Upper Respiratory Tract Infections

Upper Respiratory Tract Infections
By:Dr. Meenakshi Aggarwal MD
Emory Family Medicine

Definition

* Inflammation of the respiratory mucosa from the nose to the lower respiratory tree, not including the alveoli.

Objectives
* List the various categories of upper respiratory tract infections
* Obtain a pertinent history in a patient with a suspected URI.
* Perform a targeted and thorough physical examination to confirm the diagnosis of URI.
* Perform and interpret selected tests to diagnose URI
* Manage and treat uncomplicated URI’s.

Categories
* Acute Rhinosinusitis
* Acute Pharyngitis
* Acute Bronchitis

Differential Diagnosis
* Influenza
* Pneumonia
* Tuberculosis
* Asthma

Anatomy of Sinuses
Acute Rhinosinusitis (Viral)
* Common Symptoms: Nasal discharge, nasal congestion, facial pressure, cough, fever, muscle aches, joint pains, sore throat with hoarseness.
* Symptoms resolve in 10-14 days
* Common in fall, winter and spring.
* Treatment: Symptomatic

Acute Bacterial Sinusitis
* Causative agents are usually the normal inhabitants of the respiratory tract.
* Common agents:

Streptococcus pneumoniae
Nontypeable Haemophilus Influenzae

Moraxella Catarrhalis
Signs and Symptoms
* Feeling of fullness and pressure over the involved sinuses, nasal congestion and purulent nasal discharge.
* Other associated symptoms: Sore throat, malaise, low grade fever, headache, toothache, cough > 1 week duration.
* Symptoms may last for more than 10-14 days.

Diagnosis
* Based on clinical signs and symptoms
* Physical Exam: Palpate over the sinuses, look for structural abnormalities like DNS.
* X-ray sinuses: not usually needed but may show cloudiness and air fluid levels
* Limited coronal CT are more sensitive to inflammatory changes and bone destruction

Ethmoid Sinusitis
Coronal computed tomographic scan showing ethmoidal polyps. Ethmoid opacity is total as a result of nasal polyps, with a secondary fluid level in the left maxillary antrum.

Treatment
* About 2/3rd of patients will improve without treatment in 2 weeks.
* Antibiotics: Reserved for patients who have symptoms for more than 10 days or who experience worsening symptoms.
* OTC decongestant nasal sprays should be discouraged for use more than 5 days
* Supportive therapy: Humidification, analgesics, antihistaminics
a) Amoxicillin (500mg TID) OR
b) TMP/SMX ( one DS for 10 days).
c) Alternative antibiotics: High dose amoxi/clavunate, Flouroquinolones, macrolides

Antibiotics
Acute Pharyngitis
* Fewer than 25% of patients with sore throat have true pharyngitis.
* Primarily seen in 5-18 years old. Common in adult women.

Etiology
A) Viral: Most common.
Rhinovirus (most common).
Symptoms usually last for 3-5 days.

B) Bacterial: Group A beta hemolytic streptococcus (GABHS).
Early detection can prevent complications like acute rheumatic fever and post streptococcal GN.

Signs and Symptoms
* Absence of Cough
* Fever
* Sore throat
* Malaise
* Rhinorrhoea
* Classic triad of GABHS: High fever, tonsillar exhudates and ant. cervical lymphadenopathy.

NO COUGH
Diagnosis
* Physical Exam: Tonsillar exhudates, anterior cervical LAD
* Rapid strep: Throat swab. Sensitivity of 80% and specificity of 95%.

Throat Cultures: Not required usually. Needed only when suspicion is high and rapid strep is negative.

Exhudates
Management
A) Symptomatic: Saline gargles,

analgesics, cool-mist humidification and throat lozenges.

B) Antibiotics:
a) Benzathine Pn-G 1.2 million units IM x 1OR Pn V orally for 10 days
b) For Pn allergic pts:Erythromycin 500mg QID x 10 days OR Azithro 500 mg Qdaily x 3 days.

Acute Bronchitis
Inflammation of the bronchial respiratory mucosa leading to productive cough.
Acute Bronchitis
* Etiology: A)Viral
B) Bacterial (Bordetella pertussis, Mycoplasma pneumoniae, and Chlamydia pneumoniae)
* Diagnosis: Clinical
* S/S: Productive cough, rarely fever or tachypnea.

Treatment
* Symptomatic
* If cough persists for more than 10 days:

Azithro x 5 days OR
Clarithro x 7 days
Non specific URI’s

* Common Cold
* Etiology: Rhinovirus
Adenovirus
RSV
Parainfluenza
Enteroviruses
Diagnosis: Clinical
Treatment: Adequate fluid intake, rest, humidified air, and over-the-counter analgesics and antipyretics.

Influenza
* Etiology: Influenza A & B
* Symptoms: Fever, myalgias, headache, rhinitis, malaise, nonproductive cough, sore throat
* Diagnosis: Influenza A &B antigen testing
* Treatment: Supportive care, oseltamivir, amantidine

Upper Respiratory Tract Infections.ppt

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Hepatitis A & B

Hepatitis A

The virus that does not cause chronic liver disease

Hepatitis A
* “Infectious Hepatitis”
* First characterized in 1973
* Detected in human feces
* Hepatovirus genus
* A reportable infectious disease
* U.S. rate of infection 4/100,000
* Highest among children

Risk Factors
* Sexual or household contact
* International travel
* Men who have sex w/ men (MSM)
* Intravenous drug abuse (IVDA)
* Daycare

Transmission
* Unwitting contact w/ infected person
* Most cases unknown
* Primary route is fecal oral either by person to person contact or ingestion of contaminated food or water

Pathogenesis
* After ingestion, the HAV survives gastric acid, moves to the small intestine and reaches the liver via the portal vein
* Replicates in hepatocyte cytoplasm
o Not a cytopathic virus
o Immune mediated cell damage more likely
* Once mature the HAV travels through sinusoids and enters bile canaliculi, released into the small intestine and systemic circulation, excreted in feces

Clinical Features
* Incubation is usually 2 to 4 weeks, rarely 6 weeks
* Complete recovery within 2 months for > 50%
* Within 6 months for almost all others
* Low mortality in healthy people
o High mortality when older than age 60
o High in presence of chronic liver disease
* High morbidity
o Around 20% need hospitalization
o Lost work days
o Most become jaundiced
* Asymptomatic < 2 year old * Symptomatic – 5 and older ill about 8 weeks * Cholestatic – jaundice lasts > 10 weeks
* Relapsing w/ 2 or more bouts acute HAV over a 6 to 10 week period
* Acute liver failure – rare in young. When it occurs, is rapid i.e., within 4 weeks

Signs and Symptoms
* Prodrome lasts 1-2 weeks: fatigue, asthenia, anorexia, nausea, vomiting, and abdominal pain
* Less common: fever, cephalgia, arthralgia, myalgia, and diarrhea
* Dark urine is followed by jaundice and hepatomegaly
* Less common: splenomegaly, cervical lymphadenopathy

Diagnosis
* During acute infection, anti HAV IgM appears first
* HAV IgG antibody appears early in the course of infection and remains detectable for life, providing lifelong immunity

Prevention Immunization
* All children 12 – 24 months
* Travelers, occupational exposure risk
* All patients w/ hepatitis B or C or those awaiting liver transplantation
* HIV positive patients
* MSM
* IVD users
* People w/ clotting factor deficiencies
* Lab workers handling live hepatitis A vaccine
* Need for post exposure prophylaxis uncommon. Administration of the vaccine is effective. If needed, administer immune serum globulin within 2 weeks 0.02 ml/Kg IM

Hepatitis A Vaccine
* The vaccine is inactivated HAV
* Schedule for 2 – 18 years depends upon the manufacturer:
o Havirx: 720 EL U/.5mL @ 0, 6-12 mo
o Vaqta: 25 U.5mL @ 0, 6-18 mo
* For those over age 18:
o Havirx: 1440 EL U/1mL @ 0, 6-12 mo
o Vaqta: 50 U/1mL @ 0, 6-18 mo
* Adverse effects: rarely anaphylaxis, injection site induration, erythema, edema, fatigue, mild fever, malaise, anorexia, nausea
* Twinrix:
o 720 El U/1mL 0, 1, 6 mo plus
o 20 mcg HBV

Questions?
Hepatitis B
The Virus
* The hepatitis B virus is among the smallest genomes of all known animal viruses
* A DNA virus that infects only humans
* Belongs to the family Hepadnaviridae
* Knowledge of the viral proteins that are perceived by the immune system as “antigens” aids understanding of the various tests used to diagnose acute, chronic, and resolved infection and verify response to immunization

HBV Antigens
* Outer envelope contains a surface protein called hepatitis B surface antigen
* HBsAg is a marker of viral replication
* Inner core contains the genome, the DNA polymerase w/ reverse transcriptase activity, hepatitis B core antigen (HBcAg) particles. This antigen is not detectable in serum
* A truncated form of the major core polypeptide known as hepatitis e antigen (HBeAg) is the third antigen generated by virus activity. Marker of high infectivity

Hepatitis B Antibodies
* Hepatitis B surface antibody is the antibody to surface antigen. HBsAb is protective and indicates either resolved infection or immunization
* HBcAb is the antibody to core antigen. This is not a protective antibody. Only those who have been exposed to the virus will have this antibody
* HBcAb is measured in serum as:
o Anti HBc IgM (usually indicates new infection)
o Anti HBc IgG (appears later)
* HBeAb is the antibody to e antigen. Loss of e antigen w/ gain of e antibody is called seroconversion. Not a protective antibody

Epidemiology
* Prevalence of HBV varies markedly around the world, w/ > 75% of cases in Asia and the Western Pacific
* Vaccine available > 20 years, but perinatal and early life exposure continue to be a major source of infection in endemic areas
* Most acute HBV cases in the U.S. are seen among young adults, males > females, who use injection drugs and in those who engage in high risk sexual behaviors
* In the U.S., hundreds of people die each year of fulminant HBV
* World wide, chronic HBV and its complications including hepatocellular carcinoma account for > 1 million deaths each year

Risk Factors

* Percutaneous and mucous membrane exposure. The virus is 100 x more infectious than HIV, 10 x more infectious than HCV and is present in all body fluids. Present on horizontal surfaces, eating utensils, personal hygiene items, etc.
* Babies born to infected mother
* Household contact
* Hemodialysis
* Receipt of blood products prior to the early 1970s
* Receipt of previously infected donor liver

Markers of Exposure
* Surface antigen appears as early as 1-2 weeks following exposure, as late as 11-12 weeks
* HBV DNA measurable soon after
* HBeAg appears shortly after HBsAg
* Hepatitis occurs 1 – 7 weeks after appearance of HBsAg

Pathophysiology
* Governed by interaction between the virus and host immune response
* Following inoculation by the HBV, cytokine release, cell injury and viral clearance follow
* HBsAg disappears by six months and is accompanied by sero conversion to protective HBsAb
* Persistent virus replication after six months ->chronic hepatitis and is the result of a compromised (newborn/HIV) or relatively tolerant immune system status

