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Home , Eosinophilia, Leukocytosis, Lymphocytosis

Evaluation of Patients with LYRAD K. RILEY, MD, and JEDDA RUPERT, MD, Eglin Air Force Base Family Medicine Residency, Eglin Air Force Base, Florida

An elevated white cell count has many potential etiologies, including malignant and nonmalignant causes. It is important to use age- and pregnancy-specific normal ranges for the white count. A repeat with peripheral smear may provide helpful information, such as types and maturity of white blood cells, uniformity of white blood cells, and toxic granulations. The leukocyte differential may show in parasitic or allergic conditions, or it may reveal in childhood viral illnesses. Leukocytosis is a common sign of , particularly bacterial, and should prompt physicians to identify other of infection. The peripheral count can double within hours after certain stimuli because of the large stor- age and intravascularly marginated pools of . Stressors capable of causing an acute leukocytosis include surgery, exercise, trauma, and emotional stress. Other nonmalignant etiologies of leukocytosis include certain medi- cations, , smoking, obesity, and chronic inflammatory conditions. Symptoms suggestive of a hematologic include , weight loss, bruising, or fatigue. If malignancy cannot be excluded or another more likely cause is not suspected, referral to a hematologist/oncologist is indicated. (Am Fam Physician. 2015;92(11):1004-1011. Copyright © 2015 American Academy of Family Physicians.)

CME This clinical content eukocytosis, often defined as an ele- (4.5 to 11.0 × 109 per L; 95% confidence conforms to AAFP criteria vated white blood cell (WBC) count interval) by about 21 years of age.3 There is for continuing medical 3 education (CME). See greater than 11,000 per mm (11.0 also a shift from relative to neu- CME Quiz Questions on × 109 per L) in nonpregnant adults, trophil predominance from early childhood page 977. Lis a relatively common finding with a wide to the teenage years and adulthood.4 During Author disclosure: No rel- differential. It is important for clinicians to pregnancy, there is a gradual increase in the evant financial affiliations. be able to distinguish malignant from non- normal WBC count (third trimester 95% malignant etiologies, and to differentiate upper limit = 13,200 per mm3 [13.2 × 109 between the most common nonmalignant per L] and 99% upper limit = 15,900 per mm3 causes of leukocytosis. [15.9 × 109 per L]), and a slight shift toward Leukocytosis in the range of approxi- an increased percentage of neutrophils.5 In mately 50,000 to 100,000 per mm3 (50.0 to one study of afebrile postpartum patients, 100.0 × 109 per L) is sometimes referred to as the mean WBC count was 12,620 per mm3 a . This level of elevation (12.62 × 109 per L) for women after vaginal can occur in some severe , such as deliveries and 12,710 per mm3 (12.71 × 109 Clostridium difficile infection, sepsis, organ per L) after cesarean deliveries. Of note, pos- rejection, or in patients with solid tumors.1 itive bacterial cultures were not associated Leukocytosis greater than 100,000 per mm3 with leukocytosis or , making is almost always caused by or leukocytosis an unreliable discriminator in myeloproliferative disorders.2 deciding which postpartum patients require antibiotic therapy.6 Patients of black African Normal Variation descent tend to have a lower WBC count (by The normal range for WBC counts changes 1,000 per mm3 [1.0 × 109 per L]) and lower with age and pregnancy (Table 1).3 Healthy absolute counts.7 newborn infants may have a WBC count from 13,000 to 38,000 per mm3 (13.0 to Normal Leukocyte Life Cycle 38.0 × 109 per L) at 12 hours of life (95% and Responses confidence interval). By two weeks of age, The life cycle of leukocytes includes devel- this decreases to approximately 5,000 to opment and differentiation, storage in the 20,000 per mm3 (5.0 to 20.0 × 109 per L), and bone marrow, margination within the vas- gradually declines throughout childhood to cular spaces, and migration to tissues. Stem reach adult levels of 4,500 to 11,000 per mm3 cells in the bone marrow produce cell lines

