POC
The Value of High-sensitivity CRP
in Clinical Use
POC
The Value of High-sensitivity CRP
in Clinical Use
Contents
Introduction........................................................................................................... 7
Baseline CRP values in general population......................................................... 8
Determinants of baseline CRP level.................................................................... 8
Main indications for QuikRead go hsCRP+Hb................................................... 10
HsCRP in diagnosis of recurrent coronary events.............................................. 11
HsCRP in patients with stable and unstable angina ......................................... 12
HsCRP in patients with Myocardial Infarction (MI)............................................ 13
Cut-off values for increased likelihood of recurrent coronary events................. 14
Markers for recurrent coronary events............................................................. 16
Guideline on use of hsCRP when assessing likelihood of recurrent CVD .......... 16
HsCRP in diagnosis of neonatal sepsis............................................................... 17
CRP reference intervals for healthy neonates.................................................... 18
CRP concentrations in early-onset sepsis (EOS)................................................. 19
Deciding on antibiotic treatment..................................................................... 20
Practical advice on using CRP in diagnosis of neonatal sepsis........................... 21
HsCRP in diagnosis of Chronic obstructive pulmonary disease (COPD)........... 22
HsCRP is a long-term predictor of COPD hospitalization and COPD death........ 24
Disclaimer
This booklet is intended to provide healthcare practitioners with an overview of QuikRead go hsCRP+Hb, its
diagnostic potential and value in clinical use.
Although every effort has been made to provide accurate information, Orion Diagnostica accepts no responsibility whatsoever for the accuracy, correctness or completeness of the information contained in this booklet. It is
the responsibility of the healthcare practitioner to evaluate the contents of this booklet and to verify the information presented. The ultimate judgment regarding the care and appropriate treatment of a particular individual
must always be made by the healthcare practitioner in the light of all the clinical information available about the
individual.
Orion Diagnostica therefore accepts no liability for any injury or damage to person or property resulting from
acceptance of the information in this booklet. Hence, liability claims regarding possible injury or damage will be
rejected.
The information in this booklet may contain references to products that are not available or approved by the
regulatory authorities in your country. Orion Diagnostica assumes no responsibility for you accessing information
that may not comply with legislation, regulations or usage applicable in your country. You are advised to consult
Orion Diagnostica’s local business contact or marketing partner for information about the availability of Orion
Diagnostica products in your country.
Orion Diagnostica does not market or encourage the use of QuikRead go hsCRP+Hb for any other coronary
indications than the ones mentioned in this booklet. For further information please contact Orion Diagnostica. Smoking and COPD......................................................................................... 24
CVD in COPD patients..................................................................................... 25
CRP in diagnosis of Rheumatoid arthritis (RA).................................................. 25
CVD in patients with RA.................................................................................. 26
Other indications ................................................................................................ 27
QuikRead go ....................................................................................................... 30
References.......................................................................................................... 32
Introduction
The purpose of this booklet is to describe how Orion Diagnostica’s QuikRead
go® hsCRP+Hb- test can be used in the diagnostics of various clinical conditions. QuikRead go hsCRP+Hb is a point-of-care test for measuring low
C-reactive protein (CRP) and Hemoglobin (Hb) values in situations where
an accurate and rapid treatment decision is needed. Regardless of the test
measuring two analytes, this booklet focuses mainly on the use of CRP.
CRP is an extremely valuable hepatocytic marker, which is activated by
a wide range of stimuli including inflammation, infection, tissue damage,
and neoplasty. The major transcriptional upregulators of CRP are proinflammatory cytokines, especially IL-6. 1
CRP is present in low concentrations in the blood of healthy individuals, but following an acute-phase stimulus the concentrations can increase
thousand fold 1–4. Elevated CRP concentrations can be detected within 6–12
hours after the stimulus 1,5. The half-life of CRP is constant 19 hours regardless of the cause of elevation, indicating that the concentration in blood is
determined only by the synthesis rate 6.
Traditionally CRP assays have been used in evaluating inflammation,
infection and tissue damage and thus providing valuable information to support diagnosis and treatment decisions. Later CRP has become valuable in
distinguishing bacterial from viral infections, as CRP concentrations increase
prominently in the former but more modestly in the latter case 2, 3, 5, 7–11. This
information is critical for rapid diagnostics of infections and decisions on
starting antibiotic treatment. Unnecessary use of antibiotics exposes patients to
adverse drug effects and leads to emergence of resistant bacterial strains 12, 13.
Recent development of highly sensitive CRP (hsCRP) assays has opened
up the field for wider use of CRP in diagnostics. Modestly elevated CRP
values as well as patient specific variations within the range of 0.5–5 mg/l,
previously considered being within the reference interval of healthy adults 1 or
undetectable before 6–12 hours after symptoms 1, 5, have shown to be clinically
relevant in numerous patient groups and clinical applications.
