Download Zika Virus - ascls-nd

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Current Topics in
Immunohematology
PRESENTED BY JACIE MUNDAHL, MLS (ASCP)CM
Objectives

Upon completion of this presentation the participant will be able to
recognize the effects of daratumumab in immunohematology
patient testing and manage those patients in future visits.

Upon completion of this presentation the participant will appreciate
the need for Zika virus testing in the blood donor population.

Upon completion of this presentation the participant will be able to
define monoclonal B-cell lymphocytosis and state the risk it has
been suspected to pose in blood donation and transfusion.
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Daratumumab, What Is It?

Daratumumab is an immunoglobulin G1 kappa human monoclonal
antibody
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Mechanism of Action


Produced in mammalian cell line (Chinese Hamster Ovary) using
recombinant DNA technology
CD38 is a transmembrane glycoprotein expressed on the surface of
hematopoietic cells. Daratumumab binds to CD38 and inhibits the growth of
CD38 expressing tumor cells by inducing apoptosis directly through Fc
mediated crosslinking as well as by immune-mediated tumor cell lysis through
complement dependent cytotoxicity(CDC), antibody dependent cellmediated cytotoxicity (ADCC) and antibody dependent cellular
phagocytosis (ADCP).
Brand Name: Darzalex
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https://www.myelomacrowd.org/wp-content/uploads/2016/07/darzalex.png
Patient Treatment

First approved for therapeutic use by the FDA in November, 2015

Daratumumab is used for multiple myeloma patients with
dexamethasone and either bortezomib or lenalidomide in patients
who have already received at least one other type of treatment.

Or used alone in patients who have already received at least three
other types of treatment, including a proteasome inhibitor and an
immunomodulating agent.

CD38 is highly expressed on myeloma cells
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Efficacy for treatment of other types of cancers is being researched.
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https://www.researchgate.net/publication/294279352/figure/fig1/AS:330008867426304@1455691653182/Figure-1-Mechanisms-of-action-of-daratumumab.png
Effects On Transfusion Testing

CD38 is weakly expressed on red blood cells

Anti-CD-38 binds to CD38 on reagent RBCs causing panreactivity in vitro

Positive indirect antiglobulin (IAT) tests

Agglutination may occur in all media and all methods
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Saline, low ionic strength saline, polyethylene glycol
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Gel, tube, solid phase
Reactions are usually weak (1+), but stronger reactions have been
observed in solid phase (up to 4+)
Anti-CD38 could mask a clinically significant alloantibody
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Impact on Transfusion Testing
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ABORh
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Not affected
Antibody Screen
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Panreactivity
Crossmatch
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Immediate Spin: No interference
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AHG: Incompatible
DAT
Autocontrol
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Variable reactivity
Variable reactivity
Adsorption

Panreactivity not eliminated
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Treatment of Red Blood Cells

Dithiothreitol (DTT)
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Disrupts daratumumab binding, allowing detection of underlying atypical
alloantibodies in patient plasma
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Test in conjunction with a k positive cell to confirm effectiveness of DTT
treatment

Antigens sensitive to DTT include; Kell blood group antigens, Yta, Doa/Dob

Adsorptions using ZZAP and untreated RBC’s failed to remove
interference

Other methods of mitigating anti-CD38 interference

Neutralization using recombinant soluble human CD38 or daratumumab
idiotype antibody

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Neither reagent is widely available at this time
Antigen-typed cord cells have been used for the antibody screen as an
alternative to DTT-treated cells
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Managing Patients on
Daratumumab

Anti-CD38 interference may cause delays in issuing RBCs
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Before a patient begins anti-CD38 treatment
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Perform baseline ABORh and antibody screen
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Perform baseline phenotype or genotype
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Managing Patients on
Daratumumb
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After a patient has begun anti-CD38 treatment
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ABORh performed normally
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Perform antibody screen and identification using DTT treated RBCs
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Managing Patients on
Daratumumb
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Crossmatch
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Antibody screen negative (using DTT-treated cells)
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IS or electronic crossmatch ABORh compatible, K matched RBCs
Known alloantibody
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Give phenotypically similar RBCs
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May perform AHG crossmatch using DTT-treated donor cells