Four Stages of Infection
* Age at time of infection predicts chronicity in most cases. Infants and young children usually become chronically infected. When acquired in adults, the virus is cleared by the healthy immune system in about 95% of cases, leading to natural immunity
* Immune tolerant phase, there is active viral replication. ALT and AST are normal. Immune system does not recognize HBV as “foreign”
* In the immune clearance phase, enzymes rise reflecting immune mediated lysis of infected hepatocytes. This phase can last for years. Seroconversion of HBeAg to HBeAb occurs

Stages of Infection
* Low or non-replicative phase. Also known as inactive carrier (or inappropriately “healthy carrier”). Characterized by resolution of necroinflammation, normalization of enzymes and low levels of HBV DNA. This stage may last for life
* Reactivation. Spontaneous or immunosuppression mediated (cancer chemotherapy or high dose corticosteroid therapy)

Signs and Symptoms
* Incubation period: a few weeks to 6 months
* About 30% develop jaundice
* 10% to 20% of patients develop serum sickness, i.e., fever, arthralgias, rash
* Fulminant hepatitis B occurs in < 1% of cases. 80% mortality without liver transplantation * Enzyme elevations of 1,000-2,000 typical Signs and Symptoms * Fatigue, RUQ discomfort may be the only symptoms * Those in the immune tolerant phase are usually asymptomatic. The phase lasts until late puberty into adulthood Signs of Decompensation * See section on Cirrhosis and Portal Hypertension * Refer to a liver transplantation center * Patient education for people with chronic liver disease should be reinforced * Refer to “Ten Tips for People w/ Chronic Liver Disease” Prevention * Two forms of vaccine now available. * Twinrix – contains both hepatitis A and B vaccines available in an accelerated schedule or standard series * Individual hepatitis B vaccine * Standard schedule is given: o Time 0 o 1 mo o 6 mo Prevention * Educate to avoid IVDU, high risk sexual activity * Prevent peri natal transmission. Serology of pregnant women for HBsAg is standard of practice in U.S. * If pregnant female has high viremia, refer to hepatologist for treatment during the 3rd trimester to reduce risk of transmission to neonate * Babies of HBsAg mothers receive hepatitis B immune globulin with 12 hours of birth and begin the vaccine series immediately Treatment * Six approved medications as of July 2008 o Interferon alpha o Pegylated interferon o Lamivudine o Adefovir Dipivoxil o Entecavir o Telbivudine o Tenofovir approved * Refer to hepatologist The Cholestatic Liver Diseases Adults Cholestatic Liver Disease Etiologies * Immune Mediated: PBC, PSC, autoimmune cholangitis, liver allograft rejection, graft-versus-host disease * Infectious: acute viral hepatitis * Genetic and Developmental: cystic fibrosis, Alagille’s syndrome (syndrome w/ paucity of intrahepatic bile ducts), fibro polycystic liver disease * Neoplastic: Cholangiocarcinoma * Drug-Induced Ductopenia: amoxicillin, amitriptyline, cyproheptadine, erythromycin, tetracycline, thiabendazole * Ischemic * Idiopathic Pathogenesis of Cholestatic Disorders * Immune response (inflammation, auto-antibody) or hepatotoxic injury to bile ducts * Bile duct injury by bile acids - >
* Retention of bile acids in hepatocytes - >
* Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis - > liver failure

Complications of Chronic Cholestasis
* Pruritis believed to be 2/2 increased opioid receptor tone, or centrally mediated
* Fatigue
* Bone disease: osteopenia, osteoporosis
* Fat soluble vitamin deficiency
* Malabsorption (Sprue, bile salt deficiency, pancreatic insufficiency)

Pruritis in Cholestasis

* Therapy:
o Urso in AICP, PBC (15-30mg/Kg/day)
o Opiate antagonist naltrexone (50mg/day)
o 5-HT3 antagonist odansetron
o SSRI sertaline
o Bile acid sequesterant cholestyramine 4gm t.i.d. to q.i.d.
o Antihistamines rarely effective
o Rifampin 150mg to 300mg b.i.d.

Fatigue in Cholestasis
* High prevalence in Primary Biliary Cirrhosis unrelated to disease severity or duration
* Pathogenesis
o ?decreased hypothalamic cortico-tropin-releasing hormone
o ?CNS accumulation of manganese
* Prognosis worse
* No effective treatment

Bone Disease in Cholestasis
* Clinical manifestations: low bone density, fractures of axial and/or appendicular skeleton
* Pathogenesis: hyperbilirubinemia impairs osteoblast proliferative activity
* Therapy: bisphosphonates, calcium, vitamin D, weight bearing exercise, estrogens appear to be safe

1. Primary Biliary Cirrhosis
A chronic and progressive disease of unknown etiology affecting primarily middle-aged women

Primary Biliary Cirrhosis
* Affects all races
* 9:1 ratio female > male, age 20 – 65
* Characterized by small intrahepatic bile duct destruction and cholestasis
* In the presence of cirrhosis, male > likely than female to develop hepatocellular carcinoma

PBC
Laboratory Findings
* Alk Phos 2x to 20x ULN in > 90% of patients
* AST-ALT 1x to 5x ULN > 90%
* Bilirubin – variable. When elevated, may indicate advanced cirrhosis or 2nd condition
* Hypercholesterolemia in 80% of patients

Hypercholesterolemia Unique in PBC
* Hypercholesterolemia
* IgM 1x to 5x ULN > 90%
* Anti mitochondrial antibody > 1:20 titer >90%
* Anti nuclear and/or smooth muscle antibody > 1:80 may be seen in “overlap syndrome”
* Liver biopsy helpful to grade and stage disease, determine if cirrhosis present

PBC Treatment
* Slowly progressive, even if asymptomatic
* Ursodeoxycholic acid only effective therapy. May improve natural history
* Transplant curative
* Manage disease specific complications

Effects of Ursodeoxycholate
* Urso is a hydrophilic bile acid having multiple anti-inflammatory and immunomodulatory actions
* Urso administration in the setting of pro-apoptotic stimuli (bile salts, ethanol, TGF-beta, FAS ligand) inhibits in vitro apoptosis (programmed cell death)
* Reduces mitochondrial membrane permeability

Monitor for and Treat PBC Associated Disorders
* Keratoconjunctivitis Sicca
* Scleroderma, CREST syndrome
* Gallstones
* Arthropathies:
o Rheumatoid, psoriatic arthritis, Raynaud’s phenomenon, Hypertrophic osteodystrophy, Avascular necrosis, Chondrocalcinosis
* Thyroid disease, renal tubular acidosis

PBC Associated Disorders
* Malabsorption
* Celiac Sprue
o 6% of PBC patients have Celiac Sprue
o 3% of Sprue patients have PBC
* Bile salt deficiency
* Pancreatic insufficiency

Manage PBC Complications
* Standard liver disease recommendations
* PBC specific symptom management
* Refer for liver transplantation
* Primary Sclerosing Cholangitis
Rare
* One of the most important cholestatic liver diseases in the western world
* Chronic, cholestatic liver disease characterized by
o Inflammation
o Obstruction
o Fibrosis of both intrahepatic and extrahepatic bile ducts

Primary Sclerosing Cholangitis
* Many patients will progress to cirrhosis
* Highly variable in and between individuals
* Usually fatal important complication is cholangiocarcinoma
* Etiology largely unknown, though evidence points to immune system involvement

PSC
* No specific treatment
* Treatment aimed at management of disease associated conditions
* Prevalence unknown
* Almost half are asymptomatic at diagnosis
* No specific diagnostic marker for PSC

PSC Clinical Features
* Labs:
o Two- fold increase in alk phos, most have increased AST and ALT
o Albumin and protime normal in early disease
o Bilirubin initially normal, but gradually increases and fluctuates widely w/ extrahepatic biliary strictures, infection, obstructing stone sludge or stone
* Imaging
* Magnetic resonance cholangio-pancreatography demonstrates intrahepatic duct changes
* Histology
* Liver biopsy for staging the disease
* Liver biopsy to rule out other potentially treatable causes of cholestasis

PSC Patient Presentation
* Large bile duct PSC may have asymptomatic elevation of LFTs. Can be cirrhotic w/ no symptoms
* Symptomatic patients will have cholestasis-type symptoms plus:
o Abdominal pain
o Weight loss
o Hepatomegaly
o Acute cholangitis

PSC Associated Diseases
* Inflammatory bowel disease, most often ulcerative colitis
* These patients have increased risk for colorectal carcinoma
* 25% have another autoimmune disease

PSC Complications
* Related to cholestasis: pruritis, fatigue, fat soluble vitamin deficiency, osteoporosis
* Related to cirrhosis: liver failure, peristomal varices
* Extra-hepatic disease: IBD, pancreatitis, sprue, diabetes, thyroid disease
* PSC specific

PSC Disease Specific Complications
* Fever
* Abdominal pain
* Dominant stricture
* Gall stones
* Cholangiocarcinoma

PSC Prognosis
* Factors of Importance:
o Older age
o Increasing bilirubin
o Histological advanced stage
o Child-Pugh-Turcotte Class C

PSC Treatment Goal Improve Quality of Life
* Medical support
* Endoscopic treatments
* Surgical interventions
* Liver transplantation – PSC recurrence is more frequent than PSC

Case Study
Reference

Hepatitis A & B .ppt

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Magnetic Resonance CholangioPancreatography

Magnetic Resonance CholangioPancreatography
By:Falguny Bhavan MS4
Oregon Health & Sciences University
Radiology Clerkship


Objectives
* Introduction
* Technique
* Advantages
* Limitations
* Clinical applications