QuikRead go hsCRP+Hb is a user-friendly test for fast and reliable
measurement of low CRP values. The measuring range is wide (0.5–75 mg/l)
7
Factors elevating baseline CRP
Factors lowering baseline CRP
• Smoking
• Moderate alcohol consumption
• Elevated BMI / Obesity
• Increased activity
• Low HDL cholesterol
• Weight loss
Baseline CRP values in general population
• High LDL cholesterol
• Smoking cessation
• High triglyceride levels
• Medication (e.g. statins)
The median value of CRP in apparently healthy adults is 0.8 mg/l, with a
• Elevated blood pressure
distribution including 90% of the population below 3 mg/l and 99% below
• Metabolic syndrome / Diabetes mellitus
10 mg/l . Normal baseline CRP values in healthy adults are therefore usually
• Chronic infections
measurable only by hsCRP assays.
• Chronic systemic inflammatory
and suitable for various needs. The test is performed on a finger-prick blood
sample and results are available in minutes during the patient consultation.
14
It is important to establish the true individual baseline CRP values before
making assessments. Besides occasional spikes, CRP levels are stable on long
processes
• Estrogen/progesteron hormone use
term 1, 15, 16 and two separate measurements are considered adequate and take
sufficiently into account the within-individual variability 15, 17. The variation
Smoking
within the normal distribution in healthy adults is a consequence of differ-
CRP concentrations are higher in active smokers
ent individual hereditable as well as environmental factors, presented below.
increasing amount of cigarette consumption
25, 29
, and rise with
20, 24, 25, 28–30
. The elevation in CRP con-
centration is probably due to persistent low-grade inflammatory and tissuedamaging effects as well as increased susceptibility to respiratory infections 20.
Determinants of baseline CRP level
Metabolic syndrome
CRP concentrations vary slightly between ethnic groups
18, 19
and are some-
what higher in women compared to men 20, 21. The difference between genders
likely reflects effects of estrogen
marginally with age
in older population
22, 23
. CRP concentrations tend to increase
, assumedly due to more subclinical disease
1, 20, 21, 24, 25
. Baseline CRP levels are also affected by choice of
20, 21
lifestyle and several conditions presented on the next page
A low-level systemic inflammation has been identified as the driving force
for metabolic syndrome
21, 31
. CRP levels rise in metabolic syndrome and
many metabolic factors, especially BMI, blood pressure and lipid levels, are
significantly associated with CRP
. The association between CRP and
21, 32
metabolic risk exists across all age groups and in both genders 21.
.
26, 27
Obesity
Obesity raises CRP levels, possibly due to greater amount of adipose tissue
and increased cytokine production 24, 33, 34. Elevated CRP levels are associated
with both central abdominal obesity 32 and elevated BMI 24, 25, 34, 35. Even young
persons with BMI ≥25 kg/m2 are likely to have elevated CRP levels, which
suggests the presence of a low-grade systemic inflammation in all overweight
and obese persons 34.
8
9
Main indications for
QuikRead go hsCRP+Hb
HsCRP in diagnosis of recurrent coronary
events
Mild elevations in CRP concentrations are associated with various disorders
Atherosclerosis is the major cause of premature death in Europe
and clinical conditions. The most prominent therapeutic areas, where measur-
chronic disease includes thickening of arterial walls due to accumulation of
ing low CRP concentrations is of value are presented in the following chapters.
lipids and formation of plaques, and a chronic inflammatory process 1, 62, 63. All
The main areas of use with clinical importance are:
stages in development of atherosclerotic plaques are considered inflammatory
61
. The
responses to injury 26. Morphological changes in blood vessel walls, erosion
• Recurrent coronary events 36–42
and rupture of atherosclerotic plaques, thrombosis, narrowing of blood ves-
Use: Prediction of recurrent coronary events and course of disease,
sels and restricted blood flow to the heart form the basic pathophysiological
selection of individuals for treatment and intensified patient monitoring
mechanisms in most cardiac events 63, 64.
Recurrent coronary events, some of which are listed below, are serious
• Neonatal sepsis
43–46
Use: Diagnosis and exclusion of bacterial infection, guidance in an-
cardiac complications in patients that have already experienced a previous
coronary event.
tibiotic treatment, management of infection, monitoring response to
treatment
• Stable angina is an often exertion-induced chest pain appearing in a
typical pattern when the heart is working harder. Symptoms ease during
• Chronic obstructive pulmonary disease (COPD) 47–54
Use: Prediction of prognosis and complications, assessment of disease
activity, monitoring response to treatment, CVD risk assessment
rest or with medication. 65
• Unstable angina is a cardiac-induced unexpected chest pain. The condition is critical and might lead to myocardial infarction or revert. It is
also considered to be intermediate in severity between stable angina and
• Rheumatoid arthritis (RA) 55–60
Use: Prediction of outcome and complications, assessment of disease
activity, monitoring response to treatment, CVD risk assessment
myocardial infarction. 66
• Myocardial infarction (MI) is a coronary event that involves damage or
death of heart muscle cells caused by limited blood supply to the heart.
Depending on the extent of damage the condition can be fatal. 67, 68
• Other conditions that include systemic inflammation
Asthma, Systemic Lupus Erythematosus, Osteoarthritis, Osteoporosis,
Diabetes Mellitus.
Elevated plasma hsCRP levels are associated with increased likelihood
of recurrent coronary events in patients with stable angina 37, unstable angina
36–40
and MI
. The acute-phase response may reflect the intrinsic
36, 41, 42
inflammation and tissue damage within arterial lesions 37. The elevation is
associated with poor outcome at the time of event
from 6 months up to 4 years
10
, and on long term
36–39
.