1004Downloaded American from the Family American Physician Family Physician website at www.aafp.org/afp.www.aafp.org/afp Copyright © 2015 American AcademyVolume of Family 92, NumberPhysicians. 11 For ◆ theDecember private, noncom 1, 2015- mercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. Leukocytosis SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence Clinical recommendation rating References of erythroblasts, which become red blood Leukocytosis greater than 100,000 per mm3 C 2 cells; megakaryoblasts, which become plate- (100.0 × 109 per L) is almost always caused lets; lymphoblasts; and . Lym- by leukemias or myeloproliferative disorders. phoblasts develop into various types of T Leukocytosis is not a reliable indicator of C 6 postpartum bacterial infection. and B cell . Myeloblasts further Patients with leukocytosis and no other signs of C 19 differentiate into and granulo- systemic inflammatory response syndrome do cytes, a designation that includes neutro- not require blood cultures. phils, , and (Figure 1). Once WBCs have matured within the bone A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited- quality patient-oriented evidence; C = consensus, -oriented evidence, usual marrow, 80% to 90% remain in storage in practice, expert opinion, or case series. For information about the SORT evidence the bone marrow. This large reserve allows rating system, go to http://www.aafp.org/afpsort. for a rapid increase in the circulating WBC count within hours. A relatively small pool (2% to 3%) of leukocytes circulate freely in 1 the peripheral blood ; the rest stay depos- Table 1. White Blood Cell Count Variation with Age ited along the margins of blood vessel walls and Pregnancy or in the . Leukocytes spend most of their life span in storage. Once a leukocyte is Patient characteristic Normal total leukocyte count released into circulation and peripheral tis- 3 sues, its life span ranges from two to 16 days, Newborn infant 13,000 to 38,000 per mm (13.0 to 38.0 × 109 per L) depending on the type of cell. Infant two weeks of age 5,000 to 20,000 per mm3 (5.0 to 20.0 × 109 per L) Differentiation by Type of White Adult 4,500 to 11,000 per mm3 Blood Cell (4.5 to 11.0 × 109 per L) Changes in the normal distribution of Pregnant female (third trimester) 5,800 to 13,200 per mm3 types of WBCs can indicate specific causes (5.8 to 13.2 × 109 per L) of leukocytosis (Table 2).8 Although the differential of the major types of WBCs is Information from reference 3. important for evaluating the cause of leu- kocytosis, it is sometimes helpful to think in terms of absolute, rather than relative, and leukocytoses. To calculate the absolute cell count, the total leukocyte count is multiplied by the differential per- Stem cell centage. For example, with a normal WBC count of 10,000 per mm3 (10.0 × 109 per L) Bone marrow Bone and an elevated percentage of 12, the absolute monocyte count is 12% or 0.12 Megakaryoblast Erythroblast Lymphoblast times the WBC count of 10,000 per mm3, yielding 1,200 per mm3 (1.2 × 109 per L), which is abnormally elevated.

The most common type of leukocytosis Platelets Erythrocyte Lymphocyte is neutrophilia (an increase in the absolute number of mature neutrophils to greater than 7,000 per mm3 [7.0 × 109 per L]), which Blood can arise from infections, stressful condi- tions, chronic , medication use, and other causes (Table 3).1-7,9,10 Lymphocy- Neutrophil Monocyte ILLUSTRATION DAVE BY KLEMM tosis (when lymphocytes make up more than Figure 1. White blood cell maturation. The life cycle of leukocytes 40% of the WBC count or the absolute count includes development and differentiation, storage in bone marrow, is greater than 4,500 per mm3 [4.5 × 109 margination within vascular spaces, and migration to tissues.

