Appendix-A-BV-Protocol

NHSN Biovigilance Component
Protocol v1.3.1
www.cdc.gov/nhsn

Appendix A. Adverse Reaction Case Definition Criteria
Allergic reaction: The result of an interaction of an allergen with preformed antibodies. In some
instances, infusion of antibodies from an atopic donor may also be involved. It may present with only
mucocutaneous signs and symptoms.
Case Definition Criteria
Signs/Symptoms
Laboratory/Radiology
Definitive:
Definitive:
2 or more of the
N/A
following occurring
during or within 4
hours of cessation of
transfusion:
Maculopapular
rash
Urticaria (hives)
Pruritus (itching)
Generalized
flushing
Localized
angioedema
Edema of lips,
tongue and uvula
Erythema and
edema of the
periorbital area
Conjunctival
edema
Respiratory
distress;
bronchospasm
Hypotension
Probable:
ANY 1 of the following
occurring during or
within 4 hours of
cessation of
transfusion :
Maculopapular
rash
Urticaria (hives)
Pruritus (itching)
Localized
angioedema
Edema of lips,
tongue and uvula
Erythema and
edema of the
periorbital area
Conjunctival
edema

Probable:
N/A

Possible:
N/A

Possible:
N/A

Severity

Imputability

Grade 1:
No immediate risk to the life of
the patient
AND
Responds quickly to
symptomatic treatment.

Definite:
Occurs during or within 2
hours of cessation of
transfusion
AND
No other evidence of
environmental, drug or
dietary risks.

Grade 2 – 4:
Involves respiratory and/or
cardiovascular systems and
presents like an anaphylactic
reaction. There is anaphylaxis
when, in addition to
mucocutaneous symptoms,
there are airway symptoms,
hypotension, or associated
symptoms like hypotonia and
syncope. The respiratory signs
and symptoms may be laryngeal
(tightness in the throat,
dysphagia, dysphonia,
hoarseness, stridor) or
pulmonary (dyspnea, cough,
wheezing, bronchospasm,
hypoxemia). Such a reaction
usually occurs during or shortly
after cessation of transfusion.
For the purpose of classification,
this type of allergic reaction
would be graded as:
2: severe
3: life-threatening
4: death.

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Probable:
Occurs during or within 2
hours of cessation of
transfusion
AND
Other potential causes
are present in an
individual with known
susceptibility (atopic;
previous allergic
reactions to transfusions).
Possible:
Occurs 2 - 4 hours after
cessation of transfusion
OR
Other causes such as
medication or exposures
likely, but transfusion
cannot be ruled out.

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Acute hemolytic transfusion reaction (AHTR): Rapid destruction of red blood cells during, immediately
after, or within 24 hours of cessation of transfusion. Clinical and laboratory signs of hemolysis are
present. No single criterion exists to definitively diagnose this rare disorder. See Appendix D for common
antibodies associated with AHTR.
Case Definition Criteria
Signs/Symptoms
Definitive:
Occurs during, immediately
after, or within 24 hours of
cessation of transfusion with
ANY of the following:
Chills/rigors
Fever
Back/flank pain
Hypotension
Hemoglobinuria
occurring during or
shortly after cessation of
transfusion
Epistaxis
Oliguria/anuria
Renal failure
Disseminated
intravascular
coagulation (DIC)
Pain and/or oozing at IV
site
AND EITHER
ABO incompatibility or
other allotypic RBC
antigen incompatibility
OR
Clerical check indicates
that the patient’s name
and blood group on the
blood unit are different
than the recipient’s name
and blood group.

Laboratory/Radiology
Definitive:
Positive direct antiglobulin
test (DAT) for anti-IgG or
anti-C3
AND
Positive elution test with
alloantibody present on the
transfused red blood cells
AND
2 or more of the following:
Elevated LDH
Elevated bilirubin
Low haptoglobin
Hemoglobinuria
Low fibrinogen
Elevated plasma
hemoglobin

Severity

Imputability

Use severity
grades as defined
in Appendix C.

