Download CM Heme-Onc Exam 2 Lecture 15

CM Heme-Onc Exam 2
Lecture 15-Lymphadenopathy I
 Lymphadenopathy is a normal immune response that leads to proliferation and expansion of cellular
matrix.
o Common clinical finding
o Multiple etiologies, can be caused by a vast array of diseases and drugs.
o Some nodal presentations suggest a specific disease process
 Diagnostic approach
o H&P-etiology is often obvious after complete H&P
 Age: cervical adenopathy in a child much less worrisome than 60yr old smoker
 Symptoms of malignancy or infection: fever or weight loss, night sweats
 Duration: acute (days) vs chronic (weeks-months)
 Exposures associated w/infection
 Cat scratch
 Undercooked meat-toxoplasmosis
 Tick bite-Lyme dz
 Travel to endemic areas
 High risk behavior-IV drugs/sexual behavior
 ROS for other systemic illnesses
 Meds
 Number of meds can cause serum sickness: fever, arthralgias, rash and generalized
adenopathy
 Phenytoin associated with generalized adenopathy, not associated with serum
sickness
 Physical Exam
 Evidence of infectious process: open wound/sore; pharyngitis, vaginitis
 Focus on other signs of systemic illnesses: splenomegaly
 Distinguishing between localized and generalized lymphadenopathy
 Localization of Nodes-useful to classify if localized
o Cervical: commonly encountered d/t high visibility and prevalence of
infections affecting head and neck region. Hard nodes in smoker is cancer
until proven otherwise.
o Epitrochlear: never palpable so if present always pathologic
o Supraclavicular: more often associated with malignancy
o Axillary: drain multiple areas, cancer often found in absence of upper
extremity lesions.
o Inguinal: frequent finding d/t lower extremity infection, STD or cancer.
 Generalized Location
o Predom feature of systemic illnesses.
o HIV: nontender nodes primarily involving axillary, cervical and occipital
nodes.
o Mycobacterial infection-present with adenopathy alone; usually nontender
and enlarge over weeks-months
o Infectious Mono-typically symmetric cervical nodes associated w/fever and
pharyngitis
o SLE: seen in 50% of pts, typically nontender discrete cervical, axillary and
inguinal nodes.
 Size does matter:
o <1cm is rarely malignant
o ‘Shotty’ used to describe multiple small nodes, but no diagnostic significance
 Consistency
o Hard-post inflammatory fibrosis or solid tumors
o Firm/rubbery-hematologic malignancy
o Soft-inflammatory or infectious
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 Fixation-freely mobile or matted/fixed to surround tissues/nodes
 Tenderness-typical for inflammatory processes
o Diagnostic Tests
 Labs
 Confirm suspected diagnosis-Rapid Strep
 Unknown diagnosis: CBC, consider PPD, HIV, RPR and ANA
 Imaging studies
 Can define size and distribution more precisely
 CT, US or MRI are useful at providing clues to Dx but cannot replace biopsy
 CXR
 To Biopsy or Not
 Goal is to identify pts most likely to benefit from bx (cancer, granulomatous disease)
 Open Biopsy
o Generally the best diagnostic test bc histologic exam of intact tissue provides
info about both the presence of abnormal cells and abnormal node
architecture.
o False negative occurs when wrong node is taken
o Outpt under anesthesia
o Choose the most abnormal node
o Choice in descending order if no predom node: supraclavicular, neck, axilla
and groin.
 Fine Needle Aspirate
o Cytology and no histology
o False negatives common
 Core Needle Biopsy
o Increasingly utilized when node isn’t acceptable
o Improved ancillary studies
o Differential
 Infection
 Bacterial, mycobacterial, fungal, chlamydial, parasitic, viral, etc.
 Benign disorders of the immune system
 RA, SLE, serum sickness/drug reaction, Langerhans’ cell histiocytosis, Kawasaki
syndrome, Kimura’s dz.
 Malignant disorders of the immune system
 Lymphoma-Hodgkin vs. non-Hodgkin’s
 Leukemia-acute/chronic
 Plasma cell dyscrasias-myeloma, Waldenstrom’s macroglobulinemia
 Metastatic cancer
 Storage diseases
 Endocrinopathies
 Miscellaneous: sarcoidosis/amyloidosis
o Most common causes in the US
 Unexplained and infection
 Immune disorders: RA
 Neoplasms
Infectious Mono
o Classic triad: fever, tonsillar pharyngitis, and cervical adenopathy
o Pathogenesis: EBV, spread by intimate contact
o Evaluation
 CBC w/lymphocytosis and atypical lymphocytes on peripheral smear.
