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Journal club: Use of leukocyte count and differential in the evaluation of abdominal pain
Journal Club: Use of Leukocyte Count and Differential in the Evaluation of Abdominal Pain ERIC A. DAVIS, MD, HOWARD A. WERMAN, DOUGLAS A. RUND, MD Ohio State University
College
of Medicine
Dr. Davis: The topic of the journal club today is the use of the leukocyte count and differential in the assessment of abdominal pain. Clearly, this is an important subject. Not only do many patients present to the emergency department with a chief complaint of abdominal pain, but in virtually all of these cases, a leukocyte count and differential is ordered. Many of the articles focus on the use of the leukocyte count and differential in distinguishing appendicitis from other causes of right lower quadrant abdominal pain. Only recently have studies begun to appear that address the more relevent question of the value of the leukocyte count and differential in determining significant causes of abdominal pain. The leukocyte count and differential are among the most common laboratory tests ordered in the emergency department. Despite their frequent use, physicians rarely realize the limitations associated with these tests. There are several potential sources of variability that are inherent in the leukocyte count and differential. Three major types of error have been identified. Mechanical error is introduced into the process in preparation of the samples for analysis. In the case of the leukocyte count, the important step involves lysis of erythrocytes. If this is inadequate, a falsely elevated leukocyte count is noted. If leukocytes are lysed in addition to erythrocytes, the reported leukocyte count is falsely lowered. The most common method of slide preparation for a differential count introduces error by distributing largers cells to the periphery of the smear, resulting in a non-uniform distribution of leukocytes. The second source of error is inter-technician variability, which can acount for discrepancies of as much as 8- 10% in the differential count of the same smear. Finally, there is sampling error, the variability in the differential count introduced when one attempts to define the true distribution of 50,000,OOO circulating leukocytes by counting a sample of only 100-200. In addition to these sources of error, there is an inherent variation in these tests that occurs with differences in age, sex. smoking habits, and race. Thus, there are many sources of potential variability that exist in the leukocyte count, and particularly the differential, that limit the usefulness of these tests as diagnostic tools. One final point that deserves comment is the apparent interpretative errors in the differential that occur when the re-
Address reprint requests to Dr. Rund: Division of Emergency Medicine, Rhodes Hall, University Hospitals, 450 W. 10th Ave., Columbus, OH 43210-1228. 482
MD,
sult is reported as percentage, instead of an absolute number. Wessen (Lancet 1980;1:552) reporting on 122 healthy males, found that 51% of their counts showed at least one abnormal value when expressed as percentages, whereas only 10% were outside the normal range when reported as absolute counts. The importance of this point will become clear in the discussion. Acute appendicitis in children. 1963;106:938-942.
Lansden
F. Am J Surg
Dr. Howard Bernstein: This is an early retrospective study of 1,000 children with a mean age of 9.8 years who were taken to surgery for suspected appendicitis. The physicians making the diagnosis were not blinded to the leukocyte count. The author reported significant leukocytosis (values unreported in the paper) in 84% of patients with histologically proven appendicitis and a left-shift (not defined) in 88%. In contrast, 58% of those patients with a normal appendix at the time of surgery had an absence of leukocytosis, left shift, or both. The authors concluded that an elevated leukocyte count and a left-shift on the differential count support the diagnosis of appendicitis. Those patients with a normal leukocyte count and differential should be considered for observation with repeated examination and laboratory studies.
Commentary Dr. Davis: This often-quoted early study documents how long this debate has been waged. Because it is a retrospective study, it is hard to separate out the effect of the leukocyte count and differential on the surgeons’ decision to operate and, thus, remove this bias from the study. Additionally, the focus of the study is very narrow, limited only to operative cases of suspected appendicitis. This study does not examine the population of interest to the emergency physician, i.e., patients presenting with general complaints of abdominal pain. importantly, the author neglected to define the exact limits of leukocytosis and left shift, nor was any consideration given to age variation. Dr. Berstein: Although the author supports the use of the leukocyte count as a diagnostic tool in appendicitis, it must be noted that 16% of those with a histologically normal appendix had a normal leukocyte count, and a large percentage of those with a normal appendix had an elevated leukocyte count. Also, there is really no control group used in this retrospective study. Although the author supports the use of the leukocyte
JOURNAL
count and differential in the diagnosis of acute appendicitis, the problems in the study largely negate his findings. Diagnostic value of the white blood cell count and neutrophil percentage in the evaluation of abdominal pain in children. Bower R, Bell M, Tomberg J. Surg Gynecol Obstet 1981;152:424-426. Dr. Warren Yamarick: This retrospective study evaluates the leukocyte count and neutrophil percentage in a group of children undergoing surgery for suspected appendicitis. Only the initial leukocyte count and neutrophil percentage were included. Adjustment was made for the increase in the normal neutrophil percentage that occurs with age, using the upper limits of normal to be 50% up to the age of 5 years, 65% from ages 5 through 10 years, and 75% for children 11 years old or older. A total of 484 patients were included, and three groups of patients were defined. Of these, 382 patients had histologically proven appendicitis, 27 had a normal appendix but other pathological findings at the time of surgery, and 71 patients had no abnormality found at operation. The authors found that of the patients with histologically proven appendicitis, 51 had a normal leukocyte count, 31 had a normal neutrophil percentage, and only 15 had both a normal leukocyte count and neutrophil percentage. These values were statistically different from those patients without abnormalities identified at laparotomy. Twenty nine (41%) of these patients had both a normal leukocyte count and neutrophil percentage. The patients with a normal appendix but other pathological findings formed an intermediate group with a greater number of abnormal elevations in leukocyte counts and neutrophil percentage than those with normal appendices. The authors thus concluded that although an elevated leukocyte count or neutrophil percentage can support the diagnosis of appendicitis, it does not distinguish other inflammatory processes. A normal value for these laboratory tests may help distinguish a group of patients who may benefit from further re-evaluation and observation instead of undergoing unnecessary laparotomy.