Definite:
ABO or other allotypic RBC
antigen incompatibility is
known
OR
Serologic work-up is
consistent with AHTR and
no other cause of acute
hemolysis is present.
Probable:
No serologic evidence of
AHTR
OR
Blood bank testing may
show abnormal results but
AHTR may also be due to
erythrocyte auto-antibodies
in the recipient.
Possible:
Evidence of non-immune
contributing factors such as
hemolysis-inducing
mechanical factors (e.g.
malfunction of a pump, use
of a blood warmer, use of
hypotonic solutions, etc.) is
present.

Probable:
Same as definitive case
criteria.

Probable:
Incomplete laboratory
confirmation to meet
definitive case definition
criterion.

Possible:
N/A

Possible:
N/A

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Delayed hemolytic transfusion reaction (DHTR): The recipient develops antibodies to RBC antigen(s)
between 24 hours and 28 days after cessation of transfusion. Clinical signs of hemolysis are usually
present. If performed, post-transfusion LDH and bilirubin levels increase and subsequently fall back to baseline in
the following days. See Appendix D for common antibodies associated with DHTR.
Case Definition Criteria
Signs/Symptoms
Definitive:
Patient may be
asymptomatic or have
symptoms that are similar
to but milder than AHTR.
Examples of symptoms
include:
Chills/rigors
Fever
Jaundice
Back/flank pain
Hypotension
Hemoglobinuria/
hematuria
Oliguria/anuria.
NOTE: These symptoms
are NOT required to meet
definitive case criteria.

Laboratory/Radiology
Definitive:
Positive direct antiglobulin test
(DAT) for antibodies developed
between 24 hours and 28 days
after cessation of transfusion
AND EITHER
Positive elution test with
alloantibody present on the
transfused red blood cells
OR
Newly-identified red blood cell
alloantibody in recipient serum
AND EITHER
Inadequate rise of posttransfusion hemoglobin level or
rapid fall in hemoglobin back to
pre-transfusion levels
OR
Otherwise unexplained
appearance of spherocytes.

Probable:
Same as definitive case
criteria.

Probable:
Newly-identified red blood cell
alloantibody demonstrated
between 24 hours and 28 days
after cessation of transfusion
BUT
Not enough laboratory evidence
to meet definitive criteria.

Possible:
N/A

Possible:
N/A

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Severity

Imputability

Use severity
grades as defined
in Appendix C.

Definite:
Meets definitive case
definition criteria
AND
No other explanation for
drop in hemoglobin.
Probable:
Meets probable case
definition criteria
AND
No other explanation for
drop in hemoglobin.
Possible:
Meets definitive or
probable case definition
BUT
Other explanation(s) for
drop in hemoglobin are
present.

NHSN Biovigilance Component
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Delayed serologic transfusion reaction (DSTR): Demonstration of new, clinically significant
alloantibodies against red blood cells between 24 hours and 28 days after cessation of a transfusion
despite an adequate, maintained hemoglobin response. See Appendix D for common antibodies
associated with DSTR.
Case Definition Criteria
Signs/Symptoms
Definitive:
Absence of clinical signs of
hemolysis.

Laboratory/Radiology
Definitive:
Demonstration of new,
clinically-significant
antibodies against red blood
cells between 24 hours and
28 days after cessation of a
transfusion that were not
present in the pre-transfusion
specimen
BY EITHER
Positive direct antiglobulin
test (DAT)
OR
Positive antibody screen
with newly identified RBC
alloantibody.

Probable:
N/A

Probable:
N/A

Possible:
N/A

Possible:
N/A

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Severity

Imputability

Use severity grades
as defined in
Appendix C.