 CMP w/elevated AST/ALT
 Monospot positive
o Tx is supportive
Cat Scratch Disease
Infectious disease characterized by self-limited regional lymphadenopathy
Epidemiology/pathogenesis
 Bartonella henselae is the etiologic agent.
 Cats are reservoir
 Organism typically causes local infection tat manifest as regional lymphadenopathy
 More common in children
o Clinical Manifestations
 Typically begins with cutaneous lesion at site of inoculation; develops 3-10 days after
bite/scratch and evolves through vesicular erythematous and papular phases.
 Regional lymphadenopathy is hallmark of dz
 Other symptoms
 Visceral organ involvement: liver/spleen
 Constitutional: weight loss
 Ocular: neuroretinitis, Parinaud’s Oculoglandular syndrome
 Neuro: encephalopathy
 MSK: myalgias/arthralgias
o Diagnosis
 Typical H&P
 Serology for B. henselae
 PCR or positive warthin-starry stain
o Tx
 Most pts have gradual resolution w/o intervention
 Recommend to tx with azithromycin x 5 days
Kikuchi’s Disease
o Rare, benign condition of unknown cause usually characterized by cervical lymphadenopathy and
fever
o Most commonly seen in young women
o Dx by biopsy and exclusion
o Self-limited illness
o No effective tx
Dr. Armitage Approach
o Does the pt have a known illness causing lymphadenopathy?
 Watch and monitor for resolution
o Is there an obv infection to explain lymphadenopathy?
 Tx and monitor for resolution
o Are the nodes very large and/or firm and suggestive of malignancy?
 Biopsy
o Is the pt concerned about a malignancy and unable to be reassured that cancer is unlikely?
 Biopsy
o If none of the preceding are true, perform CBC and if normal then monitor with follow up in 2-6
weeks. Biopsy if progression or no regression.
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Lecture 16-Lymphadenopathy II
 Malignancy
o Primary lymphoproliferative neoplasms: lymphoma, leukemia, plasma cell dyscrasia
o Metastatic disease: breast, lung, GI, melanoma, head and neck, GU.
o Features of malignant adenopathy
 Duration-develop over a period of weeks-months although may occur in shorter period
with aggressive lymphomas
 Size/consistency: typically larger than 1 cm and frequently multiple nodes present; hard
fixed nodes suggest mets. Firm/rubbery seen with hematologic cancers.
 Timing-initial diagnosis; relapsed/recurrent disease
 Symptoms:
 Systemic ‘B’ symptoms (weight loss/fevers/night sweats)
 Local: pain, direct invasion, swelling
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Lymphedema
o Interstitial collection of protein rich fluid.
o Etiology
 Primary-congenital condition associated w/pathologic development of the lymphatic
vessels.
 Secondary-usually cancer, trauma, infection or prior therapies
o Cancer Associated
 Mechanism-obstruction of lymphatic channels/nodes
 Infiltration of lymphatic vessels
 Cancers most often associated with lymphedema; breast is the number 1 cause.
o Risk Factors
 Treatment-related
 Lymphadenectomy-strongest predictor, sentinel lymph node dissection
 Radiation-higher rates following radiation
 Nontreatment
 Obesity
 Delayed wound healing
 Post op infection
 Post op seroma
Supraclavicular Adenopathy
o Associated with higher risk of malignancy
o Right: lungs, mediastinum, esophagus
o Left:
 Virchow’s Node-Associated with gastric cancer
 Troisier’s node-associated w/abd cancer
 Abdominal malignancy-gastric, gallbladder, pancreas, kidney, and GU
Axillary Adenopathy
o Isolated nodes often benign
o Lymphoma most common malignant tumor presenting in axilla
o Adenocarcinoma: breast, lung, gastric, pancreatic, colon, thyroid
 Isolated node very uncommon.
o Occult Breast CA
 Becoming less common, accounting for at most 1% of cases
 Improved MRI has identified primary site 75% of the time
 Surgical series w/mastectomy reveal primary in 71% of cases
o Pathology
 Thorough eval the pathologist often provides info regarding the nature and likely site of
primary cancer
o Molecular Tumor Profiling
 Specific gene expression profiles observed in cancers from different sites of origin,
reflecting the different gene expression profiles
 Several assays available.
Neck Mass
o Differential is extensive including benign and malignant.