Introduction
Anatomy of the Hepato-Biliary and Pancreatic system

Technique
* Basic principle: body fluids (bile and pancreatic secretions) have high signal intensity on heavily T2-weighted MR sequences therefore, appear white
o Background tissues generate little signal appear dark
* Stationary or slow-flowing fluid within the bile and pancreatic ducts appears bright relative to low signal intensity produced by adjacent solid tissues
* New MR advancements allow faster imaging in which imaging is performed during single breath-holding session to reduce motion artifact due to respiration
* New variants such as rapid acquisition with relaxation enhancement (RARE) and half-Fourier acquisition single-shot turbo spin-echo (HASTE) can be performed in a breath-hold period with a scan time of <20 seconds provide superior images Advantages * Does not require intravenous or oral contrast material to be administered into the ductal system * Avoids complications of ERCP such as pancreatitis (3-5%), sepsis, perforation, hemorrhage, sedation * Can be completed in 10 minutes, easily performed as outpatient examination * Passive procedure; displays the ducts in the resting state and more accurately displays native caliber of the duct than ERCP. o In ERCP, segments may be overdistended because of attempt to visualize the duct upstream from a stricture, or segments may be underdistended because of the operator's fear of inducing cholangitis or pancreatitis. Limitations * Purely diagnostic, does not provide access for therapeutic intervention (e.g. stone extraction, stent insertion, or biopsy) * Image artifact due to other structures in abdomen with high fluid content * Lack of patient compliance; claustrophobia, inability to breath-hold * Dropout of signal can be caused by metallic clips, crossing defects induced by the right hepatic artery, or from severely narrowed ducts, such as occurs with primary sclerosing cholangitis * Lower resolution than direct cholangiography o Can miss small stones (<4 mm), small ampullary lesions, primary sclerosing cholangitis, and strictures of the ducts Clinical applications: Diseases Diagnosed by MRCP Biliary Disease * Screening examination in patients with low or intermediate probability of choledocholithiasis * Cholangiocarcinoma * Anatomic variants (low or medial duct insertion, aberrant right hepatic duct) * Failed or incomplete ERCP * Post-operative anatomy or screening for biliary complications * Primary sclerosing cholangitis * Cystic disease of bile duct (choledochal cyst, choledochocele, Caroli’s disease) Pancreatic Disease * Anatomic variants (pancreas divisum) * Chronic pancreatitis * Pancreatic cancer Clinical Applications: General guidelines for selection of MRCP or ERCP Obstruction of the Common Bile Duct * MRCP can visualize the normal or dilated common bile duct in 96 to 100 percent of patients. * Strictures typically appear as focal areas of ductal narrowing or signal void with proximal dilatation. * Cause of biliary strictures may be more difficult to determine on the basis of MRCP alone. o lacks specificity o differentiation between benign and malignant causes is based on a combination of clinical, radiographic, and pathological data * Obstruction 2° to calculi, pancreatic adenocarcinoma, or pancreatitis is usually obvious with MRCP, and with aid of conventional MRI or CT Obstruction Combined Biliary-Duct Obstruction and Pancreatic-Duct Obstruction Due to a Small Mass in the Pancreatic Head. The biliary-duct obstruction is indicated by the curved arrow, and the pancreatic-duct obstruction by the straight arrow. The mass was identified on axial, contrast-enhanced, T1-weighted images (not shown) obtained by routine MRI during the same examination. Arrowheads indicate the pancreatic duct. * ERCP is more beneficial in pts with dilatation of the common bile duct who have obstruction at the ampulla, since it permits direct visualization of the ampulla, biopsy of lesions, manometry, or endoscopic sonography. * MRCP Study of 79 cases of biliary obstruction found 14 due to malignant cause; 6 cases due to ampullary carcinoma. o 2 of 6 cases were misdiagnosed as benign obstructions, and 2 cases of benign obstruction were thought to be ampullary cancers. (This study used an early form of the technique, and results may be more accurate with the currently available technology.) * MRCP performed after pharmacologic stimulation with secretin has been shown to be helpful in evaluating ampullary obstruction Secretin-enhanced MRCP * Visualization of the pancreatic duct can be improved with imaging after administration of IV secretin * Secretin frequently used when pancreatic duct is not apparent on MRCP * Reduces the incidence of false positive findings of strictures Secretin-enhanced MRCP Dynamic MRCP with Intravenous Injection of Secretin in Patient with Abdominal Pain after a Whipple Procedure. (ERCP was not attempted because the patient had a pancreaticoenteric anastomosis.) In Panel A, the pancreatic duct (arrowheads) is incompletely visualized on MRCP before the administration of secretin. In Panel B, an MRCP obtained 15 minutes after the administration of secretin shows prominent and prolonged dilatation of the pancreatic duct upstream of a stricture (arrow) at the pancreaticoenteric anastomosis. Common duct stones * Displayed by MRCP as a signal void within bright signal arising from bile * MRCP is a useful means of determining presence or absence of CBD stones, as well as number, size, and location * MRCP is as accurate as ERCP for detecting choledocholithiasis o Sensitivity = 95-100% o Specificity = 85-100% * Increased sensitivity in pts with suspected gallstone pancreatitis, and pts with non-specific abdominal pain and normal LFTs * Stones larger than 4 mm are readily seen but difficult to differentiate from filling defects such as blood clots, tumor, sludge, or parasites o Other mimickers include flow artifacts, biliary air, and a pseudostone at the ampulla * In the presence of a dilated CBD, MRCP has a 90 to 95 percent concordance with ERCP in diagnosing CBD stones over 4 mm in diameter * ERCP is preferred in pts with cholangitis because it allows therapeutic drainage Cholangiocarcinoma * Role of MRCP in the diagnosis and management of bile duct malignancy is not yet defined * Useful noninvasive adjunct * Capability to evaluate the bile ducts both above and below a stricture while also identifying any intrahepatic mass lesions * Study of 126 patients with suspected bile duct obstruction showed that MRCP alone has limited specificity in the diagnosis of malignant strictures o Malignant obstruction dx by MRCP in 12 out of 14 pts o Positive predictive value = 86% o Negative predictive value = 98% Pancreatitis * Acute pancreatitis o MRCP is useful for evaluating bile ducts and cystic duct remnants for stones, for evaluating the pancreatic ducts, and for documenting the presence of cysts in or around the pancreas. o ERCP is often preferred in patients with gallstone pancreatitis since endoscopic papillotomy can be performed in pts with obstructive jaundice or biliary sepsis. * Chronic pancreatitis o MRCP is useful in demonstrating complications such as, ductal dilatation, strictures, intraductal calculi, fistulas, and pseudocysts o Defines ductal anatomy and extent of ductal disease prior to surgical drainage * MRCP is as accurate as ERCP for distinguishing pancreatic cancer from chronic pancreatitis. o In study of 124 patients who were suspected of having pancreatic cancer, pts underwent a number of diagnostic studies, including ERCP and MRCP. The correct diagnosis was confirmed histologically and clinically. 37 patients (30 percent) dx with pancreatic cancer; others had chronic pancreatitis (46 percent) or other causes. o MRCP sensitivity (84%) and specificity (97%) for diagnosis of pancreatic cancer o ERCP sensitivity (70%) and specificity (94%) * Secretin-enhanced MRCP is being increasingly studied for evaluation of pancreatic exocrine function and in the early diagnosis of chronic pancreatitis Variant ductal anatomy * MRCP is also useful in demonstrating variant anatomy and congenital anomalies of the biliary tract and pancreatic duct o Pancreas divisum o Choledochal cyst o Annular pancreas o Abnormal pancreaticobiliary junctions o Aberrant bile ducts * And in evaluation of pts prior to laparoscopic cholecystectomy Normal Extrahepatic Bile Duct and Incidental Pancreas Divisum. Magnetic resonance cholangio-pancreatography is an accurate method of diagnosing pancreas divisum because it shows the dominant dorsal pancreatic duct (arrowheads) continuously from the tail to the head of the pancreas, crossing the common bile duct (curved arrows) and draining at the minor papilla (straight arrow) superiorly and separately from the common bile duct. GB denotes gallbladder. Failed or incomplete ERCP * ERCP is technically challenging o Associated with 10-20% failed cannulation rate o Anatomic variants can contribute to failed ERCP attempts * MRCP is useful in demonstrating variant anatomy o MRCP may have advantages compared to ERCP in specific settings such as pts who have gastric outlet or duodenal stenosis or who have had surgical rearrangement (eg, Billroth II) or ductal disruption, resulting in ducts that can’t be assessed by ERCP * MRCP also allows evaluation of ducts in pts with contraindications for ERCP: o Cervical spine fractures, head and neck tumors, sleep apnea, other diseases/ injuries that preclude placement of endoscope or positioning Post-surgical anatomy Normal Results of Magnetic Resonance Cholangiopancreatograpy in a Patient after Cholecystectomy. Imaging was performed in two seconds with the thick, single-slice technique. The normal common bile duct (arrow) and pancreatic duct (arrowheads) are clearly visible. Du denotes duodenal bulb. References Magnetic Resonance CholangioPancreatography.ppt

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Cholangitis & Management of Choledocholithiasis

Cholangitis & Management of Choledocholithiasis
By: Ruby Wang MS 3


* Cholangitis
o Clinical manifestations
o Diagnosis
o Treatment
* Diagnosis and management of choledocholithiasis
o Pre-operative
o Intra-operative
o Post-operative

Case
* HPI:
o 86 yo lady p/w 3-4 episodes of RUQ/mid-epigastric abdominal pain over the last year, lasting generally several hours, accompanied by occasional emesis, anorexia, and sensation of shaking chills.
o ROS: negative otherwise
* PE:
o VS: T 36.2, P98 , RR 18, BP 124/64
o Abdominal exam significant for RUQ TTP
* Labs
o AST 553, ALT 418. Alk Phos 466. Bilirubin 2.7
o WBC 30.3
* Imaging
o Abdominal US: multiple gallstones, no pericholecystic fluid, no extrahepatic/intrahepatic/CBD dilatation
Introduction
* Cholangitis is bacterial infection superimposed on biliary obstruction
* First described by Jean-Martin Charcot in 1850s as a serious and life-threatening illness
* Causes
o Choledocholithiasis
o Obstructive tumors
+ Pancreatic cancer
+ Cholangiocarcinoma
+ Ampullary cancer
+ Porta hepatis
o Others
+ Strictures/stenosis
+ ERCP
+ Sclerosing cholangitis
+ AIDS
+ Ascaris lumbricoides
Epidemiology
Pathogenesis
Clinical Manifestations
* RUQ pain (65%)
* Fever (90%)
o May be absent in elderly patients
* Jaundice (60%)
* Hypotension (30%)
* Altered mental status (10%)
Additional History
Additional Physical
Diagnosis: lab values
* CBC
o 79% of patients have WBC > 10,000, with mean of 13,600
o Septic patients may be neutropenic
* Metabolic panel
o Low calcium if pancreatitis
o 88-100% have hyperbilirubinemia
o 78% have increased alkaline phosphatase
o AST and ALT are mildly elevated
+ Aminotransferase can reach 1000U/L- microabscess formation in the liver
o GGT most sensitive marker of choledocholithiasis
* Amylase/Lipase
o Involvement of lower CBD may cause 3-4x elevated amylase
* Blood cultures
o 20-30% of blood cultures are positive
Diagnosis: first-line imaging
Ultrasonography
o Advantage:
+ Sensitive for intrahepatic/extrahepatic/CBD dilatation
# CBD diameter > 6 mm on US associated with high prevalence of choledocholithaisis
# Of cholangitis patients, dilated CBD found in 64%,
+ Rapid at bedside
+ Can image aorta, pancreas, liver
+ Identify complications: perforation, empyema, abscess
o Disadvantage
+ Not useful for choledocholithiasis:
# Of cholangitis patients, CBD stones observed in 13%
+ 10-20% falsely negative - normal U/S does not r/o cholangitis
# acute obstruction when there is no time to dilate
# Small stones in bile duct in 10-20% of cases

CT
o Advantages
+ CT cholangiograhy enhances CBD stones and increases detection of biliary pathology
# Sensitivity for CBD stones is 95%
+ Can image other pathologies: ampullary tumors, pericholecystic fluid, liver abscess
+ Can visualize other pathologies- cholangitis: diverticuliits, pyelonephritis, mesenteric ischemia, ruptured appendix
o Disadvantages
+ Sensitivity to contrast
+ Poor imaging of gallstones
Diagnostic: MRCP and ERCP
Magnetic resonance cholangiopancreatography (MRCP)
o Advantage
o Disadvantage:
Endoscopic retrograde cholangiopancreatography (ERCP)