Commentary Dr. Yamarick: This study begins to address some of the criticisms raised in the previous discussion. This authors adjusted the normal limits of the neutrophil percentage based on the patient’s age. Unfortunately, a similar correction should have been used for the leukocyte count. These authors perform statistical comparisons on the differences in abnormal values between the three groups. In this case, however, this does not give the reader a true sense of the ability of each laboratory test to distinguish between certain clinical states (inflamed versus normal appendix). This may be more appropriately demonstrated by calculating the test’s sensitivity and specificity. There can be some doubt regarding the usefulness of the neutrophil percentage found in this study. The introductory remarks referred to the errors associated with a differential count performed on a peripheral smear. In this case, only 100 cells were counted. In addition, the importance of expressing the results as an absolute count in order to minimize factitious abnormalities has already been emphasized. All of these considerations suggest that the differences in
neutrophil studies.
percentage
would
not be supported
CLUB
in other
Dr. Werman: This report does suggest that the diagnosis of acute appendicitis should be made cautiously in patients with a normal leukocyte count, a point that will be re-emphasized in other studies. It should also be noted that although this study focuses primarily on acute appendicitis, there is the inclusion of a third group of patients with other pathological findings at the time of surgery. The ability of the leukocyte count and differential to distinguish this group from those with a histologically normal appendix is less clear. This finding begins to suggest that the leukocyte count may not be very useful in differentiating significant causes of abdominal pain from less significant causes.
An assessment of the value of the white cell count in the management of suspected acute appendicitis. Bolton JP, Craven ER, Croft RJ, et al. Br J Surg 1975;62:906-908. Dr. Gregory Hess: The purpose of this article was to examine the leukocyte count and its value in the management of appendicitis. The first part of the study was a prospective evaluation of the effect of the leukocyte count on the initial treatment plan in patients with suspected appendicitis. In addition, the authors examined the neutrophil morphology retrospectively to determine the possible diagnostic value of this laboratory test in patients with suspected appendicitis. Of the 100 patients included in the analysis, 51 underwent immediate operation. Forty six of these patients had histologically proven appendicitis. The remaining 49 patients were observed and did not develop further signs of acute appendicitis. In 61 of the 100 patients the leukocyte count supported the diagnosis; that is, it was elevated in patients with appendicitis and normal in those observed. The remaining 39 patients had some conflict between the leukocyte count and the presence or absence of appendicitis. Twenty nine of the 39 patients proved to have the correct diagnosis based on clinical findings. In ten other patients, use of the leukocyte count (neglecting the clinical findings) would have lead to correct management of the patient. In reviewing the differential counts, 78% of the patients with proven appendicitis demonstrated some abnormality, as did 41% of the non-appendicitis cases. The presence of a left shift or toxic granulations was found in 24% of appendicitis cases and 11% of non-appendicitis cases. The authors concluded that there was considerable overlap in the leukocyte count, total neutrophil, and neutrophi1 morphologic abnormalities between patients with appendicitis and those with suspicious abdominal pain. The study suggests that when the leukocyte count is in conflict with the clinical findings, relying on the laboratory test will lead to improper management in a majority of cases.
Commentary Dr. Hess: Several important points are notable regarding the study design. The method of determining the leukocyte count is clearly stated (Coulter counter). There was, however, no attempt to present demographic data on the study population, nor were the leukocyte or total neutrophil counts corrected for age. 483
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Most importantly, the approach taken by these authors does not appear to be clinically relevant. It appears as if the study is addressing the question of which is a better predictor of acute appendicitis: the historical and physical findings or the leukocyte count. The more important question seems to be the value of the leukocyte count in equivocal cases once the history and physical examination are not strongly suggestive of acute appendicitis. As will be seen, this question is addressed in subsequent studies. Dr. Werman: Once again, it must be pointed out that this study is limited in scope, focusing on the specific problem of acute appendicitis. This does not begin to address the larger question of the utility of the leukocyte count in the patient presenting to the emergency department with acute abdominal pain. More important, it is not surprising that investigations that confine the study population to patients either undergoing surgery or admitted for observation demonstrate considerable overlap in the leukocyte count among the groups studied. This is because in most cases, the elevation in the leukocyte count is one factor that leads to a clinical suspicion of appendicitis. Thus, there is a selective bias for patients with elevated leukocyte counts present in the study design, lessening the likelihood of finding useful diagnostic value in the test. Leukocyte count in the diagnosis and prognosis of acute appendicitis in children. Doraiswamy NV. Br J Surg 1979;66:782-784. Dr. David Lemak: In one of the most widely quoted articles on the use of the leukocyte count in children, the author examines the total leukocyte count and differential in 225 children with histologically proven appendicitis, 50 children with a normal appendix at the time of surgery, and 100 children with acute abdominal pain who recovered without intervention. Any child aged 5- 15 years was eligible for inclusion in the study. The total leukocyte count and neutrophi1 percentage were adjusted for the patient’s age. The author found that the neutrophil percentage was increased in 216 (96%) of those patients with appendicitis, but in only 15 (30%) and 32 (32%) of the remaining groups. This difference was found to be statistically significant. In addition, they found a significantly higher leukocyte count in the appendicitis group when compared with the remaining two groups, but it was noted that 131 (58%) of the patients with appendicitis had a normal leukocyte count. These findings lead the author to suggest that an elevated neutrophil percentage on the differential count is a useful diagnostic tool in acute appendicitis. This author also cautioned that the diagnosis of acute appendicitis should be made with reservation in the presence of a normal differential count. The leukocyte count, while significantly different among the three groups, did not appear to be helpful in this study.
