Study on reactive thrombocytosis in febrile young infants with serious bacterial infection in a tertiary care hospital

INTRODUCTION

Fever is the commonest chief complaint in infants aged less than three months attending either emergency departments or outpatient clinics. Numerous studies have reported that serious bacterial infections are common among such patients.¹ The overall prevalence of SBI seems to be 7-18% among such febrile infants. SBI has been a major cause of morbidity and mortality in children in the developing world, which accounts for about 60% of childhood mortality.² Early recognition and appropriate antibiotic treatment can significantly reduce morbidity and mortality.³ Managing such patients is further challenged by the resultant complications and the sensitive nature of their health. Also, it is often hard to differentiate between infants with SBI and those with simple infections.⁴ Definitive diagnosis of SBI necessitates a positive culture of the CSF, blood, urine or a physical examination to identify bacterial focus and radiography.⁵ Owing to the generally unrevealing physical examination of the infants and the culture results are not readily available, it is challenging for the attending clinicians to decide the appropriate patient management based on history, physical examination and laboratory tests.⁶ Considerable time has been spent to develop and implement screening tests to identify the biomarkers using which the physicians can reliably differentiate and diagnose febrile children having a higher risk for SBI than those with low risk.⁷ Many markers have been identified and seem to be closely associated with SBI. C-reactive protein (CRP), an acute-phase reactant that swiftly rises during infection, inflammation and trauma is one such marker. WBC count and differential count in the form of absolute neutrophil count (ANC) is another marker evaluated to be associated with most of the febrile infants.⁸ The common causes of thrombocytosis reported by large-scale prospective studies among children are infection, hemolytic anemia, tissue damage, rebound thrombocytosis, chronic inflammation, renal disorders and malignancy.⁹ Thrombocytosis associated with multiple, simultaneous causative factors was also reported in many children. Among all patients with infections, osteomyelitis and septic arthritis were associated with higher platelet counts than other infections Thrombocytosis secondary to infections was significantly more common in children under 5 years of age, whereas chronic inflammation, malignancy and renal disorders were more common causes of thrombocytosis in children over 5 years of age.¹⁰

METHODS

The study was a cross-sectional study conducted in the department of paediatrics, Kanchi Kamakoti child's trust hospital, Nungambakkam, Chennai after getting approval from institutional ethical committee. 140 children were included in the study from August 2019 to August 2020 (12 months). The study group involved young infants, presenting to the study setting with febrile illness and diagnosed with reactive thrombocytosis.

Inclusion criteria

The inclusion criteria was infants aged 29 to 365 days with temperature >38°C.

Exclusion criteria

The exclusion criteria was infants who had a fever for more than 72 hours and had received antibiotics or vaccination in the last 48 hours, age group <29 days and >365 days, infants with pre-existing hemato-oncological diseases and infants on chronic medication known to reduce platelet count. A thorough history was taken and a detailed physical examination was done. The findings were recorded in the proforma. Venepuncture was done in all these children, the blood sample of 3 ml was collected in an EDTA tube for complete blood count and in another tube 2 ml of blood was collected for CRP. Relevant necessary investigations such as urine routine examination, chest x-ray, urine culture, blood culture, CSF culture, or other X-rays were done for each subject based on the presenting complaints and thorough clinical examination. A platelet count of >4.5 lakhs/cu mm was taken as thrombocytosis. It was assessed in the lab using an automated blood analyzer.

Statistical analysis

The association between SBI, CRP positivity and thrombocytosis was assessed by calculating the odds ratio and its 95% CI. A chi-square test was used to assess the statistical significance of this association. The mean values of quantitative variables like TC and CRP were compared between people with and without thrombocytosis using an independent sample t-test. Mean differences and 95% CI were presented. A p value less than 0.05 was considered statistically significant. IBM SPSS version 21 was used for statistical analysis.

RESULTS

Table 1 shows a total of 140 participants were included in the analysis. There were 28 (20%) children between 1-3 months in the study population. The proportion of children between 4 to 6 months, >7 to 1 year were 43 (30.7%) and 69 (49.3%) respectively. The proportion of male children was 61.4% and female children were 38.6% in the study population.

Table 2 shows the number of participants with cough was 97 (69.3%) and fast breathing was 65 (46.45) in the study population. The proportion of subjects with grunting was 9 (6.4%).

Table 3 shows the number of participants with loose stools was 27 (19.3%) in the study population, while 29 (20.7%) of them had vomiting and none had blood in stools.

Table 4 shows the proportion of participants with seizures was 13 (9.3%) and altered sensorium was 5 (3.6%) in the study population.

Table 5 shows the number of participants with rashes was 3 (2.1%) and soft tissue swelling was 3 (2.1%) in the study group. The proportion of subjects with the tenderness of swelling and restriction of joint movements were 3 (2.1%) and 0 (0.0%) respectively.