Medical Treatment
* Resucitate, Monitor, Stabilize if patient unstable
o Consider cholangitis in all patients with sepsis
* Antibiotics
o Empiric broad-spectrum Abx after blood cultures drawn
Surgical treatment
* Endoscopic biliary drainage
o Endoscopic sphincterotomy with stone extraction and stent insertion
* Surgery
o Emergency surgery replaced by non-operative biliary drainage
o Once acute cholangitis controlled, surgical exploration of CBD for difficult stone removal
o Elective surgery: low M & M compared with emergency survey
o If emergent surgery, choledochotomy carries lower M&M compared with cholecystectomy with CBD exploration
Our case…
* Condition:
* ERCP attempted
* Laparoscopic cholecystectomy planned
o Dissection of triangle of Calot
o Cystic duct and artery visualized and dissected
o Cystic duct ductotomy
o Insertion of cholangiogram catheter advanced and contrast bolused into cystic duct for IOC
* Intraoperative cholangiogram
o Several common duct filling defects consistent with stones
o Decision to proceed with CBD exploration

Choledocholithiasis
* Choledocholithiasis develops in 10-20% of patients with gallbladder disease
* At least 3-10% of patients undergoing cholecystectomy will have CBD stones

Pre-op diagnosis & management
o Diagnosis: Clinical history and exam, LFTs, Abdominal U/S, CT, MRCP
+ High risk (>50%) of choledocholithiasis:
# clinical jaundice, cholangitis,
# CBD dilation or choledocholithiasis on ultrasound
# Tbili > 3 mg/dL correlates to 50-70% of CBD stone
+ Moderate risk (10-50%):
# h/o pancreatitis, jaundice correlates to CBD stone in 15%
# elevated preop bili and AP,
# multiple small gallstones on U/S
+ Low risk (<5%): # large gallstones on U/S # no h/o jaundice or pancreatitis, # normal LFTs o Treatment: + ERCP + Surgery Intra-op diagnosis and management * Diagnosis: intraoperative cholangiography (IOC) o Cannulation of cystic duct, filling of L and R hepatic ducts, CBD and common hepatic duct diameter, presence or absence of filling defects. o Detect CBD stones o Potentially identify bile duct abnormalities, including iatrogenic injuries o Sensitivity 98%, specificity 94% o Morbidity and mortality low * Treatment o Open CBD exploration + Most surgeons prefer less invasive techniques o Laparoscopic CBD exploration + via choledochotomy: CBD dilatation > 6mm
+ via cystic duct (66-82.5%)
+ CBD clearance rate 97%
+ Morbidity rate 9.5%
+ Stones impacted at Sphincter of Oddi most difficult to extract
o Intraoperative ERCP

Early years: Open CBD exploration & Introduction of endoscopic sphincterotomy
* 1889, 1st CBD exploration by Ludwig Courvoisier, a Swiss surgeon
o Kocherization of duodenum and short longitudinal choledochotomy
o Stones removed with palpation, irrigation with flexible catheters, forceps,
o Completion with T-tube drainage
o For many years, this was the standard treatment for cholecystocholedocholithiasis
* 1970s, endoscopic sphincterotomy (ES)
o Gained wide acceptance as good, less invasive, effective alternative
o In patients with CBD stones who have previously undergone cholecystectomy, ES is the method of choice

Open surgery vs Endoscopic sphincterotomy
* In patients with intact gallbladders, ES or open choledochotomy?
o Design: 237 patients with CBD stone and intact gallbladders, 66% managed with ES and rest with open choledochotomy
o Results: No significant difference in morbidity and mortality rates
+ Lower incidence of retained stones after open choledochotomy
o Conclusion: open surgery superior to ES in those with intact gallbladders
* Is ES followed by open CCY superior to open CCY+ CBDE?
o Results: Initial stone clearance higher with open surgery
* Cochraine database of systematic reviews
* In patients with severe cholangitis, open or ES?

Laparoscopic CBD Exploration
* In 1989, laparoscopic removal of gallbladder replaced open surgery
o In the past decade, laparoscopic CBD exploration (LCBDE) developed
* Techniques
o IOC define biliary anatomy: size and length of cystic duct, size of bile duct stones
o Choledochotomy
o Transcystic approach
* Results
Post-op Diagnosis and Management
* T-tube cholangiography
* ERCP
In summary
* Non-surgical care first line
* Surgical Care if endoscopy and IR drainage fail
* Open procedure
* Cholecystectomy
* CBD exploration

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Biliary Tumors Cholangiocarcinoma and Cancer of the Gall Bladder

Biliary Tumors Cholangiocarcinoma and Cancer of the Gall Bladder
By: Larry Pennington, MD

Cholangiocarcinoma
Etiology
Ulcerative Colitis
Thorotrast Exposure
Sclerosing Cholangitis
Typhoid Carrier
Choledochal Cysts
Adult Polycystic Kidney Disease
Hepatolithiasis
Liver Flukes

Papillomatosis of Bile Ducts
Cholangiocarcinoma
Extra-hepatic: Distribution
Diagnosis and Initial Workup
Intra and Extra-hepatic Cholangiocarcinoma
Cholangiocarcinoma Intra-hepatic Disease
* Suspicious mass on CT. Quadruple phase CT with 0.5 cm cuts through the liver and portal hepatitis. Consider CTA reconstruction.
* Bx
* If adenoncarcinoma: look for primary with a chest CT and upper/lower endoscopy.
* Colon, pancreas, and stomach are common primary sites.

Cholangiocarcinoma Intra-hepatic Disease-Surgery/Ablation
* Extent of surgical therapy is determined by the location, hepatic function, and underlying cirrhosis.
* Anatomic resections have lowest recurrence rates. However nonanatomic resection increases potential surgical candidates and improves survival.
* Hepatic devascularization prior to resection is preferred
* Ablative therapy gives good local control.

Child’s Classification
Intra-hepatic Disease: Extent of Resection
Intra-hepatic Disease
Representative Case
MRCP of Extra-hepatic Cholangiocarcinoma at the Bifurcation
Klatskin tumor
Cholangiocarcinoma Extra-hepatic
Cholangiocarcinoma Pathology
Extra-hepatic Disease: Surgical Therapy
ERCP: Distal CBD Cancer
Ca of CBD Bifurcation
Node Dissection in Bile Duct Excision
Roux-en-Y Hepaticojejunostomy
Extra-hepatic Disease: Positive Margins or Unresectable
Extra-hepatic Disease: Unstentable
* Bypass if possible
* If not use proximal decompression and feeding jejunostomy
* Chemotherapy/Radiation Therapy/Brachy therapy as tolerated or clinical trial.
Cholangiocarcinoma Prognosis
* Best Result are with distal CBD tumors completely excised. Cure = 40%
* Incomplete resection plus radiation gives a median survival of 30 m.
* Stenting plus chemo/radiation gives a median survival of 17 to 27m
* Those stented alone live only a few months

Cancer of the Gall Bladder
Gall Bladder Cancer
Presentation (1)
Presentation 2
PET Scan and Cholangiocarcinoma
Sclerosing type of Cholangiocarcinoma
Cytological Brushing of Cholangiocarcinoma

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OKAP Glaucoma Review

OKAP Glaucoma Review
By:Yara Catoira-Boyle MD

Introduction to Glaucoma

* What is the definition of glaucoma?
* Group of diseases that have in common a characteristic optic neuropathy associated with visual field loss for which elevated IOP is the primary risk factor
* What are the 3 factors that determine IOP?
* Rate of aqueous production by the CB, resistance to aqueous flow (Juxtacanalicular TM) and the level of EVP
* Of those factors, what is the most common cause of increased IOP?
* Increased resistance to outflow
* What is the prevalence of glaucoma in the general population?
* 1.5-2%
* What the percentage of 1st degree relatives of POAG patients will develop the disease?
* 10-15%
* How many people over 45 y/o are estimated to have glaucoma in the US? What % is bilaterally blind?
* 2.25 million / 4%
* 10 million /2%
* 1 million / 5%
* 5 million /4%
* What is the most common cause of nonreversible blindness in AA in the US?
* Glaucoma (prevalence 3-4X higher than whites)
* What are the leading causes of blindness worldwide?
* Trachoma Cataract glaucoma
* Which one is NOT a risk factor for glaucoma?
* Increased IOP and AA race
* Positive family history
* Advanced age
* Thin central cornea
* Male gender
* DM, myopia, HTN, ischemic vascular disease, arteriosclerosis are all inconclusive
* Which one is correct about the prevalence of Chronic angle closure glaucoma?
* Inuit from Arctic Asians Whites
* Men women
* Myopes hyperopes
* Younger older
* Which one is correct about heredity of glaucoma?
* Prevalence among siblings of pts is 20%
* Lifetime absolute risk at age 89 is 10 x higher for relatives of glaucoma patients
* A single gene is likely to be discovered as the culprit
* The gene responsible for mutations of the TIGR (myocilin) protein is located on chromos 5

A little genetics of glaucoma
* TIGR protein produced by TM cells was id’d in Juvenile glaucoma, and later found to affect up to 3% of OAG
* GLC1A, the gene responsible for TIGR mutations is on chromosome 1
* It seems to be an autossomal dominant inheritance of the polygenic type with late or variable age of onset, incomplete penetrance and substantial environmental influence

IOP and Aqueous Dynamics
* What is correct about the aqueous composition?
* Has less hydrogen and chloride than plasma
* Has deficit of ascorbate
* Has excess bicarbonate
* Contains lysozyme, cAMP, steroid hormones and hyaluronic acid
* Which one is true of rate of aqueous production?
* It has a turnover of 1% per minute
* It increases during sleep
* It increases with age
* It increases during ocular inflammation
* What are the 2 major outflow pathways?
* Pressure-dependent/ TM/ conventional
* Pressure-indepdt/ Uveoscleral/ nonconventio
* What is true about facility of outflow?
* Increases with age
* Not affected by surgery, trauma, medications
* Varies widely in normal eyes, mean 0.22 to 0.28 microL/min/mmHg
* What are the 3 parts of the TM?
* Uveal, corneoscleral and juxtacanalicular
* What is false of the TM anatomy?
* TM is composed of many layers of colagenous tissue covered with endothelium
* TM has pressure-dependent flow
* TM functions as a one way valve
* The aqueous leaves the eye by bulk flow
* Laser trabeculoplasty causes apoptosis of Trabecular cells
* What is false about Schlemm’s canal?
* It is lined by endothelium and transversed by tubules
* It is a multiple channel
* Its average diameter is 370 microns
* The inner wall contains giant vacuoles that have direct communication with the intertrabecular spaces
* When IOP is low, blood may reflux into the canal
* The venous path of aqueous includes episcleral veins, anterior cyliary and superior ophthalmic veins and the cavernous sinus
* What is false about the uveoscleral outflow?
* It refers to any nontrabecular outflow
* Aqueous passes from the AC into the CBM and then into the supraciliary and suprachoroidal spaces
* It is decreased by cycloplegia, adrenergic agents, PG analogs and cyclodyalisis surgery
* It is also decreased by miotics
* It accounts for at least 5-15% of outflow

IOP and Aqueous
* What effect the following medications have on uveoscleral outflow?
* Cycloplegics
* Miotics
* Epinephrine
* Xalatan
* Brimonidine
* Timoptic ....