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per L]) can occur in patients with pertussis, Table 2. Normal White Blood Cell syphilis, viral infections, hypersensitivity Distribution reactions, and certain subtypes of or . Lymphocytosis is more likely White blood Normal percentage of to be benign in children than in adults.4 cell line total leukocyte count Epstein-Barr infection, or Neutrophils 40 to 60 fungal disease, , sple- Lymphocytes 20 to 40 nectomy, protozoan or rickettsial infections, Monocytes 2 to 8 and malignancy can cause Eosinophils 1 to 4 (monocytes make up more than 8% of the Basophils 0.5 to 1 WBC count or the absolute count is greater than 880 per mm3 [0.88 × 109 per L]).8 Information from reference 8. Eosinophilia (eosinophil absolute count greater than 500 per mm3 [0.5 × 109 per L]),

Table 3. Nonmalignant Causes of Neutrophilia

Cause Distinguishing features Evaluation

Patient Pregnancy, obesity, race, age Reference appropriate WBC count by age or pregnancy trimester characteristics Compare WBC count to recent baseline (if available) Infection Fever, system-specific symptoms Obtain system-specific cultures and imaging (e.g., sputum cultures, Physical examination findings chest radiography) Consider empiric antibiotics Consider use of other biomarkers, such as CRP and procalcitonin Reactive Exercise, physical stress (e.g., postsurgical, Confirm with history neutrophilia febrile seizures), emotional stress (e.g., panic attacks), smoking Chronic Rheumatic disease, inflammatory bowel Obtain personal and family medical history inflammation disease, granulomatous disease, Consider erythrocyte sedimentation rate and CRP levels, specific vasculitides, chronic rheumatology laboratories Consider subspecialist consultation (e.g., rheumatology, gastroenterology) Medication , beta agonists, lithium, Confirm with history; consider discontinuation of medication, induced epinephrine, colony-stimulating factors if warranted Bone marrow Hemolytic , immune Complete blood count differential; compare with baseline values stimulation thrombocytopenia, bone marrow (if available) suppression recovery, colony- Examine peripheral smear stimulating factors Consider reticulocyte and lactate dehydrogenase levels Consider , bone marrow examination, / oncology consultation History of trauma or sickle cell disease Confirm with history Congenital Hereditary/chronic idiopathic Obtain family, developmental history neutrophilia, Down syndrome, Consider hematology/oncology, genetics, and immunology leukocyte adhesion deficiency consultations

NOTE: After patient characteristics, causes are listed in approximate order of frequency. CRP = C-reactive protein; WBC = white blood cell. Information from references 1 through 7, 9, and 10.

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although uncommon, may suggest allergic significant infection. For example, the sen- conditions such as , urticaria, atopic sitivity and specificity of an elevated WBC or , drug count in diagnosing acute are reactions, dermatologic conditions, malig- 62% and 75%, respectively.15,16 For diagnos- nancies, connective tissue disease, idiopathic ing serious bacterial infections without a hypereosinophilic syndrome, or parasitic infections, including helminths (tissue par- asites more than gut-lumen parasites).11,12 Table 4. Selected Conditions Associated with Elevations Isolated (number of basophils in Certain White Blood Cell Types greater than 100 per mm3 [0.1 × 109 per L]) is rare and unlikely to cause leukocytosis White blood in isolation, but it can occur with allergic cell line Conditions that typically cause elevations or inflammatory conditions and chronic Basophils Allergic conditions, leukemias 13 myelogenous leukemia (Table 4). Eosinophils Allergic conditions, dermatologic conditions, eosinophilic esophagitis, idiopathic hypereosinophilic syndrome, Nonmalignant Etiologies , medication reactions, parasitic infections A reactive leukocytosis, typically in the Lymphocytes Acute or chronic leukemia, hypersensitivity reaction, range of 11,000 to 30,000 per mm3 (11.0 to infections (viral, pertussis) 30.0 × 109 per L), can arise from a variety of Monocytes Autoimmune disease, infections (Epstein-Barr virus, fungal, etiologies. Any source of stress can cause a protozoan, rickettsial, tuberculosis), splenectomy catecholamine-induced demargination of Neutrophils Bone marrow stimulation, chronic inflammation, congenital, infection, medication induced, reactive, splenectomy WBCs, as well as increased release from the bone marrow storage pool. Examples include surgery, exercise, trauma, , and emo- tional stress.9 One study showed an average increase in WBCs of 2,770 per mm3 (2.77 × 109 per L) peaking on postoperative day 2 after knee or hip arthroplasty.10 Medications known to increase the WBC count include corticosteroids, lithium, colony-stimulating factors, beta agonists, and epinephrine. Dur- ing the recovery phase after hemorrhage or hemolysis, a rebound leukocytosis can occur. Leukocytosis is one of the hallmarks of infection. In the acute stage of many bacte- rial infections, there are primarily mature and immature neutrophils (Figure 2); sometimes, as the infection progresses, there is a shift to lymphocyte predominance. The release of less- mature bands and metamyelocytes into the peripheral circulation results in the so-called “” in the WBC differential. Of note, some bacterial infections paradoxically cause Figure 2. Neutrophilia postsplenectomy with sepsis. An 18-year-old neutropenias, such as , rickett- woman with distal pancreatectomy and splenectomy for benign 1,14 sial infections, , and dengue. pancreatic pseudopapillary tumor two weeks earlier presents to the Viral infections may cause leukocytosis early emergency department with a temperature of 103°F (39.4°C), leuko- in their course, but a sustained leukocytosis cytosis with , tachycardia, and urinalysis results consistent 3 9 is not typical, except for the lymphocytosis in with infection. White blood cell count = 57,100 per mm (57.1 × 10 per L), hemoglobin = 12.6 g per dL (126 g per L), platelet count = 832,000 some childhood viral infections. per mm3 (832 × 109 per L). White blood cell differential: 75.4% seg- An elevated WBC count is a suggestive, mented cells, 19.3% bands. Note neutrophils (arrows) with < 3 lobes but not definitive, marker of the presence of to nuclei (band cells).