 3 Major categories:
 Congenital-branchial cleft cyst, Thyroglossal duct cyst, vascular anomalies
 Inflammatory-infectious vs noninfectious
 Neoplastic-in the adult, cancer until proven otherwise
o Neoplastic Disorders
 Both benign and malignant seen
 Thyroid-anterior neck benign nodules or Ca
 Salivary gland-parotid tumors account for 80%
 Paragangliomas-tumor of the carotid body
 Schwannoma-Schwann cell cancer associated w/vagus nerve
 Lymphoma: NHL or Hodgkin’s
Metastatic head and neck carcinoma-majority of neck masses, arising from aerodigestive
tract
o Hard cervical nodes suggest head and neck mets
o Diagnosis confirmed with FNA
o Pts should be referred to ENT for fiber optic exam of the oropharynx
Anterior Mediastinal Mass
o Anterior to the pericardium and includes lymphatic tissue, the thymus, extrapericardial aorta and
branches and great veins.
o Masses in the anterior compartment are more likely to be malignant than those found in other
mediastinal compartments
o Thymoma is most common anterior mediastinal neoplasm
 50% found on CXR
 Can be benign or malignant, requires surgical excision
 Associated with a number of paraneoplastic disorders: most common are myasthenia gravis
and pure red cell aplasia.
o Lymphoma
 Usually manifestation of systemic lymphoma
 Primary mediastinal lymphoma: second most common cause of anterior mass
 Requires large core needle biopsy or preferable incisional biopsy
o Germ Cell Tumors
 Referred to as extragonadal germ cell tumors
 Develop in rests of cells that failed to complete migration from urogenital ridge to gonads.
 Classified as: teratomas, seminomas and nonseminomatous germ cell
o Mediastinal cyst-pericardial, bronchogenic, enteric and thymic
o Thyroid tissue
 Substernal thyroid tissue may develop from intrathoracic extension of a goiter
o Parathyroid tissue
Splenomegaly
o Largest lymphatic organ in the body
 Removes senescent RBCs and RBC inclusions: Howell-Jolly bodies; and Heinz bodies
o Red pulp is more than half the volume of the spleen
o White pulp contains Macs, B and T lymphocytes and site of immunologic response.
o Spleen usually not palpable, but if it is considered enlarged.
 Ultrasound >13cm
 Liver-spleen scan: >13cm
 CT scan: >10cm
o Symptoms
 Usually asymptomatic
 Pain, sense of fullness or discomfort in LUQ
 Early satiety
o Eval and Work-Up
 Hx may provide clues as to the cause:
 Alcoholics or hepatitis w/ascites
 Young adult w/fatigue, sore throat and splenomegaly likely to have mono
 Systemic complaints such as fever, night sweats, malaise and/or weight loss may
reflect systemic dz.
 Imaging studies: CT, MRI, US, or nuc med study
 Labs:
 CBC w/peripheral smear: hypersplenism associated with cytopenias
o Neutrophilia w/left shift suggests infection
o Immature WBC suggest leukemia/lymphoma
 Chem panel to asses liver/kidney
 Biopsy of abnormal organ
 Splenic biopsy not usually performed, but can be done in special circumstances
 Diagnostic Splenectomy-performed to identify cause and resolve symptoms.
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Lecture 17-Hodgkin Lymphoma
 Background
o Monoclonal lymphocytes of B cell origin
o Named after Thomas Hodgkin who first identified abnormalities in the lymphatic system in 1832.
o Characterized by Reed-Sternberg cells with inflammatory background.
 2 Types
o Classical HL
 Subtypes
 Nodular sclerosing (75%)
 Mixed cellularity (20-25%)
 Lymphocyte rich (5%)
 Lymphocyte depleted (<1%)
 Incidence
 2.4 in 100,000
 10% of all lymphomas
 0.6% of all cancers
 Bimodal peak
 Male predominance
 Risk Factors
 Prior Mono/EBV
 Hx of solid organ or stem cell transplant with immunosuppressive drugs
 HIV (5-25x increased risk)
 Autoimmune disease
 Family hx of HL (3-5x)
 Presentation
 Painless lymphadenopathy
 Often localized
 MC location: cervical
 Can be confused as an infection, and often pretreated with antibiotics before HL
diagnosis is considered.
 Labs
 CBC, CMP
 LDH and uric acid are elevated
 Imaging studies
 CXR
 CT Cervical, abdomen, and pelvis +/- neck.
 PET/CT: good for identifying fast growing, highly metabolic cancers.