Commentary Dr. Davis: This report begins to address some of the concerns raised in previous discussions. The authors of this paper have been careful to adjust the leukocyte count and neutrophil percentage for age. As can be seen in the text, there are appreciable differences in the upper limits of 484
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normal for the leukocyte count (a leukocyte count of up to 15,000 cell/mm3 is normal for a five year old). In addition, these authors considered not only patients who had a normal appendix at the time of surgery, but also those who were admitted with abdominal pain and improved without intervention. Unfortunately, this is a retrospective study, and it is unclear what effect an elevated leukocyte count had on the decision to operate for suspected appendicitis. The authors of this study suggest that an elevated neutrophi1 percentage is useful in distinguishing acute appendicitis from other causes of abdominal pain. In addition, they point out that acute appendicitis is unlikely when the neutrophil percentage is normal. Based on our prior discussions of the inherent errors associated with the differential count, it seems unlikely that these results could be supported by other studies. In fact, the authors of the previous study concluded that this same test was not useful in the diagnosis of acute appendicitis. Appendicitis: A critical review of diagnosis and treatment of 1,000 cases. Lewis FR, Bolcroft JW, Boey J, et al. Arch Surg 1975;110:677-682. Dr. Ronald Taylor: In this study, 1,000 consecutive cases of patients with suspected appendicitis who underwent surgery were retrospectively studied, and 40 independent variables were analyzed. The negative apendectomy rate was 20%. with 12.3% in males and 33.8% in females. Pelvic inflammatory disease (PID) was the most commonly mistaken diagnosis. In evaluating the used of the leukocyte count in the diagnosis of appendicitis, it was discovered that the mean leukocyte count was 15,000 cells/mm3 and the average neutrophil percentage was between 80 and 84%, depending on the degree of appendiceal perforation. This was significantly different from the mean leukocyte count of between 11,500 and 12,470 cells/mm3 for mesenteric adenitis, gastroenteritis, and abdominal pain of unknown etiology. There was, however, no statistically significant difference between the mean leukocyte count and neutrophil percentage for acute appendicitis and PID. The authors concluded that although significant overlap did exist in the leukocyte count and differential these tests were still useful in establishing the diagnosis of acute appendicitis.
Commentary Dr. Taylor: This study is useful in that it begins to address one question of interest to the emergency physician-what is the use of the leukocyte count in distinguishing acute appendicitis from other important causes of abdominal pain? The results of the study suggest that the leukocyte count and neutrophil percentage may be useful in separating acute appendicitis from mesenteric adenitis, gastroenteritis, and abdominal pain of unknown etiology. On the other hand, the study clearly shows that there is difficulty in distinguishing appendicitis from PID on the basis of these laboratory tests. Unfortunately, expressing the results as a mean plus or minus the standard deviation is not the most effective method of demonstrating the utility of the test. Stating the sensitivity and specificity of the tests would have better shown the overlap in the leukocyte count and neutrophil percentage that the authors alluded to in their discussion.
JOURNAL
The white cell count in acute appendicitis: A prospective blind study. Miskowiak J, Burcharth F. Dan Med Bull 1982;29:210-211. Dr. Frmk Birinyi: This was a prospective study designed to evaluate the value of the leukocyte count in establishing the diagnosis of acute appendicitis. The authors followed 3 12 consecutive patients suspected of having appendicitis and witheld the results of the admission leukocyte count and subsequent counts that were done during the patient’s hospitalization. The group consisted of 238 adults and 74 children, of which 167 went on to have surgery performed. Of the 167 operative cases, 100 involved histologically proven appendicitis. The authors compared two groups of patients, those with proven appendicitis and those who were either observed or underwent operation and were found not to have appendicitis. The authors found a considerable overlap of the leukocyte counts between to two groups. The positive predictive value of leukocytosis for appendicitis was low for both children and adults (0.55 and 0.33. respectively). The negative predictive value for the leukocyte count was good for adults (0.89), but much less so for children (0.72). Three cases were reported of children with a perforated appendix and a normal leukocyte count.
CLUB
or 75% had the highest sensitivity (81-84%), with a specificity of 76% for the neutrophil count and 62% for the neutrophil percentage. In contrast, the manual band count and percentage had sensitivities of only 53% and 64%, respectively, with the manual band count having an 81% specificity. There was no difference in the positive predictive value for any of the tests studied. The leukocyte count and the absolute neutrophil count showed a significantly better negative predictive value than the other laboratory tests. The authors next considered the sensitivity, specificity, and predictive value of various combinations of these tests. The combination of a leukocyte count above 10.5 x 109/1,a neutrophil percentage above 75%. and either an absolute neutrophil count greater than 7.88 x 109/1 or a C-reactive protein level above 1.2 mg/dl had a 97% sensitivity. If an absolute band count of more than 1.15 x 109/1 or greater than 11% were used, the sensitivity was 100%. The specificity of these test ranged from 42 to 53%. The authors concluded that an elevated leukocyte count, neutrophil percentage, or absolute neutrophil count is supportive of acute appendicitis in a patient with a suggestive history and physical examination results. When these tests are all within the normal range, the patient should be considered for clinical observation.
Commentary
Commentary
Dr. Rund: This study provides further evidence that a normal leukocyte count is helpful in excluding the diagnosis of appendicitis. Elevations in the leukocyte count are nonspecific and can occur in other conditions that may give rise to physical findings suggestive of acute appendicitis. This is supported by the poor positive predictive value found with the leukocyte count in this study. It must be argued, on the other hand, that the negative operative rate in this study (40%) is extraordinarily high. It is possible that knowledge of the leukocyte count could have improved on the large number of negative appendectomies reported in this study. Unfortunately, the study was not designed to test this hypothesis.
Dr. Davis: Although this report appears to define a population in which the diagnosis of acute appendicitis can be safely excluded, one must be aware of the limitations of this study. Once again, these authors fail to correct their normal values for the age of the patient. In addition, their information is derived only from those patients in which the clinical suspicion of acute appendicitis was strong enough to merit an operation. As a result, this study does not address the crucial question of how the laboratory results effect the decision process in a patient with an equivocal history or physical findings. Also, because the predictive value of any test is dependent on the prevalence of the disease in the population studied, one cannot apply the findings of this study to all patients with a complaint of abdominal pain. Dr. Werman: The fact that the absolute neutrophil count as determined by cytochemical methods was found to be a significant predictor of acute appendicitis is not contradictory to our previous remarks regarding manual differential counts. When the neutrophil count is determined in this manner, tens of thousands of cells are counts (as opposed to only 100-200 for manual methods), which results in a large reduction in the sampling error associated with this test.
