Predicting acute respiratory distress syndrome in influenza pneumonia patients using delta mean platelet volume

Background Patients with influenza pneumonia are at high risk of rapid progression to acute respiratory distress syndrome (ARDS). Mean platelet volume (MPV), which reflects platelet size, is considered to be a crucial inflammatory marker. The study aim was to investigate the role of delta mean platelet volume (delta MPV) in predicting ARDS in patients with influenza pneumonia. Methods This retrospective study was conducted in a tertiary care centre in southern Thailand. Adult patients diagnosed with influenza pneumonia were enrolled from January 2015 to December 2020. Demographic data, laboratory investigations including delta MPV (MPV on day 2 minus MPV on day 1), management records, and clinical outcomes were collected for analysis. The study population was divided into two groups according to the development of ARDS. Results During the study, 1240 patients with laboratory-confirmed influenza were screened and 212 pneumonia patients were enrolled. Fifty-six patients (26.4%) met the diagnostic criteria for ARDS during hospitalization. Delta MPV was significantly higher in the ARDS group compared to that in the non-ARDS group (1.0 fL vs 0.2 fL, p < 0.001). Multivariable logistic regression revealed that delta MPV is an independent predictor of ARDS (OR 17.37; 95% CI 6.5–46.4; p < 0.001). Receiver operating characteristic curve analysis indicated a cut-off value of 0.7 fL for delta MPV (sensitivity 80.36%, specificity 80.77%) to predict ARDS in patients with influenza pneumonia. Conclusions Delta MPV strongly predicts ARDS in influenza pneumonia patients. Implementation of delta MPV may be useful in identifying at-risk patients who will require intensive care and ARDS prevention. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-021-01763-5.


Background
The influenza virus is a leading cause of viral pneumonia worldwide. Data from the 2009 H1N1 pandemic show that 49-72% of patients with pneumonia developed acute respiratory distress syndrome (ARDS), leading to high morbidity and mortality rates [1,2]. Early recognition and risk stratification are necessary to improve outcomes of influenza pneumonia patients.
There is a growing body of clinical evidence suggesting that platelets play an important role in immune and inflammatory responses. Mean platelet volume (MPV) is an indicator of platelet size and activity, which is simply measured using automated haematology analysers. An increased platelet size and volume reflects thrombosis and inflammatory processes [3]. A single measurement of elevated MPV has been reported to be associated with increased morbidity in various critical conditions [4, Open Access *Correspondence: vveerapong@gmail.com 2 Critical Care Medicine Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, 15 Kanjanavanich Road, Hat Yai, Songkhla 90110, Thailand Full list of author information is available at the end of the article 5]. Moreover, changes in MPV have been reported as a dynamic parameter that is associated with poor outcome in critically ill patients and pneumonia patients [6,7]. However, the MPV changes or delta MPV discussed in previous studies have different definitions, both in terms of timing and cut off [6,7]. To our knowledge, there is little data on delta MPV in prediction of ARDS in patients with influenza pneumonia.
The aim of our study was to investigate the predictive value of MPV change or delta MPV in the development of ARDS in patients with influenza pneumonia.

Study population and design
This retrospective study was conducted using a health information system database of patients admitted to wards or the medical intensive care unit (ICU) of Songklanagarind Hospital (a university-affiliated, 800-bed tertiary hospital in southern Thailand) between January 2015 and December 2020.
Patients were included if they had been admitted with pneumonia and had influenza infection. Patients were excluded from this study if they were younger than 18 years old, had initial presentation of ARDS, or inadequate complete blood cell count data. The protocol of this study was approved by the ethics committee of the Faculty of Medicine, Prince of Songkla University (EC number: 63-482-14-1). The requirement for informed consent was waived due to the retrospective nature of the study.

Data collection
The study participants' epidemiologic and clinical data were obtained from the electronic medical record. The data included age, sex, height, body weight, comorbid conditions, illness severity scores, laboratory values, respiratory intervention and clinical outcomes. Complete blood cell counts including MPV values were determined using an automated haematology analyser (XT-1800i, Sysmex Corporation, Japan).