 Diagnosis
 Excisional biopsy (not FNA)
o Morphology and Immunophenotyping done
o CD15+ and CD30+
o Variable CD20
o CD3- and CD45o Nodular Lymphocyte Predominate HL (NLPHL)
 Uncommon variety of HL
 Different pathologic and clinical features
 More indolent course
 Better prognosis
 15-30% relapse
 Transformation to aggressive NHL higher than other forms of cHD
o NLPHL vs. Classical HL
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Costwald’s Classification
 I: one lymph node group
 II: 2 LN groups on same side of diaphragm
 III: LN involvement on both sides of diaphragm
 IV: as above with BM involvement
 A or B: with or without B symptoms
 E: extranodal
All patients with HL require a bone marrow biopsy!
Adverse Prognostic Factors
 Age >45
 Stage IV disease
 Hemoglobin <10.5
 Lymphocyte count <600 or <8%
 Male
 Albumin <4.0
 WBC >15,000
5 year prognosis based on prognostic factors:
 No factors: 84 months
 1 factor: 74 mo
 2 factors: 67 mo
 3 factors: 60 mo
 4 factors: 51 mo
 5 factors: 42 mo
Early Stage (I-II) Treatment (DON’T NEED TO KNOW SPECIFICS)!!!
 Further Classification
 Favorable vs. unfavorable
 Favorable: younger age, no B symptoms (weight loss, fever) and low ESR <30
 Favorable Treatment
 2 cycles of chemotherapy + involved field radiation
 If 3 sites and/or extranodal disease: 3-4 cycles of chemo + involved field radiation
 Unfavorable Treatment
 4-6 cycles of chemo
 ABVD
Advanced stage treatment
 ABVD 6-8 cycles
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 Excalated BEACOPP
 Stanford V
Chemotherapy
 ABVD:
 Adriamycin, Bleomycin, Vincristine, and Decadron
 Adriamycin: risk of cardiotoxicity, decrease in ejection fraction
 Acute leukemia in 1%
 Pancytopenia
 Bleomycin: risk of pulm toxicity
 Impaired pulm function tests
 Abnormal CXR
 Vincristine: peripheral neuropathy and constipation
Long Term Complications of Therapy
 Radiation-induced hypothyroidism
 Cardiac disease
 Secondary malignancies
 Infertility
Relapse
 Early stage favorable: 10-20%
 Advanced stage: 30-40%
 Primary refractory: 10-15%
Management of Relapse
 Biopsy to prove recurrent disease
 Stage the relapse
 Salvage chemotherapy
 Consolidation w/autologous stem cell transplant
 Still 30% will relapse post-ASCT
 Brentuximab vedotin is an anti-CD30+ monoclonal antibody
 Salvage chemotherapy regimens
 Consideration of allogenic stem cell transplant
Lecture 18-Non-Hodgkin Lymphoma
 Background
o Heterogeneous group of neoplastic diseases derived of monoclonal lymphocytes.
o B or T cell in origin
o Indolent vs. aggressive
o Characterized by morphology, immunophenotype and genetic mutations.
o Incidence is increasing, but rates of mortality are remaining the same.
 More common in Caucasians and less in African Americans.
 Indolent Disease
o Slowly progressive lymphadenopathy
o Cytopenias
o Hepato/splenomegaly
 Aggressive Disease
o Rapidly growing mass
o Systemic B symptoms
o Elevated LDH/Uric acid
 Pediatric NHL
o 5th most common malignancy <15 yrs
o 7% of peds cancers
o 800 cases/yr in the US
o Median age is 10
o >90% remission in stage I/II
o Good prognosis
 Diagnosis of NHL
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Excisional biopsy (not FNA)
Morphology, immunophenotype
Genetic studies
 Conventional karyotype
 FISH
 PCR
Histology
 Nodular (slow growing), Diffuse (aggressive), or Cutaneous
Immunostains
 Germinal cell vs. non-germinal cell lymphoma
Risk Factors
o Family hx
o Prior hematologic malignancy
o Prior chemo or radiation
o Immunosuppressive meds
o Hx of organ transplant
o Pesticides/agent orange
o Infections
 Hep B or C
 HIV
 HTLV-1
 EBV
 Chlamydia pisittaci-can be tx with antibiotics
 Borrelia burgdorferi
o Autoimmune disorders-MC is Sjogren’s
o Immunodeficiency disorders
o Mixed cryoglobulinemia
o Multicentric Castleman’s disease
o Inflammatory GI disorders: Chron’s, Celiac, H.pylori gastritis
Presentation
o Painless lymphadenopathy
o Fatigue
o B symptoms: fever, night sweats, and weight loss
o Less Common:
 Rash, pruritus, malaise, ascites, effusion
Extranodal disease
o 50% of cases have extranodal involvement
o 10-35% present as primary extranodal
o GI-most common
o Primary CNS NHL-rare
Labs:
o CBC, CMP
o LDH and uric acid elevated
o Serum protein electrophoresis-assessment for monoclonal protein
Staging Studies
o CT cervical, abd, pelvis
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o PET/CT scan especially if aggressive disease
o Bone marrow biopsy: morphology, cytogenetics/FISH
Staging System is the same as HL
o I: one lymph node group
o II: 2 LN groups on same side of diaphragm
o III: LN involvement on both sides of diaphragm
o IV: as above with BM involvement
o A or B: with or without B symptoms
o E: extranodal
Prognostic Index
Treatment (DON’T NEED TO KNOW SPECIFICS)!!!!!