Definite:
Meets definitive case
definition criteria.
Probable:
N/A
Possible:
N/A

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Hypotensive transfusion reaction: A drop in blood pressure occurring during or within one hour of
cessation of transfusion. Other symptoms, such as facial flushing, dyspnea, or abdominal cramps may
occur but usually hypotension is the sole manifestation.
Case Definition Criteria
Signs/Symptoms
Definitive:
ALL OF THE FOLLOWING:
Hypotension
- Adults (18 years and older):
Drop in systolic BP of greater
than or equal to 30 mmHg
AND
Systolic BP less than or equal to
80 mmHg.
- Infants, children and adolescents
(1 year to less than 18 years old):
Greater than 25% drop in systolic
BP (e.g., drop in baseline systolic
BP of 120mmHg to below
90mmHg).
- Neonates and small infants (less
than 1 year old OR any age and
less than 12 kg body weight):
Greater than 25% drop in
baseline value using whichever
measurement is being recorded
(e.g., mean BP).
Occurs less than 15 minutes after
the start of the transfusion
Responds rapidly (within 10
minutes) to cessation of transfusion
and supportive treatment.
All other adverse reactions
presenting with hypotension must
be excluded.

Laboratory/Radiology
Definitive:
N/A

Possible:
N/A

Imputability

Grade 1:
The recipient required
no more than
discontinuation of
transfusion and
symptom management
AND
No long-term morbidity
resulted from the
reaction.

Definite:
Meets the
definitive protocol
criteria
AND
The patient has no
other conditions
that could explain
hypotension.

Grade 2:
The recipient required
in-patient
hospitalization or
prolongation of
hospitalization due to
hypotension or
hypotension led
directly to long-term
morbidity (e.g., brain
damage)
AND
Vasopressors were not
required.

Probable:
Meets the
probable case
definition criteria
OR
Other conditions
that could explain
hypotension are
unlikely but not
fully excluded.

Grade 3:
The recipient required
vasopressors.

Note: If the patient meets the criteria
for another adverse transfusion reaction
presenting with hypotension, the more
specific adverse reaction should be
reported.
Probable:
Same as definitive criteria
EXCEPT:
Onset is between 15 minutes after
start and 1 hour after cessation of
transfusion
OR
The patient does not respond rapidly
to cessation of transfusion and
supportive treatment.

Severity

Probable:
N/A

Possible:
N/A

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Grade 4:
The recipient died as a
result of the
hypotensive
transfusion reaction or
as a result of treatment
directly related to
resolving symptoms of
the reaction.

Possible:
Meets definitive
or probable case
definition criteria
BUT
Other conditions
that could readily
explain
hypotension are
present.

NHSN Biovigilance Component
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Febrile non-hemolytic transfusion reaction (FNHTR): Fever and/or chills without hemolysis occurring
in the patient during or within 4 hours of cessation of transfusion. If transfusion-related, the most common
cause is a reaction to passively transfused cytokines or a reaction of recipient antibodies and leukocytes
in the blood product. If blood culture of patient or residual component is performed, the results should be
negative. Laboratory findings should show no evidence of acute hemolysis.
Case Definition Criteria
Signs/Symptoms
Definitive:
Occurs during or within 4
hours of cessation of
transfusion
AND EITHER
Fever (greater than or
equal to 38oC oral or
equivalent and a change of
at least 1oC from pretransfusion value)
OR
Chills/rigors are present.

Laboratory/Radiology
Definitive:
N/A

Severity

Imputability

Use severity grades
as defined in
Appendix C.

Definite:
Patient has no other
conditions that could explain
symptoms.
Probable:
Other conditions present
that could explain symptoms
are unlikely but cannot be
ruled out.

NOTE: FNHTR can be
present in absence of fever if
chills or rigors occur.
Probable:
N/A

Probable:
N/A

Possible:
N/A

Possible:
N/A

Possible: Other conditions
are present or were present
before the transfusion that
most likely explain
symptoms.

