Periodic Hematopoiesis in Human Cyclic Neutropenia
D. Guerry IV, … , S. Perry, S. M. Wolff
J Clin Invest. 1973;52(12):3220-3230. https://doi.org/10.1172/JCI107522.
Research Article
Human cyclic neutropenia is characterized by severe depression of blood neutrophil levels approximately every 21 days. To investigate the mechanism of cyclic neutropenia four patients were studied with daily complete blood counts, serial bone marrow examinations, marrow reserve testing, serum muramidase determinations, DF22P granulocytokinetic studies, and, in one patient, in vivo [3H]TdR labeling. Periodogram analysis of the serial blood counts in the latter patient and visual inspection of multiple cycles in the others revealed periodic fluctuations in the levels of blood neutrophils, monocytes, lymphocytes, reticulocytes, and platelets. Rhythmic changes in the morphologic and radioisotopic studies as well as the marrow reserve tests and muramidase measurements were consonant with a mechanism of periodic failure of marrow production rather than peripheral destruction. Human cyclic neutropenia is analogous to cyclic neutropenia in the grey collie dog and may be viewed as the consequence of cyclic hematopoiesis.
Find the latest version: https://jci.me/107522/pdf Periodic Hematopoiesis in Human Cyclic Neutropenia
D. GUERRY, IV, D. C. DALE, M. OMINE, S. PERRY, and S. M. WOLFF From the Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, and the Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20014
A B S T R A C T Human cyclic neutropenia is charac- cyclic neutropenia and to define the mechanism of its terized by severe depression of blood neutrophil levels production we have performed detailed studies of the approximately every 21 days. To investigate the mecha- peripheral blood counts and the formation and fate of nism of cyclic neutropenia four patients were studied blood cells in four patients. The present studies indi- with daily complete blood counts, serial bone marrow cate that in man, as in the grey collie dog, cyclic fluc- examinations, marrow reserve testing, serum mur- tuations of all blood elements occur. Periodic marrow amidase determinations, DF"P granulocytokinetic failure, perhaps at the pluripotential, or early com- studies, and, in one patient, in vivo ['H]TdR labeling. mitted, stem cell level, is causal. Periodogram analysis of the serial blood counts in the latter patient and visual inspection of multiple cycles METHODS fluctuations in the levels in the others revealed periodic Patients. Two women, ages 67 and 23 yr (patients 1 of blood neutrophils, monocytes, lymphocytes, reticu- and 3), with symptoms strongly suggestive of childhood- locytes, and platelets. Rhythmic changes in the morpho- onset cyclic neutropenia and two boys, ages 9 and 8 yr logic and radioisotopic studies as well as the marrow (patients 2 and 4), with disease well documented from reserve tests and muramidase measurements were con- early childhood were the subjects of these studies. The patients were unrelated, and none had a family history of sonant with a mechanism of periodic failure of marrow neutropenia. Except for periodic fevers, aphthous stoma- production rather than peripheral destruction. Human titis, and occasional infections accompanying severe neu- cyclic neutropenia is analogous to cyclic neutropenia in tropenia (7), the patients were in good health. None had the grey collie dog and may be viewed as the conse- splenomegaly by either physical examination or technetium (9Tc) scan. Patient 1 had a normal spleen removed before quence of cyclic hematopoiesis. study without change in her disease. Blood counts. Leukocyte, erythrocyte, and plateletcounts were made on EDTA-anticoagulated samples using an INTRODUCTION electronic particle counter' and standard techniques (8-10). Cyclic neutropenia in both human beings and grey 100-400 cell differential counts were done on