Even if phenotypically similar RBCs are selected, AHG crossmatch will still be
incompatible
Transfusion emergently required: uncrossmatched ABORh compatible RBCs
can be given per local transfusion service practices
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Managing Patients on
Daratumumab

Hospitals establish procedures to inform the transfusion service
whenever any patient is scheduled to begin taking daratumumab

Set up notification in EMR when daratumamb is ordered by
physician for ABORh, Antibody Screen, DAT, and genotyping testing
to be ordered

Daratumumab-mediated positive indirect globulin tests may persist
for up to six months after the last daratumumab infusion
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Zika Virus
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First discovered in 1947 in a Rhesus monkey, named after the Zika
forest in Uganda
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First human case was detected in 1952
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RNA arbovirus from the Flaviviridae family
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Transmitted by Aedes species mosquitos
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(Ae. aegypti and Ae. albopictus)
Modes of transmission
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Mosquito bite
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Pregnant woman to fetus
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Linked with birth defects
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Sexual contact
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Blood transfusions
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Not confirmed, but very likely
https://upload.wikimedia.org/wikipedia/commons/thumb/3/3e/Aedes_aegypti_feeding.jpg/250px-Aedes_aegypti_feeding.jpg
Zika Virus
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
Most individuals infected with Zika virus will not show symptoms, or will
only have mild symptoms
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Symptoms of infection
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Fever, rash, joint pain, red eyes, muscle pain, headache
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Similar to dengue and chikungunya infections
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May lead to Guillain-Barré syndrome
Diagnosis
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Laboratory tests, travel history, symptoms
Infection during pregnancy
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Majority do not show symptoms
Microcephaly, miscarriages, brain defects
At this time, there is no vaccine or medication for treatment
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A number of vaccines are in trial phase
https://attachment.outlook.office.net/owa/[email protected]/service.svc/
Testing for Zika Virus
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Molecular Testing Method used for blood products and patients
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RNA NAT (Nucleic Acid Testing)
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RNA can be detected early in the course of illness
Other tests available - Patient testing
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Serologic IgM detection
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Zika IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (Zika MACELISA)
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Qualitative detection of IgM antibodies
Plaque-reduction neutralization testing (PRNT)
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Quantitative
Performed by the CDC on positive, equivocal, or inconclusive IgM results
Trioplex Real-time RT-PCR Assay
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Not FDA approved
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Zika Virus Outbreaks
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2007: First large outbreak in humans on the Island of Yap in
Micronesia
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2013-2014: 4 other Pacific Island groups have outbreaks
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73% of the island’s population was infected
1,505 asymptomatic blood donors are reported to be positive for Zika by
PCR. These findings alert authorities that Zika virus can be passed on
through blood transfusion.
2015: Reference lab in Brazil reports circulating Zika virus (May)
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First case in the Americas
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Other South American countries begin reporting locally acquired
infections
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Microcephaly cases increase
Virus reported in Central American countries (October)
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Zika Virus Outbreaks
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2016
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February: World Health Organization (WHO) Emergency Committee
declares Zika Virus a Public Health Emergency of International Concern
(PHEIC)
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Based on the large clusters of cases of microcephaly in Brazil and French
Polynesia
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No longer a PHEIC, but long-term response mechanisms have been
established to manage global responses
July: First case of local or non-travel related transmission reported in
Continental U.S. in Miami-Dade County, Florida
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Zika Virus in The United States
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January 1st, 2015 – April 12th, 2017
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5,234 Zika virus disease cases reported
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4,935 cases in travelers returning from affected areas
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223 cases acquired through presumed local mosquito-borne
transmission in Florida (217) and Texas (6)
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76 cases acquired through other routes, including sexual transmission,
congenital infection, laboratory transmission, and person-to-person
through an unknown route
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Zika and the Blood Supply
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Donor Questionnaire
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Travel history or residence in the 4 weeks prior to donation to an area
affected by Zika virus
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Zika virus-like symptoms
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Combination of rash or fever with muscle aches, headache, malaise, or
pinkeye
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Sexual partners of men with confirmed or suspected Zika virus infection
in the last 3 months
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Deferral for at least 28 days
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Zika and the Blood Supply
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Recipient’s physician should be notified if
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Units have been transfused from a donor with a history of Zika Virus
infection in the 4 weeks prior to the donation
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Units have been transfused from a donor who reports symptoms
suggestive of Zika Virus infection within the two weeks after donation
and have recently departed from an area with active transmission
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Zika and the Blood Supply
- FDA Guidance
