Author Affiliations: Department of Medicine, RIPAS Hospital, Bandar Seri Begawan BA 1710, Brunei Darussalam (Chong VH)

Corresponding Author: Vui Heng Chong, MD, FAMS, FRCP, Department of Medicine, RIPAS Hospital, Bandar Seri Begawan BA 1710, Brunei Darussalam (Email: chongvuih@yahoo.co.uk)

 

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60420-9

Published online September 17, 2015.

 

 

Contributors: CVH proposed the study concept and design and wrote the draft of the article. CVH is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

Infection remains an universal important cause of morbidity and mortality, with the highest mortality rate for bloodstream infections (20%-70%).^{[1, 2]} Fortunately, most community acquired infections, either bacterial or viral, are mild and self-limited or can be easily managed in the outpatient setting or several days of hospital admission. Despite this, infection remains the single most important cause of admission to the high dependency and intensive care units globally. Severe infection, such as sepsis, remains one of the leading causes of death^[3] and is associated with tremendous economic burden worldwide.^[4-6]

 

Diagnosis of infection in most instances can be made with some degree of certainty in the presence of typical symptoms in previously well immune-competent patients, guided by a thorough history, examination and investigations (basic or specialized). However, diagnosing sepsis may present a challenge especially in patients with existing inflammatory conditions, immunosuppressed, or patients in the intensive care settings. Clinicians need to be cognizant of the types of sepsis and organisms in the place they are working. In our daily practice, broad spectrum or targeted antimicrobials are often started empirically until microbiological investigations become available and thus, specific management will be guided. However, microbiological investigations need 48 hours and only between 5% and 15% of all cultures are positive. Delayed diagnosis and instituting effective antimicrobials is associated with mortality. To bridge this gap, many biomarkers and ways to detect of microorganisms have been investigated in relation to sepsis.

 

In this issue, Jiang et al^[7] evaluated the utility of soluble CD22 (sCD22) to diagnose Gram-negative sepsis, specifically intra-abdominal sepsis, in contrast to procalcitonin (PCT), interleukin-6 and the APACHE II score. sCD22 is a fragment of CD22, a B cell-specific membrane protein which is a co-receptor of the B-cell receptor and is part of the sialic acid-binding immunoglobulin-like lectin family. sCD22 is also used as a marker of B-cell malignancies.^{[8, 9]} CD22 negatively regulates B-cell receptor signaling and plays a key part in establishing the B-cell activation threshold. This is essential to ensure appropriate humoral response to pathogens and to avoid reaction to self-antigens causing autoimmunity.^[8] Jiang et al^[7] also reported that serum sCD22 levels were significantly higher in sepsis, but only slightly elevated in noninfectious systemic inflammatory responses syndrome (SIRS) or localized infection. sCD22 was as effective as PCT and interleukin-6 in differentiating between sepsis, noninfectious SIRS and localized infection. Addition of sCD22 to APACHE II score enhanced the sensitivity and specificity compared to PCT or interleukin-6. The finding is promising but further studies are required.

 

The role of biomarkers has been reviewed^[10-13] and to date, there are over 170 biomarkers studied for sepsis; most of them are for the prediction of prognosis (severity of sepsis and mortality risk) and less than 40 are for diagnosis. Only a few of these biomarkers (PCT and C-reactive protein) are applicable clinically.^[11] Some of the biomarkers are mediators in the very complicated and tightly regulated inflammation cascade, whereas others are byproducts or bystanders. These mediators include chemokines/cytokines, cell membrane markers, receptors, acute phase proteins, coagulants, vasodilatation mediators released during inflammation, markers of endothelial damage or end-organs dysfunction, etc.^[11] During an infection, the host's immune response tries to control and contain the infection. The infection may resolve or progress to sepsis or septicemia. During sepsis, the controlled release of inflammatory mediators (proinflammatory and anti-inflammatory system) is disrupted with the release of proinflammatory mediators exceeding the boundaries of the local environment (local infection), resulting in a more generalized response.^[14] If the infection is out of control, the generalized response leads to tissue damage and organ dysfunction. Noninfectious inflammatory disorders (i.e. pancreatitis) can also lead to similar manifestations, the SIRS. Therefore, it is not unexpected that biomarkers can be elevated for both infective and noninfectious processes. This also explains why none of biomarkers to date has sufficient specificity or sensitivity to be routinely employed in clinical practice for the diagnosis of sepsis.^[10-13] Biomarkers are non-microbiological and non-specific sentinel markers which merely indicate the presence of inflammation but do not provide any information on the cause of the inflammation.