air-dried, Wright's-stained peripheral blood smears. For reticulocyte collie dogs is characterized by the strikingly periodic counts, three drops of EDTA-anticoagulated blood and occurrence of profound neutropenia. It has been re- three drops of new methylene blue N (Brecher formula) 2 cently recognized that the canine disease involves peri- were mixed for 10 min and air-dried smears made. The per- odic fluctuations in all the formed elements of the centage of reticulocytes was determined by examining 1,000 monocytes, lymphocytes, eosino- erythrocytes in adjacent microscopic fields using a Miller blood-neutrophils, disk.' All samples were obtained between 8:00 and 9 :00 a.m. phils, reticulocytes, and platelets (1). Periodic changes Statistical analysis of serial blood counts. Only patient in monocyte levels (2-4) and platelet counts (5) have 1 was available for study long enough for sufficient data been noted in the human malady and the suggestion to be collected to construct the Schuster periodogram to has been made that periodic hematopoiesis underlies detect periodicity (1, 11, 12). Daily neutrophil, monocyte, and lymphocyte counts were analyzed for 206 consecutive this disease in both man and dog (6). To investigate days with less than 5% missing observations. Consecutive the extent of the hematologic abnormalities in human erythrocyte, reticulocyte, platelet, basophil, and eosinophil counts were examined for 108 days with less than 3% miss- This work was presented in part at the Annual Meeting of the American Society of Hematology, Hollywood, Fla., 'Coulter Counter Model Fn, Coulter Electronics, Inc., 6 December 1972. Fine Particle Group, Hialeah, Fla. Received for publication 24 May 1973 and in revised 'Hartman-Leddon Company, Philadelphia, Pa. form 23 July 1973. Bausch & Lomb, Tinc., Rochester, N. Y. 3220 The Journal of Clinical Investigation Volume 52 December 1973- 3220-3230 ing observations. The significance of the largest peak of the for 13 wk before development. Cells with more than 4-5 periodogram was determined by the Fisher statistic (g), grains were scored as labeled. Background was negligible which is the ratio of the height of this peak to the area and morphological identification of each cell type was not between the periodogram and the horizontal axis (1, 13). difficult. To obtain the percentage of labeled cells (label- Data from a normal volunteer studied over 89 consecutive ing index) the following number of cells were counted: days were identically analyzed for comparison (12). polymorphonuclear leukocytes (PMNs) ," more than 500 Bone marrow. Aspirates of bone marrow were taken (when abundant); monocytes, more than 100; lymphocytes, from the posterior iliac crest on 5 days of a single 21-day more than 2,000; and eosinophils, more than 50. Differential cycle in patient 1. In each of the other patients from one counts were performed separately on Wright-Giemsa- to three aspirates were obtained during the neutropenic stained smears. The total number of labeled cells of each and recovery phases of a cycle. Differential cell counts of type was calculated by the following equation: at least 500 nucleated cells were made on Wright's stained smears. Total number of labeled cells/mm3 = leukocyte count/mm3 Marrow neutrophil reserves. Marrow reserves were X % of differential count X labeling index. tested in each patient during the neutropenic and recovery phases of several cycles. Base-line (preinjection) and Serum muramidase (lysozyme). Serum was obtained hourly neutrophil counts were done for 6 h after intra- from blood samples allowed to clot at room temperature venous infusion of 0.8 ng/kg of Salmonella abortus equi for 2 h, then frozen at -20PC until used. Muramidase endotoxin (Lipexal') and 200 mg of hydrocortisone sodium concentrations were determined by the turbidimetric method succinate (Solu-Cortef 5). Counts were also done before of Litwack (15), using a Micrococcus lysodeikticus sub- and 12, 15, and 18 h after intramuscular administration of strate"' and expressed as micrograms per milliliter of egg 0.1 mg/kg of etiocholanolone.6 The maximum increase in white standard. the blood neutrophil count over baseline was used as a Diisopropylfluorophosphate (DF"P) leukokinetics. In measure of the marrow reserve. The mean neutrophil count each patient neutrophil half-disappearance time (PMN for all patients during neutropenia was 97.6+33.0/mm3 t1) and distribution were measured with a modification of and during recovery was 1,838.1+319/mm3. the methods devised by Athens and associates (16-19). Tritiated thymidine ([hH]TdR) in vivo-labeling study. Approximately 10% of the blood volume was collected in 70 jCi/kg of [3H]TdR' (sp act 2.0 Ci/mM) was admin- a plastic bag containing acid-citrate-dextrose (ACD) anti- istered intravenously to patient 1 during the neutropenic coagulant.16 After addition of 50-100 /Ci of DFaP (foot- phase of a cycle and the recovery phase of the subsequent note 17) and mixing for 45 min, blood was reinfused. cycle. The appearance of 3H-labeled cells in the peripheral 20-ml blood samples were obtained from the bag before blood was monitored at frequent intervals by liquid scin- reinfusion, and heparinized samples from the antecubital tillation counting and autoradiography (14). 20-ml samples veins of patients were drawn at 1, 3, 6, 12, and 24 h. Gran- of peripheral venous blood were dextran-dextrose-EDTA ulocytes were isolated from these blood samples by the sedimented. Leukocyte-rich plasma was removed, centri- Ficoll '-sodium diatrizoate (Hypaque) 19 method of Boyum fuged, and the leukocyte pellet subjected once or twice to (19, 20). The leukocytes of the final cell preparation were brief (30 s) hypotonic lysis to remove erythrocytes. A few regularly greater than 95% PMNs. Overall recovery of drops of the final leukocyte suspension in an equal volume PMNs was usually 40-60%c. of 10% (w/v) bovine serum albumin' was used to prepare After counting the cells with an electronic particle smears for autoradiography. The rest of the leukocytes counter, they were digested with 0.2 N NaOH at 60°C were frozen until all samples could be prepared for liquid and acidified with 10% acetic acid. This material was solu- scintillation counting. Cell recovery was in the range of bilized in the above-mentioned toluene-phosphor system 50-60% of the starting number and erythrocyte contamina- and radioactivity measured with a liquid scintillation coun- tion was minor. After digestion with 1.0 ml of NCS solu- ter.' The specific activity for each sample was expressed bilizer,9 leukocyte pellets were dissolved in 12 ml of a as counts per minute per cell. The slope and tj for the Biosolv (BBS-3)10-Liquiflour11-toluene cocktail and radio- specific activity curves were calculated by the methods of activity counted with a liquid scintillation counter.' To least squares (21). The total body, marginal, and circulat- correct for the possibility of variable counting efficiency, ing neutrophil pools and neutrophil turnover rates were reflecting erythrocyte contamination, a standard curve was measured by extrapolating the specific activity decay curves prepared relating counting efficiency and absorbence at 400 to time zero and applying the formulae of Cartwright, nm. Using this curve, we corrected efficiency for every Athens, and Wintrobe (17). All curves were of the "C" sample and found it to be between 40 and 50%. Peripheral type described by Athens et al. (18). The extrapolated blood leukocyte radioactivity was expressed in dpm/107 time zero did not differ !significantly from that estimated leukocyte. Methanol-fixed smears for autoradiographs were from the 15-min or 1-h specific activity values and pool prepared by the stripping method in a standard manner sizes measured by either method were approximately the with Kodak AK-10 stripping film' and exposed at 40C same. ' Dorsey Labs., Lincoln, Nebr. 