Definitions
Influenza infection was confirmed by a positive result from one of the following tests: rapid antigen test, or nucleic reverse transcriptase polymerase chain reaction (RT-PCR) from nasopharyngeal swab, throat swab, sputum or bronchoalveolar lavage.
Pneumonia was defined as the presence of at least one of the following: fever (body temperature > 38.2 °C) or hypothermia (temperature < 35.0 °C), new cough with or without sputum production, dyspnoea or altered breathing sound on auscultation, or presence of new chest radiographic infiltrates [8,9]. ARDS was diagnosed according to the Berlin definition: acute onset within 1 week, bilateral lung opacities, no evidence of cardiac failure-related hydrostatic oedema by echocardiography, and PaO 2 /FiO 2 ratio < 300 mm Hg with positive end-expiratory pressure (PEEP) ≥ 5 cm H 2 O [10].
Day 1 was defined as the interval from admission to 5:00 am the next day; all other days were calendar days from 5:00 am to 4.59 am.
Delta MPV was defined as MPV on day 2 minus MPV on day 1. Two sets of CBC were selected to determine delta MPV, the first one at the time of admission, and the second one on the next calendar day when blood samples are routinely taken at 6 am. MPV/platelet count ratio (MPR) was defined as MPV (fL)/platelet count (^10 9 /L) × 100%.

Statistical analysis
The sample size was determined using sample size estimation for diagnostic test studies [16]. Estimating that 30% of influenza pneumonia patients have ARDS, we calculated that a sample size of 205 would provide 95% confidence with 80% power to detect a difference of 10% from the presumptive value of 80% for sensitivity.
The data were tested for normality using the Shapiro-Wilk test. Categorical data are expressed as percentages. Continuous data are shown as mean ± standard deviation or median with minimum and maximum interquartile range (IQR), depending on the distribution of the data. Continuous variables and proportions were compared between groups using Student's t-test or the Mann-Whitney U test and chi-square tests, respectively.
We assessed the association between clinical characteristics and ARDS using multivariable logistic regression analysis. Variables that were associated with ARDS (P < 0.2) were introduced into a multiple logistic regression model after testing for association. Collinearity between variables was excluded before modelling. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used to identify the significant independent factors influencing ARDS.
Afterwards, a receiver operating characteristic (ROC) curve and a calculated corresponding area under the ROC curve (AUROC) of delta MPV and selected variables were constructed. The Youden index was introduced to select the best cut-off values of delta MPV with the best sensitivity, specificity, positive likelihood ratio (LR +), and negative likelihood ratio (LR-) for predicting ARDS. Two-tailed values of P < 0.05 were deemed statistically significant. All statistical analyses were computed using STATA version 16 (StataCorp, College station TX, USA).

Clinical characteristics between ARDS and non-ARDS groups
The baseline demographic, clinical, and biochemical data of each group, stratified according to ARDS, are presented in Table 1 Table 1).