 

The gold standard for identifying infection is still the isolation of the responsible microbial in culture. However, there are limitations of cultures mainly with the time taken for results to be available, false negative due to factors such as blood volume inoculation, time from sampling to incubation, prior use of antimicrobial therapy and importantly difficulty with fastidious pathogens. Strategy to overcome this delay is the use of nucleic-acid based technologies (NAT) for direct assessing the presence of microbial.^[14] NAT-based assays targets either specific or conversed sequences in bacterial or fungal genomes. NAT-based assays can be direct detection and identification of microorganism directly from specimens (blood, serum or plasma) or detection and identification of pathogen from blood culture bottles. The latter approach has limitation as it is subjected to limitations of blood cultures and it only speeds up identifications by several hours, not enough to shorten the gap. Assays directly on specimens can be pathogen-specific, genus-specific, broad range or multiplex PCR assays and microarrays.^[14] Assays that have broader targets will be more useful in clinical practice due to the spectrum of organisms involved in bloodstream infections. Commercial assays for both NAT-based assays are available (i.e. PNA-FISH AdvanDX, Woburn, MA; Hyplex BloodScreen, BAG, Lich, Germany; SepsiTest, Molzym, Bremen, Germany; LightCycler SeptiFast Test, Roche Molecular Systems, Branchburg, BJ; and Vyoo, SIRS-Lab, Jena, Germany). Multiplex PCR assays have been shown to be more sensitive than blood culture (positivity rate 26% vs 17%).^[15] Another study^[16] reported that DNA-based microarray (Prove-it assay; Mobidiag, Helsinki, Finland) had a clinical sensitivity of 94.7% and specificity of 98.8%, with 100% for both measures for methicillin resistant Staphylococcus aureus bacteremia with result being available 18 hours before the conventional blood culture method. However, the use of NAT-based diagnostic assays are hampered by the high cost of test kits, labor intensive and issues with PCR-based tests (i.e. false positive from contamination). Another issue is that NAT-based assays also do not provide information on antimicrobial susceptibility.^[14]

 

An ideal test will be able to identify the presence of infection rapidly and accurately with high sensitivity and specificity. Ability of a test to differentiate the types of infections (bacterial-Gram negative or Gram positive; fungal), or even better to identify the specific microbial species (perhaps through detection of the different microbial genome sequences) would be ideal. The test should be able to be applied to regularly available specimen such as blood, serum or body fluid. In addition, an ideal test should be easy to perform and not cost prohibitive. Currently, none of the existing biomarkers have a sufficient sensitivity and specificity, and currently available. NAT-based assays are not only expensive, but also not sensitive enough. Use of combinations of markers (panels testing) that include assays that detects microbial components and biomarkers may be more effective. This deserves further evaluation.

 

In conclusion, the gold standard of identifying the presence of infection is currently the isolation of the microbes through cultures. However, this takes time and there are issues of false negative and false positive. Therefore, until reliable biomarkers for sepsis become available, diagnosis of infection is still dependent on standard practice, supplemented by currently available assays. Further studies are required to assess the roles of sCD22 not just in Gram-negative intra-abdominal sepsis but sepsis in general to better define its role in the complex web of biomarkers and the difficult task of identifying infection early.

 

 

1 Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006;3:e442. PMID: 17132052

2 Lopez AD, Mathers CD. Measuring the global burden of disease and epidemiological transitions: 2002-2030. Ann Trop Med Parasitol 2006;100:481-499. PMID: 16899150

3 Kung HD, Hoyert DL, Xu J, Murphy S. Deaths: final data for 2005. Natl Vital Stat Rep 2008;56:1-120.

4 Aungkulanon S, McCarron M, Lertiendumrong J, Olsen SJ, Bundhamcharoen K. Infectious disease mortality rates, Thailand, 1958-2009. Emerg Infect Dis 2012;18:1794-1801. PMID: 23092558

5 Lever A, Mackenzie I. Sepsis: definition, epidemiology, and diagnosis. BMJ 2007;335:879-883. PMID: 17962288

6 Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S, et al. Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med 2007;33:606-618. PMID: 17323051

7 Jiang YN, Cai X, Zhou HM, Jin WD, Zhang M, Zhang Y, et al. Diagnostic and prognostic roles of soluble CD22 in patients with Gram-negative bacterial sepsis. Hepatobiliary Pancreat Dis Int 2015;14:523-529. PMID: 26459729

8 Sullivan-Chang L, O'Donnell RT, Tuscano JM. Targeting CD22 in B-cell malignancies: current status and clinical outlook. BioDrugs 2013;27:293-304. PMID: 23696252

9 Walker JA, Smith KG. CD22: an inhibitory enigma. Immunology 2008;123:314-325. PMID: 18067554

10 Marshall JC, Reinhart K; International Sepsis Forum. Biomarkers of sepsis. Crit Care Med 2009;37:2290-2298. PMID: 19487943

11 Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care 2010;14:R15. PMID: 20144219

12 Vincent JL, Beumier M. Diagnostic and prognostic markers in sepsis. Expert Rev Anti Infect Ther 2013;11:265-275. PMID: 23458767

13 Ventetuolo CE, Levy MM. Biomarkers: diagnosis and risk assessment in sepsis. Clin Chest Med 2008;29:591-603, vii. PMID: 18954695

14 Mancini N, Carletti S, Ghidoli N, Cichero P, Burioni R, Clementi M. The era of molecular and other non-culture-based methods in diagnosis of sepsis. Clin Microbiol Rev 2010;23:235-251. PMID: 20065332

15 Westh H, Lisby G, Breysse F, Böddinghaus B, Chomarat M, Gant V, et al. Multiplex real-time PCR and blood culture for identification of bloodstream pathogens in patients with suspected sepsis. Clin Microbiol Infect 2009;15:544-551. PMID: 19392905

16 Tissari P, Zumla A, Tarkka E, Mero S, Savolainen L, Vaara M, et al. Accurate and rapid identification of bacterial species from positive blood cultures with a DNA-based microarray platform: an observational study. Lancet 2010;375:224-230. PMID: 20004964