistry & lipid panel, perform genotyping to determine resistance mutations & optimize therapy, determine if co-infection with Hep A/B/C, screen for Toxoplasma IgG, RPR (syphilis), & PPD (TB) – HLA-B*5701 screening prior to abacavir (ABC) Tx → (+) for allele = refrain ABC use and make note on pt’s chart; Anti-Retroviral Therapy (ART) is recommended for all infected individuals to  morbidity, mortality & risk of transmission; Reduce risk of infection: (1) Vaccines Hep B, HPV (< 26 yr old), Flu, Meningococcal, PNA, monkeypox (2) Pre-Exposure Prophylaxis (PreP) daily combo ART (Tenofovir + Emtricitabine) use for partners of HIV (+) people, must take consistently for effectiveness (3) Post Exposure Prophylaxis (PEP) for those experiencing occupational exposure, must start within 72 hr & continue for 4 wk, combo of 3 ART drugs, can r/o after 12 wk; Opportunistic Infections: higher risk if CD4 < 200; Pathogen Characteristics & Clinical Sx, PE, & Dx Tx & Indication for Discontinuing Pneumocystis Fungus, air transmission, can become latent; subacute Regimen for 21 days: jiroveci Sx: progressive SOB, fever, nonproductive cough, chest TMP-SMX (add Prednisone if severe) discomfort, Hypoxia SEs = rash, SJS, leukopenia, (prev. carinii) PE: tachypnea & tachycardia + diffuse dry rales thrombocytopenia, hyperkalemia Dx: CXR (diffuse ground-glass, butterfly-shaped), HRCT Prophylaxis: CD4 < 14% lymphocyte (higher sensitivity), Labs (1,3--D-glucan > 80, low specificity) Discontinue: once CD4 >200 for at Definitive Dx w/ bronchoscopy + bronchoalveolar lavage or least 3 months PCR + Silver stain (below) Candida Fungus; Oropharyngeal Sx: painless, creamy-white, plaques on Oral: fluconazole, 7 days Albicans buccal surface that’s easily scraped off; Esophageal Sx: Esophageal: fluconazole or retrosternal discomfort, odynophagia, similar plaques itraconazole for 14-21 days Dx based on clinical presentation TOC Other Oral Lesions: (1) Oral Hairy Leukoplakia asymptomatic hyperkeratotic lesions linked w/EBV (lesions resolve w/ Tx underlying HIV) (2) Recurrent Oral Herpes HSV-1 or -2, Tx w/acyclovir, valacyclovir or famciclovir (3) Kaposi’s sarcoma (most frequent), may regress with ART (4) Oral HPV may have benign or malignant lesions M. avium Disseminated MAC usually in pts with CD4 < 50; Tx: daily clarithromycin + ethambutol intracellulare Sx: ‘B sx’, fatigue, diarrhea, abd pain Mycobacterium PE: hepatosplenomegaly & central LAD avium complex Labs: anemia, elevated ALP (other LFTs normal),  serum LDH (MAC) Dx: AFB blood culture, bone marrow or lymph node isolation Cryptococcus Transmitted via bird droppings to pts w/CD4 < 100; Meningitis = Tx: (induction) Liposomal neoformans gradual HA, low- fever, photophobia, neck stiffness, (maybe) Amphotericin B + flucytosine confusion, vomiting, obtundation, seizure & psychosis; (consolidation) fluconazole C. gattii (pacific May grow in CNS → CSF not absorbed from subarachnoid villi Tx  ICP with CSF decompression via NW) →  Intracranial Pressure (ICP): focal neuro Sx, papilledema, lumbar tap or ventriculoperitoneal severe HA → herniation, CN II and VIII deficit, death shunt Dx: CSF studies (opening pressure, cell differential,  protein, (+) India ink, antigen, fungal culture) or Serum antigen titer Toxoplasma Transmit by cat feces, contaminated meat/water, mother to child Tx: Pyrimethamine + Leucovorin + gondii Sx: LAD & muscle aches for 1+ month, generalized tonic-clonic Sulfadiazine COMBO seizure, gradual mental status decline Toxoplasma encephalitis