The assessment of laboratory tests in the diagnosis of acute appendicitis. Marchand A, Van Lente F, Galen RS. Am J Clin Pathol 1983;80:369-374. Dr. Cheryl Lee: In this study, the authors set out to evaluate the predictive value of several laboratory tests for the diagnosis of acute appendicitis in a group of patients presenting to the emergency department who subsequently underwent surgical exploration. The study consisted of 106 patients ranging in age from 2 to 81 years. Each patient had laboratory studies including those for leukocyte count, manual and cytochemical differential count, and C-reactive protein. The normal values for each of these studies was determined from a sample of 64 healthy hospital employees. Patients were then classified into two groups based on the pathological findings at the time of surgery: 1) acute appendicitis with or without evidence of perforation (85 patients) or 2) no appendicitis (21 patients). In evaluating each of the individual tests, the authors found that a leukocyte count of greater than 10.5 x lo”/1 and a cytochemical neutrophil count of greater than 7.88 x lo”/1
Abdominal pain: An analysis of 1,000 consecutive cases in a university hospital emergency room. Brewer RJ, Golden GT, Hitch DC, et al. Am J Surg 1976;131:219-223. Dr. Theresa Bridges: This article is a retrospective study of 1,000 consecutive patients presenting to an emergency department with the chief complaint of abdominal pain. The purpose of the study was to 1) determine the causes of abdominal pain in a large series of patients, 2) evaluate the effectiveness of the emergency department in determining the causes of abdominal pain, and 3) outline features frequently associated with the acute surgical abdomen and as485
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sess their values as screening tools. Although the article addresses many aspects of the diagnosis of abdominal pain, certain findings with regard to the leukocyte count are particularly interesting. Ninety-five percent of the patients had a leukocyte count drawn with 40% being greater than 10,000 cells/mm3. In those patients who required surgery and were younger than 65 years old, 71% had an elevated leukocyte count. Interestingly, in those patients who underwent surgery and who were older than 65 years. only 39% had an elevated leukocyte count. Acute appendicitis was associated with an elevated leukocyte count in 91% of cases, a statistically significantly higher percentage than the next two leading causes (acute cholecystitis [78%] and intestinal obstruction [56%]). Nonsurgical causes of abdominal pain showed an elevation in the leukocyte count in between 31 and 43% of cases. The authors of this study suggest that although an elevated leukocyte count is seen more often in surgical disease, it is also present in a significant number of nonsurgical cases. Thus, the leukocyte count can only be viewed as supporting evidence of disease requiring surgery. In addition, the authors indicate that the absence of leukocytosis is common in patients over age 65 with surgically treated disease, and leukocyte count is thus an unreliable test in this population.
Commentary Dr. Rund: Although this is a retrospective study, it is the first to address a question crucial to the emergency physician. This study attempts to examine the value of the leukocyte count in all patients presenting to the emergency department with abdominal pain. The inclusion of a large number of patients with nonsurgical causes of abdominal pain is critical and gives the emergency physician a better sense of the ability of the leukocyte count to distinguish this group from those with surgical disease. Once again, if the results were expressed in terms of sensitivity and specificity of the leukocyte count, this would give the reader a clearer appreciation for the overlap in these two groups. Dr. Davis: This is the first study to consider that group of patients over age 65 as a separate group. Their findings, that an elevation of the leukocyte count in patients with surgically treated disease is often absent, is significant. This is similar to the findings in children in whom advanced disease may be present in the absence of an elevated leukocyte count.
CONCLUSION Dr. Davis: In reviewing the reports on the use of the leukocyte count and differential in the diagnosis of abdomina1 pain, we have seen that the vast majority of these reports focus on the use of this test in acute appendicitis. The data in this area are sometimes conflicting, but several conclusions can be drawn. The study by Bolton et al clearly demonstrates that the history and physical examination are the most important factors in determining the presence of acute
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appendicitis. It is rare for patients with a suggestive history and physical examination results to have their management correctly determined by reliance on a normal leukocyte count. Thus, it appears that the value of the leukocyte count and total neutrophil count lies in the patient with equivocal findings. Few studies have actually been undertaken to examine this specific group of patients. However, some conclusions can be drawn from the other studies that were discussed. In the adult patient with an atypical presentation who has a normal leukocyte count and a normal absolute, the likelihood of appendicitis is low. This patient could benefit from hospitalization and further observation. In children or patients older than 6S years of age, one should feel less comfortable with a normal leukocyte count. These patients have been reported to have advanced appendicitis with perforation and a normal leukocyte count. Thus. in this group of patients, surgical exploration appears justified if there is any clinical suspicion of appendicitis or other surgically treated pathology. Dr. Wermatz: Our discussions have identified several problems common to many of the studies in this area. Most important, few studies adjust the leukocyte count and differential for factors that have been shown to influence this laboratory value. These include the patient’s age, sex, race. and history of cigarette smoking. Additionally, most studies have not included an adequate control group to assess the ability of the leukocyte count to distinguish between those patients with appendicitis and those with abdominal pain but without acute appendicitis. Finally, although many of the authors commented on the overlap that occurred in the values for the leukocyte count, neutrophil count, and the neutrophil percentage between patients with acute appendicitis and those without this process. few authors actually expressed their results in terms of the sensitivity, specificity, and predictive value for these tests. It is also apparent that the data on the use of the differential count in the diagnosis of acute abdominal pain are very conflicting. Although the studies of Doraiswamy. and Miskowiak and Burcharth. seem to find these tests useful in the diagnosis of acute appendicitis, Bolton et a/ found the differential and neutrophil morphology to be of little value. This is probably a reflection of the inherent errors associated with the performance of a manual differential count. Dr. Rand: As stated previously, most of the studies on the use of the leukocyte count in acute abdominal pain have focused on the diagnosis of acute appendicitis. The studies by Brewer et al and Lewis et al begin to address some of the crucial questions for the emergency physician: I) what is the value of the leukocyte count in separating significant causes of abdominal pain from those that require no specific therapy, and 2) what is the value of the leukocyte count in distinguishing different inflammatory processes (acute appendicitis and PID) in which therapy may be markedly different. Obviously, what is needed is a large, prospective study that can assess the value of the leukocyte count in the decision-making process for patients with acute abdominal pain.