'The Upjohn Co., Kalamazoo, Mich. 14Abbreviationzs used in this paper: DF3P, diisopropyl- 8 Sigma Chemical Co., St. Louis, Mo. fluorophosphate; 3H-TdR, tritiated thymidine; PMN, poly- 7Amersham/Searle Corp., Arlington Heights, Ill. morphonuclear leukocyte. 8 Armour Pharmaceutical Co., Kankakee, Ill. 5 Worthington Biochemical Corp., Freehold, N. J. 9Amersham/Searle Corp., Arlington Heights, Ill. 16 Fenwal Laboratories, Morton Grove, Ill. 1Beckman Instruments, Inc., Fullerton, Calif. 17 Radiochemical Centre, Amersham, England. "I New England Nuclear Corp., Boston, Mass. 18 Pharmacia, Uppsala, Sweden. 12 Packard Tri-Carb Scintillation Spectrometer, Model 1 Winthrop Laboratories, New York. 3375, Packard Instrument Co., Inc., Downers Grove, Ill. f Beckman Liquid Scintillation Spectrometer, Model LS- 3 Eastman Kodak Co., Rochester, N. Y. 250, Beckman Instruments, Inc., Fullerton, Calif. Human Cyclic Neutropenia 3221 4
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4 l w |\ p 0e , _l I 21 42 63 84 105 126 147 168 189 210 DAYS FIGURE 1 Circulating neutrophil counts over 25-200 days in 4 patients with cyclic neutro- penia and a normal volunteer. RESULTS unequivocal in each patient. Patients 1, 3, and 4 also Blood counts. The pattern of fluctuation of the neu- demonstrate the mild to moderate chronic neutropenia trophil counts of the four patients are compared to a characteristic of this disease (2). No obvious cycling series of daily counts obtained in a normal volunteer of the neutrophil count is apparent in the sequence (Fig. 1). The strikingly periodic appearance of pro- obtained in the normal volunteer. found neutropenia at approximately 21-day intervals is To explore the possibility of a broader hematopoietic easily seen. While only three cycles in patient 3 and defect in this disease, daily leukocyte, differential, one cycle in patient 4 are shown, multiple serial neu- platelet, erythrocyte, and reticulocyte counts were done trophil counts made during at least 3 yr of repeated for 107-206 consecutive days in patient 1 (Fig. 2). studies, have made the diagnosis of cyclic neutropenia Visual inspection of the graphic data demonstrates 3222 D. Guerry, IV, D. C. Dale, M. Omine, S. Perry, and S. M. Wolff PATIENT I NORMAL PMN AND BANDS per mm3 2,000 BASOPHILS 200 r per mm3 0 600 EOSINOPHILS 4 per mm3 200[- O _- I I MONOCYTES 2 000 r l A per mm3 1,000 - 7,000 lLYMPHOC~YTES 5,000 600,0003,0k% AM PLATELETS per mm3 400,000 200,000 4,400,000 ElRYTHROCYTES 4,000,000j per mm3 3,600,000 3.200,000 'II I '1 1 4 RETICULOCYTES X 105 per mm3 N,A*,^^, .. 21 42 63 84 105 126 147 168 189 210 0 21 42 63 84 DAYS FIGURE 2 Peripheral blood counts in human cyclic neutropenia (patient 1) contrasted to a series in a normal volunteer. Cyclic fluctuation is apparent only in the neutrophil, monocyte, lymphocyte, platelet, and reticulocyte counts of patient 1. periodic oscillation of monocytes, lymphocytes, platelets, the same, approximately 21 days, but the phase is and reticulocytes. No cycling is apparent in the counts different. of the eosinophils, basophils, or erythrocytes. Construction of the Schuster periodogram (Fig. 4) To demonstrate the interrelationships between the for data collected in patient 1 documents the periodicity counts of the different cell types arithmetic mean apparent in the raw data. The peaks in the periodo- counts for corresponding days of 5-10 successive 21-day gram are a measure of the strength of periodicity at a cycles in patient 1 were plotted (Fig. 3). The mean particular period length-42, 21, 10.5 days, and so on. neutrophil count on day 2 of 10 successive cycles is zero The neutrophil peak at 20.6 days, the monocyte and (day 1 = the day on which the peripheral neutrophil lymphocyte peak at 21.1 days, the platelet peak at 27.0 count is less than 250/mm3). At this time, the mean days, and the reticulocyte peak at 21.4 days are all reticulocyte count is maximal and successive peaks of highly significant (P < 0.001). For eosinophils, baso- lymphocytes, monocytes, neutrophils, and, possibly, phils, and erythrocytes a 21-day peak is seen but the platelets occur. Thus, for each cell type the period is periodogram is so noisy that statistical significance is Human Cyclic Neutropenia 3223 5.0 r PLATELETS lo^ \< _/ \_- E 4.0 E 00 , E O s -x 3.0 RET ICULOCYTES (O x w L 2.0 o -J -iw 4 wr1.t. 1.0 O0 6.0[ LYMPHOCYTES . ./ .11 5.0 / . .01 .