41, 42, 69–73
11
QuikRead go hsCRP+Hb can aid in identifying patients with increased likeli-
Elevated hsCRP after angina
hood of recurrent events and poor outcome, at the time of event and on long
Plasma hsCRP levels remain elevated (>3 mg/l) in about half of patients with
term. It can aid in assessing which patients are in need of treatment, closer
unstable angina. Elevated levels at discharge are associated with recurrent
monitoring and follow-up, which might affect course of disease as well as
episodes, including phases of instability and myocardial infarction, within
length and cost of hospital stay.
1 year. Phases of instability might be associated with persistent inflammation and seem to occur more often the higher the hsCRP concentration is.
Measuring hsCRP at discharge might be useful in identifying patients who
HsCRP in patients with stable and unstable angina
need to be treated and monitored more closely. 38
Elevated hsCRP (>2–3.6 mg/l) concentration is seen in most patients with
stable 37 and unstable 36–39 angina. The elevation of hsCRP level and subsequent
HsCRP in patients with Myocardial Infarction (MI)
coronary event rate seems to be slightly milder in stable angina compared to
unstable angina 36, 37, 39.
MI involves myocardial cell damage 67, 68, an acute inflammation
, as well as CRP and activated complement
74
in the infarcted myocardium . CRP levels reflect the
75
Elevated hsCRP level at admission
degree of tissue injury and myocardial necrosis, and a
Elevated hsCRP level at admission (>3.6 mg/l) is associated with increased
massive peak in CRP concentration, associated with
likelihood of subsequent MI or sudden coronary death
the acute-phase response, is seen approximately 50
in patients with stable or unstable angina
37
. When
comparing to unstable angina patients with normal hsCRP levels, unstable angina patients with
elevated hsCRP (>3.0 mg/l) levels also experience
longer hospital stay, more ischemic episodes and
recurrent angina during the hospital stay, as well
as poorer clinical short-term outcome including
The sensitivity of
hsCRP >3 mg/l
on admission as marker for
subsequent cardiac
events in patients with
unstable angina is 90%, the
specificity 82%, and the
positive predictive
value 90% 36.
MI and death 36.
hours after onset of pain 36, 76 –78. The peak CRP concen-
Elevated hsCRP
levels predict recurrent
MI independent of
troponins, known markers
of myocardial necrosis – hsCRP
is not only a marker of
extent of myocardial
damage. 79 – 81
tration may be 50–350 mg/l 36, 76 –78. Aside from this
major CRP response, slightly elevated CRP levels at
admission and on long-term after MI are associated
with increased likelihood of recurrent coronary events 36, 41, 42.
Elevated hsCRP at admission
Modestly elevated hsCRP levels (>3 mg/l) are seen in most patients admitted
with a diagnosis of acute MI, especially in patients with a previous history
The relative risk of coronary events is 2 times greater for patients with unstable and
of unstable angina within 48 hours before admission 36. The mild elevation
stable angina with hsCRP concentration >3.6 mg/l at admission compared to patients
is observed significantly before the massive acute-phase CRP response starts.
with lower hsCRP values .
Elevated hsCRP level at admission in MI-patients is predictive of course of
37
MI and post infarction events, such as postinfarction angina, coronary revascularization and recurrent infection. This emphasizes the need to follow
12
13
up hsCRP levels immediately after coronary events such as angina pectoris
Measuring CRP during the event:
and MI, in order to recognize recurrent complications and provide treatment
• During and immediately after acute ischemia, levels of CRP can rise
early.
substantially 36, 76, 77 and baseline CRP level might thus be hard to
41
interpret. Measures of ventricular function and infarct size might have
greater predictive value immediately after an infarct 82.
Elevated hsCRP after MI
• If CRP levels are measured during and after coronary events, serial
Permanently high or rising CRP levels after non-fatal MI might indicate poor
short-term outcome 76 –78, whereas levels normalize or at least decrease close to
normal in patients who experience a better recovery 76. Permanently slightly
measurements are recommended.
• Declining CRP levels are reassuring while increasing levels might indicate recurrence.
elevated hsCRP levels (>4.24–6.6 mg/l) among MI-survivors on long term,
from half a year to many years after the infarction, are evidence of persistent
Measuring after CRP concentrations have stabilized:
inflammation and correlate with increased likelihood of subsequent recur-
• Elevated hsCRP levels in patients after coronary events and at readmis-
rent MI or coronary death
. Follow-up of hsCRP levels in MI-survivors
41, 42
is thus also emphasized, as patients who need to be monitored more closely
sion predict poor outcome and recurrence. 36 – 42,76
• If a baseline CRP level is sought, two measurements optimally two
weeks apart should be done 26. CRP levels are stable on long term 1, 15, 16
can be identified.
and two separate measurements are considered adequate and take sufCRP concentrations >6.6 mg/l measured 9 months after MI are associated with a 1,8
relative risk of recurrence, when comparing to MI-patients with CRP concentration ≤6.6
mg/l. hsCRP tests might thus provide a mechanism of dividing post infarction patients
into groups with high and low likelihood of recurrent events.
41
ficiently into account the within-individual variability 15, 17.