o Indolent NHL
 Asymptomatic-surveillance
 Symptomatic:
 Early stage: radiation and single agent rituxan (works against CD20+ cancers,
always included in tx)
 Advanced stage: multi-agent chemo
o Diffuse Large B Cell Lymphoma
 Early stage (I-II): R-CHOP x 3 cycles (1 day every 3 weeks) and involved field
radiation!
 Advance stage (III/IV): R-CHOP x 6-8 cycles
 R-CHOP
 Rituxan (Rituximab)
o Activity is multi-targeted; to kill abnormal B cell. Identifies and binds to
CD20+ B cells.
 Cytoxan
 Adriamycin
 Vincristine
 Prednisone
Prognosis
o Low grade lymphoma has highest survival. No cure is possible
 5% will transform into large b cell lymphoma
o High grade and undifferentiated have lower survival than low grade; pts who survive to 5-10 yrs
have low risk for developing relapse. Cure is possible.
Gene Expression Profile
o Can be used to identify and characterize specific types of NHL.
o May be used to determine prognosis and in the future specific treatment regimens.
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Richter’s Transformation
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Relapsed NHL
o Alternate chemo regimens
o Radiation to symptomatic regions
o ASCT-autologous stem cell transplant
o Allogeneic transplant
o Palliative/symptomatic care
Lecture 19-Multiple Myeloma
 Background
o Neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin
o Spectrum of plasma cell dyscrasia: MGUS, Smoldering MM, Active MM
 Pathogenesis
o Cytokine release, which cause inflammation, angiogenesis
o M-protein secretion
 Epidemiology
o 1% of all cancers; 10% of hematologic malignancies
o 4-5 in 100,000
o Race: black 2-3x > Caucasian
o Gender: male > female (1.4:1)
o Median age: 66
o <50: 10%
o <40: 2%
 Risk Factors
o 1st degree relative: 3.7x
o Increasing age
o MGUS-disease spectrum
 M-spike present, 1% increased risk per year
 Presentation
o Anemia-73% (macrocytic)
o ARF-20%
o Bone pain-58%
o Infection
o Renal dysfunction-48%
o Radiculopathy
o Hypercalcemia-28%
 Labs
o CBC w/peripheral smear
 Rouleaux seen w/multiple myeloma.
o CMP
o B2-microglobulin-used for staging
o Serum protein electrophoresis w/immunofixation
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 Shows a large M-spike, and quantifies the number of M proteins (spike in gamma range)
 Immunofixation is more sensitive to m-protein
o 24 urine for electrophoresis w/immunofixation
o Free light chains
 Broken off from immunoglobulins being produced
o Quantitative immunoglobulins
 Provides IgA, IgM, and IgG levels
 IgG is normally elevated in multiple myeloma
o Bone marrow biopsy
Diagnosis
o Active Multiple Myeloma
 >10% aberrant plasma cells in bone marrow (normal is ~5%)
 Presence of serum or urine monoclonal protein (m-protein)
 End organ damage (CRABI)
 Calcium
 Renal failure
 Anemia (Hgb <10)
 Bone lesions/osteoporosis
 Infection
o Smoldering Multiple Myeloma
 M-protein in serum >3
 >10% aberrant plasma cells
 No end organ damage!!!!!
o Monoclonal gammopathy of undetermined significance (MGUS)
 Serum m-protein <3
 BM plasma cells <10
 No end organ damage
 Follow-up every 6 months (risk for developing multiple myeloma is 1%/year)
o Natural history:
 MGUS  smoldering  multiple myeloma
Immunophenotype (don’t need to know the CD types)!
