A case of refractory, severe,steroid-dependent asthma

A case of refractory, severe,steroid-dependent asthma
By: Bruce S. Bochner, M.D.

* 24 y/o AA female referred in 2/99 from southern Maryland for evaluation and management of uncontrolled asthma
* At the time, 20 weeks pregnant (G5, P4)
* Last two pregnancies were complicated by uncontrolled asthma and oral steroid use throughout the pregnancy
* H/O asthma since age 12, frequent episodes of wheezing & cough without any obvious triggers or seasonal pattern
* Review of accompanying records revealed that her FEV1 can range from 30% to 80% predicted on any given visit

* Early on, exacerbations 1x/yr, necessitating ER visits
* Initially treated with Cromolyn, Vanceril and Albuterol
* Since 1992, worsening asthma, increased ER visits and for 1998 at least 6 hospitalizations
* In 1992, found to have multiple positive skin tests, tried on ImTx w/o improvement; in fact, exacerbations of wheezing with most shots
* Frequent courses of antibiotics for bronchitis or sinusitis

* At the time of her 2/99 visit:
o Daily nocturnal symptoms
o Wheezing with minimal activity
o Normal CXR
o managed with Prednisone 30 mg qAM, Flovent 110 2 puffs BID, Serevent 2 puffs BID, Alupent 2 puffs q3h and nebs PRN, Atrovent 4 puffs BID, Accolate 20 mg BID, and Cromolyn q3h

* Drug allergy Hx: acute rashes from Penicillin, Codeine, Ceclor; Erythromycin caused GI upset
* Environ. Hx: Born and raised in MD, lives in a separate home, no pets
* Family Hx: All of her four kids (two different fathers) have asthma; current pregnancy is with a third father

* PE:
o Vitals: BP 105/66, P 112, RR 18, Wt 168 lbs, peak flow best effort 130 liters/min
o GEN: Mild Cushingoid facies, no rashes
o HEENT: Nasal exam normal, no lymphadenopathy or thyromegaly
o LUNGS: Diffuse expiratory wheezing and prolonged expiratory phase; sounds were in chest but not neck
o HEART: Normal S1, S2.
o EXTREMITIES: No peripheral edema

* SPIROMETRY
o FEV1: 1.1 liters (36% predicted), FVC: 1.62 liters (42% predicted), ratio 0.68. Post-bronchodilator FEV1 1.89 liters (79% increase), FVC 2.34 liters (44% increase)

* TREATMENT CHANGES
o At this visit, patient was switched from Flovent to Pulmicort 4 puffs bid
o The rest of her medications were continued
o Inhaler technique was observed to be correct
o Husband verified medication adherence.

* Delivered the baby on continuous nebs. Baby and Mom did fine. 5 weeks postpartum admitted to Hopkins Bayview for 5 days for worsening SOB, wheezing and leg pain
* On admission, wheezing; PEF 100 liters/min
* V/Q scan and leg dopplers normal
* FEV1 28% predicted; flow-volume loops normal
* CT scan of sinuses revealed pan-sinusitis
* 24-hr pH probe documented significant GERD
* Discharged on 24-day steroid taper with markedly improved lung function at discharge; started on antibiotics and Prilosec

* Since 2000, multiple ER visits
o two prolonged intubations in 2000 and 2001
+ 2000: complicated by full respiratory arrest and persistent doll’s eyes
+ 2001: complicated by bilateral pneumothoraces requiring chest tubes and a DVT; s/p IVC filter
* Multiple meds tried in 2000-2001 included Advair, Pulmicort respules, Theophylline, and Methotrexate. None had a significant impact on our ability to taper oral steroids.

