key: cord-0762066-vb0002nx
authors: Liu, Kuan-Ting; Lin, Tzeng-Jih; Chan, Hon-Man
title: Characteristics of Febrile Patients with Normal White Blood Cell Counts and High C-Reactive Protein Levels in an Emergency Department
date: 2008-05-31
journal: The Kaohsiung Journal of Medical Sciences
DOI: 10.1016/s1607-551x(08)70149-9
sha: 6a8c94e2a134c4569c100a761e2b3236151b40c3
doc_id: 762066
cord_uid: vb0002nx

Fever is one of the more common chief complaints of patients who visit emergency departments (ED). Many febrile patients have markedly elevated C-reactive protein (CRP) levels and normal white blood cell (WBC) counts. Most of these patients have bacterial infection and no previous underlying disease of impaired WBC functioning. We reviewed patients who visited our ED between November 2003 and July 2004. The WBC count and CRP level of patients over 18 years of age who visited the ED because of or with fever were recorded. Patients who had normal WBC count (4,000–10,000/mL) and high CRP level (> 100 mg/L) were included. The data, including gender, age and length of hospital stay, were reviewed. Underlying diseases, diagnosis of the febrile disease and final condition were recorded according to the chart. Within the study period, 54,078 patients visited our ED. Of 5,628 febrile adults, 214 (3.8%) had elevated CRP level and normal WBC count. The major cause of febrility was infection (82.24%). Most of these patients were admitted (92.99%). There were 32 patients with malignant neoplasm, nine with liver cirrhosis, 66 with diabetes mellitus and 11 with uremia. There were no significant differences in age and gender between patients with and those without neoplasm. However, a higher inhospital mortality rate and other causes of febrility were noted in patients with neoplasm. It was not rare in febrile patients who visited the ED to have a high CRP level but normal WBC count. These patients did not necessarily have an underlying malignant neoplasm or hematologic illness. Factors other than malignant neoplasm or hematologic illness may be associated with the WBC response, and CRP may be a better indicator of infection under such conditions.

examine febrile patients. Sometimes, they have significant symptoms and signs, and the diagnosis can be made by suitable examination. On other occasions, however, patients do not have obvious symptoms and signs, although physicians need an indicator to avoid a failure to diagnose severe disease.

In febrile patients, white blood cell (WBC) count is a common examination. In addition, procalcitonin, C-reactive protein (CRP) and interleukin-6 levels will be elevated in cases of severe infection [1] [2] [3] [4] [5] [6] [7] . Some studies suggest that these examinations could help to differentiate between less threatening fever and septic patients. CRP is a common available examination item in Taiwan's hospitals. In practice, however, WBC count and CRP are not always elevated at the same time [8] [9] [10] . Some obviously septic patients do not have elevated WBC count but their CRP is markedly elevated. Such a condition can also be found in some patients with hematologic disease and neoplasm [11, 12] .

We found that many patients without hematologic disease and neoplasm have normal WBC count and markedly elevated CRP. These patients usually have obvious infection or inflammation. Therefore, we analyzed the characteristics of these patients, and then compared them with those of patients with malignancy.

We retrospectively reviewed patients who visited the ED of Kaohsiung Medical University Hospital between November 2003 and July 2004 because of fever or high body temperature (tympanic temperature > 38.3°C). Because the period of study was within 1 year of the severe acute respiratory syndrome (SARS) outbreak, all febrile patients received blood examinations including WBC count and CRP level. Adult patients (> 18 years) who had normal WBC counts (4,000-10,000/μL) and high CRP levels (> 100 mg/L) were included for further analysis. Patient characteristics including gender and age were recorded. Underlying diseases including diabetes mellitus, end-stage renal disease, liver cirrhosis and malignant neoplasm were recorded by history taking and examination in hospital. The diagnosis and final condition on discharge from hospital were determined according to the chart records filled in by the doctor in charge of the ward or ED. Student's t test was used to compare age and days of hospitalization between patients with and those without underlying malignant neoplasm and/or hematologic disease. χ 2 and Fisher's exact tests were used to examine the correlation between gender, cause of fever, hospitalization, type of infection and mortality with underlying malignant neoplasm and/or hematologic disease.

