Diagnostic Value of Mean Platelet Volume and Platelet Distribution Width for Early-Onset Neonatal Infection

Introduction

Early-onset neonatal infection (EONI) is an infection presenting within the first 3 days of life. It accounts for a significant proportion of morbidity and mortality in the neonatal period, especially in low-and middle-income countries.^{1, 2} Neonatal infection is one of the 3 leading causes of neonatal mortality, after prematurity and perinatal hypoxia. It is a life-threatening condition that involves a rapid deterioration of clinical status. Therefore, a rapid diagnosis is critical to optimize the outcome for neonates.^{1, 2}

However, EONI diagnosis is still a challenge because its initial presentation is nonspecific and subtle and mimics signs associated with noninfection conditions after birth. Currently, the initial treatment of EONI is mostly based on maternal risk factors and clinical symptoms that may lead to an increasing resistance problem due to antibiotic overuse.^{2, 3} Blood culture is the gold standard recommended by the American Academy of Pediatrics, National Institute for Health and Care Excellence (NICE), and World Health Organization guidelines for diagnosing neonatal sepsis.^2–4 However, receiving the results usually takes at least 48 to 72 hours, and the pathogen is often not identified, which makes the decision of whether to stop antibiotics more difficult. Therefore, in practice, the clinical pediatrician still depends on empiric antibiotic therapy. In modern medicine, many diagnostic makers such as procalcitonin, interleukin-6, interleukin-8, CD64, and CD11b have been investigated to further improve EONI recognition. ⁵ Although these current diagnostic markers partly present promising results concerning sensitivity and specificity to make a definite EONI diagnosis, the results have not been consistent. ⁵ Furthermore, the cost and nonavailability of tests in primary health-care settings are huge obstacles to application in low- and mid-outcome countries, including Vietnam. Some indexes in the complete blood count, as a routine test for sepsis screening, such as white blood cells (WBC) and platelets (PLT), are fairly sensitive and specific predictors in diagnosing EONI. ³ Many studies have revealed that severe sepsis can affect platelet production, thereby altering the platelet size, reflected by mean platelet volume (MPV) and platelet distribution width (PDW). ⁶ Therefore, we hypothesized that MPV and PDW could be diagnostic tools in EONI.

Methods

This prospective case-control study was performed between October 2021 and September 2022 in the neonatal care unit of the Hue University of Medicine and Pharmacy Hospital, Vietnam.

Inclusion criteria: A total of 156 neonates were included in this study, divided into 2 groups. The EONI group included neonates with significant clinical signs of infection within the first 3 days of life (lethargy, irritability, altered muscle tone, hypotonia, respiratory distress, cyanosis, temperature abnormality [hypothermia or fever], poor crying, feeding refusal, feeding intolerance [vomiting, abdominal distension], skin hemorrhage, unexplained bleeding, abnormal heart rate, or jaundice in the first 24 hours of life) and positive laboratory characteristics (WBC of either <5×10⁹/L or >25×10⁹/L, PLT of <150,000/mm³, or CRP level of >10 mg/L).^{2, 3} The control group included healthy neonates. We followed up with the neonates for 36 hours after initiating antibiotic treatment to determine whether to continue or stop the antibiotics. If the neonates had not significantly improved, the initial clinical suspicion of infection remained strong, and/or the CRP levels did not show reassuring trends, we continued antibiotics, and these neonates were classified as EONI cases according to the guidelines of the NICE. If we stopped antibiotics, that meant that the neonates were not considered EONI cases and were excluded from the case group.

The complete blood count, including MPV and PDW indices, was collected for the EONI group neonates within 24 hours of life, before using antibiotics. The total blood count in venous blood samples was analyzed using an XS-800i automated hematology analyzer.

Exclusion criteria: Neonates with major congenital anomalies, cyanotic congenital heart disease, or congenital virus infection (eg, cytomegalovirus, toxoplasma, rubella) were excluded.

Results

A total of 156 newborns were analyzed during the study period. Of these, 78 were diagnosed with EONI, and 78 were healthy neonates as the control group. The baseline characteristics of the study population are summarized in Table 1. No statistical differences existed between the EONI and control groups regarding gender, gestational age, birth weight, nutritional status, or type of delivery (P >.05). In the EONI group, the mean ± SD gestational age was 37.9 ± 2.4 weeks, and the mean ± SD birth weight was 2,900 ± 727.6 g (Table 1).