* In 10/01, sent for an outpatient evaluation by me to National Jewish (made possible through philanthropic help from NJC, AAFA and her local church) with dx of severe, labile steroid-dependent asthma
* Diagnosis quickly confirmed when she required admission for worsening SOB and wheezing

* Skin tests positive to dust mites, grasses, alternaria
* Alpha-1 antitrypsin: normal
* CF genotyping: normal
* No peripheral blood eosinophilia
* Total IgE: 123 IU/ml
* Chest CT: no interstitial disease
* Bone densitometry: normal
* Sinus CT: mild sinusitis
* Oral steroid kinetics normal

* Seen by Drs. Barry Make and Sally Wenzel
* After stabilization with IV steroids and nebs, underwent bronchoscopy
* Found to have some collapsibility of her larynx with exhalation which they felt would be helped with CPAP
* Sleep study found sleep apnea for which CPAP was also recommended

* Bronchoscopy (on IV steroids) revealed prominent basal lamina thickening and a mild inflammatory infiltrate, primarily lymphocytic

* After 3 weeks, sent back to Baltimore on the following regimen:
o Serevent 3 puffs q12
o QVAR 6 puffs bid
o Atrovent 4 puffs qid
o Uniphyl 400 mg qhs
o Singulair 10 mg qhs
o Zyflo 600 mg qid
o Prilosec 40 mg qd
o Supplemental Calcium
o Prednisone 40 mg q am, 20 mg q afternoon
o Nasonex 1 spray bid
o CPAP

* Within 2 months, back to pre-Denver management
* 2002 to 2003
o Managed primarily with Prednisone (40-80 mg/day), Prilosec and Albuterol
o Extremely Cushingoid; now weighs 240 lbs
o Tried Xopenex w/o any additional benefit
* September 2003
o Started Xolair one vial q month (completely covered by her insurer)
o Still had ER visits but no hospitalizations while on Xolair
o Despite this, after seven months, Prenisone, q3h albuteral requirements and FEV1 remained unchanged
o She became frustrated, so we discussed other options (Enbrel) and stopped Xolair

Pathophysiology of allergic airway inflammation
Model of IgE-dependent acute and chronic allergic inflammatory reactions
Leukocyte recruitment in allergic disease
Soluble Tumour Necrosis Factor Alpha (TNF-a) Receptor (Enbrel) as an Effective Therapeutic Strategy in Chronic Severe Asthma
Respiratory Cell & Molecular Biology
Study design
* Open label, single center study
* Subjects with chronic severe asthma on oral corticosteroids, high dose inhaled corticosteroids, salmeterol, and/or theophylline
* 25 mg of Enbrel administered subcutaneous twice a week for 12 weeks
* Subjects aged 18-65 years
* FEV1 of at least 50% predicted
* Demonstrated a reversibility of at least 9%
* Lung function, methacholine response performed before and after treatment
* Asthma control symptom questionnaire completed before and after the trial
* Diary cards issued to assess peak flows and use of rescue medication

Results

* 15 subjects enrolled in the trial
* 11 female, 4 male
* Mean age of the patients: 41 yrs
* Mean duration of asthma: 24 years
* Mean dose of oral prednisolone: 12.1mg/day
* Mean dose of inhaled corticosteroids
o 2500 ľg/day of beclomethasone or equivalent
* Mean dose of nebulised albuterol: 8 mg/day

Changes in FEV1 with Enbrel

WEEK 1 WEEK 12
Changes in Symptom Scores with Enbrel
Symptom score (Juniper Scale)
Adverse effects
* Skin rashes (4)
* Injection site reactions (4)
* Respiratory tract infections (7)
* Weakly positive ANA (3)

Conclusions
Treatment with Enbrel in patients with chronic severe asthma:

* Improves lung function (FEV1, FEV1/FVC, morning and evening PEF)
* Markedly improves asthma control
* Markedly improves airway hyperresponsiveness
* Markedly reduces the need for rescue medications as all the subjects completely withdrew from their nebulised albuterol by the end of the study

* April - early June 2004
o Started Enbrel 25 mg sq twice weekly (completely covered by her insurer) after PPD was negative; husband trained on administration technique
o Two weeks later, she was admitted for an asthma exacerbation associated with nausea, fatigue, myalgias and unexplained fevers to 102° despite Enbrel and prednisone; discovered Prilosec had been stopped
o Infectious workup unrevealing; IV steroids given
o Enbrel dosing held for 2 weeks, fever resolved
o Enbrel restarted and 1 week later she was admitted for another asthma exacerbation
o Enbrel discontinued

* June 21: planned to restart Xolair but got admitted again
* Discharged June 22
* Seen June 23
o FEV1 60%; FVC 93%
o Diffuse wheezing on Prednisone 80 mg
o Restarted Xolair 300 mg q 4 weeks
o Restarted Serevent diskus 1 puff BID
* What next????