• If the initial result is below 1 mg/l a single measurement is considered
sufficient 1
• The assay should be performed in metabolically stable persons without signs of inflammatory or infectious conditions. CRP levels over 10
mg/l might indicate other inflammatory diseases. The result should be
discarded and the test repeated after two weeks or later, when a possible
Cut-off values for increased likelihood of recurrent
coronary events
acute inflammation has passed. 26
Using hsCRP measurement alone as an alternative to ECG (electrocardio-
Diagnosis and treatment strategies for recurrent coronary events need to
gram) and major risk factors in assessment of likelihood of recurrent CVD is
address both the acute phase and longer term management.
discouraged 1, 26. Due to the nonspecific character of the CRP response it is
of high importance to evaluate the overall situation, full history and physical
examination of the patient 1, 61. Other factors and determinants of CRP level
14
The hsCRP concentration of approximately 3 mg/l (>90th centile of normal distribution 14)
should also be taken into consideration before making decisions based on
is widely used as a cut-off value for increased likelihood of recurrent coronary events 36 – 38.
hsCRP measurements 1, 61.
15
HsCRP in diagnosis of neonatal sepsis
Markers for recurrent coronary events
Presentation of established CVD risk factors, whereof some are listed below,
increases the likelihood of recurrent CVD events 64, 83 – 86.
Neonatal sepsis is usually defined as bacterial blood stream infection within
approximately the first 28 days of life
. It is a major cause of neonatal
90 – 92
mortality and morbidity despite advances in perinatal and neonatal care 93.
• Hypertension
• Cigarette smoking
• Hyperlipidemia
• Physical inactivity
• Low HDL cholesterol
• Age
• High LDL cholesterol
• Low diastolic blood pressure
Later cases are classified as late-onset sepsis (LOS) 94,
• Previous history of CVD
97
• High BMI
Sepsis presenting within the first 3 days of life is classified
as early-onset sepsis (EOS)
45, 94 – 97
and associated with
organisms acquired in utero or during delivery 92, 98 –100.
and usually associated with bacteria acquired after
delivery from nosocomial or community sources
• Diabetes
92,
. The occurrence of EOS is 1–8/1000 live births
98 –100
Also biomarkers like e.g. troponins
, creatine kinase MB , creatinine ,
79 – 81
76
84
N-terminal prohormone brain natriuretic peptide (Nt-proBNP) 87, albuminuria
, circulating tissue plasminogen activator antigen (tPA) 88 and soluble vascu-
87
lar cell adhesion molecule (VCAM)
88
might be useful in assessing likelihood
of recurrent coronary events.
101–103,
Traditional signs
of neonatal sepsis
include fever, breathing
problems, diarrhea, low
blood sugar, reduced
movement, reduced sucking
and slow heart rate. 106
and mortality rates range from 1.5% in term
neonates to almost 40% in neonates with low birth
weight 104, 105.
Diagnostic measures for neonatal sepsis include blood culture, urine culture, CRP measurement and complete blood count 99, 106. CRP measurement
Elevation of cardiac troponins reflects myocardial cellular damage and is
has proven to be superior to many other markers in diagnosis of neonatal
especially useful as a marker on short term (30 days) outcome with respect
sepsis 102, 107. It is one of the most widely available, studied and used test for
. Elevated hsCRP on the other hand has been shown
this purpose and considered very reliable 46, 108. Besides aiding in the diagnosis,
to be predictive of long term mortality (from over 6 months up to 4 years)
serial CRP measurements can aid in monitoring response to and determining
also in patients with troponin-negative acute coronary syndromes 71, 72, 79.
duration of antibiotic treatment in septic neonates 98, 109 –111.
to MI and death
64, 69, 89
The natural CRP level and the CRP response are however lower in neonates than in adults
Guideline on use of hsCRP when assessing likelihood of
recurrent CVD
, and more sensitive tests than traditional CRP
43 – 46,109
assays are needed to diagnose neonatal sepsis fast enough. Considering the
doubling time of CRP and lower CRP concentration in cord blood, even up
to 8 hours or more might elapse before a neonate who becomes bacteraemic
The American Heart Association (AHA)/Centers for Disease Control and
at birth presents CRP levels detectable by traditional CRP assays (>5mg/l) 44.
Prevention (CDC) statement on use of markers of inflammation and cardio-
16
vascular disease state that hsCRP may be useful as an independent marker
QuikRead go hsCRP+Hb makes serial measuring of low CRP concentrations
of prognosis for recurrent events, including death, MI and restenosis after
and thus earlier detection and closer monitoring of neonatal sepsis fast and
percutaneous coronary intervention in patients with stable coronary disease
easy. The test is reliable and has a wide measuring range covering CRP
or acute coronary syndromes. The benefits of therapy based on this strategy
values of both healthy and septic neonates. QuikRead go hsCRP+Hb also
do however remain uncertain. 26
helps when making urgent decisions on starting, withholding and especially
17
on discontinuing administration of antibiotics - thus protecting the neonate
from consequences of sepsis and preventing unnecessary use of antibiotics.
Preterm neonates
100.00
CRP reference intervals for healthy neonates
Healthy newborns experience a natural physiological increase in CRP con-
CRP mg/l
10.00
1.00
centration after birth, reaching a peak during the first days after birth and
then decreasing slowly 43, 44, 46, 109. Different CRP reference intervals are needed
0.10
for healthy term and preterm neonates due to the strong positive effect of
gestational age and birth weight on the elevation (fig. 1) 43, 112.
