The application of lymphocyte*platelet and mean platelet volume/platelet ratio in influenza A infection in children

Abstract Background To explore the characteristics and regularity of complete blood count (CBC) changes among influenza A–positive child patients and to discover parameters that can help with the diagnosis and differential diagnosis. Methods One hundred and ninety‐one influenza A–positive children, two hundred and nineteen influenza A–negative children with influenza‐like symptoms, and two hundred and forty‐seven healthy children were included in this study. They were divided into three groups: influenza A–positive patient group, influenza A–negative patient group, and control group. Reverse transcriptase polymerase chain reaction testing and Sysmex XS‐800i hematology analyzer were used to obtain influenza A and CBC results, respectively. CBC along with parameters including lymphocyte‐to‐monocyte ratio (LMR), neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), mean platelet volume/platelet ratio (MPV/PLT), and lymphocyte*platelet (LYM*PLT) was calculated and recorded for each child. The differences in these parameters among different groups were tested with SPSS 15.0. The diagnostic values were also evaluated. Results The LYM and PLT of child patients with influenza A were significantly lower than those of both influenza A–negative patients with influenza‐like symptoms and healthy controls. Among all the parameters, LYM*PLT has the largest area under the curve and the highest diagnostic value, followed by MPV/PLT. Compared with using LMR or MPV/PLT, the diagnostic value of using LYM alone was, on the contrary, higher. Conclusions Low LYM*PLT and high MPV/PLT may indicate influenza A infection in children with influenza‐like symptoms, which can be a useful indicator for diagnosis and differentiation of influenza A infection.


| INTRODUC TI ON
Influenza A is an acute respiratory disease caused by influenza A virus leading to 3 to 5 million severe illness cases and more than 300,000 deaths during epidemics in both adults and children. 1 The initial symptoms of influenza A are similar to those of common seasonal colds with cough, sore throat, fever, headache, and body pain.
Although major influenza A infections were self-limiting, some patients are progressing rapidly with body temperature of more than 39℃, which can develop into severe pneumonia. 2 Additionally, severe and critical patients may suffer from decreased oxygenation and respiratory distress, which makes the mortality risk of influenza A infection greater than common seasonal colds. As there are effective treatments for influenza A and the timeliness of them is of great importance, 3 rapidly distinguishing influenza A-positive patients from common cold patients allows for prompt antiviral therapy and judicious use of antibiotics, which lead to the reduction in transmission, morbidity, and hospitalization time. 4 However, unlike severe influenza A, which has characteristic findings, mild or moderate influenza A is clinically indistinguishable from other influenza-like illnesses. 5 Early and rapid diagnosis of influenza A is challenging. 6 Complete blood count (CBC) is one of the most routine laboratory tests being examined in patients with cold symptoms, which can be carried out in hospitals of different grades and conditions.
If influenza A infection can be rapidly predicted or screened out by CBC or related results, the patients will be treated more timely with less risk of complications. Compared with adults, children have lower immunity with more dense population in active areas; thus, the risk of influenza A virus infection is higher and they are more likely to have serious complications or even death. 3 Additionally, the reference intervals of CBC for adults and children are different. Lymphopenia has been reported in adults and children with pandemic influenza A infection in several studies. [7][8][9] Lymphocyte-to-monocyte ratio (LMR) as a predictor of adult influenza A virus has also been reported before. 10 and influenza A-negative patient group (219). Simultaneously, two hundred and forty-seven child cases were selected from healthy physical examination population as the control group. There was no significant difference in gender or age among the three groups.