Staging (International Staging System)-don’t need to know how to stage pts!!!!
Risk Stratification
o Requires: conventional cytogenetics and FISH for myeloma panel
o Favorable, Intermediate, or High-Risk Disease; alters treatment plan
Solitary Plasmocytoma
o Either of the bone or extramedullary
o Treatment is localized radiation
o Increased risk of transition to active multiple myeloma
Imaging
o Skeletal survey to look for fractures and other bone lesions
o MRI-compression fracture/cord compression
o PET scan
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Treatment
o Induction chemo
o Consolidation w/autologous stem cell transplant OR stem cell harvest w/cryopreservation
 Autologous transplant:
 MM is incurable
 5-7 years disease free
 Requires RBC and platelet transfusion
 Prophylactic antibiotics
 Monitor for fever
o Maintenance therapy to prevent remission
o Chemo regimens are based on whether pt is high risk, intermediate risk or standard risk!
 Initially everyone begins with 4 cycles of:
 Revlimid-lenalinomide
o Immunomodulatory
o Induces apoptosis
o Anti-angiogenic
 Velcade-bortexomib
o Inhibits proteasome and increases apoptosis
 Decadron
Relapse
o Revlimid or Velcade depending on timing of last dose
o Other newer drugs that pt hasn’t had before
o Autologous stem cell transplant (allogenic transplant has a much higher mortality)
Plasma Cell Leukemia
o Plasma cells seen in circulation
o Median age is 55
o Poor prognosis
o Pts can transition as progression from MM
Amyloidosis
o Aberrant immunoglobulin deposition in tissues
o Complicates 10% of cases of MM
o Diagnosis: fat pad biopsy
o Cong stain-apple-red bifringence
o Clinical findings:
 Periorbital edema
 LE edema
 Macroglossia-deposits in the tongue
Lecture 20-Thalassemias
 Definitions
o Anemia-Reduction below normal limits of circulating red cell mass
o Alpha thalassemia-hemoglobin abnormality in which there is decreased alpha chain production
relative to beta chain production
o Beta thalassemia-hemoglobin abnormality in which there is decreased beta chain production
relative to alpha chain production
o Normal Hgb: 2 alpha and 2 beta chains
 Hemoglobin Production
o Fetal hemoglobin (2 alpha and 2 gamma chains) is gestation to birth and then tapers off.
o HbA2-minor hemoglobin of adults (2 alpha and 2 delta chains)
 Normally 2-3%
 4-6% in most carriers of beta thalassemia
 Alpha Thalassemia
o Alpha chain is expressed from 2 separate genes on chromosome 16
o Silent carrier-asymptomatic
o Alpha thalassemia trait-mild microcytosis, asymptomatic
HbH disease-severe anemia
Hydrops Fetalis
 Total absence of alpha globin synthesis
 No physiologically useful hemoglobin is produced, only gamma-globin. High O2 affinity, no
O2 to tissues
 Barts hemoglobin (4 gamma chains)
Beta Thalassemia
o Beta thalassemia minor (trait)
 Heterozygous; asymptomatic but have mild microcytic, hypochromic anemia
o Beta thalassemia intermedia
 Homozygous but milder phenotype
o Beta thalassemia major (Cooley Anemia)
 Homozygous and unable to produce any viable HgbA
o Skeletal Changes
 D/t expansion and invasion of erythroid bone marrow, which widens the marrow space,
thinning the cortex and leading to osteoporosis
 Can also cause ‘chipmunk facies’
Diagnosis
o Hgb electrophoresis is the confirmation test!!
