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Association and Outcome of Intracranial Haemorrhage in Newborn with Fungal Sepsis- A Prospective Cohort Study |
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N Adalarasan, S Stalin, Seenivasan Venkatasamy, S Sridevi, S Padmanaban, Ponnuraja Chinnaiyan 1. Associate Professor, Department of Paediatrics, Government Villupuram Medical College and Hospital, Tamil Nadu, India. 2. Associate Professor, Department of Paediatrics, Government Villupuram Medical College and Hospital, Tamil Nadu, India. 3. Associate Professor, Department of Paediatrics, Government Thiruvallur Medical College and Hospital, Tamil Nadu, India. 4. Associate Professor, Department of Paediatrics, Government Vellore Medical College, Tamil Nadu, India. 5. Scientist B, Department of Statistics, ICMR-National Institute for Research in Tuberculosis (ICMR-NIRT), Chennai, Tamil Nadu, India. 6. Scientist E, Department of Statistics, ICMR-National Institute for Research in Tuberculosis (ICMR-NIRT), Chennai, Tamil Nadu, India. |
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Correspondence Address : Dr. S Sridevi, 4C 4th Floor KF Dwaraka Flats Jeshwanth Nagar 4th Main Road, Mogappair West, Chennai 37, Tamil Nadu, India. E-mail: sridevisrinivasan22@gmail.com |
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| ABSTRACT |  | |||||||||||||||||||||||||||||||||||||||||
: Introduction: Neonatal sepsis is a leading cause of mortality and morbidity. Inspite of using appropriate antibiotics, those who are bacterial culture-negative, still succumb to fungal infection. Fungal sepsis is common in the neonatal Intensive Care Unit (ICU), especially with invasive procedures and prolonged empirical use of antibiotics. The incidence of fungal infection varies widely across centers, likely due to differences in practice related to modifiable risk factors such as exposure to empiric antibiotics and length of parenteral nutrition. Neonates are at high risk for acquiring infections due to their specific Central Nervous System (CNS) structure as well as functionally immature immune system causing central nervous system infection or intracranial haemorrhage due to sepsis induced coagulopathy. Being Intracranial Haemorrhage (ICH) in neonates often results in devastating neurodevelopment outcome and also having significant mortality in the neonatal period. Aim: To find the association and outcome of intracranial haemorrhage in newborn with fungal sepsis. Materials and Methods: This study was a prospective cohort study conducted at Department of Pediatrics, Government Kilpauk Medical College, Chennai, Tamil Nadu, India, on neonates admitted in newborn ward of the hospital ICU during the period January 2018 to December 2020. Neonates with the diagnosis of fungal sepsis were identified from blood cultures. They were also subjected to Complete Blood Count (CBC), Capillary Refilling Time (CRT), Prothrombin Time (PT), activated Partial Thromboblastin clotting time (aPTT) and cranial ultrasound. Chi-square analysis for descriptive data and Cox Proportional Hazard Regression for survival and non survival neonates and Kaplan-Meier curve analysis was done. Results: Out of total 80 neonates, nine had intracerebral haemorrhage, 21 neonates had intraventricular haemorrhage and no haemorrahge in 50 neonates. More the gestational age, lesser were the chances of intracranial haemorrhage and the difference was statistically significant (p-value<0.001). A total of 50 babies died, majority (42%) were in the gestational age between 37-40 weeks. All the babies diagnosed with C. albicans sepsis succumbed to infection. Conclusion: The present study highlights the fact that the lesser of the gestational age, the more or the chances of intracranial haemorrhage. A close monitoring of the coagulation profile PT and aPTT will help us to identify the babies for more prone for intracranial haemorrhage. Expert cranial ultrasound will pick up the haemorrhage early. Timely treatment measures instituted will help in preventing mortality due to bleeding manifestions in fungal sepsis. The Cox regression analysis reveals that both PT& aPTT and intracranial haemorrhage are the associated risk factors for non survival in fungal sepsis neonates. | ||||||||||||||||||||||||||||||||||||||||||
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| Keywords : Antibiotics, Candida albicans, Gestational age, Intraventricular haemorrhage, Neonatal infection | ||||||||||||||||||||||||||||||||||||||||||
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DOI and Others :
DOI: 10.7860/IJNMR/2022/57793.2356
Date of Submission: May 27, 2022 Date of Peer Review: Jun 16, 2022 Date of Acceptance: Sep 28, 2022 Date of Publishing: Sep 30, 2022 AUTHOR DECLARATION: • Financial or Other Competing Interests: None • Was Ethics Committee Approval obtained for this study? Yes • Was informed consent obtained from the subjects involved in the study? Yes • For any images presented appropriate consent has been obtained from the subjects. NA PLAGIARISM CHECKING METHODS: • Plagiarism X-checker: May 30, 2022 • Manual Googling: Sep 26, 2022 • iThenticate Software: Sep 29, 2022 (15%) Etymology: Author Origin |
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| INTRODUCTION |