College
of Medicine
Dr. Davis: The topic of the journal club today is the use of the leukocyte count and differential in the assessment of abdominal pain. Clearly, this is an important subject. Not only do many patients present to the emergency department with a chief complaint of abdominal pain, but in virtually all of these cases, a leukocyte count and differential is ordered. Many of the articles focus on the use of the leukocyte count and differential in distinguishing appendicitis from other causes of right lower quadrant abdominal pain. Only recently have studies begun to appear that address the more relevent question of the value of the leukocyte count and differential in determining significant causes of abdominal pain. The leukocyte count and differential are among the most common laboratory tests ordered in the emergency department. Despite their frequent use, physicians rarely realize the limitations associated with these tests. There are several potential sources of variability that are inherent in the leukocyte count and differential. Three major types of error have been identified. Mechanical error is introduced into the process in preparation of the samples for analysis. In the case of the leukocyte count, the important step involves lysis of erythrocytes. If this is inadequate, a falsely elevated leukocyte count is noted. If leukocytes are lysed in addition to erythrocytes, the reported leukocyte count is falsely lowered. The most common method of slide preparation for a differential count introduces error by distributing largers cells to the periphery of the smear, resulting in a non-uniform distribution of leukocytes. The second source of error is inter-technician variability, which can acount for discrepancies of as much as 8- 10% in the differential count of the same smear. Finally, there is sampling error, the variability in the differential count introduced when one attempts to define the true distribution of 50,000,OOO circulating leukocytes by counting a sample of only 100-200. In addition to these sources of error, there is an inherent variation in these tests that occurs with differences in age, sex. smoking habits, and race. Thus, there are many sources of potential variability that exist in the leukocyte count, and particularly the differential, that limit the usefulness of these tests as diagnostic tools. One final point that deserves comment is the apparent interpretative errors in the differential that occur when the re-
Address reprint requests to Dr. Rund: Division of Emergency Medicine, Rhodes Hall, University Hospitals, 450 W. 10th Ave., Columbus, OH 43210-1228. 482
MD,
sult is reported as percentage, instead of an absolute number. Wessen (Lancet 1980;1:552) reporting on 122 healthy males, found that 51% of their counts showed at least one abnormal value when expressed as percentages, whereas only 10% were outside the normal range when reported as absolute counts. The importance of this point will become clear in the discussion. Acute appendicitis in children. 1963;106:938-942.
Lansden
F. Am J Surg
Dr. Howard Bernstein: This is an early retrospective study of 1,000 children with a mean age of 9.8 years who were taken to surgery for suspected appendicitis. The physicians making the diagnosis were not blinded to the leukocyte count. The author reported significant leukocytosis (values unreported in the paper) in 84% of patients with histologically proven appendicitis and a left-shift (not defined) in 88%. In contrast, 58% of those patients with a normal appendix at the time of surgery had an absence of leukocytosis, left shift, or both. The authors concluded that an elevated leukocyte count and a left-shift on the differential count support the diagnosis of appendicitis. Those patients with a normal leukocyte count and differential should be considered for observation with repeated examination and laboratory studies.
Commentary Dr. Davis: This often-quoted early study documents how long this debate has been waged. Because it is a retrospective study, it is hard to separate out the effect of the leukocyte count and differential on the surgeons’ decision to operate and, thus, remove this bias from the study. Additionally, the focus of the study is very narrow, limited only to operative cases of suspected appendicitis. This study does not examine the population of interest to the emergency physician, i.e., patients presenting with general complaints of abdominal pain. importantly, the author neglected to define the exact limits of leukocytosis and left shift, nor was any consideration given to age variation. Dr. Berstein: Although the author supports the use of the leukocyte count as a diagnostic tool in appendicitis, it must be noted that 16% of those with a histologically normal appendix had a normal leukocyte count, and a large percentage of those with a normal appendix had an elevated leukocyte count. Also, there is really no control group used in this retrospective study. Although the author supports the use of the leukocyte
JOURNAL
count and differential in the diagnosis of acute appendicitis, the problems in the study largely negate his findings. Diagnostic value of the white blood cell count and neutrophil percentage in the evaluation of abdominal pain in children. Bower R, Bell M, Tomberg J. Surg Gynecol Obstet 1981;152:424-426. Dr. Warren Yamarick: This retrospective study evaluates the leukocyte count and neutrophil percentage in a group of children undergoing surgery for suspected appendicitis. Only the initial leukocyte count and neutrophil percentage were included. Adjustment was made for the increase in the normal neutrophil percentage that occurs with age, using the upper limits of normal to be 50% up to the age of 5 years, 65% from ages 5 through 10 years, and 75% for children 11 years old or older. A total of 484 patients were included, and three groups of patients were defined. Of these, 382 patients had histologically proven appendicitis, 27 had a normal appendix but other pathological findings at the time of surgery, and 71 patients had no abnormality found at operation. The authors found that of the patients with histologically proven appendicitis, 51 had a normal leukocyte count, 31 had a normal neutrophil percentage, and only 15 had both a normal leukocyte count and neutrophil percentage. These values were statistically different from those patients without abnormalities identified at laparotomy. Twenty nine (41%) of these patients had both a normal leukocyte count and neutrophil percentage. The patients with a normal appendix but other pathological findings formed an intermediate group with a greater number of abnormal elevations in leukocyte counts and neutrophil percentage than those with normal appendices. The authors thus concluded that although an elevated leukocyte count or neutrophil percentage can support the diagnosis of appendicitis, it does not distinguish other inflammatory processes. A normal value for these laboratory tests may help distinguish a group of patients who may benefit from further re-evaluation and observation instead of undergoing unnecessary laparotomy.