Clinical Evaluation
* Associate the external adnexae finding with a diagnosis associated with glaucoma
* “ash-leaf” sign
* Plexiform neuroma of upper lid
* Nevus of Ota
* Microdontia or hypodontia
* Port-wine stain (facial cutaneous angioma)
* Yellow or orange papules of skin of head/neck
* EOM restriction, proptosis, pulsating exophthalmos
* What is the type of glaucoma associated with the following corneal signs?
* Krukenberg spindle
* Exfoliating material on anterior chamber
* Keratic precipitates
* “stelate” KP’s
* “beaten bronze” appearance or corneal edema with iris changes
* What is not a possible cause of blood in Schlemm’s canal on gonioscopy
* Compression of episcleral veins with lip of goniolens
* Hypotony
* CC fistula
* Sturge-Weber syndrome
* Dilation of the pupil
* What is false about gonioscopy:
* Normal angle vessels are usually radial along the iris or circumferential on the CB
* Abnormal vessels cross the SS to reach the TM
* The nonpigmented TM is posterior to the pigmented TM
* A C angle indicates that SS is visible
* List potential causes for increased TM pigmentation:
* PDS
* PXF
* Malignant melanoma
* Trauma
* Surgery
* Hyphema

Gonioscopy
* It is false about gonioscopy
* It is necessary to see the angle due to total internal reflection at the tear-air interface (critical angle approximat 46’)
* Koeppe and Barkan lenses are examples of direct gonioscopy, most used in the OR
* Goldmann, Zeiss and Sussman lenses are used for indirect gonioscopy in the office
* Dynamic gonioscopy is done by asking the patient to move his eye
* It is false about gonioscopy
* The order of structures from anterior to posterior is: Schwalbe’s line-nonpigm TM-pigment TM-scleral spur-ciliary body-iris root
* Multiple methods of classification exist
* A Shaffer grade 4 angle is the narrowest
* Spaeth’s classification C40R indicates a normal and open angle

Clinical Evaluation
* What is angle recession and how is it different from cyclodyalisis on gonio:
* Angle recession is a tear between the longitudinal and circular muscles of CB= widened CB band
* Cyclodyalisis is a separation of the CB from the SS= gap between CB and sclera
* What is false of the Optic Nerve:
* Consists of about 1.2-1.5 million RGS axons
* The RGC cell body is in the ganglion cell layer of the retina
* The diameter of the intraocular ONH is about 2.5 mm
* There are 2 types of RGC’s: Magnocellular and Parvocellular...
OAG
* What percentage of patients with OAG have a screening IOP below 22?
* 30-50%
* What is the average corneal thickness by optical and ultrasound measurements?
* 534 optical and 544 ultrasound
* In the AGIS, patients had significantly better outcomes if their IOP was:
* Below 18 at all visits
* Below 18 50% of visits
* Below 14 at all visits
* Below 14 50% of visits....
Secondary OAG
* What is false about PXF?
* The odds of exfoliation glaucoma are 40% in 10 years
* The angle is often narrow with a +4 pigmented TM and a Sampaolesi line inferior
* The hyaline material is found on the lens, pupil margin, CB epithelium, iris PE, iris stroma, iris blood vessels and subconjunctiva
* SLE features include iris TI at pupil margin and iridodonesis or phacodonesis....
Traumatic OAG
* About hyphemas, is false:
* Sicke cell patients may have severe glaucoma from small hyphemas
* Acute IOP elevations may lead to AION or CRAO in patients with sickle cell
* Treatment consists of corticosteroids, cycloplegics, eye shield, limited activity, head elevation
* Aminocaproic acid is advocated since it has very few side effects and decreases rebleed
* Which drug is the best choice to control IOP in a hyphema patient with sickle cell diz?
* IV Diamox
* Iopidine
* Manitol
* Pilocarpine
* Timolol
OAG
* Regarding secondary glaucomas, which one is false?
* UGH syndrome can happen secondary to erosion of IOL haptic into the iris or CB
* UGH presents with chronic inflammation, iris NV, recurrent hyphemas
* Schwartz-Matsuo syndrome refers to elevated IOP after RD due to photoreceptor outer segmemts blocking of TM
* PKP related glaucomas can be of open or closed angle mechanism
* About 50% of people will have some elevation of IOP with the use of topical steroids
ACG
* About ACG epidemiology, what is incorrect?
* 10% of the 67 million cases of glaucoma worldwide are of ACG
* Predominant form of glaucoma in East Asia
* PACG is responsible for 91% of the bilateral blindness in China
* About the mechanisms of ACG, the incorrect is:
* Pupillary block is the most common cause of angle closure, including primary AC
* NVG is a type of ACG without pupillary block
* Marfan’s synd and Homocystinuria can lead to pupillary block by lens dislocation
* In Aniridia, Glaucoma is of open type since pupillary block can’t happen due to lack of iris
Primary ACG
* About the risk factors for ACG, the wrong one is:
* The prevalence varies with race: AA whites Japanese East asians Inuits
* White pts tend to have acute AC, while AA and asians have chronic asymptomatic diz
* Shallow AC, thick lens, short AL, small corneal diameter and radius increase risk
* Ages 30-50 are the highest risk
* More common in women and hyperopes

Acute PACG
* What is false about Acute PACG?
* Mild attacks can be broken with Pilocarpine 1-2%, but should avoid stronger miotics
* At IOP 40-50 the pupillary sphincter is too ischemic to respond to miotics and should use aqueous supressants, diamox or manitol
* The chance of acute attack in the fellow eye is 40-80% in 1 year
* High IOP during an acute attack may lead to ischemic nerve damage or retinal vascular occlusion

ACG
* What is false of iris and ACG?
* Both mydriasis and miosis can cause acute angle closure in a predisposed eye with shallow AC
* Miotics relax the lens zonules allowing it to sit forward in the AC, decreasing irido-lenticular touch
* Systemic medications including allergy, cold medicines, antidepressants, anticholinergics and topamax carry warning against glaucoma
* Peripheral iridectomy is indicated in patients with critically narrow angles, PAS, h/o previous attack, AC depth 2.0mm, +family history, +provocative test...
Childhood Glaucoma
* Mark the false :
* Primary congenital is the same as infantile glaucoma
* Glaucoma recognized after age 3 is termed Juvenile Glaucoma
* Glaucoma may present with buphthalmos if the IOP elevation starts after age 3
* Developmental glaucoma refers also to secondary glaucomas associated with inflammatory, neoplastic, hamartomatous, metabolic or congenital ocular or systemic anomalies
* Mark the false
* Congenital glaucoma is usually primary(50-70%)
* It is a rare disease (1:10,000 births)
* 60% are diagnosed in the first 6 months, 80% by one year
* 65% are female and bilateral in 70%
* Axenfeld-Rieger syndrome and aniridia are conditions associated with infantile glaucoma...
Medical therapy of glaucoma
* About beta blockers, which one is false:
* Betaxolol is selective for Beta 1 receptors
* They reduce aqueous production by 20-50%
* Are very additive to epinephrine
* Metipranolol was reported to cause iritis
* Effect starts within one hour and may last 4 weeks
* Tachyphylaxis and short term scape are seen
* Are contra-indicated in myasthenia gravis
Surgical Therapy
* What is false about surgical therapy of OAG?
* Usually undertaken when medical therapy fails
* LTP may be considered as a initial step in therapy since it decreases IOP by 20-25%
* The GLT showed that LTP patients did better than medication patients
* LTP is particularly effective in XFG and PG....

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Fetal Tissue Transplants

Fetal Tissue Transplants
By:Michelle Gomez

Words You May Need To Know
* Definitions-
+ Fetal tissue transplants
+ Parkinson’s Disease (PD)
+ Huntington’s Disease (HD)
+ Dopamine (DA)

Development of the Fetus
First Month (conception to 6 weeks)
Second Month (7-10 weeks)
Third Month (11-14 weeks)
Fourth Month (beginning of second trimester)
Fifth month (19- 22 weeks)
Seventh Month (beginning of third trimester 27-30 weeks)
Sixth Months (23-26 weeks)
Eighth month (31-34 weeks)
Ninth month (35 weeks to delivery)

History
Fun Facts
* The History of Fetal Tissue Transplants

Parkinson’s Disease
* Parkinson’s Disease
Huntington’s Disease
What does it treat?
* Parkinson’s Disease
* Huntington’s Disease
* Retina Repair
* Future:
o Epilepsy
Biological Concepts

The Process: Cell Therapy Development in PD
* Parkinson’s Disease-
o Graft Efficiency has to be increased and variability reduced
+ Patient selection
+ Graft Placement
+ Composition and Preparation of the Graft Tissue
+ Developing immunological mechanisms

2 Years After Transplantation
The Process: Cell Therapy Development in PD
Evidence and Experiments
Society for Neuroscience-
* October 24, 1999- a study was presented at the Society for Neuroscience’s annual meeting, showing that the fetal cells can produce a critical neurotransmitter, reducing patient's tremors and paralysis. (Helmuth, 886)
Retina Repair-
o The procedure that Elisabeth Bryant, from the previous slide, underwent was retinal repair. Robert Aramant at the University of Louisville in Kentucky developed the transplant technique with Magdalene Seiler. (image on next slide)

Fetal tissue inserted here
Frontier Issues
Cost and Finances
* Surgery Alone- $43,500
* Pre-Operative Costs- $4,000
* Total- Approx.- $50,000
Controversy
Pro-life vs. Fetal Tissue Transplant Supporters
Ethical Issues
* It takes six fetuses to provide enough material to treat one Parkinson’s patient.
* Who is donating?
* Cell supply is limited.
* Better areas for transplantation?
Politics
Bibliography/ References
* Barinaga, M. “Fetal neuron grafts pave the was for stem cell therapies.” Science. 5 Feb 2000 287:5457 p.1421-2. General Science Index. COSLibrary, Visalia, CA. 19 Sept 2005
* Björklund, Anders and Olle Lindvall. “Cell Therapy in Parkinson’s Disease.” NeuroRx. Oct 2004. the American Society for Experimental Therapeutics, Inc. Lund, Sweden. 13 Oct 2005. http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=534947
* Cimons, Marlene. “Bush is a threat to US stem-cell research”. Nature Medicine. 2001. COS Library, Visalia, CA. 24 Oct. 2005. http://www.nature.com/nm/journal/v7/n3/full/nm0301_263a.html
* “Dopamine.” Columbia Encyclopedia, 6th Edition. 2005. 19 Sept 2005 http://www.encyclopedia.com
* Dunnett, Stephen B. and Anne E Rosser. “Cell Therapy in HD.” NeuroRx. Oct 2004. American Society for Experimental NeuroTherapeutics, Inc. Wales, UK. 13 Oct 2005. http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=534947