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Post transfusion purpura (PTP): Thrombocytopenia usually arising 5-12 days following transfusion of
cellular blood components with findings of antibodies in the patient directed against the Human Platelet
Antigen (HPA) system.
Case Definition Criteria
Signs/Symptoms
Definitive:
Thrombocytopenia (decrease to
less than 20% of pre-transfusion
count)

Probable:
Drop in platelets to levels
between 20% and 80% of pretransfusion count.
Possible:
N/A

Laboratory/Radiology
Definitive:
Alloantibodies in the
patient directed against
HPA-1a or other platelet
specific antigen
detected at or after
development of
reaction.

Severity

Imputability

Use severity
grades as defined
in Appendix C.

Definite:
Meets definitive or
probable case definition
criteria
AND
Occurs 5-12 days posttransfusion
AND
Patient has no other
conditions to explain
thrombocytopenia.

Probable:
Same as definitive
laboratory criteria.
Possible:
HPA antibodies not
tested or negative.

Probable:
Meets definitive or
probable case definition
criteria
AND EITHER
Occurs less than 5 or
more than 12 days posttransfusion
OR
Other condition(s)
present that could explain
thrombocytopenia are
unlikely but cannot be
ruled out.
Possible:
Meets definitive or
probable case definition
criteria
AND
Alternate explanations for
thrombocytopenia are more
likely
OR
Meets possible case
definition criteria.

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Transfusion-associated circulatory overload (TACO): Infusion volume that cannot be effectively
processed by the recipient either due to high rate and/or volume of infusion or an underlying cardiac or
pulmonary pathology.
Case Definition Criteria
Signs/Symptoms
Definitive:
New onset or exacerbation of
3 or more of the following
within 6 hours of cessation of
transfusion:
Acute respiratory distress
(dyspnea, orthopnea,
cough)
Evidence of positive fluid
balance
Elevated brain natriuretic
peptide (BNP)
Radiographic evidence of
pulmonary edema
Evidence of left heart
failure
Elevated central venous
pressure (CVP)

Laboratory/Radiology
Definitive:
N/A

Severity

Imputability

Use severity
grades as defined
in Appendix C.

Definite:
No other explanations for
volume overload are possible.
Probable:
Transfusion is a likely
contributor to volume
overload
AND EITHER
The patient received other
fluids as well
OR
The patient has a history of
cardiac insufficiency that
could explain the volume
overload.

Probable:
N/A

Probable:
N/A

Possible:
N/A

Possible:
N/A

Possible:
The patient has a history of
pre-existing cardiac
insufficiency that most likely
explains volume overload.

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Transfusion-associated dyspnea (TAD): Respiratory distress within 24 hours of cessation of
transfusion that does not meet the criteria of TRALI, TACO, or allergic reaction. Respiratory distress
should not otherwise be explained by a patient’s underlying or pre-existing medical condition.
Case Definition Criteria
Signs/Symptoms
Definitive:
Acute respiratory distress that
occurring within 24 hours of
cessation of transfusion
AND
TRALI, TACO, and allergic
reaction are ruled out.

Laboratory/Radiology
Definitive:
N/A

Probable:
N/A

Probable:
N/A

Possible:
N/A

Possible:
N/A

Severity

Imputability

Use severity grades
as defined in
Appendix C.

Definite:
Patient has no other
conditions that could
explain symptoms.
Probable:
Other present conditions
are unlikely but not fully
excluded.
Possible:
Other present conditions
are more likely to explain
symptoms.

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Transfusion-associated graft vs. host disease (TAGVHD): The introduction of immunocompetent
lymphocytes into susceptible hosts. The allogeneic lymphocytes engraft, proliferate and destroy host
cells. If performed, marrow study shows hypoplasia, aplastic anemia, or marked hypocellularity with a
lymphohistiocytic infiltrate.