Generally the nonspecific elevation seen in neonates during the first days
of life is considered to reflect stress during the birth process 109, 112. Duration
0.01
0
12
24
36
48
60
72
84
96
108 120
Time (h)
of active labor, prenatal steroid exposure, PROM, intrapartum antimicrobial
prophylaxis, mode of delivery and intrapartum fetal distress
maternal infections or resuscitation
44
43
as well as
have an effect on CRP concentration
of neonates. Neonates born by vaginal delivery have higher CRP concentrations than those born by cesarean section 43, 99. Mean CRP levels at birth can
increase 0.4 – 40% due to these various factors, most by prenatal steroid
Figure 1. Median CRP levels in healthy term (gestational age 37–39 weeks) neonates rise from 0.1 mg/l at
birth to 1.5 mg/l after 21 hours, to 1.9 mg/l at 56–70 hours and then decrease to 1.4 mg/l at 96 hours 43. The
median CRP level at birth is similar in healthy preterm (gestational age 30–36 weeks) neonates 43 but the normal
physiological response is lower and shorter than in term neonates 43, 45, 113. The lower CRP baseline values and
response in preterm neonates are possibly due to prematurity of the organ system and maturational changes in
the immune system 43, 45, 46.
exposure and intrapartum antimicrobial prophylaxis 43.
CRP concentrations in early-onset sepsis (EOS)
Term neonates
100.00
Neonates suffering from sepsis present, besides other nonspecific signs of
sepsis, an acute-phase reaction and rising CRP concentrations. CRP secretion
10.00
CRP mg/l
starts 4–6 hours after stimulation and peaks at 24 – 48 hours 99. The rise is
separate from the natural physiological increase seen after birth and more
1.00
modest than the rise seen in septic adults. Most adults with severe bacterial
infection present CRP concentrations over 100 mg/l 3, 7, 8.
0.10
0.01
0
12
24
36
48
60
72
84
96
Time (h)
18
19
Median CRP concentrations are 6 mg/l and 9 mg/l during 0 – 24h after birth in septic
Neonatal infections progress rapidly and any delay in treatment can be
preterm and term neonates, respectively. After 25 – 72 hours median CRP concentra-
critical. Starting antibiotic therapy in all neonates showing symptoms exposes
tions in preterm neonates rise only to 9 mg/l whereas term neonates experience a rise
them to adverse drug effects and nosocomial complications and can lead to
in median CRP concentration up to 32 mg/l. 45
emergence of resistant bacterial strains 46, 117. Infants who receive antibiotics
for more than 3 days have an increased risk of abnormal bacterial colonization
It is worth noting that infections within 48 hours of birth occur more frequently in preterm than term neonates
114
and preterm neonates can have
lower CRP values and acute-phase responses than term neonates
118
increases the risk of necrotizing enterocolitis and death 119.
. Septic
If only bacterial culture is used, time to results can be 24 – 48 hours
43 – 45
preterm neonates might experience even hundredfold rises in CRP concentration, suggesting infection regardless of the CRP level staying very low
44
and
emphasizing the need of serial measurements.
and in extremely low birth weight infants prolonged antibiotic therapy
120
and antibiotic treatment might therefore be started before the infection is
clinically proven and the antibacterial sensitivity testing has been
completed. Obtaining adequate samples for blood cultures
from preterm neonates is challenging due to e.g. small
Most septic preterm neonates have cord CRP levels over 1.42 mg/l but below 6 mg/l.
44
blood volumes 108, and since implementation of guidelines
on maternal intrapartum antibiotic prophylaxis blood
There is no established standard of practice on how to use CRP measurements in assessment of neonatal sepsis
108,
. The most used cut-off value for
99
culture results can also often be unreliable
. Sepsis
diagnostics can thus not rely only on bacterial culture.
neonatal sepsis is 10 mg/l 46, 94, 98, 109, 110, but it does not take into consideration
gestational and postnatal age of the neonate 46.
99
Serial CRP
measurements are
especially useful for
ruling out bacterial
infections.
Besides aiding in the diagnosis of sepsis, CRP measurements are valuable when making antibiotic treatment
The values above as well as other literature suggest that the risk of EOS,
decisions. Sensitivity is more important than specificity in diagnosis of early
especially in preterm neonates, should be taken into account also when CRP
onset sepsis, as unnecessary treatment has fewer consequences than leaving
. A sen-
the neonate untreated 108. The sensitivity of CRP is lowest during early stages
sitive hsCRP assay, making serial determinations easy and quick, is valuable
of infection and increases with serial determinations 24 – 48 hours after onset
in diagnosing EOS as some neonatal infections may be missed if traditional
of symptoms 98, 121. As the negative predictive value of CRP measurement is
CRP tests are used.
high (approx. 99%) 94, 98, 109, serial measurements of CRP are especially use-
concentrations are below 6 mg/l early in the course of disease
44, 45, 115
ful for ruling out bacterial infections, monitoring the patient and guiding in
decisions on when to start or end antibiotic treatment 46, 94, 98, 109–111.