Table 6 shows the mean HR was 128.0±22.85 in the study population. The mean RR was 45.67±13.14 and 14.82±0.453 was GCS in the study population.

Table 7 shows the number of participants with dehydration was 10 (7.1%) and anemia was 5 (3.6%) in the study population. The proportion of subjects with rashes was 2.1%. The proportion of subjects with skin or soft tissue swelling, warmth and tenderness were 2.1% each in the study population.

Table 8 shows the number of participants with thrombocytosis was 50 (35.7%) and 90 (64.3%) had no thrombocytosis in the study group. The number of participants with urine pus cells >5 was 14 (10.0%), 41 (29.3%) were observed to have urine pus cells 0 to 5. The proportion of subjects with positive CRP and blood c/s were 65 (46.4%) and 4 (2.9%) respectively. The number of participants with positive urine c/s was 7 (5.0%). The number of participants with positive CXR findings (suggestive of pneumonia) was 26 (18.6%). The number of participants who reported serious bacterial infection was 41 (29.3%). The odds of having thrombocytosis was 6.37 (95% CI 2.87-14.13, p<0.001) times higher in children with a serious bacterial infection when compared to non-SBI, which was statistically significant.

Table 9 shows the proportion of SBI was highest (30.2%) in the 4 to 6 months age group. The proportion of SBI in 1 to 3 months, 7 months and above age groups was 28.6% and 29%. The differences in the proportion of SBI across the age groups were statistically not significant. (p value 0.986).

Table 10 shows the proportion of thrombocytosis was highest (50%) in the 1 to 3 months age group. The proportion of SBI in 4 to 6 months, 7 months and above age groups was 37.2% and 29%. The differences in the proportion of SBI across the age groups were statistically not significant (p value 0.143).

DISCUSSION

SBI has been a major cause of morbidity and mortality in children in the developing world, which accounts for about 60% of childhood mortality.¹¹ Early recognition and appropriate antibiotic treatment can significantly reduce morbidity and mortality. In the process of proper diagnosis of SBI and for better prognosis in a variety of clinical settings in different patient groups, numerous diagnostic markers of sepsis have been suggested.¹² They include CRP, procalcitonin (PCT), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), hemoglobin scavenger receptor (CD163) and high mobility group box 1 (HMGB1), but results have been erratic and variable depending on the selection criteria of patients. Strategies to reduce the global burden of sepsis include prevention through immunization, early recognition, treatment, development of new diagnostics and therapeutics.¹³ Of the total 140 participants, 28 (20%) children were between 1-3 months in the study population. The proportion of children between 3 to 6 months, ≥7 months to 1 year were 43 (30.7%) and 69 (49.3%) respectively. In one of their two studies, Mantadakis et al prospectively analyzed 892 infants of ≤3 months old, while in another the infants (469) were ≤4 months of age. The proportion of children with thrombocytosis was 35.7%.¹⁴ In healthy pediatric subjects normal count platelet ranges between 250,000/muL and 450,000/muL. An elevated platelet count greater than 2 SD defines a condition of thrombocytosis. The prevalence of SBI in the study population was 29.3%.¹⁵ In their study, Fouzas found a very large proportion of children (74%) having SBI. A considerable amount of evidence points to the finding that platelets can act like acute phase reactants and that their production is triggered by interleukin-6 by directly enhancing megakaryopoiesis or indirectly by stimulating hepatic thrombocytosis secondary to anemia. The odds of having thrombocytosis was 6.37 (95% CI 2.87-14.13, p<0.001) times higher in children with a serious bacterial infection, which was statistically significant.¹⁶ In line with this finding Brown LST said that reactive thrombocytosis had the highest accuracy in differentiating infants with SBI with less false positive or false negative results and that it can be a useful tool that could help the clinician to look for further investigations in infants with SBI. On the contrary, several studies opined that clinical impression and routine laboratory tests were unable to accurately identify the presence of SBI. However, certain markers have been consistently identified with SBI like leucocytosis, elevated CRP, pyuria and thrombocytosis.¹⁷ Olaciregui in their study on 377 children of whom 74% of them had SBI found that PCT and CRP as useful markers of SBI. Leucocytosis, specifically ANC a consequence of infections mainly of acute nature has also been observed to be associated with SBI.¹⁸ A study by Bilavsky et al reported that apart from the common indicators of SBI like CRP and WBC even cytokines like interleukin-6 are also useful. Though among the various makers, raised serum CRP level is a better indicator of SBI, however, no marker, either alone or in combination, has demonstrated adequate sensitivity or specificity for the diagnosis of SBI in febrile infants.^19,20 In addition, thrombocytosis secondary to anemia is a matter of concern in this age group. Reactive thrombocytosis in combination with WBC, CRP and pyuria seems to be a useful tool that could help clinician to target further investigation and follow-up strategy.