Case Definition Criteria
Signs/Symptoms
Definitive:
A clinical syndrome occurring
from 2 days to 6 weeks after
cessation of transfusion
characterized by:
Fever
Characteristic rash:
erythematous,
maculopapular eruption
centrally that spreads to
extremities and may, in
severe cases, progress
to generalized
erythroderma and
hemorrhagic bullous
formation.
Hepatomegaly
Diarrhea

Laboratory/Radiology
Definitive:
Liver dysfunction, i.e.,
elevated ALT, AST, Alkaline
phosphatase, and elevated
bilirubin
AND
Pancytopenia
AND
WBC chimerism in the
absence of alternative
diagnoses
AND
Characteristic histological
appearance of skin biopsy
or liver biopsy.

Severity

Imputability

Grade 1:
N/A

Definite:
Meets definitive or
probable case definition
criteria
AND
There are matching
chimeric alleles in the
donor and recipient.

Grade 2:
Patient had marked
symptoms and
responded to
treatment.
Grade 3:
Patient had severe
symptoms and
required life-saving
treatment (e.g.,
immunosuppression).
Grade 4:
Patient died from
TAGVHD.

Probable:
Same as definitive case
criteria.

Probable:
Meets definitive criteria
EXCEPT
Biopsy negative or not
done.

Possible:
Same as definitive case
criteria.

Possible:
Meets definitive criteria
EXCEPT
Chimerism not present or
not done.

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Probable:
Meets definitive or
probable case definition
criteria
BUT
Alleles could not be
tested in the donor to
match to the recipient.
Possible:
Meets possible case
definition criteria
OR
Alternative explanations
are more likely (e.g. solid
organ transplantation).

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Transfusion-related acute lung injury (TRALI): Acute hypoxemia with PaO2/fraction of inspired oxygen
[FIO2] ratio of 300 mmHg or less combined with chest x-ray showing bilateral infiltrates in the absence of
left atrial hypertension (i.e., circulatory overload). Onset of TRALI is abrupt in association with transfusion.
Case Definition Criteria
Signs/Symptoms
Definitive:
NO evidence of acute lung injury
(ALI) prior to transfusion
AND
ALI onset during or within 6 hours of
cessation of transfusion
AND
Hypoxemia defined by any of these
methods:
PaO2 / FiO2 less than or equal to
300 mm Hg
Oxygen saturation less than 90%
on room air
Other objective evidence
AND
No evidence of left atrial
hypertension (i.e. circulatory
overload).

Laboratory/Radiology
Definitive:
Bilateral infiltrates on
chest radiograph

Severity

Imputability

Use severity
grades as defined
in Appendix C.

Definite:
No alternative risk factors
for ALI during or within 6
hours of cessation of
transfusion.
Probable:
N/A

Probable:
N/A

Probable:
N/A

Possible:
N/A

Possible:
N/A

Possible:
Evidence of other risk
factors for acute lung
injury during or within 6
hours of cessation of
transfusion are present,
such as:
Direct Lung Injury
Aspiration
Pneumonia
Toxic inhalation
Lung contusion
Near drowning
Indirect Lung Injury
Severe sepsis
Shock
Multiple trauma
Burn injury
Acute pancreatitis
Cardiopulmonary
bypass
Drug overdose

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Transfusion-transmitted infection: A bacteria, parasite, virus, or other potential pathogen transmitted
in donated blood to transfusion recipient.
Pathogens of well-documented importance in blood safety.
These pathogens have public health significance for hemovigilance, are well-documented blood stream pathogens
and/or, are routinely screened for in blood donors. All infectious organisms are available from the full drop-down
pathogen list in NHSN.
Bacterial
Viral
Parasitic
Other
Cytomegalovirus (CMV)
Babesiosis (Babesia spp.)
Creutzfeldt-Jakob
Escherichia coli
Enterovirus
Chagas disease
Disease, Variant
Klebsiella oxytoca
Epstein Barr (EBV)
(Trypanosoma cruzi)
(vCJD)
Klebsiella pneumoniae
Hepatitis A
Malaria (Plasmodium spp.)
Pseudomonas
Hepatitis B
aeruginosa
Hepatitis C
Serratia marcescens
Human Immunodeficiency Virus
Staphylococcus aureus
1 (HIV-1)
Staphylococcus
Human Immunodeficiency Virus
epidermidis
2 (HIV-2)
Staphylococcus
Human Parvovirus B-19
lugdunensis
Syphilis (Treponema
Human T-Cell Lymphotropic (or,
pallidum)
leukemia) Virus-1 (HTLV-1)
Human T-Cell Lymphotropic (or,
Yersinia enterocolitica
leukemia) Virus-2 (HTLV-2)
West Nile Virus (Flaviviridae)