Bibliography/ References
* Fackelmann, K.A. “Study sizes up fetal cells for transplant.” Science News. 7 Jan 1995. 149:1 p.6. Academic Abstracts. COS Library, Visalia, CA. 15 Sept 2005
* "Fetal Tissue Implant." Columbia Encyclopedia, 6th Edition. 2005. 19 Sept. 2005 http://www.encyclopedia.com
* Hawaleshka, Dan. “The debate over fetal tissue. (cover-story).” Maclean’s. 1996 109:4 p.48. Academic Abstracts. COS Library, Visalia, CA. 15 Sept 2005
* Helmuth, L. “Fetal cells Help Parkinson’s patients.” Science. 29 Oct 1999. 286:5441 p.886-7. General Science Index. COS Library, Visalia, CA. 19 Sept 2005
* Hopkins, John. About Huntington's Disease and Related Disorders. 2002. John Hopkins Medicine. 24 Oct 2005. http://www.hopkinsmedicine.org/bhdc/about/
* “Huntington’s Disease.” Columbia Encyclopedia, 6th Edition. 2005. 19 Sept. 2005 http://www.encyclopedia.com
* “Introduction.” Parkinson’s Disease: Hope Through Research. Sept 2003. National Institute of Neurological Disorders and Stroke. 22 Sept 2005. http://www.ninds.nih.gov/disorders/parkinsons_disease/detail_parkinsons_disease.htm
* Rae, Scott B. “The Ethics of Fetal Tissue Transplantation.” CHRISTIAN RESEARCH INSTITUTE. 2005. Talbot School of Theology. 24 Oct 2005. http://www.equip.org/free/DE192.htm

Images-
* “Development of the Fetus.” Illustration. 1998. Development of the Baby. Parents Magazine. 24 Oct 2005 http://www.csulb.edu/divisions/students2/departments/Health_Resource_Center/pregnancy.htm
* Levivier, Marc. “PET scan in patient with PD after transplantation of human fetal neurons (before and after)”. Illustration. 7 July 2003. Neural Transplants in Parkinson’s Disease: do they work?. Lancet Neurology. 6 Oct 2005 http://www.thelancet.com/journals/laneur/article/PIIS1474442203004423/fulltext.
* Rowe, Duncan. “Retina Repair.” Illustration. 31 Jan 2003. Fetal Tissue Transplants Improve Adult Sight. New Scientist Magazine. 6 Oct 2005. http://www.newscientist.com/article.ns?id=dn3319

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Renal Failure and Dialysis in Pregnancy

Renal Failure and Dialysis in Pregnancy
By:David Shure

Differential Diagnosis
* FSGS -
Pro: HTN, non-remitting, albumin close to NL
Con: expected creatinine to be higher after several years

* Membranous Nephropathy -
Pro: wax/waning course
Con: often with lower albumin, edema

* Diabetic Nephropathy -
Pro: proteinuria, time course
Con:poor evidence for DM
4. FMD - Pro: unequal sized kidneys, young female, HTN hx, renal arteries not commented on in US

Nephrology Consult
* Is there any indication and/ or benefit to the fetus if we begin HD at this time?
* Can we preserve any residual maternal renal function?
* OB team trying to prolong in-utero growth/ length of pregnancy, not sure if pt is masking severe preeclampsia

Why did Ob Deliver the Baby?
* 7/21 pt c/o HA, and 7/23 severe RUQ tenderness and epigastric pain, decision made to deliver fetus based on:
* Severe superimposed Preeclampsia in setting of chronic HTN
* Also, mild thrombocytopenic further led to diagnosis of severe preeclampsia

Normal Physiologic Alterations of Pregnancy
Normal Renal Alterations in Pregnancy

Changes in GFR
* GFR and RBF rise markedly
* Glomerular hyperfiltration results in normal reduction in the plasma creatinine concentration to about 0.4 to 0.5 mg/dL
* Blood urea nitrogen (BUN) and uric acid levels fall for the same reason

Effects of Pregnancy on Renal Disease
* ― cases proteinuria worsen
* ž cases HTN develops
* Worsening edema if nephrotic
* 0-10% women with NL or mild reduction in GFR have permanent decline in renal function

Views on Pregnancy and Dialysis
* ‘Children of women with renal disease used to be born dangerously or not at all - not at all if their doctors had their way’, Lancet, 1975
* ‘Show me a method of birth control more effective than end stage renal disease’, Roger Rodby MD, 1991
* ‘Even if a woman on CAPD ovulates, doesn’t the egg just float away?’, Rodby, 1992

Why don’t uremic women get pregnant?
* Most beyond child bearing age
* Libido/ frequency of intercourse reduced
* Don’t ovulate
* Absence of increase in basal body temperature during the luteal phase of cycle
* Elevated circulating prolactin concentrations
* Elevated PRL impairs hypothalamic-pit function

Actually, they do get pregnant!
* 1st successful term pregnancy in 35 y/o dialysed pt in 1971, Confortini, et al.
* Yr 2000: >15,000 women of childbearing age getting dialysis
* For every person w/CKD 5, 20 have CKD 3 or 4 w/GFR <60, suggesting ~300,000 women w/CKD potentially able to bear children Course of Renal Disease in Pregnancy * Baseline azotemia = more rapid deterioration * As renal dz progresses, ability to maintain nl pregnancy deteriorates, and presence of HTN incr likelihood of renal deterioration * Renal dysfunction - greater risk for complications incl preeclapsia, premature delivery, IUGR Pregancy during dialysis: case report and management guidelines; Giatras, et al. 1998 * 32 y/o AA woman, G4, P2, A1 * FSGS and chronic interstitial nephritis * Renal/obstetric protocol implemented * Increased HD to 4 hrs/ 4 sessions/ week maintain prediaysis BUN <50 * At each HD session, blood flow gradually increased over 1st 30 minutes of HD, from 180 to 300 ml/min * Kt/V 1.02 - 1.66 Giatras Protocol * Dialysis performed in left lateral decubitus position * Est maternal dry wt incrased by 500 g every 10d * EPO administered at each HD session, to maintain HCT 32-34% * Vit D, folic acid and MVI admin * Evid of malnutrition prior to pregnancy, so 3000kcal/day diet w>100g protein/ day

Obstetric Surveillance
* From 25 wks gestation
* Serial BP
* Uterine and umbilical artery perfusion evaluation
* Cont fetal heart rate tracing before, during and after HD
* There were no signif changes in uterine or umbilical artery S/D ratios at any time of HD, and no sig alteration in maternal MAP during HD
* Pt delivered at 32 wks gestation, due to PROM

Common Themes in Dialysing Pregnant Patients

1. Keeping BUN < 50 2. Increasing dialysis time and frequency 3. BP control 4. Managing anemia with increasing doses of ESA 5. Fetal monitoring once viability reached BUN <50 Hypothesis? * 1963 150 women varying degrees of CKD, none on dialysis, found the single most important factor influencing fetal outcome was BUN * Fetal mortality directly proportional to BUN * Hypothesis: intensive dialysis in pregnant women w/renal dz might improve fetal outcomes Increasing frequency and time on dialysis? * May be beneficial in reducing incidence of polyhydramnios by reducing urea and water load * Less dialysis-induced hypotension * More liberal diet * American Jrnl Kid Diseases * Spurred by the report of 5 pregnancies in 5 pts on chronic HD in 2 dialysis units bet 1989-1996 * 1st national survey of its kind which revealed a total of 15 pregnancies in HD - all dialysis centers in Belgium questioned for pts bet 1975-1996 Study Population Figures Case Characteristics/ Outcomes Dialysis Dosing * 15 pregnancies went beyond 1st trimester * Frequency of HD was increased immediately or progressively to 16 to 24 hrs * No difference bet successful pregnancies and failed ones for # mths on HD prior to conception or age at conception. * For successful pregnancies + correlation bet birth wt and excess dialysis hrs delivered over entire pregnancy. Success Rate * 80% (4/5) when HD initiated after onset of pregnancy (pregnancy first) * 50% (5/10) when HD was the first event * ‘‘Pregnancy first’ cases have a significant residual renal function and even may benefit from ‘preventive dialysis’, to be taken on dialysis at a stage of renal failure that would not justify dialysis in the eyes of many were it not for the very special setting of a pregnant state’’ Obstetrical Problems * Main Problem: premature births * In this study 3 died due to severe prematurity * Polyhydramnios present in almost all cases, may be cause of preterm labor * Growth retarded babies at highest risk for intrauterine death * Maternal prognosis is good Should we Initiate Dialysis in Pts w/Low Cr Clearance? * Hou, S., Pregnancy in Women on Hemodialysis, 1994, revealed better outcomes of pregnancy in women w/ significant residual renal function or who initiate pregnancy before they need dialysis. * May reduce incidence of polyhydramnios, lower urea and lowers water load, also reducing risk of dialysis-induced hypotension Registry of Pregnancy in Dialysis Patients USRDS Frequency of Prematurity and Low Birth Rate is less in those conceived before beginning dialysis Women who Start Dialysis During Pregnancy * Likelihood of infant surviving is good * Termination of a pregnancy after renal function has begun to deteriorate rarely rescues the kidneys * NEJM, Jones and Hayslett, 1996, looked at 82 pregnancies in 67 women w/CRI, only 15% of those w/deteriorating renal function had a return of renal function to baseline in 6 mths post partum Survival Statistics Renal Failure and Dialysis in Pregnancy.ppt

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Hemolytic Disease of the Newborn

Hemolytic Disease of the Newborn, Current Methods of Diagnosis and Treatment
By:Terry Kotrla, MS, MT(ASCP)BB

Objectives
* List the classifications of Hemolytic Disease of the Newborn and the most antibody specificities involved.
* State the testing to perform on the mother to monitor the severity of HDN.
* List the laboratory tests and values which indicate that an infant is affected by HDN both in the fetus and newborn.
* State the treatment options for intrauterine treatment of HDN.
* State the treatment options for HDN in the moderately and severely affected newborn.
* State the requirements of blood to be used for transfusion of the fetus and newborn.

Cause of Hemolytic Disease
* Maternal IgG antibodies directed against an antigen of paternal origin present on the fetal red blood cells.
* IgG antibodies cross the placenta to coat fetal antigens, cause decreased red blood cell survival which can result in anemia.
* Produced in response to previous pregnancy with antigen positive fetus OR exposure to red blood cells, ie transfusion.

Three Classifications of HDN
* ABO
* “Other” – unexpected immune antibodies other than anti-D – Jk, K, Fy, S, etc.
* Rh – anti-D alone or may be accompanied by other Rh antibodies – anti-C, -c, -E or –e.