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February 16th, 2016
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Recommendation to screen whole blood and blood components, use pathogenreduction devices, or halt blood collection from areas with active Zika virus
transmission
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Obtain whole blood and blood components from areas without active Zika virus
transmission
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Guidance for donor screening/questionnaire to reduce the risk of transmission of Zika
virus by human cells, tissues, and cellular and tissue-based products
August 26th, 2016
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Recommendation that all states and U.S. territories screen individual units of donated
whole blood and blood components with an FDA approved testing method
November 18th, 2016
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Joint statement to the FDA presented by AABB, America’s Blood Centers, and the
American Red Cross regarding concerns of cost and ability to develop and
implement testing for Zika Virus in donors. Blood community was not consulted on
any guidances issued by the FDA.
Zika and the Blood Supply
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September 19th, 2016
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In accordance with the FDA guidance issued on August 26th United
Blood Services, Blood Centers of the Pacific, and Inland Northwest Blood
Center begin testing all donations for Zika virus
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Units labeled as “Neg for ZIKA by investigational NAT”
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Cost of the required test is passed on to the hospital customer
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Approximately $6 per unit, depending on transfusion service
November 2016
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American Red Cross begins testing all donations for Zika virus by NAT
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Monoclonal B-Cell Lymphocytosis
(MBL)
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Healthy older adults may have small numbers of monoclonal B cells
detectable in their peripheral blood
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Low count MBL: MBL clones have an immunophenotype resembling
typical CLL and represent a small number (<500/µL) of circulating B cells
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Little, to no risk of progression to CLL
High count (clinical) MBL: MBL type cells present in peripheral blood in a
larger number (>500/µL)
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Increased risk of progression to CLL
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SLL = Small lymphocytic leukemia
http://www.bloodjournal.org/content/123/9/1281?sso-checked=true
Monoclonal B-Cell Lymphocytosis
and Blood Donation
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One study suggested that blood transfusions may be associated
with an increased risk for developing B-cell malignancies due to the
higher than expected detection of MBL in the donor population
(2014)
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In a Midwestern US regional blood center MBL was detected in 149 out
of 2098 donors ages 45 years or older between 2010-2011
In contrast, a study conducted in Denmark and Sweden suggested
no association between donors with MBL and the recipient
developing CLL (2015)
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Analyzed both country’s entire computerized transfusion data from over
more than 30 years
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Database contained 1.5 million donors and 2.1million recipients
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Monoclonal B-Cell Lymphocytosis
and Blood Donation
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Further investigation needed to reach conclusion about the risk to
recipients of transfused cells from a donor with MBL
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MBL has not been reported posttransfusion, although there is an
increased risk for development of B-cell neoplasia
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MBL transfer from donor to recipient has been reported in allogeneic
stem cell transplants for CLL
Studies have been conducted to investigate the association
between allogeneic blood transfusions and non-Hodgkin lymphoma
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Mixed results, but an increased risk for non-Hodgkin lymphoma was
reported
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Risk was significantly higher for CLL/small lymphocytic lymphoma than other
non-Hodgkin lymphoma subtypes
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Other News in Immunohematology
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Labeling of Red Blood Cell Units With Historical Antigen Typing
Results
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Draft guidance issued by the FDA on January 3rd, 2017
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FDA guidance recommendation to indicate that antigen typing results
are historical
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AABB, ABC, and ARC submitted comments on how this would benefit the
recipient
Comments also made regarding language used in the guidance
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Predicted phenotype rather than likely phenotype
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Other News in Immunohematology
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Bacterial Risk Control Strategies for Blood Collection Establishments
and Transfusion Services to the Safety and Availability of Platelets for
Transfusion
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Draft guidance issued by the FDA in March 2016
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Calls for use of pathogen reduction technology (PRT) on platelets
previously bacterially-cultured before transfusion on days 4 or 5
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Most likely to be performed by the transfusion service
AABB, ABC, and ARC submitted comments on the impact on transfusion
services and platelet inventory, suggested a longer timeline for
implementation
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Other News in Immunohematology
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Transfusion Medicine Journal Article on the Distribution/Utilization
Trends of Red Blood Cells in the United States
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Significant mismatch found between the demand for O neg RBC’s and
available O neg RBC’s
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6.3% of first time donors were O neg while 10.5% of all RBC’s distributed were
O neg
Recommendation to use O positive RBC’s in emergent situations for
adult males and females of non-reproductive potential (</=50 or 55,
based on institution’s policy)
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Explore ways to shorten ABORh TAT, use type-specific whenever possible,
collect and monitor usage data
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Other News in Immunohematology
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Oldest fossilized red blood cells found by Oregon State University
entomologist
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Found in a 30 million year old tick fossilized in amber in the Dominican
Republic
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Tick also was carrying Babesia microti
http://cdn.zmescience.com/wp-content/uploads/2017/04/orn86evrwzudrrdrfetn.jpg
References