affects brain & eyes, MRI shows ring- Prophylaxis for HIV pts w/CD4 < 100 enhancing lesions + edema (usually R frontal-parietal lobe) Cryptosporidium Cryptosporidiosis (chronic intestinal infection >1 mo) Tx: Nitazoxanide + ART Sx: abd cramps + severe, persistent & watery diarrhea Dx: acid fast stain of stool (oocyst; see below) or PCR CMV High risk for CMV retinitis if CD4 < 50 Tx: Intravitreal injections of Sx: painful, swollen, erythematous eye → impaired visual field + ganciclovir of foscarnet + oral floaters + flashing lights valganciclovir Dx: eye exam (yellow-white, fluffy/granular retinal lesions), PCR or assay not helpful for Dx Primary prevention w/ART Risk for vision-loss if lesions near optic nerve or fovea Immune Reconstitution Inflammatory Syndrome (IRIS): more vigorous immune response d/t prior infection (ex. pulmonary TB) – significant  CD4 count & undetectable HIV RNA within 4 wk of ART initiation – Sx: (1) paradoxical worsening condition → improved immune function (2) unmasked undiagnosed infection after immune recovery – complication that arises from any opportunistic infection – Sx persist for 2-3 mo – Do not stop ART Pharmacology – Chemotherapy / Anti-Cancer Drugs Cancer Principles: uncontrolled multiplication & spread of abnormal endogenous cells [mutations can be inherited, acquired or d/t random errors → failed DNA repair → replication] – can arise from proto-oncogenes (regulatory genes control proliferation) mutation → unregulated growth (oncogene), inactivation of tumor suppressor genes (slow division, repair mistakes or apoptosis)  proto-oncogenes are suppressed vs tumor suppressor genes are activated; Cell Cycle: G1 (growth) → G0 (rest) or S phase (DNA duplication (synthesis)) → G2 (repair) → M (mitosis) – 3 key checkpoints: restriction vs growth (G1; mediated by cyclins + CDKs), synthesis checkpoint (G2), mitosis or metaphase (M); Drug Targets can be specific for any cell cycle phase or cell cycle-nonspecific (CCNS); Pharm Principles: killing cell population at a fraction [log-kill hypothesis (1-log = 90%, 2-log = 99%, 3-log = 99.9%) counteracts the exponential growth of cancer cells – additive  if 2 drugs each exhibit a 1-log kill → combo therapy leads to a 2-log kill] via repeated doses, especially for acute leukemia & aggressive, high-grade lymphoma – targeted therapy (‘smart bomb’) inhibits specific targets vs chemotherapy (‘cluster bomb’) inhibits cell cycle & lacks specificity – Chemotherapy can act on specific phases (heme cancers) or throughout (solid tumors) cell cycle – Multi-Drug Resistance:  uptake of drug,  [drug] in cell d/t efflux (P-glycoprotein, P-gp, = ATP-dependent efflux pump), altered cycle checkpoints, altered targets,  drug clearance, genes induced to impair apoptosis – Combining Chemo Agents maximizes cell killing, reduces injuries (w/drugs of non-overlapping toxicities), TOC suppressing drug resistance, Combos = MOPP (Mechlorethamine, Vincristine, Procarbazine, Prednisone – Hodgkin’s Lymphoma), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone – CLL), ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine – less toxic, Hodgkin’s lymphoma) – Common Toxicities: N/V, BM suppression (neutropenia, thrombocytopenia), Alopecia, hyperuricemia (tumor lysis syndrome) Alkylating Agents (CCNS): Busulfan (CML; pre-tx with phenytoin), Chlorambucil, Dacarbazine Mechlorethamine (nitrogen mustard) MOA: crosslinks DNA strands & disrupts DNA replication + transcription (Guanine) SEs: phlebitis, myelosuppression (infection risk), teratogenic & carcinogenic (acute leukemia) → adjuvant: Sodium thiosulfate Cyclophosphamide (pro-drug → aldophosphamide & Acrolein) + Ifosfamide MOA: crosslinks DNA strands [Acrolein → bladder pain, hematuria → adjuvant: MESNA] SEs: Leukopenia = high infection risk (adjuvant: Filgrastim or Sargramostim 24-72 hr after chemo cessation) Filgrastim (G-CSF): proliferation + differentiation of neutrophil progenitors Sargramostim (GM-CSF): multilineage proliferation (granulocytes, M, megakaryocytes, erythrocytes) Carmustine + Lomustine (Nitrosoureas) – cross BBB (b/c lipophilic) MOA: non-enzymatic – decompose to alkylate (DNA) or carbamoylate (protein) SEs: myelosuppression (4-6 wk post-Tx); Carmustine → pulmonary fibrosis Platinum Analogs (CCNS): Cisplatin, Carboplatin, Oxaliplatin MOA: kill at all cycle stages via strand cross-linkage (N7 of Guanine) SEs: nephrotoxicity, ototoxicity, severe emesis – Oxaliplatin → peripheral sensory neurotoxicity Antimetabolites (S phase) = analogs of folates, purines, pyrimidines – inhibit nucleotide synthesis enzymes Methotrexate (MTX) – polyglutamated folic acid analog (higher inhibitory effect) MOA: inhibits dihydrofolate reductase → FH4 depletion → inhibition of purine, thymidylate, Serine & methionine synthesis (inhibits DNA, RNA & protein formation) SEs at high doses bone marrow suppression & GI mucosa inflammation (opportunistic infections)→ adjuvant: Leucovorin (FH4 derivative) 24 to 36 hr after MTX to rescue healthy cells Pralatrexate (IV folate analog for aggressive lymphoma) Cytarabine (Cytosine Arabinoside) – pyrimidine analog MOA: replaces dCTP in DNA → steric hindrance + inhibition of chain elongation → DNA fragmentation SEs: common chemo SEs + cerebellar ataxia at high doses Depocyt (liposomal) intrathecal admin Tx spinal cord cancer (same SEs as cytarabine) 5-Fluorouracil MOA: interferes w/uracil & thymine production (inhibits DNA and RNA synthesis) SEs: photosensitivity & neurotoxicity 6-Mercaptopurine (hypoxanthine analog, prodrug) + Thioguanine – purine analogs MOA: HGPRT enzyme converts 6-MP to 6-TIMP → inhibits transcription & replication SEs: hyperuricosuria (kidney stones d/t xanthine oxidase (XO) → adjuvant: XO inhibitor = Allopurinol) Natural Products: Vincristine, Vinblastine – Vinca Alkaloids (M phase) – resistance via amplified P-gp– hepatic p450 metabolism MOA: bind to tubulin → inhibit mitotic spindle, phagocytosis → inhibit cell division → death SEs: caution w/liver dysfunction, cystitis (prevent w/hydration) → H2O intoxication in presence of SIADH, peripheral neuropathy Paclitaxel, Docetaxel – Taxanes (M phase) MOA: stabilize microtubule + prevent disassembly SEs: common chemo SEs + peripheral neuropathy Teniposide (more lipophilic = longer retention), Etoposide (Epipodophyllotoxins) – Renal Excretion MOA: Topoisomerase II inhibitor (G1-S phase) → prevents re-ligation →  apoptosis SEs: leukopenia + mild thrombocytopenia (reversible) – caution w/renal disease Irinotecan + Topotecan = Camptothecin MOA: Topoisomerase I inhibitor (G2-M phase) SEs: diarrhea, myelosuppression Daunorubicin (Daunomycin), Doxorubicin (Adriamycin) – Anthracyclines (CCNS) isolated from Streptomyces MOA: inhibit topoisomerase II + generate free radicals + intercalation → block DNA/RNA synthesis + altered cell membrane transport SEs: Doxorubicin (fatal) *cardiotoxicity* [adjuvant: Dexrazoxane (Fe chelator)], severe myelosuppression Bleomycin – Antitumor Abx (G2-M phase) – glycopeptide MOA: induces breaks