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Comparison of outcomes of thrombocytopenic and non-thrombocytopenic culture proven neonatal sepsis

Background: Due to high incidence of sepsis as a main cause of neonatal mortality, early detection and proper treatment are important in reducing neonatal mortality. Thrombocytopenia is a common hematological problem encountered during neonatal period, particularly in neonatal sepsis. This study was done to know the incidence of thrombocytopenia in neonatal sepsis and to compare clinical outcome in patients with thrombocytopenic and nonthrombocytopenic neonatal sepsis. Methods: This was a prospective study carried out at neonatal intensive care unit of a tertiary care teaching hospital of western Gujarat, India, from October 2018 to August 2020. 2739 neonates were admitted with probable sepsis during study period. 299 neonates with positive blood cultures were recruited for the study. They were divided into two groups; group-1 had patients with thrombocytopenia, while group-2 included patients without thrombocytopenia. Severity of thrombocytopenia was assessed in group-1. Micro-organisms isolated and outcome of sepsis were compared in both the groups. Results: There were 208 neonates in group-1 (thrombocytopenic) and 91 in group-2 (non-thrombocytopenic). There was no significant difference in demographic profiles of neonates in both groups. Klebsiella pneumonia was the most common organism isolated from 79 patients of group-1 and 19 patients of group-2 (p=0.033). Coagulase negative Staphylococci and Candida were the second and third most common micro-organisms isolated from 30.2% and 15.1% of blood cultures respectively. In group-1, 85 (40.8%), 72 (34.6%) and 51 (24.5%) neonates had severe, moderate and mild thrombocytopenia respectively. Klebsiella pneumoniae (45.9%) was the commonest organism isolated in severe thrombocytopenic neonates, followed by Candia (22.4%) and Enterococcus (14.1%). Conclusions: Thrombocytopenia is a specific marker of neonatal sepsis. The platelet count is a simple test that facilitates diagnostic orientation and the establishment of an early empirical treatment. Klebsiella pneumoniae was the commonest organism isolated in severe thrombocytopenic neonates.


INTRODUCTION
Neonatal sepsis is a clinical syndrome characterized by signs and symptoms of infection with or without accompanying bacteremia in the first month of life. 1 It is one of the commonest causes of neonatal mortality contributing to 19% of neonatal deaths. 2 The global burden of neonatal death is estimated to be 5 million of which 3.2 million deaths occur during the first week of life. One fourth of the burden of neonatal mortality worldwide is seen in India and about 1.2 million neonates die every year. Neonatal mortality rate in India as per 2018 data was 23 per 1000 while in Gujarat as per 2017 data it was 21 per 1000 live birth. 3,4 Thrombocytopenia is a common haematological problem encountered in the neonatal sepsis. Most of the sick, low birth weight and premature infants have low platelet count. 5 Low platelets is usually seen even before the pathogens are cultured from the blood. 6 Platelet count can be considered as one of the parameters useful in early diagnosis of sepsis in symptomatic infants. 7,8 Gram negative micro-organisms neonatal sepsis are commonly reported from India. 7 Bacteria or bacterial products may cause endothelial damage leading to platelet adhesion and aggregation or may bind directly to the platelet leading to aggregation and accelerated clearance from circulation. 9,10 There may be possibility of immune mechanism for development of thrombocytopenia in septicaemia as there is presence of circulating immune complexes in septicaemia patients and reduced number of complement complex in patients with septicaemic shock. 11,12 Hence, this study was done to know the incidence of thrombocytopenia in neonatal sepsis and to compare clinical outcome in patients with thrombocytopenic and non-thrombocytopenic neonatal sepsis.