- \ E 4.0 - E l*I0 x 3.0 _ cn -J .w-J .> n _ 0 e.1.v NEUTROPHILS I. - -,-.-- - MONOCYTES 0 17 19 .21 1 3 5 7 9 I1 13 15 17 CYCLE DAY FIGURE 3 Composite 21-day cycle in human cyclic neutropenia (patient 1). Arithmetic mean cell counts for corresponding days of 5-10 successive 21-day cycles are plotted. not achieved. No periodicity was demonstrated in the setting the stage for the subsequent development of counts of the normal volunteer. neutropenia. Examination of the bone marrows of the Periodogram analysis of the other patients was im- other patients at less frequent intervals discloses mor- possible, because long-term sequential data were not phology commensurate with the phase of the myelo- available. However, visual inspection of many partial poietic wave. Thus, in all patients bone marrow sam- and single cycles suggests that all peripheral blood. pling in the late neutropenic phase shows a paucity of cells cycle in the same manner as those of patient 1. PMNs and bands, and plentiful earlier precursors. Bone marrow. In Fig. 5, the differential counts of Sampling at the midpoint of the recovery phase shows the bone marrow aspirates and the simultaneously oc- just the opposite proportion of mature and immature curring peripheral blood neutrophil cycle are depicted granulocytes. for one cycle in patient 1. During the peripheral blood Marrow reserves. Marrow neutrophil reserves, as neutropenic phase, marrow PMNs are absent, but at measured by the increase in peripheral neutrophils, to this time a wave of myelopoiesis, successively made up etiocholanolone, endotoxin, and a glucocorticoid (22, of myeloblasts, promyelocytes, myelocytes, and meta- 23) were tested during neutropenia and recovery (not myelocytes and bands, sweeps through the marrow. necessarily in the same cycle) in each patient (Fig. 6). By the time peripheral neutrophil recovery is well es- During neutropenia, negligible or no reserves were tablished, at cycle days 12-14, earlier myeloid precur- detected in any patient. During peripheral neutrophil sors (promyelocytes and myelocytes) are on the wane, recovery, normal or near normal reserves to etiocho- 3224 D. Guerry, IV, D. C. Dale, M. Omine, S. Perry, and S. M. Wolff PATIENT I NORMAL 600- 400- Neuttrophils 200 6 Basa ophils 42. 0 10 Monocytes ____-5o AL 0.8 A 0.4 Lymphocytes -i I - Plate lets - 0.02 . Erythrocytes n00 Reticulocytes . 0442 21 10.5 5.25 42 21 10.5 5.25 PERIOD LENGTH (days) FIGuRE 4 Periodograms of serial blood counts in human cyclic neutropenia (patient 1) and a normal volunteer. Significant periodicity is seen only in the neutrophil, monocyte, lympho- cyte, platelet, and reticulocyte counts of patient 1. lanolone (2,600 or more granulocytes/mm', [24]) and/ recovery was well established, resulted in a far smaller or endotoxin (2,000 or granulocytes/mm' [25]) were peak at 6 days. Autoradiographic analysis (Fig. 7) established in three patients (patients 1, 2, and 4). showed the first peak to be made up primarily of Although the neutrophil response to these two agents labeled neutrophils and the second to be almost en- during the recovery phase was far greater than during tirely devoid of these cells. neutropenia for patient 3, the patient with the most Serum muramidase. Frequent determinations of marked it did not the normal neutropenia, approach serum muramidase were