Rapid CRP test in early detection of bacterial infection ...

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Rapid CRP Test in Early Detection of Serious Bacterial Infection in Egyptian Children, *MOHAMAD SEDKI, *HASSAN M. SALAMA, MOHAMAD G. SHOUMAN, *NAGWA ABDALLAH, ** HOAYDA EZZ ELDIN and HANY A. RAHMAN *Pediatric Department, National Research Centre ** Clinical Pathology Department National Research centre

Abstract: Background: CRP is a commonly used marker of inflammation to select serious bacterial infections (SBI). Difficult accessibility in segregated districts clinics lowers of its value for rapid prediction and start of antibiotics. A bed site rapid test is supposed to solve this problem provided having at least the same accuracy in documenting bacterial infection. Patients and methods: 96 patients of pediatric age group presenting with acute infections were subjected to CRP laboratory and radioimmunoassay Actim CRP rapid test. The definitive diagnosis was confirmed without both tests interference. Results: Of the 96 cases, 49 had simple infections and 47 SBI. Of them, 26 patients had streptococcal pharyngo-tonsillitis, 10 patients had bacterial pneumonia and 11 patients had sepsis. The sensitivity, specificity, negative predictive value, positive predictive value of CRP to serious bacterial infection were 91.5 %, 59.2 %, 68.3 %, and 87.9 % respectively. While that of Actim rapid test were 89.4 %, 63.3 %, 70.0 %, and 86.1 % respectively. The receiver-operating characteristic (ROC) area under the curve for CRP laboratory was 75.3% and that for Actim 76.3%. Conclusion: CRP laboratory and Actim are quite similar in predicting SBI. However, Actim is slightly more accurate and definitively more practical as regard time and space. Serial evaluation of rapid test increases of its sensitivity and negative predictive value to SBI. We can accept a low specificity and positive predictive value as the test is affected by non serious bacterial infection. Key words: C-Reactive Protein, Serious bacterial infection, Actim rapid test

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Introduction: C-reactive protein (CRP) is an acute phase protein produced dramatically within hours in response to inflammation, infection and tissue damage [1,2]. It is used particularly in a trial to differentiate bacterial from viral infection [3,4,5,6,7]. Fever lasting more than 48 hours in the pediatric age group remains a common cause of emergency ward and clinics visits and may express serious bacterial infection (SBI). With the absence or presence of a focus, a golden question always arises about serious bacterial origin and subsequent antibiotic choice. We are always in conflict between conservative attitudes of wait and see with all the squeals of delayed bacterial eradication and an abusive attitude of prescribing unnecessary broad spectrum antibiotics with all the financial and clinical complications. According to some investigators, CRP proved its efficacy, in determining with an acceptable sensitivity, the serious bacterial infections [8,9,10,11]. However, results are not always satisfactory, as there are still a debate about its sensitivity and specificity in bacterial infection. This deprives it from being a golden test [12,13,14]. Moreover, this biological analysis needs a technique that is not always available everywhere at anytime with sometimes unacceptable delay before delivering the results. On the other side, immunologic techniques allow nowadays rapid antigen detection tests (RADT) of the specific C reactive protein [15,16,17]. The test is applied from a simple pin prick blood drop on outpatient clinic basis. Accordingly, if we have to use laboratory CRP as a necessary but insufficient tool in retaining the diagnosis of serious bacterial infection, a 5 minute result test -if guarding at least the same accuracy-, would be more beneficial for serial readings. Depending on the revolutionary improvement in rapid diagnostic tests based on radioimmunoassay, our target is to test a new attitude for rapid diagnosis of bacterial infections helping in a rapid prompt management with avoidance of abuse antibiotics or laboratory investigations. We studied prospectively the efficacy of Actim CRP test in general pediatrics infections. Our objective is to test it as a tool to rely upon in predicting SBI especially in the setting of pediatric clinics and rural areas dispensaries. Patients, materials and methods: Patients: This prospective study aiming to evaluate the role of CRP rapid test in serious bacterial infection was conducted between January 1, 2007, and 5th September 2008 after the approval of the Ethics Committee at the National Research Centre, Cairo, Egypt. A convenience sample of children, from neonatal period to 16 years, who presented to the Abu Elrish Hospital for Children Emergency Department (Urban) or outpatient pediatric clinic of 2 medical centers at Boulak ElDakrour Hospital and Saft el Laban Unit (rural) were included in the study. These children (no recent history of antibiotics or vaccines intake) were presenting with manifestations of

