Original Article
C-REACTIVE PROTEIN, RHEUMATOID FACTOR
AND CIRCULATORY IMMUNE COMPLEX AS
MARKERS FOR MONITORING TREATMENT
OF INFECTIVE ENDOCARDITIS
Seyed Mohammad Alavi1, Fatemeh Ahmadi2, Rouhangiz Nashibi3
ABSTRACT
Objectives: To evaluate the diagnostic usefulness of serum C-reactive protein (CRP),
rheumatoid factor (RF) and circulatory immune complex (CIC) determinations in monitoring
the outcome of infective endocarditis (IE).
Methodology: In this prospective analytic descriptive study CRP, RF and CIC were measured on
admission and 4 weeks after initiation of standard antibiotic regimen in 30 hospitalized
patients with IE in an educational hospital between 2006 and 2007 in Ahvaz a city south west
Iran . Duke criteria were used for diagnosis of IE. CRP and RF were examined using quantitative
neflometry (Binding site kit, UK) and CIC was detected by semi quantitative immune diffusion
(Baharafshan SIRD kit, Iran). Data were evaluated using statistical analyses in SPSS (version 12,
USA) software for windows.
Results: The fall in serum C-reactive protein or RF was significant (P=<0.05) when a patient had
a full recovery, but no such behavior was observed in CIC (P>0.05). Only two of the 30 patients,
who had elevated CRP, RF and CIC week four failed to response and one needed cardiac surgery.
Conclusions: The C-reactive protein proved to be a good tool for monitoring the treatment of
IE. Also RF proved useful in the assessment of patients with IE, but the value of CIC was
negligible.
KEYWORDS: C-reactive protein, Rheumatoid factor, Circulatory immune complex, Infective
endocarditis.
Pak J Med Sci October - Decmber 2009 (Part-I) Vol. 25 No. 5 825-828
How to cite this article:
Alavi SM, Ahmadi F, Nashibi R. C-reactive protein, Rheumatoid factor and circulatory immune
complex as markers for monitoring treatment of infective endocarditis. Pak J Med Sci
2009;25(5):825-828.
1.
Dr Seyed Mohammad Alavi, MD,
Associated Professor of Medical College
2. Dr Fatemeh Ahmadi, MD
3. Dr Rouhangiz Nashibi, MD
1-3: Infectious disease ward, Razi Hospital,
Joundishapour University of Medical Sciences, Ahvaz, Iran,
Joundishapour Infectious Diseases and Tropical Medicine
Research Center, Ahvaz, Iran.
Correspondence
Dr Seyed Mohammad Alavi
No: 52, West 11 Avenue, Kianabad, Ahvaz, Iran
Email: alavi1329dr@yahoo.com
* Received for Publication:
May 5, 2009
* Accepted:
August 20, 2009
INTRODUCTION
Infection of the endocardial surface of the
heart called infective endocarditis (IE) is a
serious infection with significant morbidity and
mortality associated with the need for
prolonged parentral antibiotic treatment.1,2
Early diagnosis, regular follow up and monitoring treatment have greatly reduced the i
ncidence of treatment failure and mortality rate
by modifying antibiotic regimen and applying
proper intervention as well as cardiac
surgery.1-3
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Seyed Mohammad Alavi et al.
There are many laboratory tests for monitoring treatment such as erythrocyte sedimentation rate (ESR), white blood cell count (WBC),
C-reactive protein (CRP), rheumatoid factor
(RF), circulatory immune complex (CIC),
precalcitonine and interlukin-6 (IL-6).1,4-6 There
are great differences between countries in the
use of these tests. New markers of inflammation such as precalcitonine and IL-6 are used
frequently in developed countries whereas useful older tests such as CRP, ESR, RF, CIC, and
WBC are used in developing or resource limited countries.5,6 Published studies have shown
that CRP, ESR andWBC are useful laboratory
tests in monitoring the response to therapy in
patients with bacterial infection such as meningitis as well as septicemia.6,7 Previous studies
about usefulness of these tests in monitoring
treatment of IE are associated with controversial results.4-6,8-10 Because of lacking data about
utility of these tests in Iranian IE patients, we
designed this study to evaluate the clinical usefulness of CRP, RF and CIC in monitoring treatment of hospitalized patients with IE in educational hospital between 2006 and 2007in Ahvaz.