done for at least one cycle in range. In all patients the neutrophil response to the each patient. Fig. 8 demonstrates the pattern of mur- acute administration of hydrocortisone roughly paral- amidase fluctuation with the simultaneously occurring leled that of the other agents. monocyte and In vivo ['H] TdR labeling. In patient 1, ['H]TdR neutrophil cycles in patient 4. For each patient, the pattern of a was administered on day 6 of a cycle and day 14 of rising muramidase level with the subsequent cycle. After labeling during the late increasing peripheral monocytes before the return of neutropenic phase the peak of radioactivity in periph- neutrophils was maintained. The enzyme fell by the eral blood leukocytes appeared on day 12 (6 days middle of the neutrophil recovery phase and paralleled later). Labeling on day 14, when peripheral neutrophil the falling monocyte count. Human Cyclic Neutropenia 3225 MARROW % 2p MYELOBLASTS 0 10 _ PROMYELOCYTES 5 % 20- MYELOCYTES OL_ % PMNS BLOOD 3000r 2000 NEUTROPHILS/mm3 1000 FrI -I 3 5 7 9 13 15 17 19 21 CYCLE DAY FIGURE 5 500 cell -bone marrow differential counts in human cyclic neutropenia (patient 1) over one cycle (upper five panels) and the simultaneous absolute peripheral neutrophil count (bottom panel). Leukokinetic studies. In each patient a neutrophil cytes, lymphocytes, platelets, and reticulocytes all cycle blood half-time was obtained just before the develop- with strict periodicity suggests that this disease in ment of neutropenia by following the disappearance man should be viewed as cyclic hematopoiesis, not of in vitro DF3'P-labeled autologous neutrophils (Table merely as cyclic neutropenia. That the period length I). In the four patients studied on cycle days 15, 17, 18, is approximately the same for each cell type and that and 20, neutrophil ti was normal or slightly prolonged. each cell type follows an entirely separate pattern of The mean for our patients was 8.5 h, compared to 6.6 fluctuation suggest that production of all marrow ele- h in normals (26). Blood granulocyte pool sizes-cir- ments is simultaneously disturbed at one point in the culating, marginal, and total blood granulocyte pools- cycle. If marrow production fails at an early precursor were generally small and probably reflect the degree of cell level between cycle days 12 and 16, at about the peripheral neutropenia. zenith of peripheral neutrophil recovery, and subse- quently resumes, then successive peaks of each cell type DISCUSSION should appear in the peripheral blood. The time and These studies demonstrate that human cyclic neutro- order of appearance of each cell type should reflect its penia is remarkably periodic. The finding in the pa- marrow transit time. The invariable appearance of tient most thoroughly studied that neutrophils, mono- increasing numbers of reticulocytes at 4-5 days after 3226 D. Guerry, IV, D. C. Dale, M. Omine, S. Perry, and S. M. Wolff cycle day 16 and of neutrophils 9-11 days after this Neutropenia Recovery 9000{ time (Fig. 3) is in keeping with what is known of T7 a 900 the time required for these cells to transit the marrow 5000o proliferating and maturing pools (27, 28). From our -nE data, it would seem that the time required to generate 400 X Etiocholonolone -:fi a blood monocyte from early precursors is intermedi- .. 0 Endotoxin .