ABO Hemolytic Disease
* Mother group O, baby A or B
* Group O individuals have anti-A, -B and –A,B in their plasma, fetal RBCs attacked by 2 antibodies
* Occurs in only 3%, is severe in only 1%, and <1:1,000 require exchange transfusion. * The disease is more common and more severe in African-American infants. “Other” Hemolytic Disease * Uncommon, occurs in ~0.8% of pregnant women. * Immune alloantibodies usually due to anti-E, -c, -Kell, -Kidd or -Duffy. * Anti-K o disease ranges from mild to severe o over half of the cases are caused by multiple blood transfusions o is the second most common form of severe HDN * Anti-M very rare Rh Hemolytic Disease * Anti-D is the commonest form of severe HDN. The disease varies from mild to severe. * Anti-E is a mild disease * Anti-c can range from a mild to severe disease - is the third most common form of severe HDN * Anti-e - rare * Anti-C - rare * antibody combinations (ie anti-c and anti-E antibodies occurring together) - can be severe HDN * Maternal antibodies destroy fetal red blood cells o Results in anemia. o Anemia limits the ability of the blood to carry oxygen to the baby's organs and tissues. * Baby's responds to the hemolysis by trying to make more red blood cells very quickly in the bone marrow and the liver and spleen. o Organs enlarge - hepatosplenomegaly. o New red blood cells released prematurely from bone marrow and are unable to do the work of mature red blood cells. * As the red blood cells break down, bilirubin is formed. o Babies unable to get rid of the bilirubin. o Builds up in the blood (hyperbilirubinemia ) and other tissues and fluids of the baby's body resulting in jaundice. o The placenta helps get rid of some of the bilirubin, but not all. Complications During Pregnancy * Severe anemia with enlargement of the liver and spleen When these organs and the bone marrow cannot compensate for the fast destruction of red blood cells, severe anemia results and other organs are affected. * Hydrops Fetalis This occurs as the baby's organs are unable to handle the anemia. The heart begins to fail and large amounts of fluid build up in the baby's tissues and organs. A fetus with hydrops is at great risk of being stillborn. Hydrops Fetalis Clinical Presentation * Varies from mild jaundice and anemia to hydrops fetalis (with ascites, pleural and pericardial effusions) * Chief risk to the fetus is anemia. * Extramedullary hematopoiesis due to anemia results in hepatosplenomegaly. * Risks during labor and delivery include: o asphyxia and splenic rupture. * Postnatal problems include: o Asphyxia o Pulmonary hypertension o Pallor (due to anemia) o Edema (hydrops, due to low serum albumin) o Respiratory distress o Coagulopathies ( platelets & clotting factors) o Jaundice o Kernicterus (from hyperbilirubinemia) o Hypoglycemia (due to hyperinsulinemnia from islet cell hyperplasia) Kernicterus * Kernicterus (bilirubin encephalopathy) results from high levels of indirect bilirubin (>20 mg/dL in a term infant with HDN).
* Kernicterus occurs at lower levels of bilirubin in the presence of acidosis, hypoalbuminemia, prematurity and certain drugs (e.g., sulfonamides).
* Affected structures have a bright yellow color.
* Unbound unconjugated bilirubin crosses the blood-brain barrier and, because it is lipid soluble, it penetrates neuronal and glial membranes.
* Bilirubin is thought to be toxic to nerve cells
* The mechanism of neurotoxicity and the reason for the topography of the lesions are not known.
* Patients surviving kernicterus have severe permanent neurologic symptoms (choreoathetosis, spasticity, muscular rigidity, ataxia, deafness, mental retardation).

Laboratory Findings
* Vary with severity of HDN and include:
* Anemia
* Hyperbilirubinemia
* Reticulocytosis (6 to 40%)
* nucleated RBC count (>10/100 WBCs)
* Thrombocytopenia
* Leukopenia
* Positive Direct Antiglobulin Test
* Hypoalbuminemia
* Rh negative blood type or ABO incompatibility
* Smear: polychromasia, anisocytosis, no spherocytes

Blood Smear
* Polychromasia
* Anisocytosis
* Increase NRBCs
* no spherocytes

Blood Bank Testing
Bilirubin Nomogram
* Total Serum Bilirubin (TSB) monitored to determine risk of kernicterus.
* Measure bilirubin in cord blood and at least every 4 hours for the first 12 to 24 hours. Plot bilirubin concentrations over time.

Transcutaneous Monitoring
* Transcutaneous bilirubinometry can be adopted as the first-line screening tool for jaundice in well, full-term babies.
* This leads to about 50% decrease in blood testing.
* http://tinyurl.com/36jazx

Intrauterine Transfusion (IUT)
* Given to the fetus to prevent hydrops fetalis and fetal death.
* Can be done as early as 17 weeks, although preferable to wait until 20 weeks
* Severely affected fetus, transfusions done every 1 to 4 weeks until the fetus is mature enough to be delivered safely. Amniocentesis may be done to determine the maturity of the fetus's lungs before delivery is scheduled.
* After multiple IUTs, most of the baby’s blood will be D negative donor blood, therefore, the Direct Antiglobulin test will be negative, but the Indirect Antiglobulin Test will be positive.
* After IUTs, the cord bilirubin is not an accurate indicator of rate of hemolysis or of the likelihood of the need for post-natal exchange transfusion.

Intrauterine Transfusion
* An intrauterine fetal blood transfusion is done in the hospital. The mother may have to stay overnight after the procedure.
* The mother is sedated, and an ultrasound image is obtained to determine the position of the fetus and placenta.
* After the mother's abdomen is cleaned with an antiseptic solution, she is given a local anesthetic injection to numb the abdominal area where the transfusion needle will be inserted.
* Medication may be given to the fetus to temporarily stop fetal movement.
* Ultrasound is used to guide the needle through the mother's abdomen into the fetus's abdomen or an umbilical cord vein.
* A compatible blood type (usually type O, Rh-negative) is delivered into the fetus's abdominal cavity or into an umbilical cord blood vessel.
* The mother is usually given antibiotics to prevent infection. She may also be given tocolytic medication to prevent labor from beginning, though this is unusual.
* Increasingly common and relatively safe procedure since the development of high resolution ultrasound particularly with colour Doppler capability.
* MCA Doppler velocity as a reliable non-invasive screening tool to detect fetal anemia.
o The vessel can be easily visualized with color flow Doppler as early as 18 weeks’ gestation.
o In cases of fetal anemia, an increase in the fetal cardiac output and a decrease in blood viscosity contribute to an increased blood flow velocity
* The risk of these procedures is now largely dependent on the prior condition of the fetus and the gestational age at which transfusion is commenced.
* Titer greater than 32 for anti-D and 8 for anti-K OR four fold increase in titer indicates need for analysis of amniotic fluid.
* Amniocentesis
o Perform at 28 wks if HDN in previous child
o Perform at 22 wks if previous child severely affected
o Perform if maternal antibody increases before 34th wk.
* High values of bilirubin in amniotic fluid analyses by the Liley method or a hemoglobin concentration of cord blood below 10.0 g/mL.
* Type fetus -recent development in fetal RhD typing involves the isolation of free fetal DNA in maternal serum. In the United Kingdom, this technique has virtually replaced amniocentesis for fetal RhD determination in the case of a heterozygous paternal phenotype
* Maternal plasma exchange may be instituted if the fetus is too young for intrauterine transfusion.

Liley Graph
Selection of Blood
* CPD, as fresh as possible, preferably <5 days old. * A hematocrit of 80% or greater is desirable to minimize the chance of volume overload in the fetus. * The volume transfused ranges from 75-175 mL depending on the fetal size and age. * CMV negative * Hemoglobin S negative * IRRADIATED * O negative, lack all antigens to which mom has antibodies and Coomb’s compatible. Treatment of Mild HDN * Phototherapy is the treatment of choice. * Phototherapy process slowly decomposes/converts bilirubin into a nontoxic isomer, photobilirubin, which is transported in the plasma to the liver. * HDN is judged to be clinically significant (phototherapy treatment) if the peak bilirubin level reaches 12 mg/dL or more. Bilirubin Degradation by Phototherapy Phototherapy * The therapy uses a blue light (420-470 nm) that converts bilirubin so that it can be excreted in the urine and feces. * Soft eye shields are placed on the baby to protect their eyes from damage that may lead to retinopathy due to the bili lights. Phototherapy * Lightweight, fiberoptic pad delivers up to 45 microwatts of therapeutic light for the treatment of jaundice while allowing the infant to be swaddled, held and cared for by parents and hospital staff. * Compact unit is ideal for hospital and homecare. Exchange Transfusion * Full-term infants rarely require an exchange transfusion if intense phototherapy is initiated in a timely manner. * It should be considered if the total serum bilirubin level is approaching 20 mg/dL and continues to rise despite intense in-hospital phototherapy. * The procedure carries a mortality rate of approximately 1% and there may be substantial morbidity Goals of Exchange Transfusion * Remove sensitized cells. * Reduce level of maternal antibody. * Removes about 60 percent of bilirubin from the plasma, resulting in a clearance of about 30 percent to 40 percent of the total bilirubin. * Correct anemia by providing blood that will have normal survival. * Replacement with donor plasma restores albumin and any needed coagulation factors. * Rebound – usually a 2 volume exchange is needed as bilirubin in tissues will return to blood stream. Testing Baby * Antibody elution testing from cord red blood cells. * ABO/D typing o If baby received intrauterine transfusions will type as O negative o If baby’s Direct Antiglobulin Test is strongly positive due to anti-D may get FALSE NEGATIVE immediate spin reaction with reagent anti-D (blocking phenomenon), weak D (Du) test will be STRONGLY positive * Antibody screen * Coomb’s crossmatch antigen negative donor. Testing Mom * Type and screen on mom. * Identification of unexpected antibodies. * More than 40 antigens have been identified as causing HDN. * Select blood that lacks antigens to which mom has antibodies. * Perform coomb’s crossmatch with Mom and baby’s blood. Selection of Donor Blood * CPD, as fresh as possible, preferably <5 days old. * CMV negative * Hemoglobin S negative * Irradiated if possible Preparation of Donor Unit * Physician will specify a hematocrit. * Reconstitute donor unit with plasma. * Most facilities prefer to use group O red cells and AB plasma. * Reference for procedure at end of this presentation. Summary * Three types of HDN vary in severity. * Laboratory testing key to diagnosing and monitoring- great care to be taken when interpreting ABO/D typing on affected infants. * Therapy dependent on severity: phototherapy alone or with transfusion. References Hemolytic Disease of the Newborn, Current Methods of Diagnosis and Treatment.ppt

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Hemolytic Disease of the Newborn and Fetus

Hemolytic Disease of the Newborn and Fetus
By:Renee Newman Wilkins, MS, MT(ASCP), CLS(NCA)
CLS 325/435 Clinical Immunohematology
School of Health Related Professions
University of Mississippi Medical Center