Our ongoing work on TNFa and allergic inflammation

* There is a tissue-specific pattern of chemokines/cytokines/adhesion molecules involved in human allergic inflammation
* This pattern is TNF- dependent
* The primary source of TNF- released in human allergic inflammation is the mast cell

Etanercept in late phase cutaneous allergic inflammation: study overview

* Randomized DBPC Trial
* To evaluate effects of etanercept (Enbrel) on cutaneous allergen LPR in 10 perennial allergic rhinitis/dust mite sensitive patients
* 15 visits to JHAAC over 8.5 wks
* Lead investigators: Lisa Beck, Ed Conner, Bruce Bochner

Study Purpose

* To evaluate the clinical effects of etanercept on cutaneous allergen challenge late phase responses
* To evaluate the effects of etanercept on the allergen dose response
* To characterize a variety of biomarkers in the cutaneous late phase responses
* To assess limited pharmacokinetic data of etanercept in the serum and nasal washings

DBRPC Crossover Study Design
A case of refractory, severe,steroid-dependent asthma.ppt

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Occupational Exposures to Bloodborne Pathogens

Occupational Exposures to Bloodborne Pathogens
By:Arjun Srinivasan
Johns Hopkins Hospital

Outline
* What’s an exposure?
* 1st step in all exposures - Clean the site!!
* Specific pathogens
o Hepatitis C
o Hepatitis B
o HIV

Scope of the Problem
Impossible to measure the psychological stress that an exposure places on a health care worker
At Risk Exposures
1. Percutaneous injury
Hollow needle > Solid sharp
Visible blood
Deep injury
Device in patient’s artery or vein
2. Splash on non-intact skin
3. Splash on mucous membrane

Risks From Body Fluids
* Known to be infectious:
o Blood
o Any fluid visibly contaminated with blood
o Semen
o Vaginal secretions
o Concentrated virus (used in labs)
* Potentially infectious
o CSF
o Pleural fluid
o Pericardial fluid
o Peritoneal fluid
o Amniotic fluid
o Synovial fluid
o Tissue samples
* Not Infectious (if not visibly bloody)
o Tears
o Saliva
o Urine
o Feces
o Sweat
o Emesis

The Solution to Pollution . . .
* Exposure site should be cleaned IMMEDIATELY! This may be the most important part of PEP
* Skin wounds should be washed with soap and water
* No evidence that antiseptics are useful and caustic agents (bleach) may do more harm than good
* Mucous membranes should be flushed thoroughly with water
* Eyes should be irrigated with a liter of saline

A word from our lawyers . . .
* ALL exposures should be reported to the proper people (Occupational health, Employee health etc.)
* Disability claims can be denied if follow up reporting was not done right

Hepatitis C
Hepatitis C: Risk of Exposure
Hepatitis C: Risk of Disease
Post Exposure Recommendations
* Clean the site immediately
* Hepatitis B immune globulin has NOT been effective
* Interferon is NOT recommended at this time
Hepatitis C: Follow Up
* Enzyme linked immunoassay (EIA) is screening test of choice
* ALL exposed HCWs should have LFTs monitored
* Average interval between exposure and seroconversion with EIA is 8-10 weeks
* Follow up guidelines vary - CDC recommends follow up at 4-6 months
Hepatitis C: Follow up issues
* EIA is falsely positive in up to 50% of HCW and falsely negative in 5% - results must be confirmed by RIBA or VL
* PCR may catch infection earlier but detection is highly variable
* Immediate referral for treatment if HCW seroconverts
Hepatitis C: Counseling
* Risk of transmission to infants and partners is thought to be low
* Exposed HCW do not need to modify sexual practices, stop breast feeding or refrain from becoming pregnant
* Should not donate blood

Hepatitis B
Hepatitis B: Risk of Exposure
Hepatits B: Outcome of Infection
* In patients who are infected with Hep B:
o 25% get jaundice
o 5% require hospitilization
o 6-10% become chronically infected
o .125% die of fulminant hepatitis