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infections including fever without source, with temperature 38°C lasting more than 48 hours, or infection of special sites. All children were subjected to demographic information, careful history and clinical evaluation of various system infections as a part of the score sheet subjected to the approval of the committee and after the informed consent of the tutor. All patients were subjected to CBC and differential counts by automated coulter counter and laboratory quantitative CRP by immunoassay technique: negative up to 6 mg%, mild positive 6-20 mg%, moderate 20-40 mg%, severe 40-80 mg% and very severe >80 mg%. Other complementary investigations were done according to clinical orientation: throat culture on blood agar and antistreptolysin O titre (ASOT) for upper respiratory tract infection (URTI), chest X-ray showing the presence of a focal infiltrate in lower respiratory tract infection (LRTI), lumbar puncture with differential count, gram stain bacteria, chemistry for meningitis, urine analysis using standard sterile techniques where samples with pus cells exceeding 10/ hpf were subjected to culture and sensitivity tests leading to a single urinary tract pathogen at 104 CFU/ml for urinary tract infection, echocardiography for carditis, CT scan for other localized infections. Manifestations of sepsis especially for infants less than 3 months of age or older with a special orientation, justified a complete infection panel including: blood culture monitored by isolator blood culture system (trade mark), urine analysis, lumbar puncture, chest X-ray. Laboratory personnel and radiology staff were blinded to clinical information. Serious bacterial infection was defined according to the sequels of virulence in morbidity or mortality. It has been confirmed by the golden test culture at first rank that could be associated to other clinical, biological (except CRP conventional or rapid tests) and radiological parameters. Depending on the presence or absence of SBI, we divided patients in 2 groups: The first group included URTI streptococcal pharyngo-tonsillitis, LRTI bactertial pneumonia, Sepsis grouping: pyelonephritis, bacterial meningitis and localized central CNS infection, infective endocarditis, suppurative osteoarthritis and suppurative otitis media. Patients not fulfilling previous criteria formed the other group. Laboratory CRP and Actim rapid test were not used initially in disease grouping or decision taking as they are the subject of evaluation. However their role will be interpreted on a retrospective pattern. Rapid CRP test: Actim ™ CRP was kindly offered by Femmouse laboratories Principle: The test is based on immuno chromatography. It involves monoclonal antibodies to human c reactive protein for semi quantitative determination and monitoring of CRP concentrations. Materials: The kit is formed of a test pack containing: 1) one dipstick formed of a dip area, a result area containing latex particle and a carrier membrane including a control line, followed by 3 positive lines 2) one tube of specimen dilution buffer solution (0,5 ml) 3) vial to end to end capillary 10 μl.

