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Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Safety of Blood(from an infectious disease standpoint)
David M. Smith, M.D.
Medical Director
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
History of CBC/CTS
• CBC Founded in 1964; Serves 27 hospitals in 15 counties in Southwestern Ohio and Eastern Indiana
• Full service blood center that collects, processes and distributes blood components, provides red cell and platelets reference laboratory, HLA typing, stem cell collection and processing, therapeutic phlebotomy and therapeutic apheresis, and transfusion medicine expertise.
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
History of CBC/CTS
• CTS developed in 1985; since 1994 has expanded to seven branches in six states with recovery partners throughout the US
• Collects, processes and distributes musculoskeletal tissue and skin
• Distributes tissue first to local communities, then nationally and internationally
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Community Blood Center
• Not-for-profit 501 (c)(3) company established in 1964 to provide blood products to the Dayton community – independent blood center member of America’s Blood Centers (ABC)
• Dayton Regional Tissue Bank established as a Division of CBC in 1986 in response to the needs of local surgeons for allograft tissue
• Name changed to Community Tissue Services in 1995 to reflect growth into communities across the nation (and currently internationally)
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Community Blood Center • Two operational units
• Community Blood Center• Local/regional service• Supporting multiple local hospitals• Distribution of approximately 130K blood products• Other internal and external services
• Reference Laboratory• HLA/Molecular• Testing Laboratory• Microbiology• Therapeutic Apheresis
• Community Tissue Services• National and international service• Multiple branches nationwide• Supporting health care facilities and workers nationwide and internationally• Distribution of over 80K tissue products
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Strategies for Minimizing Risks
• Volunteer donor base – no financial incentive to donate blood products
• Donor screening – least effective• Directed donation – no safer than allogeneic• Autologous donation - safe• Testing of blood – largest effect on safety• Processing of blood (including leukoreduction,
pathogen inactivation)
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Major Infectious Diseases(screening blood tests)
• HBV – HBsAg, HBcAb, HBV NAT*• HCV – antibody to HCV, HCV NAT• HIV 1, 2 – antibody to HIV, HIV NAT• Syphilis – RPR• HTLV I &II – antibody to HTLV• WNV – WNV NAT• CMV –antibody to CMV
* Currently available but not required
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Major Infectious Diseases(not currently screening blood)
• HIV type O
• Malaria
• Chagas Disease
• vCJD
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Donor Screening
• Screening is least effective tool to prevent transmission of infectious diseases
• FDA regulates screening requirements and defines permanently deferred categories as well as temporary deferrals
• There are some inconsistencies between deferrals for blood donation and tissue donation
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Viral Disease Screening in Blood Banking 1993-Present
Updated from AuBuchon, Birkmeyer, Busch. Ann Intern Med 1997;127:904-9.
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Reaction to Viral Infections
• Virus enters host (infection)• Virus enters target organ and begins replicating, no
virus in blood (eclipse phase)• Virus in blood (viremic phase)• Immune reaction to virus • Antibody production (days to weeks); antibodies can
be protective or non-protective• The window phase is the time interval between
infection and presence of detectable viral NA, viral antigens, or antibody to viral antigens
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
What Tests are Available to Detect Viral Infectious Diseases?
• Tests that look for antibody produced by the body against viral antigens• Window phase for current antibody tests is 22
days for HIV, 59 days for HBV, and 70 days for HCV
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
What Tests are Available to Detect Viral Infectious Diseases?
• Tests that look for virus specific antigens (HIV p24Ag, HBsAg)
• Tests that look for viral DNA or RNA (NAT)• Become positive more quickly• Remain positive as long as virus is present • Window period for HIV is 11 days, HBV 20-30
days, and HCV 10-12 days
• Virus can be transmitted in the window period
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Methods of Nucleic Acid Testing• Polymerase chain reaction (PCR)
• Roche Amplicor, AmpliScreen, TaqMan
• Transcription-mediated amplification (TMA)• Gen-Probe/Chiron Procleix, Procleix Tigris
• Others• Nucleic acid sequence-based amplification
(NASBA), ligase chain reaction (LCR), branched DNA signal amplification (bDNA)
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Nucleic Acid Tests (NAT)General Characteristics
• Sample preparation, including viral concentration and extraction of DNA or RNA
• Amplification of the target viral DNA or RNA
• Detection of the amplified product
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
What NAT means to the Window Period (Blood)
EIA Window Post-NAT Window
• HCV 70-80 days 10 days
• HIV 16 days 10 days
• HBV 56 days 20-30 days
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Viral Characteristics
• HBV-DNA harder to detect by virtue of the slower reproductive cycle of the virus
• Virus Doubling Times• HCV--17.7 hrs.• HIV-- 21.5 hrs.• HBV--2.8 days (67.2 hrs.)
