Professionals for Infection Control

1
Safety of Blood(from an infectious disease
standpoint)

• David M. Smith, M.D.
• Medical Director

2
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.

3
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

4
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
  Americas 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)

5
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

6
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)

7
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
8
Major Infectious Diseases(not currently
screening blood)

• HIV type O
• Malaria
• Chagas Disease
• vCJD

9
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

10
Viral Disease Screening in Blood Banking
1993-Present
Updated from AuBuchon, Birkmeyer, Busch. Ann
Intern Med 1997127904-9.
11
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

12
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

13
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

14
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)

15
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

16
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

17
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.)

18
HIV Viremia During Early Infection
Peak viremia
HIV RNA (plasma)
Ramp-up viremia
HIV Antibody EIA
HIV p24 Ag
p24 Ag EIA ------

1st gen
Pooled NAT -
2nd gen
Individual NAT -
3rd gen
11
16
22
19
HCV Markers During Early Infection
Plateau phase viremia
HCV RNA
Anti-HCV EIAs 1st gen 150 d 2nd gen 80
d 3rd gen 70 d
Ramp-up phase

Pre-ramp-up blip viremia
ALT
0
10
20
30
40
50
60
70
80
90
100

20
HBV Viremia in Early Infection
21
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

22
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

23
Modes of Transmission

• Mosquito Bite
• Transplantation
• Transfusion
• Breastfeeding
• Transplacental Exposure
• Occupational Exposure

24
A Culex quinquefasciatus Mosquito on a Human
Finger
25
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

26
8 cases WNV
27
21 cases, 2 deaths
28
66 cases, 9 deaths
29
4161 cases, 277 deaths
30
9862 cases, 264 deaths
31
Human WNV Infections 2004
2470 cases, 88 deaths
32

WNV Activity 2005
2949 cases, 116 fatalities
33
Human WNV Viremic Blood Donors 2005
399 presumptive viremic blood donors
34
West Nile Virus Infection in an Organ Donor and
Four Transplant RecipientsAugust 2002
Blood components from 63 donors
Organ Donor
Organ Donor
WNV PCR Culture IgM
WNV PCR IgM
35
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

36
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

37
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

38
Stage-II IDNAT MPNAT- IgM-
Stage-IV IDNAT MPNAT- IgM IgG/-
Stage-V IDNAT /- MPNAT- IgM
IgG
Stage-I IDNAT/-MPNAT- IgM-
Stage-III MPNAT IgM-
West Nile Virus
IgM
6-7 days
RNA
105
WNV RNA (gEq per mL)
IgG
104
103
102
ID-NAT
101
2 3 4 5 6 7 8 9 10
11 12 13 14 15 16 17 18
Days post infectious mosquito bite
39
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

40
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

41
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

42
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

43
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

44
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

45
LA Seroprevalence 1996-98
Leiby, D. et al. Transfusion. 2002
46
Nationwide risk of Chagas
Leiby, D. Pers. Comm.
47
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
48
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

49
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

50
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

51
Bacterial Contamination of Blood and Blood
Products (Review)

• Discussions of bacterial contamination as early
  as 1939 in JAMA
• In the 1950s, bacterial contamination of blood
  was identified in up to 2.2 of bottles
• In the late 1960s and early 1970s, 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)

52
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

53
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

54
1100
Comparison of Residual Risks
Transmission risk, per unit
HIV
11000
Bacterial Contamination (platelets)
110 000
HBV
HCV
1100 000
Septic Fatalities (platelets)
Mistransfusion Fatalities (red cells)
11 000 000
2002
1996
1994
1992
1990
1988
1986
1984
1998
2000
Updated from Goodnough LT e t al. NEJM
1999341126-7
55
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.

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 Dec41(12)1493-149
9.
56
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 7859-67
  Kuehnert MJ et al. Transf 2001
  Dec41(12)1493-1499.

57
BACTERIAL CONTAMINATION OF PLATELETS
BaCon Study
UHC Prospective Surveillance

58
Clinical Significance of Platelet Bacterial
Contamination

• - 12000 units (RD and SD) are contaminated
• - 1500 pooled unit transfusions are
  associated with septic transfusion reactions
• - 110,000 pooled unit transfusions are
  associated with a fatality
• R. Yomtovian in Engelfriet et al
  International Forum. Bacterial Contamination of
  Blood Components. Vox Sanguinis 2000 7859-67

59
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

60
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

61
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

62
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

63
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

64
Planning activities

• International
• National
• State/local health authorities
• Blood organizations
• Interagency task force

65
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
66
H5N1 strand RNA in lung and gut only(human
autopsy x 1)
Uiprasertkul, M et al. EID July 2005
67
Our major concerns

• Donor loss due to flu or fear
• Donor deferrals
• Staff protection and absence
• Blood needs