Within the study period, 54,078 patients visited our ED. Of 5,628 febrile adults, 214 (3.8%) had an elevated CRP level and normal WBC count. The age of these patients ranged from 20 to 97 years. The characteristics of these patients are shown in Table 1 . There were 32 patients with malignant neoplasm, nine with liver cirrhosis, 66 with diabetes mellitus and 11 with uremia. The major cause of febrility was infection (82.24%). Pneumonia and urinary tract infection were the leading diagnoses of infection ( Table 2) . Most of the patients *Data presented as mean ± standard deviation or n (%). were admitted (92.99%). There were no significant differences in age and gender between patients with and those without neoplasm (Table 3 ). However, a higher inhospital mortality rate and other causes of febrility were noted in patients with neoplasm.

Febrile patients who have normal WBC counts and elevated CRP levels usually have infection (82.24%). CRP is an acute-phase reactant produced by the liver that can increase markedly in response to infection or inflammation. In a previous study [13] , markedly increased CRP level (> 100 mg/L) was highly associated with severe sepsis. This makes it possible to distinguish pyelonephritis from cystitis, bacterial pneumonia from acute bronchitis, acute bronchitis from uncomplicated acute or chronic obstructive pulmonary disease, and bacterial meningitis from aseptic meningitis. However, the range of elevation is large: the higher the CRP level, the more sensitivity there is to an association with sepsis. For this reason, a cutoff point of 100 mg/L was selected in this study for its higher ability to detect the factor results in normal WBC counts in those patients. In Putto et al's study [14] , CRP of > 40 mg/L could detect 79% of bacterial infection with 90% specificity. However, CRP of 20-40 mg/L has been recorded in both viral and bacterial infections. Many studies found that CRP was more sensitive than WBC counts in distinguishing bacterial infection [1, 10] .

Many studies have focused on the use of CRP in patients with malignancy, hematologic disease or neutropenia, because these patients do not have normal WBC response to infection [3, 4, 12, [15] [16] [17] [18] [19] [20] [21] [22] . Such studies have shown that CRP could help to diagnose sepsis in such patients. In a study of children with cancer, Santolaya et al [18] showed that patients with CRP level > 40 mg/L had bacterial infection (sensitivity of 100%, specificity of 76.6%). Arber et al [12] found that levels of CRP in sepsis were higher than in graft-versushost disease. Although CRP is elevated in cancer itself, fever with elevated CRP could still reveal infection. Most of the patients in our study did not have malignancy or hematologic disease, but WBC count did not increase in those with infections. Although some of these patients had chronic disease, further study is needed to determine the cause of impaired WBC response in these patients. Other biomarkers like CRP may be more suitable to detect infection in such patients. In our study, there were no differences in age and gender between patients with and those without malignancy. Although most causes of febrility were infection in both types of patients, patients with malignancy still had higher incidences of causes of febrility other than infection. The inhospital mortality rate was higher in patients with malignancy. Our data did not attribute the mortality to the difference in severity of infection or underlying malignancy. The patients with malignancy had a greater possibility of having a rare infection or multiple site infection.

As fever is one of the most common complaints of patients who visit the ED, it is very important to [1, 4, 5, 7, 23] .

Although studies have shown the value of these examinations, the majority, except for CRP and WBC count, are unavailable in the ED of most hospitals. Most infections can be diagnosed by clinical symptoms and signs, but diagnosis may be difficult in patients who cannot express their symptoms well, such as children.

Accordingly, CRP could be used in febrile children [1, 7, 16, 18, [23] [24] [25] [26] to distinguish bacterial infection. Furthermore, the causes of febrility may be difficult to distinguish in some situations including trauma [27] and bone marrow transplantation [12] . The CRP level test has value in such cases. Furthermore, many infectious or inflammatory diseases have no specific symptoms; marked elevation of CRP has significant diagnostic value in such cases as well.

There are several limitations to this study. First, the major goal of the study was to analyze the characteristics of febrile patients with normal WBC count and high CRP level. We lacked the data to confirm the roles in differential sepsis in this study. Secondly, this study did not determine whether CRP itself affects the disposition of the doctors. Further study is necessary to determine if doctors tend to suggest that patients with high CRP level be hospitalized. Finally, this study analyzed the data in an ED, so the results can be applied to patients in an ED, but it did not determine if these patients had normal WBC counts throughout the course of disease or whether some patients developed high CRP levels during the course of the disease.

It was not rare for febrile patients who visited the ED to have high CRP level but normal WBC count. These patients usually had significant infection or inflammation and needed hospitalization and further treatment, but they did not necessarily have an underlying malignant neoplasm or hematologic illness. This suggests that some factors other than malignant neoplasm or hematologic illness may be associated with the WBC response, and that CRP may be a better indicator of infection under such conditions. Further studies are needed to elucidate what these factors may be. We believe that it is reasonable to check CRP level in addition to WBC count for patients who visit the ED due to fever. 

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