Deciding on antibiotic treatment
Neonates need to be protected both from the consequences of sepsis and
adverse effects of unnecessary antibiotics
108
. Current recommendations
Practical advice on using CRP in diagnosis of neonatal
sepsis
support initiation of antibiotic therapy in all neonates showing infection-like
symptoms 46, 108, 116. Detecting subtle and various non-specific clinical features
Measuring CRP is the preferred index in most neonatal intensive care units
is however difficult and can lead to unnecessary antibiotic therapy, based
120
solely on clinical grounds .
antibiotic treatment 46. Nor is a single CRP determination enough to diagnose
44
20
but current literature does not support use of only CRP when deciding on
21
sepsis. The prognostic value of CRP in neonatal sepsis improves when doing
Elevated hsCRP levels are associated with increased risk of
incident COPD, and hsCRP levels are higher in COPD pa-
serial determinations or using many markers in parallel.
tients compared to healthy individuals 47 – 54. The median
• An hsCRP assay is recommended when measuring neonatal CRP values .
hsCRP concentration in COPD patients is 1.92–5 mg/l
• Serial hsCRP measurements are valuable in determining neonatal
50, 51, 53, 54
44
baseline CRP level, recognizing significant rises in hsCRP and ruling out
infection when suspecting sepsis 44, 94, 98, 109.
depending on severity of disease.
COPD patients are classified in different disease
or GOLD (Global Initiative for Chronic Obstructive
• Serial hsCRP measurements can be used to guide duration of antibiotic
48, 50, 52 – 54, 126
Lung Disease) stages according to degree of airflow
treatment in septic neonates 98, 109–111, thus restricting unnecessary use of
limitation. CRP correlates with disease stage and thus
antibiotics.
severity of disease
• If at least two hsCRP measurements are normal at 48 hours and the
CRP correlates with
many physiological
parameters, e.g. forced
expiratory volume in 1
second (FEV1), known to
predict COPD outcome.
51, 53
during exacerbations
, and rise in COPD patients
.
127
infant is stable, discontinuing antibiotics can be considered 98, 99.
• Due to the nonspecific character of the CRP response and confounding
factors it is of high importance to evaluate the overall situation, history
as well as physical and clinical course of the mother and neonate 98. The
natural physiological rise of CRP in the neonate after birth should also
be taken into consideration.
• Best diagnostic accuracy is reached when measurement of CRP is combined with other confirmative methods such as bacterial culture or white
Table 1. Effects of pulmonary function, airflow limitation 128, predicted severity of airflow limitation, mean CRP
levels, and age-adjusted percentages of subjects with CRP over 3.0 or 10.0 mg/l, in a study made as part of the
Third National Health and Nutrition Examination Survey (NHANES III) 51. The fixed FEV1/FVC ratio of <0.70, defines
airflow limitation and confirms the presence of COPD, whereas FEV1 is used for classification of severity of airflow
limitation 129. FEV1 = Forced expiratory volume in 1 second, FVC = Forced vital capacity.
Lung
function
Airflow
limitation
(FEV1/FVC)
Severity
of airflow
limitation
(FEV1)
Mean CRP
(mg/l)
CRP ≥ 3.0
mg/l (%)
CRP ≥ 10.0
mg/l (%)
Severe
COPD
<0.70
<50%
4.7
52
23
Moderate
COPD
<0.70
≥50 to
<80%
3.6
41
12
Mild
COPD
<0.70
≥80%
2.9
27
6
blood cell differential count 98, or another infection marker like procalcitonin, IL-6 or IL-8 43, 46, 96, 108, 120, 122. Combining CRP measurement with
early sensitive markers increases the sensitivity to 90–100% 46.
HsCRP in diagnosis of Chronic obstructive
pulmonary disease (COPD)
COPD is a complex inflammatory disease and an increasing cause of morbid-
COPD treatment is intended to slow down disease progression and to
ity and mortality worldwide 47, 123, 124. It is often progressive and untreatable,
prevent exacerbations. COPD is commonly treated with inhaled corticos-
includes airflow limitation through airway obstruction, lung inflammation
teroids
and low grade systemic inflammation
47 – 52, 123, 124
.The regulation of inflamma-
tion in the pulmonary and systemic compartments as well as the relationship
between the compartments are still unclear
22
.
53, 125
, bronchodilators
49, 50, 130
, antibiotics
131
132 – 134
or some combination
of the aforementioned. Inhaled corticosteroids decrease CRP concentrations
significantly
49, 50
and withdrawal of inhaled corticosteroid treatment can
result in a drastic increase in baseline CRP 49.
23
QuikRead go hsCRP+Hb can be used as an aid in predicting patient-specific
CVD in COPD patients
extrapulmonary complications and COPD prognosis, and in assessing risk
Over half of COPD patients die from cardiovascular causes
of cardiovascular mortality or adverse cardiac events in patient with COPD.
and poor lung function are known risk factors for atherosclerosis, ischemic
The test can also aid in decisions on administration of treatment and in fol-
heart disease and other cardiac complications, elevating the risk of CVD to
lowing efficacy of treatment.
2–3 fold 48, 137 – 139.