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Methods: Besides the CRP blood sample directed for laboratory quantitative CRP, a pin prick fingertip blood drop was absorbed through the capillary tube 10μl and embedded in the specimen dilution buffer solution tube (0,5 ml). An immediate mixture of the sample with the buffer solution is obtained by inverting the tube upside down 10-15 times until no more blood in the capillary tube and the sample has completely transferred to the buffer. When the dipstick is dipped in the diluted sample, it absorbs the liquid which starts to flow up the dipstick. One is bound to latex particles which is the detecting label. In the carrier membrane there are 3 CRP specific antibody zones to which the blue latex particles will bind if the sample contains CRP. After a period of 5 minutes, the cut-off value for the Actim ™ CRP is 10 mg/l which gives one positive blue line, If the serum concentration of the sample is > 40 mg/l, a second blue line will appear. The 3ed blue line will become visible if the serum concentration of CRP > 80 mg/l. Statistical analysis: SPSS for Windows, version 16.0 computer program was used for statistical analysis. Data were represented as frequency, percent, median and range. Demographic characteristics and laboratory values of children with SBI and non SBI were compared using the Chi square for frequencies, the 2 tailed t test for normally distributed continuous variables, and the Mann-Whitney U test otherwise. A p value of less than 0.05 was considered statistically significant. In order to evaluate the accuracy of the CRP and Actim test, the sensitivity, specificity, negative and positive predictive values for the detection of an SBI were determined. The sensitivity indicates the chance of testing positive among those with the condition; it is calculated as the percent of true positive cases in relation to true positive cases plus false negative cases. Specificity is the chance of testing negative among those without the condition. It is calculated as the percent of true negative cases in relation to true negative cases plus false positive cases. The Positive Predictive value is the chance of having the condition among those that test is positive, it is calculated as the percent of the true positive cases in relation to true positive cases plus false positive cases. The negative predictive value is the chance of not having the condition among those that test is negative, it is calculated as the percent of the true negative cases in relation to true negative cases plus false negative cases. Receiver-operating characteristic (ROC) curves for CRP and Actim concentration were constructed to confirm the accuracy of the test. Values with 95% confidence intervals (CI) were tabulated. Results: 100 patients were subjected to the study. Of them 4 were excluded due to failure of CRP technique. 96 children, 49 males and 47 females, with infections manifestations were eligible for analysis. The median age was 6.2 years (2 months to 13 years). The large diagnosis was distributed as follows: 67 patients had upper respiratory tract infections (URTI), 18 had lower respiratory tract infection (LRTI) and 11 had other infections: 4 had urinary tract infection, 4 had Septicemia, 2 had infective endocarditis and one osteomyelitis. The final diagnosis was divided in 2 groups: serious bacterial infection (n=47) and non serious bacterial or viral infections (n=49). Patient's characteristics are showed in table 1. Depending on the clinical course of infection

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the final diagnosis of serious bacterial infection in URTI (n=26) was proved by a positive streptococcal throat culture (table 2). While in LRTI (n=10) it was proved by chest x- ray, hyper leucocytosis and neutrophilia and the rapid response to antibiotics. Finally, other SBI (n=11) were confirmed by one or more of the following: positive bacterial blood culture, urine culture, echocardiography, CT scan, leucocytosis and neutrophilia. The mean rank of total leucocytic count was 42.87 x 10E3 and 48.25 x 10E3 per cubic millimeter in non SBI and SBI respectively and the difference is not statistically significant. As regard absolute neutrophil count the mean rank was 35.64 x 10E3 and 44.25 x10E3 in non SBI and SBI respectively p 0.09. When compared qualitatively and quntitatively the number of each positivity of Actim (test under estimation) to CRP (test of reference), the results were homologous and p < 0.01% (table 3 and table 4). When we tested the sensitivity of both CRP laboratory test and the Actim rapid test in relation to SBI (to what extent the test is positive in the presence of SBI) we found it 91.5% and 89.4 %% respectively. The specificity of both CRP laboratory test and the Actim rapid test (to what extent the test is negative in the absence of SBI) was 59.2 % and 63.3 % respectively. Considering the positive predictive value (the ability to predict a test as positive and it is truly positive) it was 68.3 % and 70.0 % respectively and finally the negative predictive value (the ability to predict the test as negative and is truly negative) and it was 87.9 % and 86.1 % respectively (table 5). The area under the curve that evaluates the accuracy of laboratory CRP and Actim rapid CRP test in order to rely upon to confirm SBI was 75.3 % in CRP laboratory and 76.3% in Actim CRP (Fig. 1 and Fig. 2). Discussion: Revolution in newer inflammatory markers as procalcitonin proved its efficacy over CRP in serious bacterial infection [18,19,20]. However, it is difficult for mass screening in developing countries due to high expenses. So, conventional CRP remains one of the tools of choice in these circumstances [8,13]. However, being a laboratory investigation, it exist difficult logistics in rural areas lacking labs or subjected to delayed results due to pediatric dispensaries and laboratory schedules discrepancies. We conducted a perennial prospective study, in order to test the rapid bed site test in a trial to treat promptly and rapidly potential SBI and to limit investigations and antibiotics abuse. SBI represents nearly 25-30% of emergency cases [18,21]. In our study it was nearly 50%. The equal representation of SBI/Non SBI could be explained by the inclusion of streptococcal pharyngo tonsillitis as a SBI as it is endemic in Egypt. In our study, both laboratory and rapid tests were used prospectively without directing the proper diagnosis or decision making. But their reliability was tested retrospectively after a diagnosis has been reached based on clinical evolution and other investigations. Depending on the dramatic increase of CRP in severe infections [22], laboratory CRP and Actim CRP were evaluated qualitatively and quantitatively. The level of positivity, expressed in laboratory CRP by mg/dl was homologous to that of Actim rapid test expressed by fluorescence lines color change. This concordance is significant which proves the efficacy of the Actim test. In our study for laboratory CRP, the sensitivity and negative predictive value were around 90% expressing a true positive majority and a false negative minority