o Peripheral smear usually ordered when microcytic, hypochromic anemia
 Shows dacrocytes (teardrops), target cells and Heinz bodies
 Won’t tell what hemoglobin is predom
Treatment
o Alpha thalassemia
 Silent carrier and trait are asymptomatic, no tx required
 HbH may require periodic transfusions and monitoring for iron overload
 Hydrops fetalis is lethal in utero
o Beta thalassemia
 Minor-asymptomatic and no tx required
 Intermedia
 Transfusions eventually required
 Closely monitor iron stores
 Consider splenectomy in severe cases
 Major
 Hypertransfusion: 1-3 units of pRBCs q3-5 weeks to keep Hgb >9
 Splenectomy
 Iron chelation therapy
o Splenectomy d/t splenomegaly
 Intact spleen causes shortened survival of transfused RBCs and progressive worsening of
anemia
 Vaccines for encapsulated organisms
Practice Qs
o Anemia associated with beta thalassemia minor
 Mild, microcytic, hypochromic, asymptomatic
o Anemia associated with beta thalassemia major
 Severe, microcytic, hypochromic, symptomatic
o Anemia w/alpha trait
 Mild, microcytic, hypochromic, asymptomatic
o Hydrops Fetalis
 Lethal, alpha thalassemia. Hgb barts
o What Hgb is made of 4 beta chains
 Hgb H in alpha thalassemia
o What Hgb is made of 4 gamma chains
 Hgb Barts in Hydrops fetalis
o Tx of types of thalassemias
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Screening and confirmation tests of thalassemias
 CBC w/peripheral smear and Hgb electrophoresis to confirm
Lecture 21 HIV and AIDS I
 Epidemiology
o ~1.1 million living w/ HIV/AIDS.
o ~40% not receiving care
o ~20% who don’t know they are infected
o 56,000 new cases/year
 RNA Virus
o Contains reverse transcriptase
o GP120 for binding to cells
o Primarily infects Helper T cells
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o Various drugs interact with these different steps.
CD4+ T Cell Count and HIV Virus
o CD4 total amount and the HIV virus are inverse of each other.
o CD4 total tells how strong the immune system is, represented by a total and a percentage
o Normal levels are 500-1500 T cells; 35-40%
o Associated with certain diseases when either is low.
o See slide 20 for inverse relationship of CD4 and HIV viral load.
Host Factors that Influence HIV transmission
o Reduced susceptibility
 CCR5 mutation
 If homozygous then profound reduction in acquiring HIV infection and no progression of
AIDS; if heterozygous minimal reduction in acquiring infection and minimal delay in
progression.
AIDS
o Positive HIV test and CD4 count <200, or positive test w/certain infections
o Terminal stage of disease
o Highly infectious
o Could appear completely healthy.
o Defining Conditions
 Candida of esophagus, trachea or lungs
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 Invasive cervical cancer
 Extrapulm coccidiomycosis
 Extrapulm crypto
 Cryptosporidiosis
 CMV retinitis
 Extrapulm histoplasmosis
 HIV associated dementia
 HIV wasting
 Kaposi’s Sarcoma
 Certain lymphomas
 TB
 PCP pneumonia
 Recurrent bacterial pneumonia
 Progressive leukoencephalopathy
 Recurrent salmonellosis
 Toxoplasmosis
o CD4 counts <200 and below 14%, will put patient at higher risk for opportunistic infections
HIV-2 vs HIV-1
o HIV-2
 West Africa
 Steady or decreasing infection rate
 Avg age is 45-55
 2x avg mortality
 Can’t use NNRTI or fusion inhibitors
 Screen + HIV 1/2
o HIV-1
 Worldwide spread
 Increasing infection rate
 Avg age 20-34
 10x avg mortality
 Native virus susceptible to all drugs
 Screen + HIV 1/2
Transmission and Testing
o Who should be tested
 Routine, voluntary testing for all persons 13-64 not based on risk
 Likely ‘opt out screening is better’-screen everyone, and choose not to test if pt doesn’t want
testing.
 Repeat annual HIV screening of person’ with known risk
 Testing easy and available in all healthcare settings
o Transmission Factors
 AIDS
 STDs
 Genital lesions
 Frequency of unprotected sex
 Circumcision-debate if there’s increased acquisition or increased transmission
 Viral load
o Testing
 Two stages of testing: screening and confirmation
 HIV Screening tests (very sensitive >99.5%) not as specific (>95%)
 Several types available: ELISA and Nucleic Acid testing
 ELISA
o Non-reactive or reactive
o Very easy to perform, cheap, available in home testing
o 4th generation, detection in window period ~16 days
o Detects both HIV-1 and HIV-2
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Nucleic Acid Testing (HIV-1 RNA)
o Detects virus even in window phase (acute HIV)
o Only able to detect HIV-1
o Non-FDA gives false positives in low prevalence populations
Confirmation Testing
 Western Blot: looks at different HIV surface proteins
o Positive, negative, or indeterminate
 HIV-1 RNA Genprobe Aptima (only one HIV approved)
o Quantitative amount or undetectable
 Immunofluorescence
o Not commonly used; positive, negative or indeterminate
False Negatives/Positives
 Affected by window period primarily (lag time after infection where antibodies
aren’t produced)
 Several other causes, see slide 37 for more details.