Hepatitis B: Good News
* Most HCWs have been vaccinated and vaccine offers virtually complete protection to responders
Hepatitis B: Bad News
* Some employees are NOT vaccinated
* 6-10% of vaccinees do NOT develop antibody
* Really bad news:
CDC estimates that 50-75 HCW die from Hep B each year
Hepatitis B: Post Exposure
* Clean the site immediately
* Determine the vaccine status of the HCW
* Determine the surface antigen status of the source patient

Hep B: HCW Never Vaccinated
* HCW should receive vaccine ASAP
1. Source patient is sAg positive:
HCW should also receive one dose of Hep B immune globulin (HBIG) .06ml/kg (1 vial=5 ml) ASAP and absolutely within 7 days of exposure
2. Source patient sAg neg or unknown
Vaccine alone
Hep B: HCW Vaccinated (one or more doses)
* Source patient should be tested for sAg AND HCW should be tested for sAb
* If HCW has adequate Ab >10 IU/mL (now or at any time) then no additional treatment
* IF HCW has inadequate Ab:
1. If pt is sAg negative:
HCW should get booster dose of vaccine (or complete series)
2. If pt is sAg positive:
HCW should receive HBIG AND a booster dose of vaccine at different sites (complete series if necessary)
If HCW has inadequate Ab:
3. Unknown source:
Give vaccine booster or complete series
Vaccine non-responders
* If HCW has inadequate Ab after 3 dose series they should get another series: 30-50% chance of responding to 2nd series
* If no response to 2nd series HCW should be considered susceptible
* PEP for known non-responders exposed to Hep B positive or high risk unknown sources: 2 doses of HBIG- 1 at exposure then 4 weeks later
Hep B: Follow Up Testing
* Hepatitis B sAg is the test of choice as it rises in about 6 weeks
* LFTs should be monitored at regular intervals
Post Exposure Counseling
* Risk of transmission to infants and partners is thought to be low
* Exposed HCW do not need to modify sexual practices, stop breast feeding or refrain from becoming pregnant
* Should not donate blood
HIV
HIV: Risk of Exposure
* Risk of transmission from percutaneous expsosures involving HIV positive pts estimated at 0.3%
* Risk from mucous membrane exposure estimated at 0.1%
* As of 2000 there were 56 confirmed and 138 possible cases of occupational transmission in the US
Rationale for PEP
* HIV infects dendritic cells and then regional lymph nodes before becoming systemic
* AZT blocks infectivity of HIV infected dendritic cells
* Goal of PEP is to halt viral replication before systemic infection is established

Does It Work?
* Several animal studies showing efficacy
* Peri-natal prophylaxis has been effective
* Retrospective study showed that risk of seroconversion after exposure was 81% lower in HCWs who took AZT PEP.
Time is Virus
What To Use?
* Before: AZT+3TC +/- IDV or NFV
* Now: Becoming more difficult to answer!
* Regimens may need to be tailored based on the treatment history of the source patient -Surveillance study from 1998-1999 found that 39% of virus from source patients had some NRTI resistance and 10% had some PI resistance.

Nucleoside Reverse Transcriptase Inhibitors (NRTI)
* Still form the backbone of most regimens
* AZT has been formally studied thus it should be included if possible
* Addition of 3TC is recommended because:
1. It appears non-toxic
2. It has some synergistic effect with AZT with respect to mutations
* If source patient’s virus is felt to be resistant to AZT or 3TC alternatives include:
* d4T + 3TC
* d4T + ddI
* Role of abacavir?
* Role of tenofovir?
Protease Inhibitors (PI)
* Are very potent anti-virals and work very well in patients
* BUT they have significant side effects and can cause HCW to stop PEP altogether
* PI should be recommended primarily when the exposure is high risk
* Any PI can be used but indinavir and nelfinavir have been used the most
Non Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
* Not much experience using these for PEP
* Use should be reserved for situations when source patient’s virus is thought to be resistant to all PIs
* Nevirapine should probably be avoided as PEP: from 1997-2000 there were 22 reports of serious toxicity in HCW taking it for PEP

Toxicity of PEP
Side Effects of PEP
PEP Counseling
* Clean the site immediately
* Determine the HIV status of the source
* Determine the extent of the exposure
PEP management: Source Patient Testing
* Crucial 1st step as most exposures do NOT involve HIV positive patients
* Rapid test kit (SUDS) is available and yields an answer in about 30 minutes
* Rapid test is an EIA that is >99.9% sensitive
* Testing of blood on sharps is NOT recommended
* Patient consent is required in Maryland
HIV RNA Testing of Source
* No official recommendations and test is not approved for this indication
* Should be reserved for cases where there is a suspicion of acute retroviral conversion