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
HIV Viremia During Early Infection
HIV RNA (plasma)HIV Antibody EIA
11
0 10 20 30 40 50 60 70 80 90 100
HIV p24 Ag
16 22
Ramp-up viremia
1st gen
2nd gen3rd gen
p24 Ag EIA ------
Pooled NAT -
Individual NAT -
Peak viremia
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
HCV Markers During Early Infection
HCV RNAAnti-HCV EIAs
1st gen 150 d 2nd gen 80 d 3rd gen 70 d
0 10 20 30 40 50 60 70 80 90 100
Ramp-up phase
Plateau phase viremia
Pre-ramp-up blip viremia
ALT
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
HBV Viremia in Early Infection
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Advantages of NAT testing in Blood
• Test manufacturers have incentive to develop and market tests • 14 million donor units per year in the United
States alone• Uniform test samples are available because donors
are alive
• Required for HIV, HCV, and WNV; currently optional for HBV
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
West Nile VirusBackground Information
• WNV is a mosquito-borne flavivirus
• WNV has a positive strand RNA genome of about 11 kb that encodes several proteins
• Primarily infects birds, occasionally also infects humans and horses
• About 80% of infected persons remain asymptomatic, rest 20% develop mild febrile illness (flu-like illness)
• Meningitis or encephalitis develops in ~1 in 150 infected persons
• Viremic period can occur up to 2 weeks prior to symptoms and last up to several months from the initiation of the infection
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Modes of Transmission
• Mosquito Bite• Transplantation• Transfusion• Breastfeeding• Transplacental Exposure• Occupational Exposure
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
A Culex quinquefasciatus Mosquito on a Human Finger
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
West Nile Fever: Classic Clinical Description
• Mild illness of sudden onset• Duration 3-6 days• Fever, lymphadenopathy, headache, abdominal pain,
vomiting, rash, conjunctivitis, eye pain, loss of appetite
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
8 cases WNV
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
21 cases, 2 deaths
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
66 cases, 9 deaths
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
4161 cases, 277 deaths
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
9862 cases, 264 deaths
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Human WNV Infections 2004
2470 cases, 88 deaths
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
WNV Activity 2005
2949 cases, 116 fatalities
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Human WNV Viremic Blood Donors 2005
399 presumptive viremic blood donors
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
West Nile Virus Infection in an Organ Donor West Nile Virus Infection in an Organ Donor and Four Transplant Recipientsand Four Transplant Recipients
August 2002August 2002
Organ Donor
WNV PCR –IgM –
Organ Donor
WNV PCR +
Culture +IgM –
Kidney recipientWNME (fatal)
Kidney recipientWNME
Liver recipientWNF
Heart recipientWNME
Blood Blood components components
from 63 donorsfrom 63 donors
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Infectivity of WNV and Laboratory Testing
• The infectious dose is low compared with many other viruses
• NAT tests are very sensitive• It was recognized that pooled testing was missing
WNV due to dilution (low level viremia in one sample was diluted leading to negative pool results)
• Blood Centers instituted policies to switch to single donor testing from pooled testing when prevalence of disease increases
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Serologic and NAT Testing
• It was initially felt that once donors developed antibodies that they would be non-infectious, even though there is some overlap with viremia
• It was later recognized that viremia can persist for several months, even in the presence of antibodies, leading to increased deferral period for blood to 120 days
• Most recently, evidence suggests that the virus can be transmissible when antibodies are present but virus is undetectable by NAT
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Serologic and NAT Testing
• Within the last approximate year, it is now recognized that you can have initially reactive WNV NAT, but when multiple additional aliquots from the same sample are tested, they can be negative (up to 10 replicates before another positive)
• Not false positive or negative, but samples tested may not contain enough virus particles to get a positive reaction
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
101
102
103
104
105
WN
V R
NA
(gE
q pe
r m
L)
Days post infectious mosquito bite2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
RNA
IgM
IgG
6-7 days
Stage-II
IDNAT+ MPNAT- IgM-
Stage-IV