The study protocol was approved by the Tongji Hospital Ethics
Committee for Research in Health (TJ-IRB20192421).  Table 1.

| Results of CBC and related hematological parameters in different patient groups
The age, gender, and CBC results of the influenza A-positive patient, influenza A-negative patient, and control groups are shown in Table 1. There were no significant differences in age or gender among the three groups.

| Diagnostic values of LMR, MPV/PLT, and LYM*PLT for distinguishing influenza A-positive patients from suspected but influenza A-negative patients or controls
With

| D ISCUSS I ON
Influenza was first clearly described by the English physician Caus in 1551 as a ''sweating disease'' characterized by fever, headache, and myalgias that killed some patients rapidly but lasted only a few days in those that survived. 12   The Youden index of receiver operating characteristic curve was the largest when this cutoff value was used. Normally, influenza is a relatively mild respiratory infection with high morbidity and low mortality. Although the mortality was relatively low, the total number of fatalities involved was huge, which happened more common in the very young, the very old, and the immunosuppressed. 12 As mild-to-moderate influenza is clinically indistinguishable from influenza-like illnesses caused by other respiratory viruses, laboratory tests are necessary. 5 There are many tests that can help with the diagnosis of influenza A, such as RT-PCR testing, virus isolation and culture, rapid detection of viral antigen, and serological antibody tests, but these tests are often unavailable especially in primary or community hospitals with poor basic conditions. 19 The inability to rapidly diagnose or rule out influenza A presented great difficulties in infectious disease control. Under this circumstance, using routine tests to help with the diagnosis and differential diagnosis of influenza A is of great significance. We undertook this study to discover laboratory parameters to help identify influenza A infection among child patients presenting with influenza-like symptoms while awaiting throat swab RT-PCR or virus isolation reports.
Results in our study showed that LYM*PLT could assist in the diagnosis and differential diagnosis of influenza A in children population, and had higher diagnostic value than using either LYM or PLT alone or other calculated parameters such as LMR and MPV/PLT. Besides, compared with using LMR or MPV/PLT, the diagnostic value of using LYM alone was, on the contrary, higher.
In the study, LYM of child patients with influenza A was significantly lower than that of both influenza A-negative patients with influenza-like symptoms and healthy controls, which is consistent with the results in other studies. 9,20,21 The decrease in LYM may be due to A swine influence study in India indicated that NLR < 2 along with a decrease in WBC count can be used as a screening tool in patients presenting with influenza-like symptoms, while awaiting throat swab culture reports for confirmation. 25 Another study in Turkey observed a significant decrease in LYM and a significant increase in MON and declared that relative lymphopenia and monocytosis may be considered as a surrogate marker of pandemic influenza A. 26   This means the diagnostic value of hematological parameters is not good. It is worth noting that the best sensitivity and specificity of F I G U R E 2 Receiver operating characteristic (ROC) curve of lymphocyte (LYM), platelet (PLT), mean platelet volume (MPV), lymphocyte-to-monocyte ratio (LMR), MPV/PLT, and LYM*PLT in influenza A. A, The influenza A-negative patient group was used as reference; B, the control group was used as reference MPV/PLT are 73.82% and 50.68% if the influenza A-negative group is used as reference, which may be used in combination with LYM*PLT to improve the differential diagnostic value. However, LYM*PLT and MPV/PLT may be mainly involved in a balanced state of promoting inflammation and antiviral response in influenza virus infection. When using these parameters as diagnostic and predictive indicators, epidemiological history and comprehensive situation should be combined in order to avoid overuse and unnecessary treatment. According to the data in this study, we considered that if the LYM*PLT values were lower than 781.55 and the MPV/PLT values were higher than 0.040, the results may indicate influenza A infection in children.
There are several limitations in this study. First, relatively few cases were enrolled in this study, so large-scale multicenter clinical studies are required to corroborate this evidence. Second, it is a retrospective study, which cannot completely resolve some confounding factors and may produce a certain degree of deviation.

| CON CLUS IONS
Low LYM*PLT and high MPV/PLT may indicate influenza A infection in children with influenza-like symptoms, which can be a useful indicator for the diagnosis and differential diagnosis of influenza A infection.

CO N FLI C T O F I NTE R E S T
The authors stated that there are no conflicts of interest regarding the publication of this article.

E TH I C A L A PPROVA L
The study protocol was approved by the Tongji Hospital Ethics Committee for Research in Health (TJ-IRB20192421).