ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 12, No. 3 Copyright © 1982, Institute for Clinical Science, Inc.

Transient Reticulocytopenia in Viral Illness JAMES J. BIEMER, M. D. and FRANK M. TAYLOR III, M.D. Department of Pathology, St. Joseph’s Hospital, and University of South Florida, College of Medicine, Tampa, FL 33677

ABSTRACT resulting in transient reticulocytopenia and , the so called “aplastic crisis,” has frequently been documented in patients with congenital . However, this association with hematologi- cally normal patients has been less well recognized. Its occasional sever­ ity is illustrated by this report of two cases of marked reticulocytopenic anemia in association with probable viral . These were previously healthy children whose could be explained oply by a temporary interruption of erythropoiesis. These patients recovered spontaneously and were in good health one year later. A subsequent separate survey of leukopenic patients with a wide variety of viral infections demonstrated significant reticulocytopenia in seven of 35 patients (20 percent). It is con­ cluded that in addition to the more widely appreciated neutropenia and thrombocytopenia of viral infections, reticulocytopenia is a common mani­ festation of many viral infections and may occasionally result in profound anemia.

Introduction Anemia owing to depressed erythropoi­ esis with reticulocytopenia has been fre­ The leukopenic and less frequent quently described in association with a thrombocytopenic effects of viral infec­ variety of congenital hemolytic states, tions upon hematopoiesis are well known.4 particularly hereditary and Reticulocytopenia is also said to be com­ sickle cell anemia.6,7,12 Although these mon in viral infections1; however, that “aplastic crises” with erythropoietic ar­ association seems less well appreciated, rest are frequently thought to be idio­ probably because counts are pathic in nature, many have been ascribed not ordinarily performed in the diagnosis to infections, particularly viral infections. and management of most viral infections. Obviously, in those hemolytic diseases 194 0091-7370/82/0500-0194 $00.90 © Institute for Clinical Science, Inc. RETICULOCYTOPENIA IN VIRAL ILLNESS 195 associated with poor red cell survival, forms. Patients with cancer or those re­ a transient hiatus in erythropoiesis may ceiving radiation or chemotherapy, which quickly result in significant anemia. On are known to be associated with mar­ the other hand, since normal erythrocytes row depression, were excluded from the enjoy a survival approximating 120 days, study. Once a patient was selected for in­ erythropoietic arrest to cause clinically clusion in the study, a reticulocyte count significant anemia must be present for a was performed within 24 hours on the period of at least several weeks. Transient portion of blood left over from the erythroblastopenia of childhood, that is, CBC. The reticulocyte preparations were temporary anemia, reticulocytopenia, and stained with new methylene blue, and the marrow erythroblastopenia, have been percentage of was based described far less frequently in otherwise upon a count of 1,000 red blood cells and hematologically normal patients.1 converted to absolute numbers of reticu­ Having recently encountered two dra­ locytes utilizing the total matic cases of severe anemia with count as determined by the Coulter S Plus. transient reticulocytopenia in normal Total reticulocyte counts of less than children, it was suggested that viral 0.5 percent of erythrocytes or 21,000 per suppression of erythropoiesis may be far cmm for females and 23,000 per cmm for more common than is generally appre­ males were considered to be reticulocyto- ciated. To evaluate further possible tran­ penic.20 All low reticuloctye counts were sient depression of erythropoiesis, reticu­ verified by one of the authors. A total of 52 locyte counts have been, performed in a cases was included in this study. A diag­ variety of clinically diagnosed viral ill­ nosis of “” was based upon nesses as they were presented to our insti­ the history and physical findings aug­ tution. It is the purpose of this report to mented by the usual laboratory studies emphasize the frequency of transient re­ available in a clinical setting. Some pa­ ticulocytopenia by describing two new tients were inpatients, while others were cases of transient erythroblastopenia, as seen in the Emergency Room. Laboratory well as to report the results of the survey studies included many bacterial cultures of reticulocytes in a group of patients with and some viral serological tests, but most a variety of viral illnesses. diagnoses of “viral disease” were of a clinical nature and did not include spe­ cific serological confirmation or agent P a t ie n t s a n d M e t h o d s isolation. The two case reports consisted of rou­ tine pediatric admissions for the study Case Reports and treatment of anemia in 1978 and 1979 CASE 1. The patient was a 17 month old white at St. Joseph’s Hospital, Tampa, Florida. female who, when seen for a sore throat and fever, A second group of patients was studied was found to be anemic. Hemoglobin and hematocrit to determine if reticulocytopenia could be results at that time were 6.8 g per dl and 20 percent, respectively. The reticulocyte count was 0 percent. detected in a variety of viral illnesses. The patient’s past medical history was essentially Both inpatients and outpatients were stud­ unremarkable, except for a presumably viral upper ied on the basis of a presenting complete respiratory tract infection, three months previously, and with diarrhea, two months pre­ blood count (CBC) report. Selected for viously. Recovery from each was prompt and com­ study were those patients whose CBC’s plete. The family history included no evidence of suggested a viral illness, that is, exhibited anemia, excepting for the maternal grandmother who had iron deficiency anemia at one time. primarily an absolute neutropenia, (2,500 Upon admission, the patient’s temperature was per cmm), with a relative or absolute lym­ 101° F and pulse rate was 120 per min. She was well phocytosis and with or without reactive developed and nourished with a height and weight 196 BIEMER AND TAYLOR TABLE I