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encouraging this test to rely upon to decrease missing antibiotics prescription and close follow up. As regards the specificity, positive predictive value were at much lower levels reaching nearly 60% and 80% respectively expressing a considerable false positive number and lower predictability of a true positive test leading to a liability to increase antibiotics abuse. This could be partially explained by the fact that CRP test was positive in all bacterial infection not discriminating serious from non serious. However the results are low, it remains better than prescribing antibiotics blindly when lacking investigations. Even if the test is less specific to SBI it may be more specific in other bacterial infection. In other studies, worse results were showed by Sanders et al, 2008, in a systematic review of the diagnostic accuracy of C-reactive protein to detect serious bacterial infection in non-hospitalized infants and children with fever. In that study, the sensitivity was 77% (68-83%), the specificity 79% (7483%), concluding that CRP provides moderate and independent information for both ruling in and ruling out serious bacterial infection in children with fever at first presentation [14]. In A meta-analysis performed to evaluate the accuracy of determination of C-reactive protein (CRP) levels for the diagnosis of hospitalized children for bacterial infection, the sensitivity was 75% [95% CI, 62%-84%] and the specificity 67% [95% CI, 56%-77%] [19]. C-reactive protein has moderate diagnostic accuracy for serious bacterial infection in children with fever [23]. On the other side, in another study testing C-Reactive Protein in Febrile Children 1 to 36 Months of Age with Clinically undetectable Serious Bacterial Infection, sensitivity were 79%, and specificity 91% [8]. Other studies confirmed CRP to have good sensitivity and specificity [24]. In our study the accuracy of the test to rely upon by using Receiveroperating characteristic analysis, demonstrated CRP (area under curve [AUC] 0.753, 95% CI: 0.654-0.853). Better data were showed by a CRP (area under curve [AUC] 0.905, 95% CI: 0.808, 1.002) [8]. As regards the Actim rapid test, we found that results in relation to SBI were comparable to that of conventional laboratory CRP with slightly lower sensitivity and negative predictive value but higher specificity and positive predictive value. The decrease in sensitivity could be partially explained by the time at which the test was done and to what extent the inflammatory markers are expressed in relation to the time of disease and whether it is a secondary bacterial infection on top of viral or primary bacterial progressing slowly. In a study conducted by Esposito et al. 2005 [15], where they compared the results of a rapid test for the bedside assay of Creactive protein with those of a standard laboratory assay in samples taken from 231 children attending the Emergency Department. This study shows that the rapid CRP test gives the same quantitative results as those obtained using a more complex routine laboratory method. Another study by showed in127 children the quick read CRP test is easy to use, provides reliable results and reduces the need for antibacterial therapy [16]. In another study testing the reliability of two different bedside assays for C-reactive protein in newborn infants, both bedside tests had good specificity 80.5%, 83.3% and sensitivity 97.2%, 94.4% when CRP concentrations are >10 mg/L The accuracy of the results of both bedside tests somewhat decreased when CRP concentrations are >100 mg/L. Both methods did not show any statistically significant systematic proportional bias when compared with the central laboratory values [25]. In order to increase the sensitivity of the rapid Actim CRP test, and according to its