Commentary Dr. Yamarick: This study begins to address some of the criticisms raised in the previous discussion. This authors adjusted the normal limits of the neutrophil percentage based on the patient’s age. Unfortunately, a similar correction should have been used for the leukocyte count. These authors perform statistical comparisons on the differences in abnormal values between the three groups. In this case, however, this does not give the reader a true sense of the ability of each laboratory test to distinguish between certain clinical states (inflamed versus normal appendix). This may be more appropriately demonstrated by calculating the test’s sensitivity and specificity. There can be some doubt regarding the usefulness of the neutrophil percentage found in this study. The introductory remarks referred to the errors associated with a differential count performed on a peripheral smear. In this case, only 100 cells were counted. In addition, the importance of expressing the results as an absolute count in order to minimize factitious abnormalities has already been emphasized. All of these considerations suggest that the differences in
neutrophil studies.
percentage
would
not be supported
CLUB
in other
Dr. Werman: This report does suggest that the diagnosis of acute appendicitis should be made cautiously in patients with a normal leukocyte count, a point that will be re-emphasized in other studies. It should also be noted that although this study focuses primarily on acute appendicitis, there is the inclusion of a third group of patients with other pathological findings at the time of surgery. The ability of the leukocyte count and differential to distinguish this group from those with a histologically normal appendix is less clear. This finding begins to suggest that the leukocyte count may not be very useful in differentiating significant causes of abdominal pain from less significant causes.
An assessment of the value of the white cell count in the management of suspected acute appendicitis. Bolton JP, Craven ER, Croft RJ, et al. Br J Surg 1975;62:906-908. Dr. Gregory Hess: The purpose of this article was to examine the leukocyte count and its value in the management of appendicitis. The first part of the study was a prospective evaluation of the effect of the leukocyte count on the initial treatment plan in patients with suspected appendicitis. In addition, the authors examined the neutrophil morphology retrospectively to determine the possible diagnostic value of this laboratory test in patients with suspected appendicitis. Of the 100 patients included in the analysis, 51 underwent immediate operation. Forty six of these patients had histologically proven appendicitis. The remaining 49 patients were observed and did not develop further signs of acute appendicitis. In 61 of the 100 patients the leukocyte count supported the diagnosis; that is, it was elevated in patients with appendicitis and normal in those observed. The remaining 39 patients had some conflict between the leukocyte count and the presence or absence of appendicitis. Twenty nine of the 39 patients proved to have the correct diagnosis based on clinical findings. In ten other patients, use of the leukocyte count (neglecting the clinical findings) would have lead to correct management of the patient. In reviewing the differential counts, 78% of the patients with proven appendicitis demonstrated some abnormality, as did 41% of the non-appendicitis cases. The presence of a left shift or toxic granulations was found in 24% of appendicitis cases and 11% of non-appendicitis cases. The authors concluded that there was considerable overlap in the leukocyte count, total neutrophil, and neutrophi1 morphologic abnormalities between patients with appendicitis and those with suspicious abdominal pain. The study suggests that when the leukocyte count is in conflict with the clinical findings, relying on the laboratory test will lead to improper management in a majority of cases.
Commentary Dr. Hess: Several important points are notable regarding the study design. The method of determining the leukocyte count is clearly stated (Coulter counter). There was, however, no attempt to present demographic data on the study population, nor were the leukocyte or total neutrophil counts corrected for age. 483
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Most importantly, the approach taken by these authors does not appear to be clinically relevant. It appears as if the study is addressing the question of which is a better predictor of acute appendicitis: the historical and physical findings or the leukocyte count. The more important question seems to be the value of the leukocyte count in equivocal cases once the history and physical examination are not strongly suggestive of acute appendicitis. As will be seen, this question is addressed in subsequent studies. Dr. Werman: Once again, it must be pointed out that this study is limited in scope, focusing on the specific problem of acute appendicitis. This does not begin to address the larger question of the utility of the leukocyte count in the patient presenting to the emergency department with acute abdominal pain. More important, it is not surprising that investigations that confine the study population to patients either undergoing surgery or admitted for observation demonstrate considerable overlap in the leukocyte count among the groups studied. This is because in most cases, the elevation in the leukocyte count is one factor that leads to a clinical suspicion of appendicitis. Thus, there is a selective bias for patients with elevated leukocyte counts present in the study design, lessening the likelihood of finding useful diagnostic value in the test. Leukocyte count in the diagnosis and prognosis of acute appendicitis in children. Doraiswamy NV. Br J Surg 1979;66:782-784. Dr. David Lemak: In one of the most widely quoted articles on the use of the leukocyte count in children, the author examines the total leukocyte count and differential in 225 children with histologically proven appendicitis, 50 children with a normal appendix at the time of surgery, and 100 children with acute abdominal pain who recovered without intervention. Any child aged 5- 15 years was eligible for inclusion in the study. The total leukocyte count and neutrophi1 percentage were adjusted for the patient’s age. The author found that the neutrophil percentage was increased in 216 (96%) of those patients with appendicitis, but in only 15 (30%) and 32 (32%) of the remaining groups. This difference was found to be statistically significant. In addition, they found a significantly higher leukocyte count in the appendicitis group when compared with the remaining two groups, but it was noted that 131 (58%) of the patients with appendicitis had a normal leukocyte count. These findings lead the author to suggest that an elevated neutrophil percentage on the differential count is a useful diagnostic tool in acute appendicitis. This author also cautioned that the diagnosis of acute appendicitis should be made with reservation in the presence of a normal differential count. The leukocyte count, while significantly different among the three groups, did not appear to be helpful in this study.
