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Research paper

Indian Pediatr 2010;47: 937-943

Reactive Thrombocytosis in Febrile Young Infants with Serious Bacterial Infection


S Fouzas, L Mantagou, E Skylogianni and A Varvarigou

From the Department of Pediatrics, University Hospital of Patras, Patras, Greece.

Correspondence to: Fouzas Sotirios, Department of Pediatrics, University Hospital of Patras, Rio,
Patras, 265 04, Greece.
Email: [email protected]
 
Published online 2010 March 15.

PII: S097475590900522-1
 

Abstract

Objective: To estimate the incidence of reactive thrombocytosis among febrile young infants and to asses the utility of platelet count as a potential predictor of serious bacterial infection (SBI).

Design: Retrospective study between January 2005 and December 2008.

Setting: Tertiary care pediatric unit.

Participants: All infants 29 to 89 days of age, admitted with rectal temperature >38oC without a focus of infection.

Main Outcome Measures: The results of the sepsis evaluation on admission were recorded. SBI included all cases of occult bacteremia, urinary tract infection, bacterial meningitis, pneumonia, bacterial gastroenteritis and infections of the soft tissues and bones.

Results: Of the 408 infants studied, 103 (25.2%) had SBI. Platelet count was significantly higher in infants with SBI compared to those without (median 513000 /mm3 [interquartile range 455,000–598,000/mm3] vs median 398000/mm3; [interquartile range 313,000–463,000/mm3]; P<0.001). Thrombocytosis had only moderate ability in predicting SBI (area under the curve: 0.74, 95%CI 0.70-0.79). The combination of platelet count ³450,000/mm3, WBC ³15,000/mm3, C-reactive protein ³2 mg/dL, and pyuria ³10 WBC/hpf would lead to misclassification of 4 infants with SBI (3.9% of SBIs; negative likelihood ratio 0.08).

Conclusions: Reactive thrombocytosis was a frequent finding in young infants with SBI. Thrombocytosis ³450,000 cells/mm3, in combination with leucocytosis, elevated CRP and pyuria, may help in early recognition of febrile young infants at risk for SBI.

Key words: Diagnosis, Fever, Infants, Serious bacterial infection, Thrombocytosis.


F
ebrile infants less than 3 months of age present a management challenge, as many of these have no identifiable source of fever, and the prevalence of serious bacterial infection (SBI) in this age group is high(1-7). The most commonly suggested strategy is for the febrile neonates to be admitted to a hospital and undergo full sepsis workup(5-7). In the past decade, several management strategies based on the combination of physical and laboratory findings have been proposed, but no protocol has been universally adopted(8-11). Furthermore, a series of laboratory parameters such as white blood cell (WBC) count, absolute neutrophil count, pyuria, C-reactive protein (CRP), and more recently, interleukin-6 and procalcitonin, have been extensively evaluated and compared as potential predictors of SBI(8-16). These laboratory tests lack adequate predictive ability and the idea of a simple, rapid and inexpensive diagnostic test that could accurately identify bacterial infections among febrile infants, remains unattainable(3,4,6, 13,15,17).

Reactive thrombocytosis is a common finding in infants that occurs in the preponderance of cases secondary to an infection(18-25). To our knowledge, no study has previously focused on the incidence and characteristics of reactive thrombocytosis in young infants with SBI. Moreover, the platelet count has neither been considered nor evaluated as a potential predictor of SBI among young febrile infants.

The objective of our study was to estimate the incidence of reactive thrombocytosis in febrile young infants, especially in those with bacterial infections, and assess the value of platelet count as a potential predictor of SBI.

Methods

We retrospectively reviewed the case-records of infants aged 29 to 89 days, admitted to our tertiary care pediatric unit between 1 January 2005 and 31 December 2008 for investigation of fever (defined as rectal temperature >38oC) without a focus of infection. Infants who had fever for more than 72 hours, and had received antibiotics or vaccination within 48 hours of presentation, were excluded.