-: ate, 6-8 days, but little data in humans bear on this Hydrocortisone ..,.. point. This time-course would appear to be a reasonable .... z 2000- -.. same .: one since monocytes probably arise from the .., (29, 30), but do 1000 committed stem cell as the neutro'hil ..... not reside in any marrow storage pool for an appre- ,..: Kill L.L .,. ciable period of time (31). In addition, the return of 2 3 4 2 3 4 monocytes often precedes by a few days the return of PATIENT granulocytes after periods of marrow suppression. The FIGURE 6 Bone marrow neutrophil reserves to three agents model of monocytopoiesis recently constructed by Meu- during neutropenia and recovery in four patients with ret (31) giving a marrow to blood transit time of 56 h human cyclic neutropenia. Endotoxin was not used in is considerably less than our data would indicate, but patient 2 during the recovery phase. this time span represents an absolute minimum. Be- cause the precise time of onset of marrow recovery Serum muramidase levels rise during midneutropenia cannot be pinpointed, a more exact transit time cannot and peak just before the recovery of the peripheral be designated for each cell type. A platelet peak fixed in neutrophil count and would seem to reflect marrow relationship to the other cell types is not apparent in granulocytopoietic activity (33). That this enzyme our data, but in the dog the platelet is invariably the parallels the monocyte count may indicate an important first element to increase (1). contribution by these cells to the serum enzyme levels. Unfortunately, similar detailed investigation of the These morphological and functional data indicate other three patients could not be performed because of that fluctuation in blood neutrophils is secondary to their unavailability for long-term study. Thus the data fluctuating rates of cell production. Marrow production are not adequate to permit a categorical statement that is turned on during neutropenia and switched off after all blood elements cycle, but that this obtains is strongly the peripheral blood neutrophil count is reconstituted. suggested by examination of many short-term observa- That neutrophil production is qualitatively normal dur- tions in these patients and corroborated by the com- ing the late neutropenic period is demonstrated by the mon observation of cyclic monocyte fluctuations (2-4) first in vivo [3H]TdR-labeling study. In a similar in- and the single report of periodic platelet oscillations vestigation Meuret and Fliedner (32) have shown, by (5) in human cyclic neutropenia. To convincingly labeling slightly later in the cycle, a shortened com- demonstrate periodicity requires a long-term, equally spaced series of observations with few gaps. Such data must be examined by statistical methods as well as TABLE I visual inspection (12), a goal often difficult to achieve Leukokinetic Studies in Human Cyclic Neutropenia with patients. The balance of the data collected in this group of Patient Cycle tJ* C Pt MGPJ TBGPII GTR¶ events patients relates directly to the marrow myeloid day h X 107/kg X 107/kg X 107/kg X 107/ determining the peripheral blood cycle. Marrow mor- kg/day phological studies in our patients are in agreement 1 15 8.4 14.8 24.4 39.2 79.0 and demonstrate a 2 17 8.7 10.3 37.0 47.3 90.5 with those of others (2, 32) myeloid 3 18 7.3 14.3 52.6 66.9 152.8 wave made up of increasingly mature granulocyte 4 20 9.5 2.95 7.35 10.3 18.2 precursors preceding the increasing peripheral blood Mean 8.5 10.6 30.9 40.9 85.1 neutrophil counts. That morphological marrow re- +1 SE 0.46 2.7 9.6 11.7 27.6 covery is accompanied by functional recovery of the Normals** 6.6 37.1 33.3 65.0 179.9 marrow storage pool of bands and polymorphonuclear 411 SE 1.16 11.1 16.0 22.4 74.3 leukocytes as well as by population of the peripheral * Neutrophil half-disappearance time. blood is supported by the results of the bone marrow Circulating granulocyte pool. reserve tests. Exhaustion of the marrow reserves was § Marginal granulocyte pool. II Total blood granulocyte pool. seen with the descending limb of the blood neutrophil ¶ Granulocyte turnover rate. count. ** From Athens et al. (26). Human Cyclic Neutropenia 3227 PATIENT [3H] TdR AUTORADIOGRAPHY neutrophil destruction (33) is not involved in this disease. The muramidase fluctuations probably reflect 0 Lymphocytes the periodic increase in both monocyte and neutrophil 0 I__ 3230 D. Guerry, IV, D. C. Dale, M. Omine, S. Perry, and S. M. Wolff