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Neonatal sepsis poses a challenge for every Paediatrician. It is the leading cause of mortality and morbidity. With advances in the field of neonatology, the doctors can save most newborn babies with sepsis by using appropriate antibiotics, inspite of appropriate antibiotics those are bacterial culture negative, still succumb to fungal infection (1). Fungal sepsis has been found to be a major cause of mortality in the Neonatal Intensive Care Unit (NICU), especially with invasive procedures and prolonged empirical use of antibiotics. Infection with fungal species is associated with significant morbidity and mortality in infants. The incidence of fungal infection varies widely across centers, likely due to differences in practice related to modifiable risk factors such as exposure to empirical antibiotics and length of parenteral nutrition (2). As neonatal fungal infections especially candidiasis is associated with 20% mortality, and 50% of survivors have severe neurodevelopmental impairment. End-organ damage in the central nervous system is more common in neonatal fungal sepsis (2). According to the national neonatal-perinatal database, 2002-03 report over 1 million newborn infants died every year in the neonatal period (first 4 weeks of life) in India, amounting to the highest-burden of newborn deaths for any country in the world (1). Neonatal sepsis presents as a multi-spectrum of symptoms and signs. They can be subtle or stormy, varying from diminished spontaneous activity, poor sucking, temperature instability, jitteriness, seizure, irritability, vomiting, respiratory distress, jaundice, feeding intolerance, apnoea and increased need for ventilatory support, hypoglycaemia as well as hyperglycemia and perfusion abnormalities (2). Most fungal sepsis presents as late-onset sepsis in newborn infants, often after the second and third week of life. Although persistent thrombocytopenia leads to the suspicion fungal sepsis. It is not consistently presenting every case. If fungal sepsis is not recognized early, it can lead to meningitis, sepsis induced coagulopathy causing intracranial haemorrhage. The degree of Central Nervous System (CNS) involvement is directly proportional to the mortality rate (2). Although bloodstream infection due to Candida species in the neonatal intensive care unit is less frequent than that due to Gram positive or Gram negative bacteria, it has higher morbidity and mortality rates (3). The incidence of candidiasis in Extremely Low Birth Weight (ELBW) infants is approximately 10%. This varies as much as 20 fold between various centres. Neonatal candidaemia is associated with 20% mortality and 50% of survivors have a severe neurodevelopmental impairment (4), either due to sepsis or fragile vascularity of intracranial vessels. The babies who survive candida septicaemia have a high incidence of complications. Severe CNS sequelae such as hydrocephalus, mental retardation and aqueductal stenosis are known to occur due intracranial haemorrhage. Diagnosis of neonatal candidaemia has to have a high index of suspicion. A thorough evaluation is a must when blood culture is positive for candida. The blood culture is the gold standard for the detection of candidiasis, even though its sensitivity is so poor. A positive blood culture should never be considered a contaminant (5). Only 37% of infants with proven candida meningitis had positive blood cultures for candida. In addition to this, normal Cerebrospinal Fluid (CSF) parameters are present in half of the infants with candida meningitis (5). The doctors must also perform urine culture, CSF analysis and CSF culture, opthalmological examination, echocardiogram, renal ultrasound and even skeletal survey, if necessary (5). Non albicans candida species were predominant in Asia with proportions ranging from 25-92% with a median of 75 % (6). Candida albicans was known to contribute to 60% of candidaemia reported till recently. However many studies show that non albicans candida such as C. glabrata, C. krusei, C. parapsilosis and C. tropicalis were found to account for the majority of fungal infection. This is a major change (7). Very Low Birth Weight (VLBW) infants are known to be at high risk of candidaemia because of more aggressive and invasive therapies such as indwelling central lines, mechanical ventilation, parenteral hyperalimentation and longer hospital stay (8),(9). Earlier studies have shown that candida has emerged as a major cause of neonatal sepsis and that it leads to morbidity and mortality. Studies have also highlighted the predominant organism isolated mostly candida non albicans species. Previous study states that once fungal sepsis is suspected, a coagulation profile done early with a cranial Ultrasonography (USG) will pick up early onset of intracranial haemorrhage. Timely medical measures instituted will prevent the high rate of mortality (2). Hence, this study aimed to provide association of various factors like gestational age, birth weight, platelet, Prothrombin Time (PT), activated Partial Thromboplastin Time (aPTT), and cranial ultrasound with intracranial haemorrhage and outcome of intracranial haemorrhage in newborn with fungal sepsis. | ||||||||||||||||||||||||||||||||||||||||||
| Material and Methods |