All patients had sepsis evaluation including WBC count, platelet count, blood culture, urine microscopy and culture and CRP. Lumbar puncture for cerebrospinal fluid (CSF) analysis and culture, as well as stool culture and chest radiographs, were obtained at the discretion of the attending pediatrician.

The WBC count with differential and the platelet count were quantified using automated laboratory equipment (Sysmex SE 9500, GMI, Inc). Blood cultures were monitored by an automated system (BacT/ALERT 3D, bioMérieux, Inc). Urine was obtained by suprapubic needle aspiration or by urethral catheterization using a sterile technique. The WBC in the urine were quantified by standard microscopic examination and expressed as WBC per high power field (hpf)(28). The urine, CSF and stool cultures were monitored using standard laboratory techniques.

Serious bacterial infection (discharge diagnosis) was defined as occult bacteremia, urinary tract infection (UTI), bacterial meningitis, pneumonia, bacterial enteritis and infection of soft tissue or bones. Isolates such as Staphylococcus epidermidis or Streptococcus viridans in the blood culture were considered contaminants unless they were isolated from more than two consecutive cultures. Urinary tract infection was defined as a single known pathogen growth ³1000 colony-forming units (cfu) /mL of urine obtained by suprapubic needle aspiration or ³100,000 cfu /mL of urine obtained by urethral catheterization. Pneumonia was defined as the presence of a focal infiltrate on chest radiograph as interpreted by the attending radiologist(29).

The data were analyzed using the SPSS 15.0 for Windows (SPSS, Inc). Non parametric data are presented as medians with interquartile ranges (IQR). Differences between the groups were assessed for statistical significance using either the Mann Whitney U or chi-squared test, as appropriate. Individual differences between nonparametric variables were evaluated by the Kruskal-Wallis multiple-comparison z-value test with Bonferroni correction (alpha=0.05; medians significantly different if z-value >2.93), using the statistical package NCSS 2004 (Number Cruncher Statistical Systems, Kaysville, UT, USA). The overall performance of individual parameters in predicting SBI was assessed by receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) comparisons, using the statistical software MedCalc 8.1 (MedCalc, Mariakerke, Belgium). The study was approved by the ethics committee of the University Hospital of Patras, Greece.

Results

During the study period, 464 infants 29 to 89 days of age, were admitted for investigation of fever >38oC without a source. Of these, 12 had fever for more than 72 hours, 9 had received vaccination, 23 were treated with antibiotics within 48 hours of presentation, and 12 had incomplete medical records.

Of the remaining 408 infants, SBI was documented in 103 (25.2%). Of these, 88 (85.4%) had UTI (74 with Esherichia coli), 9 occult bacteremia (2 with Streptococcus pneumoniae, 3 with Group B Streptococcus, 2 with Staphylococcus aureus and 2 with Esherichia coli), 6 infants had pneumonia, and 2 were diagnosed with bacterial meningitis (1 with Neisseria meningitidis and 1 with Group B Streptococcus). Two infants had concurrent positive blood and urine cultures for Esherichia coli. None of the infants with pneumonia had documented bacteremia. The remaining 305 infants (74.8%) with negative sepsis evaluation were categorized in the non–SBI group.

Clinical and laboratory characteristics of the non–SBI and SBI groups are presented in Table I. A comparison of platelet counts between the non–SBI and SBI groups is shown in Table II. We also noted a substantial overlap between the two groups (Fig. 1).

TABLE I



Clinical and Laboratory Characteristics of the Non-SBI and SBI Groups
  Non-SBI (n=305) SBI (n=103) P Value
Age (d) 57 (42-72) 60 (44–75) 0.10
Sex (male/female) 162/143 57/46 0.78
Duration of fever (h) 14 (6–27) 14 (6–29) 0.49
Fever on admission (oC) 38.5 (38.1–38.8) 38.5 (38.1-39.0) 0.22
Hemoglobin (g/dL) 10.5 (9.7–11.0) 10.4 (9.6–11.0) 0.30
WBC (103/mm3) 9.65 (7.15–14.20) 16.0 (11.1–20.2) <0.0001
PLT (103/mm3) 398 (313–463) 513 (455–598) <0.0001
CRP (mg/dL) 0.2 (0.0–1.2) 1.6 (0.1-–4.2) <0.0001
Pyuria (WBC/hpf) 1 (1–3) 10 (3–45) <0.0001
Data are expressed as median (interquartile range); All comparisons by  Mann-Whitney U test except sex difference by  x2 test; SBI: serious bacterial infection; WBC: white blood count; PLT: platelet count; CRP: C-reactive protein; hpf: high power field.
 