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source in febrile children, the discrimina- tory value of leukocytosis is less than that of other biomarkers, such as C-reactive protein or procalcitonin.17 Although a WBC count greater than 12,000 per mm3 (12.0 × 109 per L) is one of the criteria for the systemic inflammatory response syndrome (or sepsis when there is a known infection), leukocy- tosis alone is a poor predictor of bacteremia and not an indication for obtaining blood cultures.18,19 Other acquired causes of leukocytosis include functional asplenia (predominantly lymphocytosis), smoking, and obesity. Patients with a chronic inflammatory condi- Figure 3. Lymphocytosis in a 70-year-old woman with a history of tion, such as , inflam- chronic lymphocytic leukemia presenting to the emergency depart- matory bowel disease, or a granulomatous ment with a five-day history of subjective , sore throat, and disease, may also exhibit leukocytosis. cough. White blood cell count = 147,500 per mm3 (147.5 × 109 per L), Genetic causes include hereditary or chronic hemoglobin = 8.8 g per dL (88 g per L), platelet count = 82,000 per idiopathic neutrophilia and Down syndrome. mm3 (82 × 109 per L). White blood cell differential: 96.6% lympho- cytes (monomorphic). Note many mature lymphocytes (small nuclei near the size of a red blood cell with thin rim cytoplasm; black arrows) Malignant Etiologies and many smudge cells (white arrows). Leukocytosis may herald a malignant dis- order, such as an acute or chronic leukemia (Figure 3), or a myeloproliferative disorder, such as , myelofibrosis, or essential thrombocytosis. A previous article on leukemia in American Family Physician reviewed the features and differentiation of malignant hematopoietic disorders.20 Many solid tumors may lead to a leukocytosis in the leukemoid range, either through bone marrow involvement or production of gran- ulocyte colony-stimulating or - colony-stimulating factors1,3,21 (Figure 4). Chronic leukemias are most com- monly diagnosed after incidental findings of leukocytosis on complete blood counts in asymptomatic patients. Patients with fea- tures suggestive of hematologic malignancies require prompt referral to a hematologist/ oncologist (Table 5).3,22

Approach to Evaluation A systematic approach to patients with leu- Figure 4. Eosinophilia in malignancy in a 76-year-old man with a his- kocytosis includes identifying historical tory significant for metastatic prostate presenting for che- clues that suggest potential causes (Figure 5). 3 9 motherapy. White blood cell count = 26,600 per mm (26.6 × 10 Fever and pain may accompany infections per L), hemoglobin = 10.8 g per dL (108 g per L), hematocrit = 32.6%. White blood cell differential: 51.8% eosinophils, 36.8% neutrophils, or malignancies; other constitutional symp- 6% lymphocytes, 4.5% monocytes, 0.9% basophils. Note eosinophils toms, such as fatigue, night sweats, weight (arrows). loss, easy bruising, or bleeding, might suggest