Commentary Dr. Davis: This report begins to address some of the concerns raised in previous discussions. The authors of this paper have been careful to adjust the leukocyte count and neutrophil percentage for age. As can be seen in the text, there are appreciable differences in the upper limits of 484
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normal for the leukocyte count (a leukocyte count of up to 15,000 cell/mm3 is normal for a five year old). In addition, these authors considered not only patients who had a normal appendix at the time of surgery, but also those who were admitted with abdominal pain and improved without intervention. Unfortunately, this is a retrospective study, and it is unclear what effect an elevated leukocyte count had on the decision to operate for suspected appendicitis. The authors of this study suggest that an elevated neutrophi1 percentage is useful in distinguishing acute appendicitis from other causes of abdominal pain. In addition, they point out that acute appendicitis is unlikely when the neutrophil percentage is normal. Based on our prior discussions of the inherent errors associated with the differential count, it seems unlikely that these results could be supported by other studies. In fact, the authors of the previous study concluded that this same test was not useful in the diagnosis of acute appendicitis. Appendicitis: A critical review of diagnosis and treatment of 1,000 cases. Lewis FR, Bolcroft JW, Boey J, et al. Arch Surg 1975;110:677-682. Dr. Ronald Taylor: In this study, 1,000 consecutive cases of patients with suspected appendicitis who underwent surgery were retrospectively studied, and 40 independent variables were analyzed. The negative apendectomy rate was 20%. with 12.3% in males and 33.8% in females. Pelvic inflammatory disease (PID) was the most commonly mistaken diagnosis. In evaluating the used of the leukocyte count in the diagnosis of appendicitis, it was discovered that the mean leukocyte count was 15,000 cells/mm3 and the average neutrophil percentage was between 80 and 84%, depending on the degree of appendiceal perforation. This was significantly different from the mean leukocyte count of between 11,500 and 12,470 cells/mm3 for mesenteric adenitis, gastroenteritis, and abdominal pain of unknown etiology. There was, however, no statistically significant difference between the mean leukocyte count and neutrophil percentage for acute appendicitis and PID. The authors concluded that although significant overlap did exist in the leukocyte count and differential these tests were still useful in establishing the diagnosis of acute appendicitis.
Commentary Dr. Taylor: This study is useful in that it begins to address one question of interest to the emergency physician-what is the use of the leukocyte count in distinguishing acute appendicitis from other important causes of abdominal pain? The results of the study suggest that the leukocyte count and neutrophil percentage may be useful in separating acute appendicitis from mesenteric adenitis, gastroenteritis, and abdominal pain of unknown etiology. On the other hand, the study clearly shows that there is difficulty in distinguishing appendicitis from PID on the basis of these laboratory tests. Unfortunately, expressing the results as a mean plus or minus the standard deviation is not the most effective method of demonstrating the utility of the test. Stating the sensitivity and specificity of the tests would have better shown the overlap in the leukocyte count and neutrophil percentage that the authors alluded to in their discussion.
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The white cell count in acute appendicitis: A prospective blind study. Miskowiak J, Burcharth F. Dan Med Bull 1982;29:210-211. Dr. Frmk Birinyi: This was a prospective study designed to evaluate the value of the leukocyte count in establishing the diagnosis of acute appendicitis. The authors followed 3 12 consecutive patients suspected of having appendicitis and witheld the results of the admission leukocyte count and subsequent counts that were done during the patient’s hospitalization. The group consisted of 238 adults and 74 children, of which 167 went on to have surgery performed. Of the 167 operative cases, 100 involved histologically proven appendicitis. The authors compared two groups of patients, those with proven appendicitis and those who were either observed or underwent operation and were found not to have appendicitis. The authors found a considerable overlap of the leukocyte counts between to two groups. The positive predictive value of leukocytosis for appendicitis was low for both children and adults (0.55 and 0.33. respectively). The negative predictive value for the leukocyte count was good for adults (0.89), but much less so for children (0.72). Three cases were reported of children with a perforated appendix and a normal leukocyte count.
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or 75% had the highest sensitivity (81-84%), with a specificity of 76% for the neutrophil count and 62% for the neutrophil percentage. In contrast, the manual band count and percentage had sensitivities of only 53% and 64%, respectively, with the manual band count having an 81% specificity. There was no difference in the positive predictive value for any of the tests studied. The leukocyte count and the absolute neutrophil count showed a significantly better negative predictive value than the other laboratory tests. The authors next considered the sensitivity, specificity, and predictive value of various combinations of these tests. The combination of a leukocyte count above 10.5 x 109/1,a neutrophil percentage above 75%. and either an absolute neutrophil count greater than 7.88 x 109/1 or a C-reactive protein level above 1.2 mg/dl had a 97% sensitivity. If an absolute band count of more than 1.15 x 109/1 or greater than 11% were used, the sensitivity was 100%. The specificity of these test ranged from 42 to 53%. The authors concluded that an elevated leukocyte count, neutrophil percentage, or absolute neutrophil count is supportive of acute appendicitis in a patient with a suggestive history and physical examination results. When these tests are all within the normal range, the patient should be considered for clinical observation.
Commentary
Commentary
Dr. Rund: This study provides further evidence that a normal leukocyte count is helpful in excluding the diagnosis of appendicitis. Elevations in the leukocyte count are nonspecific and can occur in other conditions that may give rise to physical findings suggestive of acute appendicitis. This is supported by the poor positive predictive value found with the leukocyte count in this study. It must be argued, on the other hand, that the negative operative rate in this study (40%) is extraordinarily high. It is possible that knowledge of the leukocyte count could have improved on the large number of negative appendectomies reported in this study. Unfortunately, the study was not designed to test this hypothesis.
Dr. Davis: Although this report appears to define a population in which the diagnosis of acute appendicitis can be safely excluded, one must be aware of the limitations of this study. Once again, these authors fail to correct their normal values for the age of the patient. In addition, their information is derived only from those patients in which the clinical suspicion of acute appendicitis was strong enough to merit an operation. As a result, this study does not address the crucial question of how the laboratory results effect the decision process in a patient with an equivocal history or physical findings. Also, because the predictive value of any test is dependent on the prevalence of the disease in the population studied, one cannot apply the findings of this study to all patients with a complaint of abdominal pain. Dr. Werman: The fact that the absolute neutrophil count as determined by cytochemical methods was found to be a significant predictor of acute appendicitis is not contradictory to our previous remarks regarding manual differential counts. When the neutrophil count is determined in this manner, tens of thousands of cells are counts (as opposed to only 100-200 for manual methods), which results in a large reduction in the sampling error associated with this test.