What is HDN?
* Destruction of the RBCs of the fetus and newborn by antibodies produced by the mother
* Only IgG antibodies are involved because it can cross the placenta (not IgA or IgM)
Mother’s antibodies
Pathophysiology
* Although transfer of maternal antibodies is good, transfer of antibodies involved in HDN are directed against antigens on fetal RBCs inherited by the father
* Most often involves antigens of the Rh and ABO blood group system, but can result from any blood group system
* Remember: The fetus is POSITIVE for an antigen and the mother is NEGATIVE for the same antigen

Pathophysiology
* HDN develops in utero
* The mother is sensitized to the foreign antigen present on her child’s RBCs usually through some seepage of fetal RBCs (fetomaternal hemorrhage) or a previous transfusion
* HDN occurs when these antibodies cross the placenta and react with the fetal RBCs

ABO HDN
* ABO incompatibilities are the most common cause of HDN but are less severe
* Usually, the mother is type O and the child has the A or B antigen…Why?
* ABO HDN can occur during the FIRST pregnancy b/c prior sensitization is not necessary
* ABO HDN is less severe than Rh HDN because there is less RBC destruction
o Fetal RBCs are less developed at birth, so there is less destruction by maternal antibodies
Diagnosis of ABO HDN
* Infant presents with jaundice 12-48 hrs after birth
* Testing done after birth on cord blood samples:
Treatment of ABO HDN
* Only about 10% require therapy
* Phototherapy is sufficient
* Rarely is exchange transfusion needed
* Phototherapy is exposure to artificial or sunlight to reduce jaundice
* Exchange transfusion involves removing newborn’s RBCs and replacing them with normal fresh donor cells

Phototherapy
Fluorescent blue light in the 420-475 nm range
Exchange transfusion
* CMV negative
* Irradiated
* Fresh Whole Blood (to avoid Ca++)
* Maternal blood if possible
* Leukoreduced

What type of blood to give fetus:

Rh HDN
* Mother is D negative (d/d) and child is D positive (D/d)
* Most severe form of HDN
* 33% of HDN is caused by Rh incompatibility
* Sensitization usually occurs very late in pregnancy, so the first Rh-positive child is not affected
o Bleeds most often occur at delivery
o Mother is sensitized
o Subsequent offspring that are D-positive will be affected

About 1 in 10 pregnancies involve an Rh-negative mother and an Rh-positive father
FetoMaternal Hemorrhage
* Sensitization occurs as a result of seepage of fetal cells into maternal circulation as a result of a fetomaternal hemorrhage

Risk
* Rh-negative women can be exposed to Rh-Positive cells through transfusion or pregnancy
* Each individual varies in their immune response (depends on amount exposed to)
Pathogenesis
* Maternal IgG attaches to antigens on fetal cells
o Sensitized cells are removed by macrophages in spleen
o Destruction depends on antibody titer and number of antigen sites
o IgG has half-life of 25 days, so the condition can range from days to weeks
* RBC destruction and anemia cause bone marrow to release erythroblasts, hence the name “erythroblastosis fetalis”)

Increased immature RBCs
Pathogenesis
* When erythroblasts are used up in the bone marrow, erythropoiesis in the spleen and liver are increased
Bilirubin
* Hemoglobin is metabolized to bilirubin
Diagnosis & Management
* Serologic Testing (mother & newborn)
* Amniocentesis and Cordocentesis
* Intrauterine Transfusion
* Early Delivery
* Phototherapy & Newborn Transfusions

Serologic testing on mother
* ABO and Rh testing
* Antibody Screen
* Antibody ID
* Paternal phenotype
* Amniocyte testing
* Antibody titration
Marsh score
Example:
Amniocentesis & Cordocentesis
* About 18-20 weeks’ gestation
* Cordocentesis takes a sample of umbilical vessel to obtain blood sample
* Amniocentesis assesses the status of the fetus using amniotic fluid
Analysis of amniotic fluid (example)
Liley graph
What to do?
* Intrauterine transfusion is done if:
* Removes bilirubin
* Removes sensitized RBCs
* Removes antibody

Other treatments
* Early Delivery
* Phototherapy (after birth)
* Newborn transfusion

Postpartum testing
* ABO – forward only
* Rh grouping – including weak D
* DAT
* Elution
Prevention
* RhIg (RhoGAM®) is given to the mother to prevent immunization to the D antigen

Postpartum administration of RhIg
Dose
Rosette Test
* A qualitative measure of fetomaternal hemorrhage

Fetomaternal Hemorrhage:
Kleihauer-Betke acid elution
Calculating KB test
Step 1) stain and count the amount of fetal cells out of 1000 total cells counted
Step 2) calculate the amount of fetal blood in cirulation by multiplying %fetal cells by 50 mL
Step 3) divide mL of fetal blood by 30 (each vial protects against a 30 mL bleed
Step 4) Round the calculated dose up and add one more vial for safety

Considerations
* RhIg is of no benefit once a person has formed anti-D
* It is VERY important to distinguish the presence of anti-D as:
o Residual RhIg from a previous dose OR
o True immunization from exposure to D+ RBCs
* RhIg is not given to the mother if the infant is D negative (and not given to the infant)

* Make sure presence of anti-D is not due to antenatal administration of Rh immune globulin
Hemolytic Disease of the Newborn and Fetus.ppt

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Zoonotic Helminthiasis

ZOONOTIC HELMINTHIASIS
* Helminth: parasitic worm (Greek)
o Platyhelminthes (flukes, tapeworms)
o Nematodes (roundworms)

* Pathogenic helminths are some of most common parasites
* Worlwide distribution
* Toxocariasis (visceral/ocular larval migrans)
o Toxocara canis, T. cati
* Meningoencephalitis
o Balysascaris procyonis
* Trichinosis
o Trichinella spiralis
* Taeniasis
o Taenia soleum, T. saginata
* Hydatid disease
o Echinococcus granulosus, E. multilocularis

TOXOCARIASIS
* Agent:
o Toxocara canis - roundworm of dogs and cats
o Toxocara cati - roundworm of cats (less frequently involved)
* Other names for diseae:
o visceral larval migrans (VLM)
o ocular larval migrans (OLM)

TOXOCARIASIS
Egg
Adult female - head
* Life cycle:
Epidemiology
* Reservoir:
o dogs, cats, small mammals
* Distribution:
o worldwide, most attention in US and UK
o seroprevalence: 3%; 23% in some groups
* Transmission:
o direct or indirect by ingestion of infective eggs from fecal contamination or contaminated soil
o larvae in contaminated undercooked liver from poultry, beef

Clinical features
* Incubation period:
o children - weeks to months
o OLM may be 2-4 years later
* Symptoms:
o asymptomatic to chronic, mild disease (usually)
o predominantly in young children
o increasingly recognized in adults
o symptoms related to migration of larval stage through tissues
* Symptoms:
o VLM - may persist for year or longer
+ fever
+ anorexia
+ weight loss
+ cough
+ eosinophilia
+ rash
+ hepatosplenomegaly
+ death (rarely) due to severe cardiopulmonary and neurologic manifestations
* Symptoms:
o OLM
+ misdiagnosed as retinoblastoma, leading to surgical enucleation
+ endophthalmitis at entry of larva
+ loss of vision
+ eosinophilia rare
+ visceral manifestation rare
+ occurs in children and adults
Diagnosis
* Direct (fecal) examination no use - larva does not develop into adult, no ova passed in feces
* Antibody detection confirmatory only in presence of clinical signs and history
o EIA (enzyme immunoassay)
+ larval antigen extracts from
# embryonated eggs
# cultured TES (Toxocara excretory-secretory antigens) - preferred
+ 1:32

Treatment
* Supportive treatment
* Anthelmentics - effectiveness uncertain
o DEC (diethylcarbamazine)
o Albendazole
o Mebendazole
* Corticosteroids for severe eye problems

Prevention/Control
* Education, especially pet owners
* Routine examination of pets
* Effective deworming program for puppies and kittens
* Removal of feces from environment
* Routine hygiene after handling pets, soil

TAENIASIS
* Agent:
o Tanea soleum - pork tapeworm
o T. saginata - beef tapeworm
* Other names for disease:
o taeniasis - intestinal infection of either tapeworm in animals or humans
o cystiserciasis; cysticercosis - tissue infection with T. soleum larva

Epidemiology
* Reservoir:
o humans definitive host for both T. saginata and T. soleum
* Occurrence:
o worldwide
o highest in Latin America, Africa, SE Asia, Eastern Europe
o T. soleum rare in US, Canada, UK, but increasingly recognized in immigrants

Epidemiology
* Transmission:
Clinical features
* Incubation period:
o taeniasis - eggs appear in 8-14 weeks
o cystercosis - days to years
* Symptoms:
o Taeniasis
+ mild abdominal symptoms
+ occasionally appendicitis or cholangitis from migrating proglottids
+ passage of proglottids (active or passive)
Clinical features
* Cysticercosis:
TANEIASIS
Diagnosis
* Taeniasis
* Cysticercosis
Treatment
* Taeniasis
o praziquantel
* Cystercosis
o praziquentel if active cystercosis, but only under hospitalization due to acute inflammatory reaction; steroids given to control inflammation
o surgical
+ shunt - ventriculoperitoneal shunt to drain CSF
+ cyst removal
+ endoscopic fenestration (hole in cyst wall)

Prevention/Control
* Education
* Identification and immediate treatment of infected individuals
* Freezing meat at -5ºC (23ºF) for > 4 days effectively kills cysticerci
* Irradiation

Agent
Echinococcus granulosus
E. multilocularis
E. vogeli
E. oligarthrus
Disease
Cystic hydatid disease;
unilocular echinococcosis
Alveolar hydatid disease;
multilocular echinococcosis
Polycystic alveolar disease
Rare in humans

UNILOCULAR ECHINOCOCCOSIS
Hydatid “sand”-protoscolices from fluid aspirate of hydatid cyst
Note: normally invaginated; evaginates in saline (right)

Epidemiology
* Transmission:

Clinical features
* Incubation period: months to years
* Symptoms:
o cysts grow slowly, asymptomatic until noticeable mass effect
o compatible with slow-growing tumor
o symptoms depend on location, size, and number of cysts
o anaphylactoid reaction if cyst ruptures/leaks

MULTILOCULAR ECHINOCOCCOSIS
Epidemiology
Clinical features
POLYCYSTIC ECHINOCOCCOSIS
Clinical features
Diagnosis
Serological diagnosis
Treatment
DIPHYLLOBOTHRIASIS
Epidemiology
* Occurrence:
Clinical features
Diagnosis
Treatment
Prevention and Control
ANISAKIASIS
Epidemiology
* Occurrence:
Clinical features
Diagnosis
* Direct examination:
o parasite coughed up
o Fiber optic exam
o laparotomy
* Radioallergosorbent (skin test) developed but not available commercially

Treatment
* surgical excision
Prevention and control
* Avoid ingestion of raw/undercooked fish
* Heating for 10 minutes @ 140ºF (60ºC)
* Freezing:
o “blast freezing” for 15 hours @ -31ºF (-35ºC)
o regular freezing for 7 days @ -10ºF (-23ºC)
* irradiation
* proper cleaning/evisceration as soon as caught

Zoonotic Helminthiasis.ppt

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