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easy accessibility and practicability, it is advisable to do bed site serial assessment, and to be supported by clinical picture. In our study there were significant clinical pictures in favor of SBI: fever + pharyngo tonsillitis, signs of sepsis, respiratory distress. On the other hand, fever + stomatitis, rhinitis, and sore throat were in favor of simple non SBI. Complementary laboratory investigations especially neutrophilia proved to increase in SBI. The presence of a rapid test with nearly similar accuracy to laboratory CRP reaching 75%- 85% as confirmed by ROC for both, confirms the superiority of Actim to conventional test as its easy and rapid application support it for serial applications on outpatient basis to prescribe antibiotics or further investigations with the minimal deviation of fluorescence mark.. On the other hand, relying on the easy rapid application of the test, the antibiotic response may be tested by serial evaluation of decreasing or disappearing fluorescent marks. Conclusion and recommendations: Although Actim CRP gives similar results to SBI as CRP laboratory, it can be considered even more potent with its rapidity and practicability. Serial bed site tests are possible in order to refine the diagnosis and follow -up. Our recommendation is to rely upon Actim CRP test at least in diagnosing bacterial infections so specificity would increase. The clinical picture orientation would increase the sensitivity.

References: [1] Nudelman R, Kagan BM. C-reactive protein in pediatrics. Adv Pediatr. 1983;30:517-47. [2] James K: Immunoserology of infectious diseases. Clin Microbiol Rev,1990; 3: 132–52.

[3] Korppi M, Kröger LC-reactive protein in viral and bacterial respiratory infection in children. Scand J Infect Dis. 1993;25(2):207-13. [4] Tejani NR, Chonmaitree T, Rassin DK, Howie VM, Owen MJ, Goldman AS.Use of C-reactive protein in differentiation between acute bacterial and viral otitis media. Pediatrics. 1995 May;95(5):664-9. [5] Virkki R, Juven T, Rikalainen H, Svedstrom E, Mertsola J, and Ruuskanen O Differentiation of bacterial and viral pneumonia in children Thorax. 2002 May; 57(5): 438–441. [6] Monteny M, ten Brinke MH, van Brakel J, de Rijke YB, Berger MY. Point-of-care C-reactive protein testing in febrile children in general practice. Clin Chem Lab Med. 2006;44(12):1428-32. [7] Shaoul R, Lahad A, Tamir A, Lanir A, Srugo I.C reactive protein (CRP) as a predictor for true bacteremia in children. Med Sci Monit. 2008 May;14(5):CR255-261. [8] Patrick N. Pulliam, Magdy W. Attia, Kathleen M. Cronan. C-Reactive Protein in Febrile Children 1 to 36 Months of Age With Clinically Undetectable Serious Bacterial Infection PEDIATRICS Vol. 108 No. 6 December 2001, pp. 1275-1279. [9] Lacour AG, Gervaix A, Zamora SA, Vadas L, Lombard PR, Dayer JM, Suter S. Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identificators of serious bacterial infections in children with fever without localising signs. Eur J Pediatr. 2001 Feb;160(2):95-100. [10] Hsiao AL, Baker MD.Fever in the new millennium: a review of recent studies of markers of serious bacterial infection in febrile children. Curr Opin Pediatr. 2005 Feb;17(1):56-61.