ELISA is best test for screening plus HIV-1 RNA detection to confirm.
 HIV-1 western blot
Lecture 22-HIV and AIDS II
 Acute Retroviral Syndrome
o HIV ELISA can be negative during acute retroviral syndrome
o Requires high index of suspicion
 May have fever, fatigue, rash, pharyngitis as MC symptoms
 Duration usually <2weeks
 DDx includes mono, secondary syphilis, acute hep A or B, roseola or other viral exanthems,
toxoplasmosis.
 Primary HIV Infection
o Period from initial infection with HIV to complete sero-conversion
 Acute retroviral syndrome
 Window period
 Time during which a recently infected person will have a negative HIV test
 Up to 6 months
 Associated w/very high HIV viral load
 Can be associated w/symptoms
 Condom use required
 Retesting necessary
 When to Start Therapy
o Varies depending on resources
o In the US, CD4: 350-500 to start HAART
 If CD$>500, panel recommends consideration strongly for starting treatment
o No longer is HIV viral load considered in starting treatment
o Exceptions, regardless of CD4 count
 Pregnancy
 Hx of AIDS-defining illness
 HIV associated nephropathy
 HIV/Hep B virus co-infection
o Delay HAART:
 AIDS and cryptococcal meningitis: delay preferred
o Issues When Selecting HAART regimen
 Activity of HAART on load and CD4
 Prior HAART use
 Chance of drug resistance
 Tolerability
 Convenience
 Preserving future tx options
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 Other co-illness
 Drug-drug interaction
 Access and cost
o Prior to Starting
 Genotype is important!!!
 Hep B/C status
 Renal function
 Hepatic function
 CD4 count
 Pregnancy status or chance of
o Several drugs available!!
o Starting Regimens
 1 NNRTI + 2 NRTIs
 Preferred NRTI is all regimens is tenofovir/emtricitabine
 1 Protease inhibitor + 2 NRTIs
 Preferred protease is atazanavir alternative is darunavir
 1 integrase inhibitor + 2 NRTIs
 Raltegravir
o Med Side Effects
 Life threatening
 Hepatitis: NNRTI and PI
 Hypersensitivity syndrome: abacavir
 Lactic acidosis: NRTIs
 Pancreatitis: DDIs/stavudine
 Teratogencity: efavirenz
 Kidney stones: indinavir >>atazanavir
 Morphologic fat changes: PIs and stavudine
 Peripheral neuropathy: DDIs and stavudine
 Dreams: efavirenz
 Indirect hyperbilirubinemia: atazanavir
 Anemia, neutropenia: zidovudine (AZT)
o Morphologic Complications
 Fat loss (lipoatrophy)-occurs d/t some of the older drugs.
HIV and Pregnancy
o Transmission
 Antenatal ~20%
 Intrapartum ~80%
 Breastfeeding ~14%
o Genotype if possible
o 3 drug treatment
o Lopinavir/ritonavir + lamivudine and zidovudine
HIV and Hep B
o Co-infection very common, early testing recommended if either virus found
o Lamivudine, emtricitabine and tenofovir all have activity against Hep B
o Two active Hep B-HIV drugs recommended
o Once started do not abruptly stop HIV meds if tx Hep B co-infection, can lead to fulminate
liver failure.
Immune Reconstitution Inflammatory syndrome
o Happens to pts 4-8weeks after being started on HAART therapy
o Dysfunction of the immune system coupled w/presence of opportunistic pathogen
o Clinical presentation depends on organ or system involved
o Tx with steroids
AIDS and Systemic Disease
o Hematologic
 Thrombocytopenia, ITP
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 Improves w/HAART
 TTP can occur, but rare
 Anemia d/t HIV induced BM suppression
 Neutropenia and eosinophilia can also be seen, improves w/meds
Oncology
 Kaposi’s sarcoma-non painful, papular purplish skin lesions
 Non-Hodgkin’s lymphoma
 CNS lymphoma
 Anal cancer-HPV related in almost all cases, painful or painless anal mass. HPV related.
GI Tract
 Nausea, anorexia, diarrhea, dysphasia
 Can be related to common non-HIV related disease, HAART therapy, opportunistic
pathogens or advanced AIDS
 Sometimes requires biopsy of GI tract
Neurological
 Mostly in advanced AIDS
 Neuropathy, radiculopathy, and dementia
 Few conditions occur early in course
Renal
 Very common complications
 HAART medications, tenofovir (induced RTA) and indinavir (renal stones), other AIDSrelated tx or opportunistic prophylaxis