The assessment of laboratory tests in the diagnosis of acute appendicitis. Marchand A, Van Lente F, Galen RS. Am J Clin Pathol 1983;80:369-374. Dr. Cheryl Lee: In this study, the authors set out to evaluate the predictive value of several laboratory tests for the diagnosis of acute appendicitis in a group of patients presenting to the emergency department who subsequently underwent surgical exploration. The study consisted of 106 patients ranging in age from 2 to 81 years. Each patient had laboratory studies including those for leukocyte count, manual and cytochemical differential count, and C-reactive protein. The normal values for each of these studies was determined from a sample of 64 healthy hospital employees. Patients were then classified into two groups based on the pathological findings at the time of surgery: 1) acute appendicitis with or without evidence of perforation (85 patients) or 2) no appendicitis (21 patients). In evaluating each of the individual tests, the authors found that a leukocyte count of greater than 10.5 x lo”/1 and a cytochemical neutrophil count of greater than 7.88 x lo”/1
Abdominal pain: An analysis of 1,000 consecutive cases in a university hospital emergency room. Brewer RJ, Golden GT, Hitch DC, et al. Am J Surg 1976;131:219-223. Dr. Theresa Bridges: This article is a retrospective study of 1,000 consecutive patients presenting to an emergency department with the chief complaint of abdominal pain. The purpose of the study was to 1) determine the causes of abdominal pain in a large series of patients, 2) evaluate the effectiveness of the emergency department in determining the causes of abdominal pain, and 3) outline features frequently associated with the acute surgical abdomen and as485
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sess their values as screening tools. Although the article addresses many aspects of the diagnosis of abdominal pain, certain findings with regard to the leukocyte count are particularly interesting. Ninety-five percent of the patients had a leukocyte count drawn with 40% being greater than 10,000 cells/mm3. In those patients who required surgery and were younger than 65 years old, 71% had an elevated leukocyte count. Interestingly, in those patients who underwent surgery and who were older than 65 years. only 39% had an elevated leukocyte count. Acute appendicitis was associated with an elevated leukocyte count in 91% of cases, a statistically significantly higher percentage than the next two leading causes (acute cholecystitis [78%] and intestinal obstruction [56%]). Nonsurgical causes of abdominal pain showed an elevation in the leukocyte count in between 31 and 43% of cases. The authors of this study suggest that although an elevated leukocyte count is seen more often in surgical disease, it is also present in a significant number of nonsurgical cases. Thus, the leukocyte count can only be viewed as supporting evidence of disease requiring surgery. In addition, the authors indicate that the absence of leukocytosis is common in patients over age 65 with surgically treated disease, and leukocyte count is thus an unreliable test in this population.
Commentary Dr. Rund: Although this is a retrospective study, it is the first to address a question crucial to the emergency physician. This study attempts to examine the value of the leukocyte count in all patients presenting to the emergency department with abdominal pain. The inclusion of a large number of patients with nonsurgical causes of abdominal pain is critical and gives the emergency physician a better sense of the ability of the leukocyte count to distinguish this group from those with surgical disease. Once again, if the results were expressed in terms of sensitivity and specificity of the leukocyte count, this would give the reader a clearer appreciation for the overlap in these two groups. Dr. Davis: This is the first study to consider that group of patients over age 65 as a separate group. Their findings, that an elevation of the leukocyte count in patients with surgically treated disease is often absent, is significant. This is similar to the findings in children in whom advanced disease may be present in the absence of an elevated leukocyte count.
CONCLUSION Dr. Davis: In reviewing the reports on the use of the leukocyte count and differential in the diagnosis of abdomina1 pain, we have seen that the vast majority of these reports focus on the use of this test in acute appendicitis. The data in this area are sometimes conflicting, but several conclusions can be drawn. The study by Bolton et al clearly demonstrates that the history and physical examination are the most important factors in determining the presence of acute
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appendicitis. It is rare for patients with a suggestive history and physical examination results to have their management correctly determined by reliance on a normal leukocyte count. Thus, it appears that the value of the leukocyte count and total neutrophil count lies in the patient with equivocal findings. Few studies have actually been undertaken to examine this specific group of patients. However, some conclusions can be drawn from the other studies that were discussed. In the adult patient with an atypical presentation who has a normal leukocyte count and a normal absolute, the likelihood of appendicitis is low. This patient could benefit from hospitalization and further observation. In children or patients older than 6S years of age, one should feel less comfortable with a normal leukocyte count. These patients have been reported to have advanced appendicitis with perforation and a normal leukocyte count. Thus. in this group of patients, surgical exploration appears justified if there is any clinical suspicion of appendicitis or other surgically treated pathology. Dr. Wermatz: Our discussions have identified several problems common to many of the studies in this area. Most important, few studies adjust the leukocyte count and differential for factors that have been shown to influence this laboratory value. These include the patient’s age, sex, race. and history of cigarette smoking. Additionally, most studies have not included an adequate control group to assess the ability of the leukocyte count to distinguish between those patients with appendicitis and those with abdominal pain but without acute appendicitis. Finally, although many of the authors commented on the overlap that occurred in the values for the leukocyte count, neutrophil count, and the neutrophil percentage between patients with acute appendicitis and those without this process. few authors actually expressed their results in terms of the sensitivity, specificity, and predictive value for these tests. It is also apparent that the data on the use of the differential count in the diagnosis of acute abdominal pain are very conflicting. Although the studies of Doraiswamy. and Miskowiak and Burcharth. seem to find these tests useful in the diagnosis of acute appendicitis, Bolton et a/ found the differential and neutrophil morphology to be of little value. This is probably a reflection of the inherent errors associated with the performance of a manual differential count. Dr. Rand: As stated previously, most of the studies on the use of the leukocyte count in acute abdominal pain have focused on the diagnosis of acute appendicitis. The studies by Brewer et al and Lewis et al begin to address some of the crucial questions for the emergency physician: I) what is the value of the leukocyte count in separating significant causes of abdominal pain from those that require no specific therapy, and 2) what is the value of the leukocyte count in distinguishing different inflammatory processes (acute appendicitis and PID) in which therapy may be markedly different. Obviously, what is needed is a large, prospective study that can assess the value of the leukocyte count in the decision-making process for patients with acute abdominal pain.