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[11] Andreola B, Bressan S, Callegaro S, Liverani A, Plebani M, Da Dalt L. Procalcitonin and Creactive protein as diagnostic markers of severe bacterial infections in febrile infants and children in the emergency department. Pediatr Infect Dis J. 2007 Aug;26(8):672-7. [12] Herrera P, Duffau G.Usefulness of C-reactive protein for the diagnosis of bacterial infections in children. A review Rev Med Chil. 2005 May;133(5):541-6. [13] Jaye DL, Waites KB. Clinical applications of C-reactive protein in pediatrics. Pediatr Infect Dis J. 1997 Aug;16(8):735-46. [14]Sanders S, Barnett A, Correa-Velez I, Coulthard M, Doust J.Systematic review of the diagnostic accuracy of C-reactive protein to detect bacterial infection in nonhospitalized infants and children with fever. J Pediatr. 2008 Oct;153(4):570-4. [15] Esposito S, Tremolati E, Begliatti E, Bosis S, Gualtieri L, Principi N. Evaluation of a rapid bedside test for the quantitative determination of C-reactive protein. Clin Chem Lab Med. 2005;43(4):438-40. [16] Papaevangelou V, Papassotiriou I, Sakou I, Ferentinos G, Liapi G, Kyrka A, Konstantopoulos A. Evaluation of a quick test for C-reactive protein in a pediatric emergency department. Scand J Clin Lab Invest. 2006;66(8):717-21. [17] Marcus N, Mor M, Amir L, Mimouni M, Waisman Y.The quick-read C-reactive protein test for the prediction of bacterial gastroenteritis in the pediatric emergency department. Pediatr Emerg Care. 2007 Sep;23(9):634-7. [18] Galetto-Lacour A, Zamora SA, Gervaix A. Bedside procalcitonin and C-reactive protein tests in children with fever without localizing signs of infection seen in a referral center. Pediatrics. 2003 Nov;112(5):1054-60. [19]Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J.Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis. 2004 Jul 15;39(2):206-17. [20] Olaciregui I, Hernández U, Muñoz JA, Emparanza JI, Landa JJ.Markers that predict serious bacterial infection in infants under 3 months of age presenting with fever of unknown origin. Arch Dis Child. 2009 Jul;94(7):501-5. [21] Chen CJ, Lo YF, Huang MC, Chung RL, Tang RB, Wu KG. A model for predicting risk of serious bacterial infection in febrile infants younger than 3 months of age. J Chin Med Assoc. 2009 Oct;72(10):521-6. [22] Clyne B, Olshaker JS.The C-reactive protein. J Emerg Med. 1999 Nov-Dec;17(6):1019-25. ) [23] Attia MW.Review: C-reactive protein has moderate diagnostic accuracy for serious bacterial infection in children with fever. Evid Based Med. 2009 Apr;14(2):56. [24] Peltola H, Jaakkola M. C-reactive protein in early detection of bacteremic versus viral infections in imunocompetent and compromised children. J Pediatr.1988; 113:641–64. 25) Zecca E, Barone G, Corsello M, Romagnoli C, Tiberi E, Tirone C, Vento G.. Reliability of two different bedside assays for C-reactive protein in newborn infants. Clin Chem Lab Med. 2009;47(9):1081-4.

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Table 1: Demographic data Variable Total number Male Female Median age (years) Upper respiratory Lower respiratory Others

Total 96 49 47 6 67 (70%) 18 (19%) 11 (11%)

Non Serious Infections 49 (51%) 21 (43%) 28 (60%) 7 41 (61%) 8 (44%) 0

SBI 47 (49%) 28 (57%) 19 (40%) 5 26 (39%) 10 (56%) 11 (100%)

(4) (4) (2) (1)

(0) (0) (0) (0)

(4) (4) (2) (1)

Sepsis UTI Endocarditis Osteomyelitis

Table 2: Serious versus non serious factors predictors as clinical picture Variable Fever Sore throat Dysphagia Rhinitis Fever Cough Respiratory Distress Signs of Sepsis

Pharyngotonsillitis

0 1 0 1 0 1 0 1 0 1 0 1 0 1 0 1 0 SP FT MT

Non Serious Bacterial 6 43 12 37 17 32 36 13 6 43 23 26 44 5 43 6 8 36 5 0

Serious 3 44 22 25 22 25 43 4 3 44 27 20 36 11 32 15 21 15 10 1

P ns 0.02 ns 0.02 ns ns 0.08 0.02 0.00

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0 1 0 1 0 1 0 1 0 1

Stomatitis Lymphadenopathy

(LDNP) Generalized LDNP Hepatomegaly Spleenomegaly

46 3 37 12 48 1 47 2 49 0

47 0 39 8 47 0 43 4 45 2

0.08 ns ns ns ns

FT: follicular tonsillitis, MT: membranous tonsillitis; ns:non specific, SP: simple pharyngitis.

Table 3 Quantitative CRP and Actim tests Lab CRP Negative 6 > 40 Actim

40 > 80

>= 80

Total

Negative

27

9

0

0

36

10 > 40

6

26

5

6

43

40 > 80

0

0

8

0

8

>= 80

0

0

0

9

9

33

35

13

15

96

Total

Table 4 Quantitative CRP and Actim tests Quantitative

Total

P

CRP

Actim

Total

Neagtive

Positive

Negative

27

9

36