METHODS
This prospective comparative study was conducted at NICU of a tertiary care teaching hospital of Western Gujarat, India, from October 2018 to August 2020. During the study period, total 2739 neonates were admitted in our NICU, out of which 299 neonates, with blood culture positive neonatal sepsis, were included in the study. Written informed consents were obtained from parents.
Detailed antenatal history including history of antenatal risk factors for sepsis; such as prolonged rupture of membrane >24 hours prior to delivery (PROM), foul smelling liquor, maternal fever within 2 weeks of delivery or during labor, prolonged labor and >3 sterile or single unclean per vaginal examination, were noted. 13 Detailed natal and postnatal history were also noted. Detailed physical examination was done in all neonates. Demographic profile, type of sepsis (early/late onset sepsis) and presentation (non-specific/systemic) were noted. Sepsis screening tests included estimation of Creactive protein (>1 mg/dl), total leukocyte count (<5000/mm 3 or >25000/mm 3 ), micro-ESR (> 15 mm in first hour), low absolute neutrophil counts (as per Manroe chart for term and Mouzinho's chart for very low birth weight neonates) and immature/total neutrophil ratio >0.2. [14][15][16][17] Platelet counts were measured. A normal platelet count ranges from 1,50,000 to 4,50,000 platelets per microliter of blood. Mild, moderate, severe and very severe thrombocytopenia were defined as platelets counts between 1,00,000-1,50,000/mm 3 , 50,000-1,00,000/mm 3 , 20,000-50,000/mm 3 and <20,000/mm 3 respectively. 18 Confirmation of sepsis was done by blood culture and sensitivity. Blood sample collection was done under full aseptic precautions to avoid contamination. One ml of blood was taken from fresh venipuncture site for blood culture in a bottle containing 5-10 ml of culture media. All samples were incubated at 37 degree celsius and observed for 72 hours for growth of micro-organisms. Reporting of micro-organism growth and antibiotic sensitivity was done as per CLSI guidelines. 19 Lumbar puncture for cerebrospinal fluid examination was done prior to starting antibiotics. 20 On the basis of platelet counts, all neonates with culture proven sepsis were divided into two groups. Patients with platelet counts <1,50,000/mm 3 were included in group-1 (thrombocytopenic) while patients with platelet counts >150,000/mm 3 were included in group-2 (nonthrombocytopenic).
Statistical analysis was done using Chi-Square test for categorical variables and independent one tailed t-test for continuous variables. Significance was defined as p<0.05.

DISCUSSION
In current study, incidence of sepsis was 10.9%, as 299 out of 2739 admitted neonates in our NICU had blood culture proven sepsis. In a study by Ree et al, 460 of 6551 (7%) neonates had sepsis. 21 In current study, Klebsiella pneumonia was more commonly isolated in patients with thrombocytopenia that who were non-thrombocytopenic. Ree et al also found than gram negative sepsis is more commonly associated with thrombocytopenia (15%) as compared to non-thrombocytopenia (6%) (p=0.004). 21 Heena et al, also found Klebsiella pneumoniae in 54% neonates with sepsis. 22 In current study 67.2% neonates with CPNS had thrombocytopenia. This indicates that the low platelets count in newborns has an important correlation with sepsis. The incidence of thrombocytopenia in our study is comparable with other studies conducted by Ree 25 Ree et al and Goudar et al found severe thrombocytopenia in 20% and 15% neonates with CPNS respectively, which is low as compared to our study. 21,23 In our study, we found that Klebsiella pneumoniae was the most common organism associated with thrombocytopenia (37.9%) and also with severe thrombocytopenia (45.9%). Among all the organisms responsible for thrombocytopenia, Pseudomonas was the least common organism (0.01%). Charoo et al and Arif et al also found Klebsiella pneumoniae as the most common organism associated with thrombocytopenia in 58% and 73.3% neonates respectively. 24,26 In current study, there was no significant difference in mortality rates (p=0.411) between non-thrombocytopenic and thrombocytopenic neonates.

CONCLUSION
It was observed that 69.3% neonates with culture proven neonatal sepsis had thrombocytopenia. So, thrombocytopenia is specific marker of neonatal sepsis. The platelet count is a simple test that facilitates diagnostic orientation and the establishment of an early empirical treatment for neonatal sepsis. In our study, Klebsiella pneumoniae was the commonest organism isolated in severe thrombocytopenic neonates. So, whenever a neonate has thrombocytopenia with sepsis, effective antibiotics against Klebsiella pneumoniae should be started till confirmed culture report is obtained.