In Japan, COVID-19 is diagnosed mainly by pathogenic genetic testing or antigen testing. Since genetic testing is more sensitive than antigen testing, pathogenic genetic testing is widely used for definitive diagnosis for COVID-19 in Japan [24, 25]. However, dedicated equipment and skilled human resources are required to perform genetic testing, and strict infection control measures are required for collection of nasopharyngeal swabs. There are other challenges: for example, it takes from several tens of minutes to several hours to obtain results  and reagent cost per test is relatively high. Therefore, it is desirable that COVID-19 screening can be performed easily in a routine clinical examination.
MDW generated by DxH 900 which was evaluated in this study, is a new cytometric parameter that reflects monocyte changes in cell volume caused by the activation of monocytes. The result is obtained in around 1 minute with routine CBC and WBC differential testing without the need for ordering additional tests. Therefore, MDW values can be easily confirmed as a routine clinical examination. Therefore, MDW can be considered a promising screening test parameter for COVID-19 if its diagnostic performance for COVID-19 is superior.
Originally, monocytes play an important role in the innate immune system against infection, and are believed to be involved in phagocytosis, antigen presentation, cytokine production, and activation of acquired immune system. Also, activation of monocytes is considered to result in the expression of various functions and the diversity of morphology [9-14]. Similarly, neutrophil volume and distribution width are changed, however, Crouser et al. evaluated MDW in patients in the emergency department and reported that MDW was superior in detecting sepsis patients and effective as the initial biomarker to aid in diagnosis [1-3].
In addition, Ognibene et al. reported that MDW may be useful as a diagnostic aid for COVID-19 based on an observational study analyzing 147 patients suspected to have COVID-19 presenting to the emergency department . The mean MDW in 41 SARS-CoV-2-positive patients was 27.3 ± 4.9, and that in 106 patients negative for SARS-CoV-2 was 20.3 ± 3.3 (P < 0.01). ROC analysis showed AUC of 0.91 and MDW was quite effective in distinguishing SARS-CoV-2-positive patients from negative patients. It was reported that the sensitivity, specificity, positive predictive value, and negative predictive value were 98%, 65%, 51.9%, and 98.6%, respectively at the MDW cut-off value of 20 . Although our results were not superior to the results of this report, this study showed that MDW was highly effective in distinguishing SARS-CoV-2-positive patients from negative patients with AUC of 0.844. At the MDW cut-off value of 21.3, the sensitivity and specificity were 81.3% and 78.2%, respectively. Although the specificity was inferior to that of antigen testing , it was considered that MDW could be used as a screening test in daily clinical practice.
The study of MDW reported by Ognibene et al. includes the fact that the age of SARS-CoV-2-positive patients is higher than that of negative patients, and COVID-19 severity and breakdown of SARS-CoV-2 negative patients were not shown in the study. In our study, although the age of patients in the COVID-19 group was lower than that of patients with acute respiratory infection in the Non-COVID-19 group, multiple regression analysis showed that age was not a factor associated with MDW. Therefore, it was considered possible to compare MDW by severity between the COVID-19 group and patients with acute respiratory infection in the Non-COVID-19 group.
In diagnosis for outpatients with fever, it is required to differentiate COVID-19 patients from Non-COVID-19 with acute respiratory infection. We compared Non-COVID-19 with acute respiratory infection by severity. MDW in each severity was significantly higher in the COVID-19 group compared with patients with acute respiratory infection in the Non-COVID-19 group. These results suggest that COVID-19 is associated with more substantial morphological diversity of monocytes than Non-COVID-19 patients with acute respiratory infection, suggesting that SARS-CoV-2 has a higher ability to activate cytokine production and adaptive immunity. Furthermore, COVID-19 and CRP were found to be independent factors associated with MDW, suggesting that MDW (cut off value: 21.3) may be used as a screening test for COVID-19 in fever outpatients.
On the other hand, some patients with non-respiratory infection also showed increased MDW values. This may be attributable to the fact that many severe patients were included in the non-respiratory infection group because CRP was high. It is interesting that increased MDW values were observed in one patient with generalized herpes zoster, which is a viral infection. Since MDW is not a specific marker for COVID-19, it should be noted that MDW increases also in severe infections such as sepsis.
Although this study is limited by the fact that it is a single center study and does not include severe patients, it is the first study to evaluate MDW for COVID-19 in Japan, and it is considered significant because there have been no reports of studies evaluating MDW by severity and it has been demonstrated that age is not a factor associated with MDW.
MDW can be performed easily in a short time as a routine clinical examination without using nasopharyngeal swab samples. Therefore, MDW is expected to be used as a screening test for COVID-19 before PCR testing. Furthermore, it is expected to be widely used clinically as a screening test at various medical institutions such as small and medium-sized hospitals and clinics where the introduction of genetic testing has been difficult.