Source Patient
1. Patient HIV negative - No PEP
2. Patient HIV positive
Low viral load / high CD4 = class 1
High viral load / low CD4 = class 2
3. Patient HIV positive, unknown CD4, VL
Use best judgement - err towards class 2
4. Unknown source
Exposure Types
1. Non-infectious fluids - No PEP
2. Mucous membrane, non-intact skin
Small volume
Large volume
3. Percutaneous injury
Less severe
More severe
HIV PEP Recommendations
Percutaneous injuries
Less severe
* Source pt HIV negative - No PEP
* Source pt class 1 - Recommend 2 drugs
* Source pt class 2 - Recommend 3 drugs
* Source of unknown status- Consider 2 drugs in setting where exposure to HIV positive pt likely or if pt has HIV risk factors

HIV PEP
More severe injury
* Source pt HIV negative - No PEP
* Source pt HIV class 1 or 2 - Recommend expanded 3-drug regimen
* Source of unknown status - Consider 2 drugs in setting where exposure to HIV positive pt likely or if pt has HIV risk factors
HIV PEP
Mucous membrane exposures
Small Volume
* Source pt HIV negative - No PEP
* Source pt class 1 - Consider 2 drugs
* Source pt class 2 - Recommend 2 drugs
* Source of unknown status- Consider 2 drugs in setting where exposure to HIV positive pt likely or if pt has HIV risk factors
Large volume
* Source pt HIV negative - No PEP
* Source pt class 1 - Recommend 2 drugs
* Source pt class 2 - Recommend 3 drugs
* Source of unknown status- Consider 2 drugs in setting where exposure to HIV positive pt likely or if pt has HIV risk factors
Duration of Treatment
* Current recommendation is 4 weeks but this is an arbitrary selection
* Animal studies suggest 10 days is too short but 28 days conferred protection
Resistance
* Becoming a significant problem now that so many patients are getting treated
* Treatment history can be helpful in the acute setting
* Recent history may be more important than remote
Resistance Issues
* Full medical history often not available when the exposure occurs - PEP should NOT be delayed
* Data from maternal transmission studies shows viral resistance does not preclude benefit
* Consultation with someone experienced in HIV treatment is recommended in cases where HIV resistance is possible
* PEP may need to be modified once more history is available
* Resistance testing is too slow to be of use right now

PEP and Pregnancy
* Women of child bearing age should be offered a pregnancy test before starting PEP
* BUT, recommendations on starting PEP should NOT change just because HCW is pregnant

HIV medications to avoid in Pregnant HCW
* d4T, ddI: have been associated with severe lactic acidosis in pregnant women
* Efavirenz: is teratogenic in primates
* Indinavir: causes hyperbilirubinemia in newborns if given near time of delivery

Post Exposure Testing
* Testing should be done at regular intervals (eg 6,12 weeks and 6 months)
* Testing should continue for 12 months if the HCW contracts HCV from the exposure
* Unclear if testing should be prolonged in exposures to pts with HIV and HCV or in HCW who have history of impaired Ab responses
* EIA is test of choice
* Viral loads and p24 assays should be reserved for suspected cases of acute seroconversion given high false pos rate
Counseling
* For 3 months following exposure HCW should avoid:
-unprotected sex
-donating blood
-sharing razors, toothbrushes
* HCW should consider stopping breast feeding (risk of perinatal transmission and drugs may get into breast milk)

Time to Seroconversion
* Most HCW seroconvert in 6-12 weeks with median time of 46 days
* 95% seroconvert within 6 months
* 100% seroconvert in one year
* Co-infection with HCV may delay HIV seroconversion

Acute Retroviral Conversion
* Symptomatic seroconversion develops in 50-90% of cases
* Average time from exposure to symptoms is 2-6 weeks
* ANY HCW who develops a flu-like illness in the follow up period should be encouraged to get HIV RNA testing

Resources
Conclusion

* People react very differently to exposures - be prepared for anything!
* The psychological impact of an exposure can be enormous
* Your patience and understanding may be the best PEP of all