Investigation triggers for infections potentially transfusion-transmitted:
1. Identification by testing (e.g., gram stain, other smear/staining, culture, or other method) of an
unexpected bacterial, mycobacterial, or fungal organism in a recipient within the time period from
exposure (i.e., transfusion) to onset of infection appropriate for the suspected pathogen.
2. Identification of an unexpected virus in the recipient by testing (e.g., culture, direct fluorescent
antibody or polymerase chain reaction) within the time period from exposure (i.e., transfusion) to
onset of infection appropriate for the suspected virus.
3. Identification of an unexpected parasite in the recipient by blood smear, histopathology or stool
testing for ova/parasites within the time period from exposure (i.e., transfusion) to onset of infection
appropriate for the suspected parasite.
4. Any of the above laboratory findings in the recipient unit upon residual testing.
5. Unexplained clinical events occurring after transfusion that are consistent with transfusiontransmitted infection, such as:
a. Encephalitis, meningitis, or other unexplained central nervous system abnormalities.
b. Sepsis with or without multi-organ system dysfunction.
c. Hemolytic anemia and/or fever (e.g., in cases of transfusion-associated babesiosis or malaria).
d. Recipient death.
6. For pathogens routinely screened in the blood donor, any infection in the recipient occurring within
6 months after transfusion if:
a. The index donation testing was negative but
b. The donor was subsequently found to be infected, and
c. The recipient had no pre-transfusion history of the same infection.
For a decision on imputability, consider various types of evidence such as the following:
1. Evidence of contamination of the recipient unit upon residual testing.
2. Pre- and post- transfusion infection status (e.g., seroconversion) in the recipient.
3. Evidence of other recipients with infection from the same organism who received blood from the
same donor.
4. Evidence of the donor infection with the same organism.

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Transfusion-transmitted infection (continued): A bacteria, parasite, virus, or other potential pathogen
transmitted in donated blood to transfusion recipient.
Case Definition Criteria
Signs/Symptoms Laboratory/Radiology
Definitive:
Definitive:
N/A
Laboratory evidence of
a pathogen in the
transfusion recipient.
Probable:
N/A

Probable:
N/A

Possible:
N/A

Possible:
N/A

Severity

Imputability

Use severity
grades as
defined in
Appendix C.

Definite:
Evidence that the recipient was not infected with
this organism prior to transfusion
AND
Laboratory evidence of infection with the same
organism in the donor by testing of the donor,
the recipient unit (or retained segment), or cocomponent from the original donation
OR
Laboratory evidence of infection with the same
organism in another recipient that received
blood from the same donor.

NOTE: An investigation can be initiated
based on clinical events occurring after
transfusion that are consistent with
transfusion-transmitted infection. However;
there must be laboratory evidence of the
suspected pathogen in the transfusion
recipient to call an adverse reaction a
transfusion-transmitted infection.

Probable:
Any two of the following:
Evidence that the recipient was not infected with
this organism prior to transfusion
OR
Laboratory evidence of infection with the same
organism in the donor by testing of the donor,
the recipient unit (or retained segment), or cocomponent from the original donation
OR
Laboratory evidence of infection with the same
organism in another recipient that received
blood from the same donor.
Possible:
Recipient infection fails to meet imputability
criteria for definite, probable or ruled out
because essential information is missing, not
available, or cannot be obtained.
Doubtful:
Laboratory evidence that the recipient had was
infected with this organism prior to transfusion.
Ruled Out:
Laboratory evidence that the donor was negative
for infection at the time of donation.

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