1008 American Family Physician www.aafp.org/afp Volume 92, Number 11 ◆ December 1, 2015 Leukocytosis

painful, inflamed joints suggestive of con- Table 5. Findings Suggestive nective tissue disease or infection. of Hematologic Malignancies Initial laboratory evaluation should in the Setting of Leukocytosis include a repeat complete blood count to confirm the elevated WBC level, with differ- Symptoms ential cell counts and a review of a peripheral Bruising/bleeding tendency blood smear. The peripheral smear should be Fatigue, weakness examined for toxic granulations (suggestive Fever > 100.4°F (38°C) of inflammation), platelet clumps (which Immunosuppression may be misinterpreted as WBCs), the pres- Night sweats ence of immature cells, and uniformity of the Unintentional weight loss WBCs. On evaluation of a leukocytosis with Physical examination findings lymphocyte predominance, a monomorphic population is concerning for chronic lym- Petechiae phocytic leukemia, whereas a pleomorphic or hepatomegaly (varying sizes and shapes) lymphocytosis is Laboratory abnormalities suggestive of a reactive process.4,23 With all Decreased red blood cell count or forms of leukocytosis, concurrent abnor- hemoglobin/hematocrit levels malities in other cell counts (erythrocytes Increased or decreased platelet count or platelets) suggest a primary bone mar- Monomorphic lymphocytosis on peripheral row process and should prompt hematology/ smear oncology evaluation. Predominantly immature cells on peripheral smear As indicated by the history and examina- White blood cell count > 30,000 per mm3 tion findings, physicians should consider (30.0 × 109 per L), or > 20,000 per mm3 performing cultures of blood, urine, and (20.0 × 109 per L) after initial management joint or body fluid aspirates; rheumatol- ogy studies; a test for heterophile antibod- Information from references 3 and 22. ies (mononucleosis spot test); and serologic titers. Radiologic studies may include chest radiography (to identify infections, some malignancy.22 Previous diagnoses or comor- malignancies, and some granulomatous dis- bid conditions that cause chronic inflam- eases) and, as indicated by history, computed mation should be noted, as well as recent tomography or bone scan. If hematologic stressful events, medication use, smoking malignancy is suspected, additional confir- status, and history of splenectomy or sickle matory testing may include flow cytometry, cell anemia. A history of an elevated WBC cytogenetic testing, or molecular testing of count is important, because duration will the bone marrow or peripheral blood. help determine the likely cause. Leukocy- Data Sources: The primary literature search was tosis lasting hours to days has a different completed using Essential Evidence Plus and included differential diagnosis (e.g., infections, acute searches of the Cochrane, POEM, and NICE guideline leukemias, stress reactions) than a case that databases using the search term leukocytosis. In addition, PubMed searches were performed using the terms leu- persists for weeks to months (e.g., chronic kocytosis and white blood cell. Search dates: October 31 inflammation, some malignancies). and December 17, 2014, and September 2015. The physical examination should note The authors thank Melissa King, MD, Department of erythema, swelling, or lung findings sug- Hematology/Oncology, Eglin Air Force Base Hospital, for gestive of an infection; murmurs suggestive reviewing the manuscript, and Niquanna Perez, Eglin Air of ; lymphadenopathy Force Base laboratory services, for procuring peripheral smear images. suggestive of a lymphoproliferative disor- der; or splenomegaly suggestive of chronic The views expressed in this article are those of the authors and do not reflect the official policy or position myelogenous leukemia or a myeloprolifera- of the U.S. government, the Department of Defense, or tive disorder; petechiae or ecchymoses; or the U.S. Air Force.