Occupational Exposures to Bloodborne Pathogens.ppt

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Prenatal Testing And Screening

Prenatal Testing And Screening
By:Adel D. Gilbert, MS, CGC
Genetic Medicine Education Coordinator
Institute of Genetic Medicine
Johns Hopkins University

Genetics Board Review Lecture
Lecture Outline
* Definitions
* Age related risks
* Etiology and phenotype of chromosome anomalies
* Risks, phenotype and testing options of ONTD
* 1st and 2nd Trimester Prenatal Testing Options
* 1st and 2nd Trimester MS Screening Options
* New approaches to combining these tools
* Ultrasound as a screening tool

Testing Defined
Screening Defined
* Identify those at increased risk who are not be perceived to be at risk
* Does not dx definitively
* Follow-up options available for definitive information
* Sensitivity=True positives/all affected
* Specificity=True negatives/all unaffected
Baseline Risk for Having a Child With a Serious Birth Defect
Phenotype
* Moderate mental retardation
* Characteristic facies
o upslanting palpebral fissures
o epicanthic folds,
o midface hypoplasia,
o macroglossia
* Congenital malformations
o heart (30-40%), atrioventricular canal
o gastrointestinal tract, such as duodenal stenosis or atresia, imperforate anus, and Hirschsprung disease
o Leukemia (both ALL and AML) 10-20x
o acute megakaryocytic leukemia occurs 200 to 400 times more frequently in the Down syndrome
o 90% have significant hearing loss, usually of the conductive type
Facial
* microcephaly with prominent occiput
* narrow bifrontal diameter
* short palpabral fissures
* low-set malformed ears
* cleft lip +/- palate
* narrow palatal arch
* micrognathia

Skeletal
* neck
* webbed
* chest
* short sternum
* widely spaced nipples
* hips:
* small pelvis, congenital dislocation of the hips, limited hip abduction
* extremities:
* phocomelia
* rockerbottom feet or equinovarus short dorsiflexed big toes fixed flexion deformity of the fingers (overlapping of the 2nd and 5th fingers over the 3rd and 4th fingers)simple arch pattern of the fingers and toes

hypoplasia of fingernails single crease of 5th finger or all fingers (absence of interphalangeal flexion creases)
Trisomy 18
Kleinfelter syndrome
Miscarriage
Turner syndrome
Neural Tube Defects
* Second most common major congenital defect (1-2/1000)
* Not a chromosome anomaly
* Routinely tested and screened for in pregnancy
* Failure neural tube to close at 28 days gestation
* 20% are closed lesions and difficult to detect prenatally

Open Neural Tube Defects
Closed lesions
Open lesions
INDICATIONS FOR PRENATAL DIAGNOSIS
PRENATAL DIAGNOSTIC PROCEDURES
* AMNIOCENTESIS
* CHORIONIC VILLUS SAMPLING
* PERCUTANEOUS UMBILICAL CORD SAMPLING

AMNIOCENTESIS
ULTRASOUND GUIDED
AMNIOCENTESIS
Amniocentesis Testing
* Chromosome analysis
* AF-AFP levels
* Acetylcholinesterase
* Risk of miscarriage associated with procedure 1/100-1/400
Advantages
* Highly reliable results 99+%
* Familiar
* Long standing reputation
* NTD detection
Disadvantages
* Late in gestation
o Decision making
o Privacy
o Mom feels movement
* Fear of needles
* Needle invades the sac

Fetus: 12 weeks gestation
Transcervical
Chorionic Villus Sampling
Transabdominal
Performed >10 wks-13 weeks
Chromosome analysis
Risk 1/100-1/200
* trophoblastic shell cells
* Syncitiotrophoblasts – poly-proliferate tissue type=directs
* cytotrophoblasts
* Mesodermal core=tissue culture
* frorm finger-like extensions

Disadvantages
* Placental mosaicism 1% of CVS is confirmed in the fetus ~ 10-40%
* Second trimester amniocentesis mosaicism ~ 0.1-0.3% & confirmed in a fetus up to 70% of the time.
* ?LRD risk prior to 70 days gestation (10 weeks)
* Higher loss rate
* Less access to procedure
* Higher chance of insufficient sample
* Early test=risk of sampling a fetus potentially destined to miscarry
* No ONTD testing
* More risk of vaginal bleeding
* Speculum