Fig. 1 Box plots presenting the distribution of platelet counts in the non–SBI and SBI group. The central box represents the values from the lower to upper quartile (25th to 75th percentile). The middle line represents the median. A line extends from the minimum to the maximum value, excluding "outside" values or "outliers" which are displayed as separate points.

 

TABLE II



Platelet Counts in the Non–SBI Group and SBI Subgroups
Group* N Platelet count (103/mm3) Significant to:
Median IQR (z-value)
UTI (7.85)
non–SBI 305 398 313–463 OB (3.95)
PN (3.23)
UTI 88 513 453–597 non–SBI (7.85)
OB 9 523 500–611 non–SBI (3.95)
PN 6 490 477–541 non-–SBI (3.23)
IQR, interquartile range; SBI: serious bacterial infection; UTI: urinary tract infection; OB: occult bacteremia; PN: pneumonia* Infants with Bacterial meningitis (n=2) were not included in comparison; † four UTIs with concomitant bacteremia considered as OB; ‡ Kruskal-Wallis multiple-comparison z-value test with Bonferroni correction (for alpha=0.05 medians are considered significantly different if z-value >2.93).

The ROC curve depicting the ability of platelet count in identifying infants with SBI was also compared with WBC, CRP and pyuria (Fig. 2).

Fig. 2 Receiver operating characteristics curve for PLT, WBC, CRP and pyuria predicting serious bacterial infection in febrile young infants. Area under the curve (AUC) for PLT 0.74 (95%CI: 0.70–0.79); for WBC 0.72 (95%CI: 0.67–0.76); for CRP 0.75 (95%CI: 0.71–0.80); and for pyuria 0.82 (95%CI: 0.78–0.86). The AUC for WBC was significantly lower compared to the AUC for pyuria (P=0.02). No statistically significant differences were found between the AUCs of the other parameters. WBC white blood count; PLT platelets count; CRP C-reactive protein.

To explore further the utility of platelet count in identifying SBI, test characteristics were calculated for different decision thresholds (Table III). A platelet count of ³450,000/mm3 had the highest accuracy for identifying high-risk infants. At this decision threshold, 18 infants with SBI (17.4% of SBIs) were falsely classified as low-risk and 90 infants without SBI (22.0% of the study population) were falsely classified as high risk (negative LR 0.25; positive LR 2.8).

TABLE III



Test Characteristics for Different Platelet Count Thresholds
Platelet threshold n SBI Sensitivity Specificity PPV* NPV* LR + LR –
 (103/mm3)   (n) (%) (%)  (%)  (%)    
≥400 253 88 85.4 45.9 34.8 90.3 1.6 0.32
≥450 175 85 82.5 70.5 48.6 92.3 2.8 0.25
≥500 122 54 52.4 77.7 44.3 82.9 2.4 0.61
≥600 53 23 22.3 90.2 43.4 77.5 2.3 0.86

* The prevalence of SBI was 25.2% (103/408 infants); SBI: serious bacterial infection; PPV: positive predictive value; NPV: negative predictive value; LR + likelihood ratio for positive test; LR – likelihood ratio for negative test.