December 1, 2015 ◆ Volume 92, Number 11 www.aafp.org/afp American Family Physician 1009 Leukocytosis Evaluation of Leukocytosis

Leukocytosis (white blood cell count > 11,000 per mm3 [11.0 × 109 per L])

Repeat complete blood count Order peripheral smear Leukocytosis confirmed?

No Yes

No further workup necessary Obtain additional history and perform physical examination Leukocytosis explained by history or patient characteristics (e.g., pregnancy, newborn, splenectomy, smoking, medications)?

No Yes

No further workup necessary Patient presents with: Weight loss, fatigue, night sweats, fevers Abnormal red blood cell and platelet count Immature leukocyte forms (blasts) Chronic duration (weeks or years) History of or risk factors for malignancy, splenomegaly, lymphadenopathy, bruising?

No Yes

Consider nonmalignant etiologies Consider malignancy: Which cell line is affected? Hematology/oncology consultation Consider additional testing to include flow cytometry, cytogenetic testing, or molecular testing of the bone marrow or peripheral blood

Neutrophilia (> 7,000 per Monocytosis (> 880 per mm3 [0.88 × 109 per L]): Basophilia (> 100 per mm3 mm3 [7.0 × 109 per L]): Infections (Epstein-Barr virus, tuberculosis, [0.1 × 109 per L]; rare): Infection fungal, protozoan, rickettsial) Search for malignancy Chronic inflammation Autoimmune disease (or allergic condition, much less likely) Recent stressors Splenectomy Medication induced Bone marrow stimulation

Splenectomy Lymphocytosis (> 4,500 per Consider: Eosinophilia (> 500 per 3 9 3 9 Tobacco use mm [4.5 × 10 per L]): Sick contact, surgical, mm [0.5 × 10 per L]): (see Table 3) Infections (viral, pertussis) and travel history Allergic conditions Hypersensitivity reaction Imaging (chest Eosinophilic esophagitis radiography) Medication reactions Pathogen-specific Consider: Dermatologic conditions testing (mononucleosis Parasitic infections Medical, medication, Consider: spot test, purified family, travel, sick Sick contact and protein derivative) contact, surgical, immunization history ESR, CRP, and ANA and social history Imaging (chest measurement Consider: ESR, CRP, and ANA radiography) measurement Medication, travel history Pathogen-specific Full skin examination Pathogen isolation testing (viral panels) (blood cultures, Skin biopsy, if warranted lumbar puncture) /immunology testing Additional imaging Parasite-specific testing (system-specific) (stool ova and parasites) Upper endoscopy

Figure 5. Algorithm for the evaluation of leukocytosis. (ANA = antinuclear antibodies; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate.) Leukocytosis