CONCLUSION

Almost 30% of the study population had a serious bacterial infection. The prevalence of SBI was highest (30.2%) in the 4 to 6 months age group. The prevalence of SBI in 1 to 3 months, 7 months and above age groups was 28.6% and 29% respectively. There was a statistically significant association between thrombocytosis and serious bacterial infection in the study population.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: The study was approved by the Institutional Ethics Committee

REFERENCES

1. 1. Shin SH, Choi CW, Lee J, Kim E, Choi EH, Kim H, et al. Risk factors for serious bacterial infection in febrile young infants in a community referral hospital. J Korean Med Sci. 2009;24(5):844-8.
2. 2. Bachur RG, Harper MB. A predictive model for serious bacterial infections among infants younger than 3 months of age. Pediatrics. 2001;108(2):311-6.
3. 3. Bleeker SE, Derksen-Lubsen G, Grobbee DE, Donders ART, Moons KGM, Moll HA. Validating and updating a prediction rule for serious bacterial infection in patients with fever without source. Acta Paediatr. 2007;96(1):100-4.
4. 4. Cincinnati V, Brescia L, Esposito S. Thrombocytosis and infections in childhood. Pediat Infect Dis J. 2012;31(1):80-1.
5. 5. Chen CJ, Lo YF, Huang MC, Chung RL, Tang RB, Wu KG. A model for predicting the risk of serious bacterial infection in febrile infants younger than 3 months of age. J Chin Med Assoc. 2009;72(10):521-6.
6. 6. Carcillo JA. Reducing the global burden of sepsis in infants and children: a clinical practice research agenda. Pediatr Crit Care Med. 2005;6:157-64.
7. 7. Bang AT, Bang RA, Baitule SB, Reddy MH, Deshmukh MD. Effect of home-based neonatal care and management of sepsis on neonatal mortality: field trial in rural India. Lancet. 1999;534(9194):1955-61.
8. 8. Hsiao AL, Baker MD. Fever in the millennium: a review of recent studies of markers of serious bacterial infection in febrile children. Curr Opin Pediatr. 2005;17(1):56-61.
9. 9. Sur DK, Bukont EL. Evaluating fever of unidentifiable a source in young children. Am Fam Physician. 2007;75(12):1805-11.
10. 10. Vlach V, Fekete G. Thrombocytosis in pediatric patients is associated with severe lower respiratory tract inflammation. Arch Med Res. 2006;37(6):755-9.
11. 11. Wang JL, Huang LT, Wu KH, Lin HW, Ho MY, Liu HE. Associations of reactive thrombocytosis with clinical characteristics in pediatric diseases. Pediatr Neonatol. 2011;52(5):261-6.
12. 12. Wiedmeier SE, Henry E, Burnett J, Anderson T, Christensen RD. Thrombocytosis in neonates and young infants: a report of 25 patients with platelet counts of > or = 1000000 micro (-1). J Perinatol. 2010;30(3):222-6.
13. 13. Yohannan MD, Higgy KE, al-Mashhadani SA, Santhosh-Kumar CR. Thrombocytosis. Etiologic analysis of 663 patients. Clinic Pediat. 1994;33(6):340-3.
14. 14. Mantadakis E, Tsalkidis A, Chatzimichael A. Thrombocytosis in childhood. Indian pediatrics. 2008;45(8):669-77.
15. 15. Sutor AH. Thrombocytosis in childhood. Semin Thromb Hemost. 1995;21(3):330-9.
16. 16. Focus S, Mantagou L, Skylogianni E, Varvarigou A. Reactive thrombocytosis in febrile young infants with a serious bacterial infection. Indian Pediatr. 2010;47(11):937-43.
17. 17. Brown LST, Wittlake WA. Does leucocytosis identify bacterial infections in febrile neonates presenting to the emergency department? Emerg Med J. 2005;22(4):256-9.
18. 18. Olaciregui I, Hernández U, Muñoz JA, Emparanza JI, Landa JJ. Markers that predict serious bacterial infection in infants under 3 months of age presenting with fever of unknown origin. . Arch Dis Chi. 2009;94(7):501-5.
19. 19. Bressan S, Andreola B, Cattelan F, Zangardi T, Perilongo G, Dalt LD. Predicting severe bacterial infections in well-appearing febrile neonates: laboratory markers accuracy and duration of fever. Pediatr Infect Dis J. 2010;29(3):227-32.
20. 20. Blavatsky E, Yarden-Bilavsky H, Ashkenazi S, Amir J. C-reactive protein as a marker of serious bacterial infections in hospitalized febrile infants. Acta Paediatrica. 2009;98(11):1776-80.