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A prospective cohort study was conducted at the Department of Paediatrics, Government Kilpauk Medical College (tertiary care centre), Chennai, Tamil Nadu, India, during January 2018 to December 2020. Ethical Committee approval was duly obtained (letter No-02A-2017.14/11/2017) and consent from the parents was also obtained. Neonates with the diagnosis of fungal sepsis were identified from blood cultures. All yeast or mold species isolated from blood cultures were cultured on Sabouraud’s dextrose agar and species were identified by the CHROMagar method. Inclusion criteria: All neonates, intramural and extramural admitted to NICU with culture-proven fungal sepsis and those who have been administered an injection of vitamin K at birth were included in the study. Exclusion criteria: Those neonates with birth asphyxia, vacuum delivery, Meconium Aspiration Syndrome (MAS), cases of outlet forceps delivery, known family history of bleeding diathesis, history of maternal anticoagulants or idiopathic thrombocytopenic purpura, not injected with vitamin K at birth, bacterial culture-positive neonates were excluded from the study. Procedure A total of 80 babies were included in the study. All neonates were subject to Complete Blood Count (CBC), CRP, PT, aPTT, cranial ultrasound and blood culture. The neonates were classified into three groups-: • Early preterm: <32 weeks gestational age • Neonates: 32-36 weeks gestational age • Term neonates: 37-40 weeks gestational age Statistical Analysis The data was analyzed using Statistical Package for Social Sciences (SPSS) and Medcalc software. Chi-square analysis for descriptive data and Cox proportional hazard regression for survival and non survival neonates and Kaplan Meier-curve analysis. | ||||||||||||||||||||||||||||||||||||||||||
| Results |
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Out of total 80 neonates, nine neonates had intracerebral haemorrhage, 21 neonates had intraventricular haemorrhage and 50 neonates had no haemorrhage. (Table/Fig 1) shows the association of intracerebral/intraventricular haemorrhage concerning different variables like the gestational score of the mother, the gestational weight of the baby, sex of the baby, birth weight, platelet count, coagulation profile and blood culture. Lesser the gestational age, the more the incidence of intracranial haemorrhage. However, the present study observed that even term babies were not exempt from such complications due to fungal sepsis. On analysis of the results of blood culture, non albicans candida, were associated with a higher incidence of ICH (Table/Fig 2). C. krusei was the most common organism isolated followed by C. parapsilosis, C. glabrata and C. tropicalis. Candida albicans was isolated in only in eight babies. The mortality due to candida non albicans species is much more than that due to C. albicans fungaemia. A total of 50 babies died and 30 only survived. However, the most alarming fact is that 42% of term babies also succumbed to fungal sepsis. Of the 50 babies who died 48 (96%) had abnormal PT, aPTT. This was found to be statistically significant (p-value<0.05). Blood culture revealed that there is a mortality of 10 (58.82%) in C. glabrata sepsis,15 (68.18%) in candida krusei sepsis, 9(47.37%) in candida parapsilosis sepsis, 8% in candida tropicalis whereas,100% mortality occurred in those babies with C. albicans sepsis. (Table/Fig 3), (Table/Fig 4) infer the difference between the median survival time of intracerebral/intraventricular haemorrhage and no haemorrhage. If there was a haemorrhage, the median survival time was lesser (p-value=0.0044). The hazard ratio for PT and aPTT abnormal was 12.85 times more contributing to non survival than normal (Table/Fig 3). Receiver Operating Curve analysis (Area Under Curve=0.29) also confirmed the above two parameters were, good predictors for non survival of the neonates. The Cox regression analysis revealed that both PT and aPTT and intraventricular haemorrhage was the associated risk factors for non survival fungal sepsis in neonates (Table/Fig 5). | ||||||||||||||||||||||||||||||||||||||||||
| Discussion |
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In the present study, 74 babies out of 80 babies had thrombocytopaenia (platelet count <1, 50,000). Thrombocytopaenia can be a specific marker of fungal sepsis. This result is similar to a study done by Farhana T et al., in which, 22 babies out of 30 (73.3%) had thrombocytopaenia (8). Amongst the 29 neonates with thrombocytopaenia, eight babies (10.8%) had intracerebral haemorrhage while 21 babies (28.4%) had Intraventicular Haemorrhage (IVH). Only five babies with candida Albicans growth had IVH. Of babies with fungal culture positive sepsis, 14.28% with C. albicans sepsis had IVH. A total of 85.7 % of babies with non albican candida culture positive sepsis had ICH/IVH. This observation is in contrast to the study by Silva R et al., who reported that neonates with C. albicans Body Substance Isolation (BSI), 41.4% had IVH and that neonates with non albican candida blood stream infections 41.5% had IVH (10). In the present study, C. glabratais found in 21.25%. C. krusei was found in 27.5%. C. paraspilosis was found in 23.75%. C. tropicalis in 17.5% C. albicans in 10%. In other studies, for example study by Yunus M et al., it was found that 63.8% had C. Krusei 26.5%, C. albicans and 6% C. tropicalis (11). In another study by Ballot DE et al., Candida parapsilosis (54.2%) was isolated in the majority of cases followed C. albicans (27.1%) (12). In the present study, it was found that term babies had higher mortality when compared to late preterm and early preterm babies. According to the birth weight, 18 babies >2.5 kg succumbed, 19 babies in the 1.5-2.5 kg group died. Nine babies in the weight category of 1-1.499 kg and four babies in the <1 kg group died. Mortality was found to be higher in 1.5-2.5 kg group and >2.5 kg group while the earlier studies showed that mortality due to fungal sepsis is very high in the very preterm and very low birth weight babies also impaired nero developmental outcome (13). Hence, the present study was unique in its observation that term babies were also affected in addition to the late preterm babies and early preterm babies. Limitation(s) Small sample size was the major limitation of the study. | ||||||||||||||||||||||||||||||||||||||||||
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