IDNAT+ MPNAT-
IgM+IgG+/-
ID-NAT
Stage-V
IDNAT +/- MPNAT- IgM+
IgG+
Stage-I
IDNAT+/-MPNAT- IgM-
Stage-III
MPNAT+ IgM-
West Nile Virus
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
vCJD• vCJD is caused by an abnormal prion protein that causes
normal prion proteins to change into abnormal proteins• It was initially unclear whether vCJD could be
transmissible by blood transfusion• Recently, the third case of presumptive transmission was
announced; statistically almost impossible to be chance occurrence
• The “epidemic”, 172 cases worldwide, is declining but may be a second wave due to longer incubation in persons heterozygous for certain normal prion proteins who may incubate vCJD for longer periods of time
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
vCJD• Current strategy is to defer blood donors
who have spent significant time in Europe
• Development of prion filters with some success
• Recently a cow in the Southern US was discovered to have BSE
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Malaria• Approximately 120 cases are diagnosed in
US every year; almost all “imported” from endemic areas
• Anopheles mosquitoes are found in Southern US so there is still risk of malaria re-establishment in US
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Chagas Disease(American Trypanosomiasis)
• Caused by Trypanosoma cruzi and spread by the Triatomine “kissing bug”
• Disease of poverty; bugs live in cracks and holes of substandard housing in Central and South America and Mexico
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Chagas Disease(American Trypanosomiasis)
• Infection from exposure to insect feces (oral, mucosal, non-intact skin)
• Vertical transmission from mother to fetus
• Blood or organ transmission
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Chagas Disease(American Trypanosomiasis
• Most asymptomatic acute infection
• Chronic infection common leading to heart failure or dilatation of gastroenteric tract
• Very long incubation; decades before chronic symptoms
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
LA Seroprevalence: 1996-98
0.000
0.002
0.004
0.006
0.008
0.010
0.012
0.014
0.016
0.018
1996 1997 1998
% D
onor
s P
ositi
ve
1/9,900
1/7,200
1/5,400Leiby, D. et al. Transfusion. 2002
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Nationwide risk of Chagas
13.2 million donations 100%
330,000 at risk donations 2.5%
528 seropositive donations 0.16%
845 seropositive donations/year
989 potentially infectious components
Leiby, D. Pers. Comm.
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Transfusion Chagas:
1987: California - Mexican donor
1989: New York City - Bolivian donor
Manitoba - Paraguayan donor
1993: Houston - unknown donor
1999: Miami - Chilean donor
2000: Manitoba - German/Paraguayan donor
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Why so few cases if there are 1000 infected donors/yr?
• Reported cases are “sentinels”
• Immunosuppressed
• Fulminant disease
• Easily detected/diagnosed
• Many cases missed
• Immunocompetent
• Misdiagnosed
• Not recognized
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
What Will We Do?
• Donor history screening
• To identify at-risk donors for deferral or testing
• Lack sensitivity & specificity
• Donor testing
• Lack of licensed tests: Will be implemented when available
• Potential strategies
• One-time testing of new donors?
• Universal testing?
• Added value of NAT testing minimal
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Bacterial Contamination of Platelets
• Incidence of bacterial contamination and consequent patient infections have remained stable for years
• As risks of viral transmissions have declined dramatically, bacterial issues have come to the forefront again
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Bacterial Contamination of Blood and Blood Products (Review)
• Discussions of bacterial contamination as early as 1939 in JAMA
• In the 1950’s, bacterial contamination of blood was identified in up to 2.2% of bottles
• In the late 1960’s and early 1970’s, concerns about bacterial contamination were raised because of RT storage; one study found 1.6% contamination rate
• 16% of transfusion fatalities reported to FDA (1986 - 1991)
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Selected History
• 1981 - 2nd generation of platelet containers providing prolonged platelet viability
• 1982 - Platelet storage extended to 5 days• 1983 - Platelet storage extended to 7 days• 1986 - In response to an increase in the number
of reports of platelet-transfusion associated sepsis, the BPAC recommended reverting to a five day old platelet storage interval
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Why is this a platelet recipient issue?
• The numbers of bacteria that circulate in the donor are usually small, and cleared by the normal immune system.