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Table 1.

General and Laboratory Characteristics of the Study Group.

Variable		EONI Group N = 78 (n ([%])	Control Group N = 78 (n [%])	P value
Gender	Male	50 (64.1)	42 (53.8)	.193
	Female	28 (35.9)	36 (46.2)
Gestational age (weeks)	<37	18 (23.1)	9 (11.5)	.092
	37-<42	59 (75.6)	69 (88.5)
	>=42	1 (1.3)	0 (0.0)
	Mean ± SD	37.9 ± 2.4	38.6 ± 1.6	.085
Birth weight (grams)	<2500 g	16 (20.5)	10 (12.8)	.879
	2500–<4000 g	57 (73.1)	63 (80.8)
	≥4000 g	5 (6.4)	5 (6.4)
	Mean ± SD (g)	2,900.0 ± 727.6	3,003.9 ± 528.0	.309
Nutritional status	SGA	13 (16.7)	7 (9.0)	.354
	AGA	62 (79.5)	68 (87.2)
	LGA	3(3.8)	3 (3.8)
Types of delivery	Vaginal	35 (44.9)	36 (46.2)	.872
	Caesarean section	43 (55.1)	42 (53.8)
Laboratory characteristics	WBC	19.47 ± 7.30	16.47 ± 6.05	.006
	PLT (x103/mm3)	260.13 ± 80.27	257.12 ± 64.22	.796
	MPV (fl)	10.09 ± 0.65	9.73 ± 0.75	.003
	PDW(%)	10.66 ± 1.22	10.19 ± 1.16	.026

Abbreviations: SGA, small for gestational age; AGA, appropriate for gestational age; LGA, large for gestational age; EONI, early-onset neonatal infection.

The laboratory characteristics of the EONI group are also shown in Table 1. Neonates in the EONI group had a significantly higher WBC compared with the control group (P <.05). No significant difference existed between the EONI and control groups for PLT (P >.05). However, the MPV and PDW values were significantly higher in the EONI group compared to the control group (P <.05). The mean MPV and PDW were 10.09 ± 0.65 fL and 10.66 ± 1.22 % in the EONI group and 9.73 ± 0.75 fL and 10.19 ± 1.16 % in the control group, respectively.

Figure 1 presents the AUC values obtained from ROC analysis for WBC, PLT, MPV, and PDW: 0.617 (95%CI: 0.529–0.705) with P =.011, 0.530 (95%CI: 0.439 – 0.622) with P =.513, 0.636 (95% CI: 0.549–0.723) with P =.003, and 0.603 (95% CI: 0.514–0.692) with P =.026, respectively. The cut-off values for MPV and PDW are shown in Table 2. For the EONI group, the cut-off for MPV was 10.00 fL, and the sensitivity, specificity, PPV, and NPV were 67.7%, 69.2%, 65.2%, and 62.1%, respectively. A PDW value of 11.2 was determined as the predictive cut-off for EONI (sensitivity 63.3%; specificity 87.2%; PPV 72.2%; NPV 56.7%) (Table 2).

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Figure 1.

ROC Curves for Correlations of WBC, PLT, MPV, PDW for Predicting Neonatal Infection.

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Table 2.

Performance Variables of MPV, PDW for Diagnosis of Early-Onset Neonatal Infection.

Variables	Cut-off Point	Sensitivity	Specificity	PPV	NPV
MPV (fL)	10.0	0.577	0.692	0.652	0.621
PDW (%)	11.2	0.633	0.872	0.722	0.567

Abbreviations: PPV, positive predictive value; NPV, negative predictive value; MPV, mean platelet volume; PDW, platelet distribution width.