METHODOLOGY
All the patients with IE diagnosed between
2006 and 2007 in an educational hospital(Razi
hospital) affiliated to Jundishapur University of
Medical Sciences in Ahvaz,the capital city of
Khuzestan south west Iran, were analyzed in a
prospective analytic descriptive study.
Duke criteria was used for diagnosis of IE
(Table-I), patients were treated by standard antibacterial regimen according AHS (American
Heart Society) accepted by Iranian Infectious
Disease and Tropical Medicine Board.1-3 The
values of CRP, RF and CIC were examined on
admission and 4 weeks after initiation of antibacterial treatment. Two blood samples (5ml)
obtained from each patient on admission and
after 4 weeks of treatment. Samples were passed
to laboratory. 2.5 ml of each sample were used
for CRP and RF, remaining 2.5 ml was preserved
at -20º C until sending to Central laboratory in
Tehran (under standard condition) for CIC examination. Samples were examined for CRP and
826 Pak J Med Sci 2009 Vol. 25 No. 5
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RF in a private laboratory in Ahvaz by using
quatitative neflometry (Binding site kit, UK).
CIC was detected by semiquantitative immune
diffusion (Baharafshan SIRD kit, Iran). Reference value for RF was <30 IU/ml, CRP concentration of <4 mg/l was considered normal and
CIC value >1.4mg/ml was considered positive.
At the day 7 of treatment, IE defined as cured
when the fever and other sign and symptoms
were subsided, patients with fever (in spite of 7
day appropriate treatment) or neurological and
embolic manifestation or the need for cardiac
surgery were defined as failure treatment. Data
was collected by medical chart included
age,sex,blood culture results,echocardiographic
findings, received antibiotic before and after
admission, clinical findings and outcome of
IE.Data were analyzed in SPSS software (version 12,USA) by using t test,chisquare test and
Fisher’s exact test. Association of laboratory
tests with the outcome of treatment was analyzed using odds ratio (OR) with 95%
confidence interval (CI). P values<0.05 were
considered significant.
RESULTS
Of total 30 patient 26(86.7%) were male and
4(13.3%) were female. The mean age ± SD of
female was 38.25 ± 22.92 years and of male was
29.19 ± 6.75 years, with the range of 20-70 for
both. CRP before treatment(on the admission)
was elevated in 30 patients(100%) with the mean
value of 72.38 ± 42.59.CRP values 4 weeks after
treatment remained significantly high in four
patients(13.3%).CRP was significantly lower in
patients who cured than in those who failed to
treatment(P<0.05). OR for cure was over two
fold (OR=2.4,95% CI,1.2-4.4;P=0.004). RF before
treatment was positive in 26 (86.6%) and four
weeks after treatment was positive in 8 (26.6%).
Significant difference in RF positivity was observed between results before and after treatment (P<0.05). Before and after treatment CIC
was positive in 27(90%) and 23(76.6%) patient
respectively. There was no difference in CIC
positivity between patients with cure and patients with failure to treatment (P>0.05).Results
of CRP,RF and CIC values are shown in
Infective Endocarditis Treatment monitoring
Table-I: The Duke criteria for the Clinical Diagnosis of Infective Endocarditis
Major criteria
1. Positive blood culture: Typical microorganism for infective endocarditis
2. Evidence of endocardial involvement: Positive echocardiograma,
Minor criteria
1. Predisposition: predisposing heart condition or injection drug use
2-fever> 38.0°C
3. Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial
hemorrhage, conjunctival hemorrhages, Janeway lesions
4. Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, rheumatoid factor
5. Microbiologic evidence: positive blood culture but not meeting major criterion as noted previouslyb or
serologic evidence of active infection with organism consistent with infective endocarditis
Transesophageal echocardiography is recommended for assessing possible prosthetic valve endocarditis
or complicated endocarditis.bExcluding single positive cultures for coagulase-negative staphylococci and
diphtheroids, which are common culture contaminants, and organisms that do not cause endocarditis frequently, such as gram-negative bacilli.Note: HACEK, Haemophilus spp., Actinobacillus actinomycetemcomitans,
Cardiobacterium hominis, Eikenella corrodens, Kingella species.
a
Table-II.Two patients failed to response to treatment because of cardiac complication needed
to cardiac surgery in one patient and glomerulonephritis in another patient.