Benefits
* Earlier in gestation
* rapidly growing cell cultures practically free of maternal cell contamination
* an efficient direct method to obtain high quality metaphases from the of the syncitiotrophoblasts tissue which the fetal karyotype is defined within a few hours of chorionic villi sampling (specialty cyto techinque)
* is suitable for a rapid, direct diagnosis of the related metabolic diseases.
* placental mosaicism (trisomic rescue in fetus) can increase the risks of genetic abnormalities such as uniparental disomy

Fetal Blood Sampling
Percutaneous Umbilical Cord Sampling
(PUBS) or Cordocentesis
* ~2% risk of loss
* Technically difficult prior to 20 weeks
* Blood disorders such as hemophilia and anemia
o Useful for detection of Rh isoimmunization of the fetus (blood cell count and oxygen level)→erythroblastosis fetalis (HDN)
* Chromosomal abnormalities Fetal karyotype in 48 hours
* Infections such as toxoplasmosis and rubella.
* The procedure is also used to perform blood transfusions to the fetus and to administer medication directly into the fetal blood supply.

Reproductive Decision Making
RISK Fetal Aneuploidy
Procedure Related RISK
TO TEST OR NOT TO TEST
* I want to know
* The benefits outweigh the risks
* Options are desirable
* Because my doctor says so…..
* Not sure I want to know
* Risks are a big worry
* Options stink
* Because my doctor says so….

SECOND TRIMESTER
MATERNAL ANALYTES FOR ANEUPLOID
SCREENING
FETAL
Alpha-fetoprotein- AFP
Estriol- uE3
PLACENTAL
Estriol- uE3
Human chorionic gonadotrophin- hCG
Inhibin-A

2nd Trimester MSS Overview
Used for detection of:
+ ONTD
+ Down syndrome
+ trisomy 18
+ Smith-Lemli-Opitz syndrome
Serum Marker
Smith Lemli Opitz Syndrome
* Defect enzyme in the conversion of 7-dehydrocholesterol to cholesterol.
* Affects 1 in 20,000 to 40,000 births
* Autosomal Recessive
* Mental Retardation
* Slow growth
* Heart defects
* Facial cleft
* Screen positive women have uE3 < 0.4 MoM
* ~2% baby affected
* Testing AF for 7-8- dehydrocholesterol (7/8-DHC) levels

Turner T13 Triploidy Pregnancy complications
ONTD screening
Detection Rates
MSAFP
Add Ultrasound
Screening for DS
2nd Trimester 1/270 Cut-off
First Trimester Integrated Screening For Trisomies =FIRST
Nuchal Translucency (NT)
First Trimester Screening
Down syndrome DR ~1:270 Cut-off
Nasal bone
Recommendations 1st Trimester Nuchal >3.5
* CVS
* Targeted ultrasound evaluation 18-20
* Echocardiogram
* Residual 5-6% risk neonate may have a yet undefined genetic syndrome…
Fetal Nasal Bone
* 65% DS have absent nasal bone
* General population 1%
o African Americans 8%-10%
* Secondary screen
* Difficult to obtain
* Higher false positive in 1st

Integrated Screening
PAPP-A and Nuchal
Quad Screen
Screen Positive
Screen Negative
Timeline weeks
Decision Making
Advantages
* Increases detection rate
* Decreases false positive rate (fewer tests and fewer procedure related losses)
Disadvantages
* Long wait time for result
* Unable to utilize CVS and early detection
* Late GA by the time amnio results final
Contingent

First Trimester Screening
High risk
Low Risk
Intermediate
Triple Screening Integration
Offer CVS
High risk
Low Risk
US and Amnio
Stop
Advantages
* Increase detection rate 90%
* Decrease FPR 2%
* Reduce the number of amnios performed in low risk pregnancies
Disadvantages
* New (limited data)
* Hard to determine uptake
* Offered at few institutions
RISK OF ANEUPLOIDY BASED ON GA AND ANOMALY

3D Ultrasound
Fetal Face
24 weeks Gestation
Fetal MRI
FETOSCOPY
Amnion (stuck twin)
Umbilical cord

Prenatal Testing And Screening.ppt

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