in DNA (ss & ds) via free radicals TOC SEs: pulmonary fibrosis (diffuse rales, dry cough), cutaneous – hyperpigmentation, hyperkeratosis, erythema ulceration L-Asparaginase (enzyme isolated from E. coli) – Pegaspraginase (used if L-Asparaginase allergy) MOA: hydrolyzes asparagine → aspartic acid + NH4 – caution: halts cell cycle & interferes with other drugs SEs: anaphylaxis, hyperglycemia d/t  insulin synthesis, bleeding Targeted Therapies: Olaparib, Niraparib, Rucaparib PARP (poly ADP-ribose polymerase) inhibitors – for BRCA mutations Tyrosine Kinase (TK) Inhibitors: Imatinib (binds to closed BCR-Abl TK), Ponatinib (all isoforms of BCR-Abl TK – SEs = arterial thrombosis & hepatoxicity), Ibrutinib (Bruton’s TK inhibitor prevents B cell proliferation → apoptosis) – involved in BCR-ABL1 gene fusion (Philadelphia chromosome) Lapatinib, Neratinib MOA: targets TK of HER-2 → inhibits autophosphorylation & downstream pathway +  cell prolif SEs: non-specific Sx including diarrhea, hepatotoxicity, Erlotinib, Gefitinib MOA: target TK of EGFR → inhibits downstream pathway +  cell proliferation SEs: non-specific Sx including partial hair loss Sunitinib, Sorafenib, Axitinib, Cabozantinib MOA: target TK of VEGF → inhibit angiogenesis & other TKs →  tumor growth & metastasis SEs: hepato- & cardio- toxicity + thrombotic events Trastuzumab, Pertuzumab MOA: mAb for extracellular domain of HER-2 → inhibits overexpression of HER-2 SEs: non-specific Sx, cardiotoxicity, neurotoxicity, risk of infection Bevacizumab (indirect TK inhibitor) MOA: binds to VEGF → inhibits neovascularization, regression of tumor vessels/growth/metastasis SEs: GI perforations, healing complications, hemorrhage Everolimus (also renal transplant rejection prophylaxis), Temsirolimus – mTOR Pathway Inhibitors MOA: bind to FK binding protein → anti-proliferative + antiangiogenic and inhibit VEGF + hypoxia- inducible factor expression SEs: myelosuppression (thrombocytopenia), risk of infection & other malignancies, hepatotoxic Cancer Immunotherapy: enhance immune response or alter cell differentiation Alemtuzumab binds CD52 → causes lysis via ADCC or Complement-Dependent Cytotoxicity (CDC) – mAbs coat cancer cells → recruitment of immune cells & MAC, respectively – SEs: cytopenia, fatal infusion rxn, infection 90Y-Ibritumomab tiuexetan (Radiation) – binds to CD-20 → 90Y covalently binds to complex→ apoptosis SEs: infusion rxn, mucocutaneous rxn (ex. Steven’s-Johnson) Rituximab (biosimilar) – anti-CD20 → ADCC and CDC – SEs: viral reactivation of Hep B or JC virus, severe mucocutaneous rxn, fatal infusion rxn (and more SEs) Checkpoint Inhibitors: reduce immune checkpoint activity for T-reg rich areas → diminishes tumor evasion – SEs for all are immune-related overactivation (pneumonitis, colitis, endocrinopathy rash) = inflammation Ipilimumab, Tremelimumab – Anti CTLA-4R → inhibit binding to B7 (APCs) → T-cell/T-reg activation Nivolumab, Pembrolizumab – Anti PD-1 → reverses T cell suppression & induces antitumor response Avelumab, Durvalumab, Atezolizumab – Anti PD-1L→ inhibit PD-1 + CD80 interaction → T cell active Chimeric Antigen Receptor T-Cell Therapy (CAR-T Cells) – used for refractory or relapsed ALL & NHL Procedure: isolate pt T cells → culture T cells to genetically modify → expand modified cells → re-introduce into Pt → spread through circulation & differentiate into memory T cells – Goal: develop recombinant receptors that have both tumor antigen-binding (SCFV) and t-cell activating (CD 3 zeta) functions