133, 136
. COPD
Airflow obstruction alone is associated with increased occurrence of ischemic changes and cardiac injury, but in the presence of elevated hsCRP the
HsCRP is a long-term predictor of COPD hospitalization
and COPD death
risk increases additionally almost 2-fold 48. This indicates an additive effect
of COPD and higher hsCRP levels on risk of cardiac injury. The persistent
systemic inflammation in COPD may contribute to the pathogenesis and
CRP is classified as a strong and independent long-term predictor of future
explain the high risk of cardiovascular mortality in patients with COPD 49 – 51.
hospitalization and death due to COPD in individuals with airway obstruction. Incidences of COPD hospitalization and COPD deaths are significantly
increased in individuals with baseline CRP >3 mg/l versus < 3 mg/l. The risk
for hospitalization due to COPD is 1.4 and for death due to COPD 2.2 when
baseline CRP is > 3 mg/l. 126
CRP in diagnosis of Rheumatoid
arthritis (RA)
RA is a chronic and progressive systemic inflammatory disease that leads to
Smoking and COPD
joint damage and functional disability 55. Disease progression occurs at any
stage but apparently faster early on in the disease
140
. Frequent assessment
Elevated hsCRP levels (>3 mg/l) in current and former smokers have been as-
of disease activity allows timely adaptation of therapy, which is essential in
sociated with a 70% increase in risk of incident COPD compared to persons
preventing disease progression 141. The ultimate goals in managing RA are to
with low hsCRP levels (<1 mg/l). Increased hsCRP levels are thus predictive
prevent or control joint damage, prevent loss of function and decrease pain 142.
for occurrence of COPD in smokers, but not in never-smokers.
Only 15–25% of smokers develop COPD
47
RA can be diagnosed by many indices, that usually include e.g. joint
.This can possibly be ex-
symptoms, serological markers such as Rheumatoid factor (RF) and/or Anti-
plained by inherited susceptibility to inflammation or to developing COPD
citrullinated protein antibody (ACPA), symptom duration (>/< 6 weeks), and
47, 50
135
and smoking being additive to other factors in development of COPD.
Active smoking is stated to be associated with higher hsCRP levels in patients who already have COPD
47, 48, 52, 54
. Smoking cessation is recommended
but might not improve the prognosis as ex-smokers are considered having
a persistent inflammation
47
and once COPD develops, cessation might not
fully diminish the inflammatory process 52.
acute-phase reactants (CRP and/or Erythrocyte sedimentation
rate [ESR])
. Acute-phase reactants are well known
143, 144
markers of RA disease progression and predictors of
HsCRP is
American College of Rheumatology (ACR) and Euro-
superior to ESR in
predicting RA disease
activity and disease
pean League Against Rheumatism (EULAR) guidelines
severity 56.
disease outcome
145 – 147
, and included both in e.g. the
for diagnosis and assessment of RA 142, 148. Despite being
well known and commonly used as an aid in the evalua-
24
25
tion of RA disease activity, acute-phase reactants are not used as independent
guides for therapy
.
of cardiovascular events (>3 mg/l) 59 and having a CRP level over 5 mg/l is associated with a 3.3 relative risk of cardiovascular death in patients with RA 162.
149
Elevated CRP levels reflect RA disease activity 56 – 58 and CRP concentrations may rise already prior to RA being clinically evident 150. CRP can help
Hemoglobin levels in patients with RA
in predicting outcome in patients with early undifferentiated inflammatory
Low Hemoglobin (Hb) levels (<130 g/l, <13 g/dl, <8.07 mmol/l for men; <120 g/l, <12
arthritis 58 as well as progression to joint replacement in patients that already
g/dl, <7.45 mmol/l for women) are prevalent in RA patients 166 – 168 and probably associ-
have established disease
. It may also aid in identifying patients likely to
57
progress rapidly and who require intensive therapy .
55
or subclinical inflammation
CRP concentrations in RA patients vary depending on disease activity
and degree of control from median values of approx. 5.0 mg/l
well into clinical range, e.g. 15 mg/l or more
ated with RA disease severity and activity
56, 59
167, 168
. The cause of anemia might be chronic
166
. Within RA anemia is independently associated with
radiographic progression 167, 168.
to values
. HsCRP assays can be
55, 60, 151
used to identify mild disease activity that is associated with inflammation
but not detectable by traditional CRP tests 56. The need of tests that measure
Other indications
both low CRP values (<5 mg/l) and higher concentrations within the clinical
HsCRP measurement is valuable in patient-specific assessment of disease
range of CRP is thus evident.
activity and response to treatment in conditions that include systemic inflammation. Elevated or increasing hsCRP levels can encourage starting treatment
QuikRead go hsCRP+Hb can be used as an aid in predicting outcome as well
while low and decreasing levels can be reassuring. Some indications where
as assessing disease activity in patients with RA. It can also aid in deciding
hsCRP seems to have a role are described below.
whether therapy is needed and in evaluating possible increased risk of CVD
In some of the conditions CRP values rise into the clinical range. As
in patients with RA. The wide measuring range of 0.5 – 75 mg/l enables the
QuikRead go hsCRP+Hb has a wide measuring range (0.5 – 75 mg/l), it is
use of QuikRead go hsCRP+Hb in various settings, regardless of whether the
suitable for these purposes as well.
RA patient’s CRP levels are below or within the clinical range.
