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Peripheral hemophagocytosis (PHP) is seen in patients with hemophagocytic syndrome (HPS), a clinical status in which activated macrophages play a role in its pathogenesis. The inflammatory state, systemic inflammatory response syndrome (SIRS), is also associated with activated macrophages. However, the link between HPS and SIRS and the clinical implications of PHP remain to be determined. In the present work, we examined the clinical utility and impact of the detection of PHP and the link between HPS and SIRS. We studied the clinical and laboratory profiles of 322 SIRS patients (174 men; mean age, 68 ± 22 years; range, 16-99 years) who visited an urban hospital specializing in respiratory, cardiovascular, digestive, renal diseases, general surgery, and orthopedics in Japan. Peripheral hemophagocytosis was detected in 40 (23 men; mean age, 81.3 ± 8.7 years; range, 63-98 years) of 322 patients on 3 ± 2 days after SIRS diagnosis as determined with a "blunt-edged-smear" method differing from the conventional "feather-edged smear" method. The incidence of advanced SIRS and ensuing death in the SIRS+PHP+ group (37 and 21 of 40, respectively) was significantly greater than in the SIRS+PHP− group (82 and 17 of 282) (P < 0.01). The duration from SIRS diagnosis to recovery in 19 SIRS+PHP+ surviving patients (26 ± 18 days) was longer than that in 19 age-matched SIRS+PHP− surviving patients who initially presented comparable clinical profiles (6 ± 3 days) (P < 0.001). Bone marrow analysis in all 7 patients having PHP and SIRS showed no HPS initially (<3% hemophagocytes), but all subsequently developed HPS at 7 ± 1 days after the diagnosis, confirmed by the presence of 9% ± 13% hemophagocytes in the bone marrow. Electron microscopic and immunohistochemical analyses revealed that PHP was derived from hemophagocytes in the bone marrow. The present data strongly suggest that PHP detection could serve as an early indicator for advanced SIRS and/or HPS and that the use of the blunt-edged method is preferable for PHP detection.