11. Ustianowski A, Zumla A. Eosinophilia in the returning The Authors traveler. Infect Dis Clin North Am. 2012;26(3):781-789. 12. Cormier SA, Taranova AG, Bedient C, et al. Pivotal LYRAD K. RILEY, MD, is a faculty member at the U.S. Air Advance: eosinophil infiltration of solid tumors is an Force Eglin Family Medicine Residency Program, Eglin early and persistent inflammatory host response.J Leu- Air Force Base, Fla., and an assistant professor in the koc Biol. 2006;79(6):1131-1139. Department of Family Medicine at the Uniformed Services 13. Munker R. Leukocytosis, , and other reactive University of the Health Sciences School of Medicine, changes of myelopoiesis. In: Munker R, Hiller E, Glass Bethesda, Md. J, Paquette R, eds. Modern Hematology: Biology and JEDDA RUPERT, MD, is a second-year resident at the U.S. Clinical Management. 2nd ed. Totowa, N.J.; Humana Air Force Eglin Family Medicine Residency Program. Press; 2007. 14. Potts JA, Rothman AL. Clinical and laboratory features Address correspondence to Lyrad K. Riley, MD, Eglin that distinguish dengue from other febrile illnesses in AFB Family Medicine Residency, 307 Boatner Rd., Eglin endemic populations. Trop Med Int Health. 2008;13 (11): Air Force Base, FL 32542 (e-mail: [email protected]). 1328-1340. Reprints are not available from the authors. 15. Yu CW, Juan LI, Wu MH, Shen CJ, Wu JY, Lee CC. Systematic review and meta-analysis of the diagnostic accuracy of procalcitonin, C- reac tive protein and white REFERENCES blood cell count for suspected acute appendicitis. Br J Surg. 2013;100(3):322-329. 1. Cerny J, Rosmarin AG. Why does my patient have leu- kocytosis? Hematol Oncol Clin North Am. 2012;26(2): 16. Van den Bruel A, Thompson MJ, Haj-Hassan T, et al. 303-319, viii. Diagnostic value of laboratory tests in identifying seri- ous infections in febrile children: systematic review. 2. Jain R, Bansal D, Marwaha RK. Hyperleukocytosis: BMJ. 2011;342:d3082. emergency management. Indian J Pediatr. 2013;80 (2): 144-148. 17. Yo CH, Hsieh PS, Lee SH, et al. Comparison of the test characteristics of procalcitonin to C- reac tive protein and 3. Hoffman R, Benz EJ Jr, Silberstein LE, Heslop H, Weitz leukocytosis for the detection of serious bacterial infec- J, Anastasi J. Hematology: Basic Principles and Practice. tions in children presenting with fever without source: a 6th ed. Philadelphia, Pa.: Elsevier/Saunders; 2013:table systematic review and meta-analysis. Ann Emerg Med. 164-20. 2012;60(5):591-600. 4. Chabot-Richards DS, George TI. Leukocytosis. Int J Lab 18. Dellinger RP, Levy MM, Rhodes A, et al.; Surviving Hematol. 2014;36(3):279-288. Sepsis Campaign Guidelines Committee including the 5. Lurie S, Rahamim E, Piper I, Golan A, Sadan O. Total Pediatric Subgroup. Surviving sepsis campaign: interna- and differential leukocyte counts percentiles in normal tional guidelines for management of severe sepsis and pregnancy. Eur J Obstet Gynecol Reprod Biol. 2008; septic shock: 2012. Crit Care Med. 2013;41(2):580-637. 136(1):16-19. 19. Coburn B, Morris AM, Tomlinson G, Detsky AS. Does 6. Dior UP, Kogan L, Elchalal U, et al. Leukocyte blood this adult patient with suspected bacteremia require count during early puerperium and its relation to puer- blood cultures? [published correction appears in JAMA. peral infection. J Matern Fetal Neonatal Med. 2014; 2013;309(4):343]. JAMA. 2012;308(5):502-511. 27(1):18-23. 20. Davis AS, Viera AJ, Mead MD. Leukemia: an overview for 7. Lim EM, Cembrowski G, Cembrowski M, Clarke G. primary care. Am Fam Physician. 2014;89(9):731-738. Race-specific WBC and neutrophil count reference 21. Granger JM, Kontoyiannis DP. Etiology and outcome intervals. Int J Lab Hematol. 2010;32(6 pt 2):590-597. of extreme leukocytosis in 758 nonhematologic cancer 8. Berliner N. Leukocytosis and leukopenia. In: Goldman patients: a retrospective, single-institution study. Can- L, Schafer AI, eds. Goldman’s Cecil Medicine. 24th ed. cer. 2009;115 (17):3919-3923. Philadelphia, Pa.: Elsevier/Saunders; 2012. 22. Racil Z, Buresova L, Brejcha M, et al. Clinical and labora- 9. Iskandar JW, Griffeth B, Sapra M, Singh K, Giugale tory features of leukemias at the time of diagnosis: an JM. Panic-attack-induced transient leukocytosis in a analysis of 1,004 consecutive patients. Am J Hematol. healthy male: a case report. Gen Hosp Psychiatry. 2011; 2011;86 (9 ):800-803. 33(3):302.e11-302.e12. 23. George TI. Malignant or benign leukocytosis. Hema- 10. Deirmengian GK, Zmistowski B, Jacovides C, O’Neil tology Am Soc Hematol Educ Program. 2012;2012: J, Parvizi J. Leukocytosis is common after total hip 475-484. and knee arthroplasty. Clin Orthop Relat Res. 2011; 469 (11):3031-3036.

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