Tisagenlecleucel (pts up to 25 yr old) or Axicabtagene ciloleucel – CD19-directed modified T cells SEs: Cytokine storm (adjuvant: Tocilizumab – targets IL-6), Neurotoxicity, Infection Bi-Specific T-cell Engager (BiTE) Blinatumomab – binds to CD19 (tumor B cells) + CD3 (T cells) MOA: CD3 binding induces T cell activation → granzyme & perforin produced, inflammatory cytokines released, T cell proliferation → CD19 B cells killed SEs: cytokine storm & neurotoxicity TOC 2. Week 2 Pathophysiology – Anemia Anemia is characterized by the  in (one or more): Hgb concentration, Hct, or RBC count; RDW measures the variation in RBC size relative to the mean corpuscular volume (MCV); Microcytic Anemia: (1) Iron-Deficient Anemia = hypochromic, microcytic anemia with anisocytosis (elevated RDW) – other forms of microcytic hypochromic anemia = Thalassemia (altered globin production) or Chronic Inflammation (often normocytic), but Fe-deficient Anemia is most common anemia – Fe source = dietary intake → used to form RBCs in BM & stored in liver/spleen before it is lost in urine & keratinized cells; Fe Storage & Measurement: EPO released by kidneys regulates iron binding to Heme in Hgb of RBCs – Transferrin = Fe binding protein = transport form of Fe – Ferritin + Hemosiderin = storage forms of Fe – Serum Fe = amount of circulating Fe bound to transferrin – TIBC indirectly measures total circulating transferrin – % Sat = Serum Fe / TIBC * 100 = proportion of available transferrin that is bound to Fe – Serum Ferritin = indirect measure of total iron stores & may  in acute disease/inflammation – Protoporphyrin = heme precursor that accumulates with impaired heme synthesis (elevated in Fe-deficiency); Dx Fe-Deficiency: ‘gold standard’ would be BM biopsy, but rarely used d/t painful extraction – common tests = serum Fe, TIBC, & Ferritin [ TIBC +  Serum Fe +  Ferritin]; Causes of Fe Deficiency (1) higher demand d/t pregnancy, growth spurt, vegetarian diet, or EPO therapy (2) more loss d/t blood loss (ex. menses) or blood draws (ex. donation or phlebotomy for polycythemia vera) (3) inefficient Fe intake/absorption d/t diet (vegetables least efficient Fe sources), disease (Celiac or Crohn’s), or surgery (gastrectomy, gastric bypass); Tx Fe Deficiency: Fe dextran (ferric hydroxide dextrans) injection has high risk of allergy so begin w/test dose & admin steroids + Benadryl prophylactically → overdose (Fe Toxicity) is lethal, Tx with chelating agent (deferoxamine) – other formulation = IV ferric carboxymaltose is effective & safer – management nutrition, oral supplement (Vit C improves Fe absorption) & address etiology if excessive bleeding present; Fe-Deficiency = low ferritin, serum Fe, & % Sat, high TIBC (2) Anemia of Chronic Disease = low Fe, TIBC, & % sat, high ferritin (3) Hemoglobinopathies: altered structure or production of Hgb, common mutation = HbS, HbC, HbE, HbH, and Hb Bart – HbH & Hb Bart = -thalassemia, HbS = Sickle Cell Anemia – Sickle Cell Anemia = structural hemoglobinopathy (mutation → abn Hgb → abn RBC) – Pathophysiology: (1) homozygotes (Hgb SS) →  solubility,  RBC stiffness/ stickiness, permanently deformed RBC → RBC life span 17 days (life-long hemolysis), multi-system effect [functionally asplenic + risk of stroke and/or retinal bleeding/detachment + priapism, hypogonadism, hematuria + aseptic necrosis (femoral head) & hand-foot syndrome + acute chest syndrome (medical-emergency, must Tx with total RBC exchange) + leg/ankle ulcers + bilirubin gallstones & hepatic crisis] + high risk of infection (asplenia) often source of morbidity/mortality (Osteomyelitis via Staph (#1) or Salmonella) – Dx: FHx, smear (sickle cell), & Hgb electrophoresis, RC, LDH– Tx: (acute) pain meds, hydration, oxygen, transfusion (chronic) hydroxyurea ( Hgb →  recurrence), BM transplantation (young pts), folic acid supplement (2) heterozygotes (Hgb AS) → single normal copy = carrier (sickle cell trait), asymptomatic, painless hematuria, normal RBC appearance Macrocytic, Normochromic Anemia = larger RBCs, spherocytes, normal central pallor – hemolytic anemia = RBC Loss →  reticulocytes (immature RBCs)  elevated MCV – mechanisms: (1)  production via B-12 / folate deficiency or MDS → Megaloblastic Anemia may present with GI discomfort, neuro deficits (B12 def), mature RBCs have normal shape but larger (nuclear division slow), hyper-segmentation of neutrophils, most often d/t low intake or absorption of folate and/or B-12 – can be idiopathic or caused by drugs impairing DNA metabolism (ex. chemo drugs) or metabolic disorders – Pathophysiology: shortage of B-12 or folate → impaired DNA synthesis & maturation of RBCs, slow cell division w/normal cytoplasmic growth → large cells abn nuclei – Folic Acid Def caused by unbalanced diet, higher requirement (ex. pregnancy, malignancy), malabsorption, or impaired metabolism (ex. DHF reductase inhibitors) → Tx: folic acid supplement for deficiency, prevent neural tube defects & maybe  risk of occlusive vascular disease – B-12 Def caused by vegetarian diet (rare), malabsorption [defective cobalamin release (ex. gastrectomy), pernicious anemia = Ab against IF and parietal cells prevent absorption, disorders of terminal ileum, competition for cobalamin (ex. fish tapeworm = Diphyllobothrium latum),] or nitrous oxide → Dx: low RC, hypercellular bone marrow,  bilirubin,  LDH, elevated serum homocysteine (both) & MMA, anti-IF or -parietal cell Ab (B-12 specific) → Tx: cyanocobalamin injection – if both B-12 and folate are low → Tx B-12 first to prevent worsening neuro deficit; (2)  survival [considered Normocytic in other lectures] via bleeding or hemolysis [autoimmune more often than mechanical → cold agglutinin = IgM (2º to infection or lymphoma/leukemia), warm agglutinin = IgG (idiopathic or drug-induced)] – Distinguish cause with reticulocyte count (RC) →  RC = hemolytic vs  or normal RC = impaired production – Hemolytic Anemia ( RC) = rate of destruction of mature RBCs > rate BM can produce, classified based on mechanism & location → (a) Intravascular Hemolysis: destruction within vessels & release of contents into circulation, rare but Hgb toxicity is life- threatening – *Thrombotic Thrombocytopenia Purpura (TTP)* → 5-characteristics: Microangiopathic Hemolytic TOC Anemia + Thrombocytopenia + Fever + Neuro Abn (ex. HA, confusion) + Renal Failure → smear will exhibit schistocytes→ Tx: total plasma exchange (b) Extravascular Hemolysis = RBCs removed from circulation via reticuloendothelial system (RES) & digested by M, more common & slower destruction = less dangerous – clinical features of hemolytic anemia: hereditary (longstanding hyperbilirubinemia + maybe jaundice + spherocytes) or autoimmune (gradual fatigue) → pallor, splenomegaly, (intravascular hemolysis) dark urine – Coombs Test detects Ab against RBCs → Direct detects Ab- or complement- coated RBCs (+ in autoimmune) vs Indirect detects circulating Ab within serum – Tx: suppress immune system, splenectomy, mAb (anti-CD20), chemo Labs:  bilirubin (accumulates w/free heme),  haptoglobin (binds free Hgb), polychromatophilia ( purple RC via  marrow activity), erythroid hyperplasia, hemosiderin sloughed into urine d/t Fe overload in renal tubule → Extravascular (-) bilirubin, hemosiderin, & Hgb Intravascular exhibits (-) bilirubin, (+) hemosiderin & (+) Hgb Pathophysiology – Disorders of Primary Hemostasis Clot Formation: (1º hemostasis) endothelial injury → endothelin and vWf release → vasoconstriction and vWf interacts w/glycoprotein (gp) Ib on platelets (adhesion to vWf & other platelets) → activated platelets release cytokines [ADP & arachidonic acid**] → more platelet release + aggregation → [** arachidonic acid (AA) → TXA2 → vasoconstriction + platelet recruitment &  gp IIb/IIIa on surface]→ fibrinogen interacts with IIb/IIIa proteins → weak plug formation – Pathophysiology: platelet defects (functional disorders or thrombocytopenia), vWf defects, vessel wall defects (ex. collagen disorders) – In Contrast 2º disorders d/t coagulation cascade; Clinical Features 1º = often immediate after trauma/surgery → superficial & mucocutaneous bleeding (ex. nose bleeds, heavy periods, etc), petechiae (pinpoint red/purple spots on skin) vs 2º = deep tissue or joint space bleeding, hematomas; Workup: CBC w/differential (platelet count & other cell line counts – confirm accuracy of low platelet count b/c EDTA may cause platelets to clump in test tube = pseudo-thrombocytopenia = lab error → redraw blood in citrate & recheck), CMP (any renal or liver dysfunction), peripheral blood smear (common findings listed below), PT/INR (extrinsic pathway), aPTT (intrinsic pathway) – 1º hemostatic disorders have normal PT & aPTT – Platelet Function Tests → prolonged bleeding time, (+) capillary fragility [both not used much anymore], PFA-100 [how well platelets aggregate] prolonged closure time – Blood Smear Findings (1) May Hegglin Anomaly often seen in children, Döhle body (basophilic inclusions) and large platelets (2) Wiskott-Aldrich low platelets + microcytopenia (3) ITP: giant platelets (4) B-12 Deficiency: pancytopenia & hyper-segmented neutrophil (5) Sepsis spiculated appearance in cytoplasm of granulocytes → low platelet count (7) Myelophthisic disease bone marrow infiltrated w/something → tear drop cells (8) Thrombotic Microangiopathy: low platelets + schistocytes (9) Paraproteinemia: Rouleaux Formation (10) Liver Disease: spur cells; Types of Defects: (1) Qualitative: normal count, but non-functional platelets → (a) Congenital = via anomalies in factors required for plug formation (ex. vWD, ITP) (b) Acquired = medications (ASA inhibits TXA2 formation, Thienopyridines inhibits receptors, IIb/IIIa inhibitors, penicillins), supplements, paraproteinemia (Waldenstrom’s, multiple myeloma), CKD, chronic liver disease, autoimmune disorders (2) Quantitative: low platelet count (thrombocytopenia) → higher risk of spontaneous bleeding caused by (a) Low Production = BM dysfunction resulting from medication/exposures, heme disorders, liver disease, malignancy/ infection, nutrition, clonal stem cell disorders, sepsis (cytokines & infiltration) (b) Destruction of platelets and RBCs (likely presents with jaundice) = DIC, infections, HIT, Rx, Autoimmune, or Mechanical (ex. endocarditis) (c) Sequestration = hypersplenism (ex. cirrhosis, amyloidosis) or Redistribution d/t many transfusions (dilution) + hypothermia vWf Disease: most common inherited bleeding disorder, mucocutaneo

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