• Only a few bacteria are required from donor• Venipuncture site• Asymptomatic transient bacteremia • Bacteria grow in the blood bag
• Increased risk with room temperature storage and nutrients in plasma
• Many blood recipients are immunocompromised
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
HIVHIV
HBVHBVHCVHCV
19961996199419941992199219901990198819881986198619841984
1:1001:100
1:10001:1000
1:10 0001:10 000
1:100 0001:100 000
1:1 000 0001:1 000 000
19981998 20002000
Transmission risk, Transmission risk, per unitper unit
Updated from: Goodnough LT Updated from: Goodnough LT e t al. NEJMe t al. NEJM 1999;341:126-7 1999;341:126-7
20022002
BacterialBacterialContaminationContamination
(platelets)(platelets)
MistransfusionMistransfusionFatalitiesFatalities(red cells)(red cells)
SepticSepticFatalitiesFatalities(platelets)(platelets)
Comparison of Residual Risks
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Bacterial Contamination of Blood Products: The BaCon Study
Between Jan. 1998-Dec. 2000, there were 34 confirmed cases of
transfusion transmitted bacteremia or infection (TTI) in the U.S.
Breakdown of Implicated Components
Confirmed TTI (34)
TTI Fatalities (9)
18SDP
11Pooled RDP
Red Blood Cells 5
4
23
Kuehnert MJ, Roth VR, Haley NR, Gregory KR, Elder KV, Schrieber GB, Arduino MJ, Holt SC, Carson LA, Banerjee SN, Jarvis WR. Transfusion-transmitted bacterial infection in the United States, 1998 through 2000. Transfusion 2001 Dec;41(12):1493-1499.
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Bacterial Contamination/100,000 Platelet Transfusions
BaCon UHC
TT Bacterial Disease 1 200
TT Bacterial Death 0.2 10
R. Yomtovian in Engelfriet et al: International Forum. Bacterial Contamination of Blood Components. Vox Sang 2000; 78:59-67; Kuehnert MJ et al. Transf 2001 Dec;41(12):1493-1499.
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
BACTERIAL CONTAMINATION OF PLATELETS
BaCon Study
UHC Prospective Surveillance
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Clinical Significance of Platelet Bacterial Contamination
- 1:2000 units (RD and SD) are contaminated - 1:500 pooled unit transfusions are associated with septic transfusion reactions - 1:10,000 pooled unit transfusions are associated with a fatality
R. Yomtovian in Engelfriet et al: International Forum. Bacterial Contamination of Blood Components. Vox Sanguinis 2000; 78:59-67
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
What are We Doing?• Single donor platelets are being tested on the
BacTAlert system• Unit sits for 24 hours• Sample drawn and inoculated into bottle• Continuous monitoring in instrument• Product released on day 3• Bottled incubated for 5 days
• Sensitivity fairly high and can subculture for identification of organisms
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
What are We Doing?• Random donor platelets
• Urine dipstick for glucose and pH• Testing occurs as close to transfusion as
possible• Sensitivity not high with significant false
positive results
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Influenza Virus
• Influenza A viruses infect birds, swine, horses, humans et al
• Antigenic “drift”• Accumulated point mutations and annual epidemics
• Antigenic “shift”• Appearance of new subtype of influenza A virus
with novel hemagglutinin (H) and/or neuraminidase (N) glycoproteins
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Clinical Influenza
• Influenza A among humans: H1N1; H1N2; H3N2
• Clinical virology:
• Incubation period ~ 2 days (1-4 days)
• Fever, myalgias, headache, chills, cough, complicated by pneumonia
• Viral shedding: 3-5 d. with onset 1 d. before symptoms
• Viremia – rare, but how hard have we looked?
• Prevention: Immunization and antiviral medications
• Treatment: Supportive and antiviral medications
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Pandemic influenza impact in US (CDC)
• Mortality:
• 89,000 - 207,000 in U.S. (ann. average 36,000)
• Medical infrastructure:
• 314,000 - 734,000 hospitalizations in U.S. (average yearly 114,000)
• Community impact:
• 20 - 47 million additional not seeking care• 20 - 30% “attack rate” in general population• 40 - 50% “attack rate” for school-age children
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Planning activities
• International• National• State/local health authorities• Blood organizations
• Interagency task force
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
Avian Influenza A (H5N1) Virus and the blood supply?
• Is it transfusable?
• Impact on donor base?
• Impact on blood center
operations
Probably not
Could be awful
Could be awful
Professionals for Infection Control
March 14, 2006
Community Blood CenterCommunity Tissue Services
H5N1 + strand RNA in lung and gut only(human autopsy x 1)
Uiprasertkul, M et al. EID July 2005