AABB. (2016). Mitigating the Anti-CD38 Interference with Serologic
Testing.
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Beckman, Y. (2016). Blood banks meet the paradox of Gabriel's
Horn: what are the options to maintain supply as demand
decreases? Transfusion Medicine, 170-6.
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Blood Systems. (2016, September 20). Blood Service Notice: Universal
donor testing for Zika Virus.
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Centers for Disease Control. (2017, April 13). Zika Virus. Retrieved April
15, 2017, from www.cdc.gov: https://www.cdc.gov/zika/

Chapuy, C. (2015). Resolving the daratumumab interference with
blood compatibility testing. Transfusion, 1545-54.
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References

Food and Drug Administration. (2016). Bacterial Risk Control Strategies
for Blood Collection Establishments and Transfusion Services to the
Safety and Availability of Platelets for Transfusion.

Food and Drug Administration. (2016). Donor Screening
Recommendations to Reduce the Risk of Transmission of Zika Virus by
Human Cells, Tissues, and Cellular and Tissue-Based Products. Food and
Drug Administration, U.S. Department of Health and Human Services,
Rockville.

Food and Drug Administration. (2016, August 26). FDA advises testing for
Zika virus in all donated blood and blood components in the US. United
States.

Food and Drug Administration. (2016). Questions and Answers
Regarding "Recommendations for Donor Screening, Deferral, and
Product Management to Reduce the Risk of Transfusion-Transmission of
Zika Virus: Guidance for Industry". Food and Drug Administration, U.S
Department of Health and Human Services, Rockville.
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References

Hjalgrim, H. (2015). No evidence of transmission of chronic lymphocytic
leukemia through blood transfusion. Blood.

Janssen Biotech, Inc. (2015). Darzalex package insert. Horsham, PA:
Janssen Biotech.

Rosecrans, D. (2016, February). AntiCD38/Daratumumab/Darzalex/Dara Lab Testing Process. Fargo, ND.

Rosecrans, D. (2016). DTT Treatment Red Cells- Transfusion. Fargo, ND.

Shim, Y. (2014). Monoclonal B-cell lymphocytosis in healthy blood
donors: an unexpectedly common finding. Blood.

Stetler-Stevenson, M. (2014). Monoclonal B-cell lymphocytosis in donors.
Blood.

Stramer, S. (2016). A Joint Statement to the Food and Drug
Administration's Blood Product Advisory Committee. AABB, America's
Blood Centers, American Red Cross.
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References

The Smithsonian. (2017, April 4). 30-Million-Year-Old Tick Full of
Monkey Blood Found in Ancient Amber. Retrieved April 17, 2017,
from www.smithsonianmag.com:
http://www.smithsonianmag.com/smart-news/first-fossilizedmammal-blood-found-amber-encased-tick-180962784/

World Health Organization. (2017). The History of Zika Virus. Retrieved
April 15, 2017, from www.who.int:
http://www.who.int/emergencies/zika-virus/history/en/

World Health Organization. (2016). Fifth meeting of the Emergency
Committee Under the International Health Regulations (2005)
regarding microcephaly, other neurologic disorders and Zika virus.

World Health Organization. (2016, February 19). Zika virus and safe
blood supply: Questions and answers. Retrieved April 15, 2017, from
www.who.int: http://www.who.int/features/qa/zika-safe-blood/en/
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