DISCUSSION
The present study revealed that determination of CRP is a useful tool to monitor the outcome of IE. The serum CRP concentration was
significantly lower when a patient cured of IE
than when failed response to antibacterial
therapy. This finding is consistent with some
earlier studies11-13 but, is in disagreement with
Hryniewiecki et al.8Thomson et al,reported that
serial determination of CRP was useful in monitoring of the patient’s response to the therapy
of IE,and failure to treatment was associated
with high CRP concentration.13 Hryniewiecki
and colleagues explained no significant correlation between CRP and outcome of IE treatment, the tendency of consecutive CRP concentrations to decrease (from 27.1 ± 23.9 mg/l to 22
± 18.3 mg/l) was not significant and CRP was
not a useful tool for IE treatment monitoring.8
These differences may be due to: 1-existence of
valvular disease in Hryniewiecki’s patients
which prevent decreasing in CRP values, 2-difference in CRP assay in these studies (ELISA
vs. neflometry).
Our study showed that RF is an acceptable
and useful marker of the therapeutic response
in treatment of IE. Effective antibiotic therapy
resulted in decreasing of RF values. This finding is in agreement with Koeglenberg’s study11
but, differs from Thomson’s work.13 Thomson
et al, reported that cure of IE was not associated with low serum concentration of RF. We
believe that these opposite results are due to
difference in clinical course of IE in study population. RF in serum of sub acute IE patients is
usually higher than in patients with acute IE.1,2
Majority of our patients were in sub acute phase
of IE whereas patients of Thomson’s study were
in acute phase of illness.
In this study serum concentration of CIC on
admission and four weeks after treatment were
equivalent. CIC was not a useful tool for clinical monitoring of IE outcome. This finding is in
Table-II: Laboratory results for monitoring infective endocarditis in Ahvaz
Lab.
On admission
After treatment
P value
OR,95% CI
tests
Cured
Failed
CRP
72.38 ± 42.59
44.16 ± 30.64
79.12 ± 47.03
0.004
OR=2.4,95% CI,1.2-4.4
RF
60.45 ± 71.42
41.25 ± 49.37
61.72 ± 69.09
0.013
OR=1.7,95%CI,0.8-2.1
CIC
0.847 ± 0.16
0.80 ± 0.19
0.814 ± 0.27
0.27
OR=1.02,95%CI,0.5-1.1
CRP;C-reactive protein (mg/l), RF; rheumatoid factor(IU/ml),CIC; circulatory immunecomplex (mg/
ml),Lab; laboratory, OR; odds ratio, CI; confidence interval, IU; international unit. Difference with Pvalue
lower than 0.05 are significant
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Seyed Mohammad Alavi et al.
agreement with Thomson et al13 and Agrawal
et al,14 but, is in disagreement with Messias-Reason et al, 15 Schned et al16 and Bayer et al.17
Messias-Reason, reported that CIC is pathogenic in IE and has high serum concentration
in complicated or died patients. CIC value in
cured patients is significantly lower than in
complicated patients.15 Schned et al explained
that CIC was significantly elevated in the patients who died when compared to those who
had a good recovery (P < 0.02 and suggested
CIC as possible markers for severity or monitoring treatment the disease.16 Bayer et al, suggested that Circulating immune-complex levels were correlated with out come of IE, and CIC
levels fell to zero with successful antimicrobial
or surgical therapy.17 This difference may be due
to our study population. Majority of our patients
were injecting drug users, in which because of
frequent injections, immune complex are frequently found in high concentration in their
serum.1,2
Our study has some limitation such as small
sample size, injecting drug users and the impact of their underlying condition ( infectious
disease and probably human immune deficiency virus infection) on the our result, In addition lacking laboratory facility for performance CIC examination in Ahvaz and possible
hazard to samples in transportation to Tehran
in spite of our extreme caution.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
ACKNOWLEDGMENT
The authors wish to thank the chief and personnel of Jundishapoor Infectious and Tropical
Research Center (JITRC)for supporting of this
study. We also acknowledge the chief and personnel of the infectious disease department of
Razi hospital and Dr Moradzadegan the chief
of Pasteur laboratory for kind assistance.
Conflict of interest: This study was funded by
JITRC and there is no conflict of interest.
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