Discussion

Neonatal sepsis is a severe systemic inflammatory condition that rapidly becomes life-threatening if diagnosis and treatment are delayed. The clinical symptoms of EONI are nonspecific. We presented the variety of clinical signs in EONI, such as vomiting (73.1%), abdominal distention (66.7%), poor sucking (61.4%), respiratory distress (55.1%), lethargy (52.6%), and jaundice in the first 24 hours (39.7%) (data not shown). Previous studies in other developing countries such as Tanzania and Indonesia have reported similar clinical signs of EONI.^{7, 8} To minimize empiric antibiotic therapy, investigations of more specific and sensitive markers for the diagnosis of EONI have emerged and received huge attention from clinical neonatologists. Given the limited economic resources, equipment, and tests in most developing countries, finding a simple, useful, and inexpensive marker of neonatal infection is necessary. In the complete blood count, besides WBC and PLT that are usually analyzed in neonatal infection, we investigated the value of MPV and PDV in EONI. Our study showed a statistically significant difference in MPV and PDW values between neonates in the EONI and control groups. The results of our study agree with those of several previous studies that revealed a significant difference in the MPV and PDW of the case group compared to the control group.^8–11 In neonatal infection, platelet production climbs in response to the elevated need for coagulation activities due to endothelial damage or increased platelet destruction; thereby, larger and younger platelets are introduced into the peripheral blood. Hence, MPV and PDW values rise in acute infection. ⁶ In our study, a negative correlation existed between MPV and PDW and platelet levels (r = –0.347, r = -0.443, respectively; P <.05; data not shown). This result also showed the association among platelet indexes. Many studies have reported that the MPV was considerably higher in the infected group compared to healthy controls.^10–12 For example, in a study of 200 neonates, Anoop et al. showed that the mean MPV in the infected group was higher than that of the control group (16.7 ± 2.1 fL and 16.3 ± 0.4 fL, respectively; P =.003), and the mean PDW showed a statistically significant difference between the infected and control groups (mean 12.1 ± 2.5% and 10.8 ± 1.9%, respectively; P =.001). ¹⁰ A study by Banu et al. in Turkey showed that the mean MPV value was higher in neonates with clinical sepsis (10.6 ± 1.1 fL) compared to healthy neonates (9.2 ± 1.2 fL; P <.001). ¹¹ Prathyusha et al. reported similar findings. ⁹ These findings could support MPV and PDW in the early assessment of infected neonates.

In the present study, because the AUC was highest for MPV among WBC and PDW values (P <.05), MPV and PDW were helpful markers for predicting EONI. The cut-offs for MPW and PDW in the diagnosis of EONI were 10.0 fL and 11.2%, respectively. Several studies have supported the point that MPV and PDW could be used as EONI diagnosis markers, but the cut-off, sensitivity, specificity, PPV, and NPV have varied.^13–15 In a meta-analysis, Milas et al. reported the MPV cut-off as 9.28 fL for EONI. At this cut-off, the sensitivity and specificity were 67.5% and 73.3%, respectively. ¹⁴ In another study, Ramkumar et al. identified an MPV value of 10.15 fL as the cut-off to identify neonates with EONI, with a sensitivity of 84% and a specificity of 74%. ¹⁵ Sugandha et al. revealed that the PDW and MPV were increased in neonates with sepsis (P <.0001), and the AUC was 0.814 for MPV. The sensitivity, specificity, PPV, and NPV were 50.77%, 52.03%, 35.87%, and 66.67%, respectively. With an AUC of 0.743 for the PDW, the sensitivity, specificity, PPV, and NPV were 44.62%, 55.28%, 34.52%, and 65.38%, respectively. ¹⁶ In general, the sensitivity and specificity of the cut-off value for MPV and PDW in our study and most other studies were medium. However, this could be acceptable compared to WBC and PLT values in the diagnosis of EONI. Our results showed that the AUC of WBC, MPV, and PDW were similar; even MPV represented a higher AUC than WBC. Moreover, the ready availability of MPV and PDW in a complete blood count helps these become promising biomarkers with no additional expense. These results indicate that MPV and PDW could be useful markers for the diagnosis of neonatal infection, mostly in developing countries.

This work has some limitations. Firstly, the number of samples limited us in the interpretation of the results. Secondly, although we performed blood cultures, we did not identify pathogens. All cases in the EONI group were diagnosed if they had clinical symptoms and altered infectious screening of low or elevated WBC, low PLT, or elevated CRP. These cases were thus not proven sepsis; they were probable sepsis. Therefore, performing longitudinal prospective studies in larger cohorts is necessary.

Conclusion

The MPV and PDW were significantly higher in neonates with early-onset infection. Therefore, high MPV and PDW values in addition to other inflammatory markers may be helpful in the diagnosis of EONI. As a part of a routine complete blood count, MPV and PDW may be used as simple diagnostic adjunct markers that combine with existing sepsis screening to define the early diagnosis and treatment of neonatal infection, especially in low- and middle-income countries.