Screening for sepsis

Xchange newsletter - Summer 2007

Severe sepsis and septic shock are the most common causes of death in intensive care units.¹ These life-threatening conditions are triggered by systemic response to infection or physical trauma (such as surgery). When combined with organ failure, tissue hypoperfusion or hypotension, sepsis becomes 'severe sepsis'. Here we review the use of neutrophil CD64 expression as a diagnostic indicator of sepsis and ask whether routine sepsis screening may become a reality.

There are an estimated 18 million cases of sepsis worldwide each year.² Between 1995 and 2000, the Intensive Care National Audit and Research Centre (ICNARC) compared data from 91 adult general intensive care units in England, Wales and Northern Ireland.³ They indicate the prevalence of severe sepsis in the first 24 hours in intensive care to be 27% - equating to just over 21,000 cases per annum in England and Wales. Despite advances in critical care, the mortality rate from severe sepsis is estimated at between 30 and 50%.

A costly business

The healthcare costs of sepsis are significant with patients requiring prolonged hospital stays and complex treatment in intensive care. The cost of treating an ICU patient with sepsis is six times greater than treating a patient without sepsis. The incidence is increasing, not just as a result of the ageing population but also because of the development of resistance to antibiotics.

Detection

The routine full blood count (FBC) traditionally forms part of the clinical assessment of infection and sepsis. Haematological parameters of particular interest include neutrophil leucocytosis, neutrophil toxic changes, and increased proportions of non-segmented band neutrophils or immature granulocytes. The sensitivity and specificity of these indices are, however, limited in young children and elderly patients. Further diagnostic difficulties arise when patients also have disturbances in neutrophil counts associated with other conditions.

Now CD64

Measurement of neutrophil membrane CD64 (PMN-CD64) brings significant advances to sepsis diagnosis. This monoclonal antibody is only weakly expressed by normal neutrophils and has a low false positive rate. PMN-CD64 expression increases under the influence of inflammatory related cytokines, such as interferon-γ (3-4 hrs), G-CSF (4-6 hrs) and IL-12. It has been shown to be a sensitive marker in adults for differentiating systemic infection from active inflammatory disease.⁴ Neutrophil CD64 expression has a superior sensitivity (94.1%), specificity (84.9%) and positive predictive likelihood ratio (6.24) compared with neutrophil counts, band counts, myeloid immaturity fraction, and flagging on an automated haematology analyser.

Previously, PMN-CD64 analysis was achieved using flow cytometry with fluorochrome-monoclonal antibody conjugates. Now it can be achieved in the routine laboratory using the CELL-DYN Sapphire.

A recently published study evaluated a combined PMN-CD64 and monocyte HLA-DR method using individual monoclonal antibody reagents on a CELL-DYN analyser.⁵ See here for further information. The authors conclude that the method described overcame a number of limitations associated with flow cytometry.

Anticipated clinical utility

CD64 measurement has potential applications in a triage role, allowing hospitals to screen patients for infection/sepsis or illness severity, and to also screen post-operative patients. In addition, it could be used for therapeutic monitoring of response to antibiotics. For further information, contact your local Abbott representative.

References

Health Technology Assessment, 2005, (9):11
Slade E, Tamber PS & Vincent J, The Surviving Sepsis Campaign: raising awareness to reduce mortality, Critical Care, 2003; 7:1-2
NICE Technology Appraisal 84, Drotrecogin alfa (activated) for severe sepsis, Sep 2004
Allen E, Bakke AC, Purtzer MZ, & Deodhar A. (2002) Neutrophil CD64 expression: Distinguishing acute inflammatory autoimmune disease from systemic infections. Annals of Rheumatic Disease 61, 522
Van der Meer W, van Dun L, Gunnewiek JK, Roemer B, & Scott CS. (2006) Simultaneous determination of membrane CD64 and HLA-DR expression by blood neutrophils and monocytes using the monoclonal antibody fluorescence capability of a routine haematology analyser. Journal of Immunological Methods 311, 207.