A combined high-risk criterion of ³15,000 /mm3 for WBC and ³10 WBC/hpf for pyuria, led to the misclassification of 17.5% of the SBIs (18 infants; negative LR 0.24), while 20.8% were falsely classified as high-risk (85 infants; positive LR 3.0). Further combination of WBC ³15000 /mm3, pyuria ³10 WBC /hpf, and CRP ³2 mg/dl, led to the misclassification of 9 infants with SBI (8.7% of SBIs; negative LR 0.16), whereas 135 infants without bacterial infection (33.1% of the population) were falsely classified as high-risk (positive LR 2.1). This 12.3% increase in the percentage of the falsely classified high-risk infants was significant (P<0.001). The addition to the above criteria of a platelet count of ³450,000/mm3, resulted in a decrease of the percentage of the misclassified SBIs to 3.9% (4 infants; negative LR 0.08), and an insignificant increase (3.6%; P=0.31) of the infants falsely classified as high-risk to approximately 36.7% (150 infants; positive LR 2.0) (Table IV).

TABLE IV



Test Characteristics for Different Decision Thresholds
Decision threshold Sensitivity (%) Specificity (%) PPV* (%) NPV* (%) LR+ LR–
WBC >15×103/mm3 52.4 78.7 45.4 83.0 2.5 0.6
Pyuria ≥10 WBC/hpf 65.0 94.1 78.8 88.9 11.0 0.37
PLT ≥450×103/mm3 82.5 70.5 48.6 92.3 2.8 0.25
CRP ≥2 mg/dL 51.5 86.6 56.4 84.1 3.8 0.56
WBC + pyuria 82.5 72.1 50.0 92.4 3.0 0.24
WBC + pyuria + CRP 91.3 55.7 41.0 95.0 2.1 0.16
WBC + pyuria + CRP + PLT 96.1 50.8 39.8 97.5 2.0 0.08

* The prevalence of SBI was 25.2% (103/408 infants) PPV: positive predictive value; NPV: negative predictive value; LR+: likelihood ratio for positive test; LR–: likelihood ratio for negative test; SBI serious bacterial infection; WBC white blood count; PLT platelets count; CRP C-reactive protein; hpf high power field.

Discussion

In this study, platelet count was significantly higher in febrile infants with documented bacterial infection, particularly in those with UTI, occult bacteremia and pneumonia. However, due to a substantial overlap, it was difficult to identify a threshold value that could clearly differentiate infants with SBI from other febrile infants. Platelet counts of ³450,000/mm3 had the highest accuracy in differentiating infants with SBI, with less false negative and false positive results. The overall ability of platelet count to identify infants with SBI was moderate (AUC 0.74), but comparable to the other parameters.

The prevalence of SBI in our population (25.2%) was quite high. This study was conducted in a tertiary care pediatric unit that represents the referral center for south-western Greece. Thus, only infants who were more ill appearing or presumably more likely to have SBI may have been referred to our unit. In fact, an appreciable percentage of well-appearing febrile infants are evaluated in primary and secondary pediatric care facilities of our region. A larger, prospective and multicenter study would yield an unbiased prevalence of SBI among young febrile infants without a source of infection and would allow for a more reliable evaluation of the predictive ability of reactive thrombocytosis.

The fact that platelets can behave like an acute phase reactant is well recognized(18-25). Stimulation of platelet production is triggered by interleukin-6 which enhances megakaryopoiesis directly and indirectly by stimulating hepatic thrombopoietin production(18,23). Yet, the role of reactive thrombocytosis, especially in the sphere of the immature immune system of young infants, needs to be further elucidated. In addition, thrombocytosis secondary to anemia is a matter of concern in this age group(18-21). In this study, platelet count was significantly higher in infants with SBI compared to those without, and this was independent to the incidence of anemia in the two groups. 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.

Contributors: SF developed the concept, helped in data collection, performed data analysis, and prepared the manuscript. LM and ES performed data collection and helped in the preparation and correction of the manuscript. AV developed the concept, interpreted the results and revised the manuscript for important intellectual content. She will act as guarantor of the study. The final manuscript was approved by all authors.

Funding: None.

Competing interest: None stated.

What is Already Known?

Reactive thrombocytosis is common in infants with bacterial infections.

What this Study Adds?

Thrombocytosis ≥450,000 cells/mm3 may help in assessing the risk for serious bacterial infection in febrile young infants.

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