Asthma
CVD in patients with RA
Asthma is a chronic inflammatory disease of the airways. HsCRP levels are
increased in asthmatics
There is excess cardiovascular mortality and morbidity linked to systemic
inflammations in RA patients
152 – 156
and this is the predominant cause to
reduced life expectancy in patients with the disease 157 – 160. CRP is an independ-
cases
175
, especially in uncontrolled
169 – 172
as well as during attacks
169, 174
172 – 174
and severe
. HsCRP levels in asthmatics correlate
with severity of disease 175, 176 and may also be related to the state of asthma
exacerbation and possibly allergic inflammation 169, 171.
ent predictor for preclinical CVD, cardiovascular events and cardiovascular
Serial hsCRP measurements can be used for assessment of grade of asthma
and especially informative when serial measure-
severity and control when monitoring patients and response to treatment.
ments are performed and clinical course evaluated. Increased incidence of CV
Publications show an hsCRP range of 1.33 – 3.15 mg/l in asthmatics 172, 174, 175.
events does not seem to be connected to traditional cardiac risk factors 156.
HsCRP measuring is also of use in distinguishing between asthma exacerba-
mortality in RA patients
160 – 165
The majority of RA patients have CRP levels associated with increased risk
tions with moderate hsCRP elevation (e.g. 9 mg/l) and antibiotic treatment
requiring respiratory illnesses 177.
26
27
Systemic Lupus Erythematosus (SLE)
Diabetes mellitus type 2 (DM2)
SLE is a systemic autoimmune disease. Impaired clearance of apoptotic cells
A low-level systemic inflammation plays a key role in pathogenesis of insulin
is important in the pathogenesis of SLE, and CRP dysregulation may play a
resistance and DM2 31, 192 – 194, and in closely linked conditions such as obesity
part in this process
178
.
and the metabolic syndrome
21, 31, 195
presented earlier in this booklet (see
Median CRP levels in SLE range from 4 mg/l in inactive SLE, to 14 mg/l
page 9). Insulin resistance correlates with the risk of CVD, thus explaining
in active SLE, with concentration increasing by severity of disease 179. Plasma
some of the excess mortality in patients with DM2 195. HsCRP is a clinically
CRP levels over 9 mg/l are associated with increased risk of cardiovascular
valid biomarker to predict and monitor development of insulin resistance
events in patients with SLE (Odds ratio 2.6) 180.
and DM2
32, 192, 193
, as well as to assess and monitor cardiovascular risk in
diabetic individuals 195.
CRP levels are chronically elevated in patients with clinical DM2 196 and
Osteoarthritis (OA)
according to publications slightly elevated CRP levels even within the con-
OA or degenerative joint disease is a common and disabling musculoskeletal
ventional healthy reference range predict development of DM2
disorder, involving destruction of cartilage and bony remodeling. Modest but
apparently healthy elderly people with hsCRP>2.86 mg/l are approximately
significant increases in hsCRP can be seen in osteoarthritis 60, 181 – 185. Elevated
two times more likely to have DM2 on 3 – 4 years’ follow-up than persons
hsCRP is considered a predictor of progressive disease
of clinical severity of OA
181, 184 – 186
and a marker
192, 193
. E.g.
with hsCRP <0.82 mg/l 193.
.
183
The hsCRP elevation in OA is more modest than in RA 187, according to
publications 2.4 – 5.9 mg/l 60, 181, 183, 184. Mean hsCRP concentration is elevated
Diabetes mellitus type 2 subtype HNF1A-MODY
e.g. in patients with inflammatory infiltrates within the synovial membrane
Maturity-onset diabetes of the young (MODY) subtypes are characterized by
, in women with early knee OA and in patients whose disease progress 181.
autosomal dominant inheritance and onset before the age of 25 197. HsCRP is a
Elevated hsCRP values predict patients whose disease will progress over 4
clinically valid biomarker for identifying the most common subtype, HNF1A-
years and could benefit from more aggressive treatment 181.
MODY
60
. Hepatocyte nuclear factor 1-a (HNF1A) is expressed in the
197 – 199
liver and involved in the regulation of several liver specific genes, but in the
MODY subtype the gene is mutated and its dysfunction causes diabetes
199
.
Osteoporosis
The HNF1A-MODY subtype requires different treatment
In osteoporosis bone resorption exceeds bone formation. Elevated hsCRP
of high costs and restricted availability of molecular testing many patients
levels are associated with lower bone mineral density in healthy women and
are left with undiagnosed or incorrectly diagnosed diabetes 199.
men
. Odds ratio for osteoporosis and osteopenia are 1.35 when hsCRP
HNF1A is required for CRP expression and CRP levels do not rise in the
188, 189
is >1.2 mg/l in pre-menopausal women, and odds ratio for osteoporosis is
1.54 when hsCRP is >1.8 mg/l in postmenopausal women
. Some indica-
188
tions also exist for an association between elevated hsCRP levels and risk of
bone fractures
.
189 – 191
, but because
198, 199
HNF1A-MODY subtype
198 – 202
. Median hsCRP levels in HNF1A-MODY
patients are 0.03 – 0.25 mg/l 198, 199, i.e. significally lower than in healthy adults
. As hsCRP assays are affordable and widely available, they could translate
14
rapidly into clinical practice and improve diagnosis rates in monogenic
diabetes considerably 198.
28
29
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30
31
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3.
4.
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17.
18.
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