Discussion
To our knowledge, this study is the first to investigate the association between ARDS and delta MPV in patients with influenza pneumonia. Our results indicate that delta MPV after hospital admission is an independent predictor of ARDS occurrence. In addition, delta MPV had greater predictive value than the well-known pneumonia severity score, CURB-65.
A recent study showed that changing values of MPV are associated with poor outcome in pneumonia. Lee et al. [6] reported that an increase in MPV on day 2, 3, 4 and discharge was associated with mortality in ICU patients with pneumonia. Gorelik et al. [17] revealed that a rise in mean platelet volume from admission to hospital discharge in pneumonia patients predicts the need for invasive mechanical ventilation and in-hospital mortality. However, using MPV at discharge may not provide advantages in ARDS prediction. According to our results, ARDS occurred on day 3 after admission on average.  Table 2 Predictors of ARDS APACHE II, acute physiology and chronic health evaluation II; ARDS, acute respiratory distress syndrome; CURB-65, confusion, urea nitrogen, respiratory rate, blood pressure, 65 years of age and older; MPR, mean platelet count volume to platelet count ratio; MPV, mean platelet volume; NEWS, national early warning score; PSI, pneumonia severity index; SOFA, sequential organ failure assessment Useful predictor parameters should be obtained before this timepoint.
The single values of MPV on day 1 or day 2 did not differ significantly between the two groups. Our results support a previous meta-analysis that suggested that initial values of MPV may not be useful as a prognostic marker of mortality in critically ill patients [18].
In addition to delta MPV, MPR on day 1 was reported as a predictor of severe pneumonia in coronavirus disease 2019 (COVID-19) patients [19]. In our study, only MPR on day 2 was significantly higher in the ARDS group, but was not associated with ARDS in the univariable analysis. A recent study showed that delta MPV between the first and the third day of hospitalization predicts mortality in COVID-19 patients [20].
Delta MPV in our results was a better predictor of ARDS than other recognised pneumonia severity scores. This may be because these scores were developed from community-acquired pneumonia patients, mostly infected with bacteria, and were designed for mortality prediction [14,15]. However, CURB-65 may be beneficial in ARDS prediction.
Our data provided some useful epidemiological information. Pneumonia occurred in approximately 32.8% of patients with a positive influenza test, and 26.4% of pneumonia patients developed ARDS. We found that influenza A was more common than influenza B, which is comparable to a previous study performed at the largest hospital in Thailand [21]. Influenza A causes more severe disease than influenza B [21,22]. White blood cell counts in the ARDS group were significantly higher than in the non-ARDS group. Patients in the ARDS group had lower lymphocyte counts compared to the non-ARDS group. Our results are compatible with those from a study by Chen et al. [23] conducted during the severe acute respiratory syndrome (SARS) epidemic, which showed that ARDS patients tended to present with more severe lymphopenia and leukocytosis.
MPV reflects the increasing production of platelets, which are involved in the complex pathogenesis of ARDS. This involves dysregulated coagulation and an excessive inflammatory response mediated by cytokines released from platelet-activated ARDS processes [24]. Antiplatelet therapy may be beneficial in halting the ARDS process [25].
Our results were used to develop the ARDS prediction tools for patients with influenza pneumonia. If patients show delta MPV > 0.7 or CURB-65 ≥ 2, the physician should pay careful attention to ARDS prevention. Our ventilator parameter data revealed an excessive tidal volume as an initial setting, and close monitoring was recommended for preventing ARDS [26].
This study has some limitations. First, this is a singlecentre study, leading to limitations in the generalizability of the results. Second, due to the retrospective design, selection bias or missing data may have distorted the results. Third, we did not evaluate all possible causes of a rise in MPV, such as renal dysfunction [27]. Further prospective studies on a larger patient population are required to establish the exact role of delta MPV in patients with influenza pneumonia, either as a predictor of ARDS or for the evaluation of response to treatment.

Conclusions
Delta MPV strongly predicted ARDS in patients with influenza pneumonia. Patients with delta MPV > 0.7 should receive ARDS prevention interventions.
Abbreviations APACHE II: Acute physiology and chronic health evaluation II; ARDS: Acute respiratory distress syndrome; CURB-65: Confusion, urea nitrogen, respiratory rate, blood pressure, 65 years of age and older; FiO 2 : Fraction of inspired oxygen; IFA: Indirect fluorescent antibody; LR: Likelihood ratio; MPR: Mean platelet count volume to platelet count ratio; MPV: Mean platelet volume; NEWS: National early warning score; PaO 2 : Partial pressure of arterial oxygen; PCR: Polymerase chain reaction; PMN: Polymorphonuclear leukocytes; PSI: Pneumonia severity index; SOFA: Sequential organ failure assessment; WBC: White blood cells.