Hematological Parameters of Case 1

Total Total Platelets Reticulocytes RBC's Hemoglobin Hematocrit WBC's Granulocytes Lymphocytes thousand (percent of Date million/cmm gm/dl percent /cmm /cmm /cmm / cmm RBC's) CO 4/18/79 Oï 20.0 0 4/18/79 6.9 17.2 7,200 144 7576 260 0 4/19/79 2.35 6.4 18.1 5,300 1272 3816 237 0 4/20/79 2.46 7.2 19.2 7,200 144 7056 266 4/21/79 2.17 6.5 17.7 7,400 2294 4588 428 1.1 4/22/79 2.29 6.2 17.9 8,600 1204 7052 563 5.2 4/23/79 2.61 7.4 2 1.1 8,800 968 7568 611 4.8 4/24/79 2.76 7.5 22.3 6,400 512 5760 552 9.0 9/20/79 11.2 37 2.8 1/8/80 11.8 37 2.2

in the 50th percentile. Physical examination was pronormoblasts and basophilic normoblasts were normal except for pallor and a grade I systolic mur­ conspicuous and possibly slightly increased, the mur along the left sternal border. polychromatophilic and orthochromic forms were The CBC on admission showed: hemoglobin, 6.9 g markedly decreased. Granulocytic and megakary- per dl; hematocrit, 17.2 percent; white blood count, ocytic elements were unremarkable. Stainable he­ 7,200 per cmm with 2 percent segmented neu­ mosiderin was slightly increased. trophils and 98 percent normal lymphocytes. The The patient’s anemia was monitored by serial platelet count was 260,000 per cmm and a repeat reticulocyte and blood counts. No transfusions, anti­ reticulocyte count was 0 percent. The urinalysis was biotics, or steroids were given. Over the six day hos­ normal. A chest x-ray showed no abnormality. Throat pital stay, the reticulocyte counts gradually rose from and nasopharyngeal cultures demonstrated only the 0 to 9 percent. A concomitant rise in hemoglobin and usual bacterial flora. Further hematologic tests in­ hematocrit was noted (table I). Follow-up studies by cluded: serum iron, 163 ¡xg per dl; iron binding ca­ the pediatrician revealed a hemoglobin of 11.2 g pacity, 250 fig per dl; normal hemoglobin electro­ per dl, hematocrit, 37 percent, and reticulocytes, phoresis with A1 = 97.1 percent, A2 = 2.6 percent; 2.8 percent five months following discharge. At and fetal hemoglobin, 0.3 percent. Stools were nega­ nine months following hospitalization, these values tive for occult blood, and both the direct and indirect were 11.8 g per dl, 37 percent and 2.2 percent, Coomb’s tests were negative. respectively. An iliac crest bone marrow done on the day of CASE 2. This patient was a previously healthy, admission had an estimated cellularity of 50 percent well developed 10-Vi month old white male who and a myeloid: erythroid (M:E) ratio of 10:1. Nor­ was first noted to be pale 10 days prior to being seen moblastic erythroid precursors were present. While by a pediatrician. Examination confirmed anemia:

T A B L E II

Hematological Parameters of Case 2

Total Total Platelets Reticuh RBC's Hemoglobin Hematocrit WBC's Granulocytes Lymphocytes thousand (percei Date million/cmm gm/dl percent /cmm /cmm /cmm /cmm RBC':

11/6/78 2.02 5.6 16.2 10,700 2568 7704 0 11/7/78 1.60 4.3 12 .6 8,300 4150 3652 325 0.2 11/8/78 1.79 5.1 14.2 16,900 0.9 11/9/78 1.64 4.5 13.1 15,100 1.2 11/10/78 3.07 9.1 26.5 11,000 3.5 11/11/78 3.46 10. 3 29.6 6,900 4278 1863 8.0 11/12/78 3.21 9.4 21.5 5,500 10.8 11/13/78 3.39 9.8 29.6 6,300 11/18/78 10.5 32 8.8 11/22/78 12 30 4.5 12/8/78 12 36 1.8 10/30/79 14 40 RETICULOCYTOPENIA IN VIRAL ILLNESS 197 hemoglobin, 5.6 g per dl, hematocrit, 16.2 percent, peared non-viral and usually bacterial in and reticulocytes, 0 percent. The child’s appetite and food intake had been normal, and there was no nature (nine cases), or there was no evi­ history of melena. the child had been seen on a dence of an acute inflammatory process routine check-up two months earlier at which time (eight cases). his hemoglobin was 13.5 g per dl. The child had previously been in good health Seven of the 35 cases (20 percent) of except for a skin rash one month earlier which viral disease had reticulocytopenia as de­ responded to small doses of diphenhydramine hy­ fined. Two of these reticulocytopenic pa­ drochloride. Two upper respiratory tract infections occurred prior to that, and these were regarded as of tients were also mildly thrombocytope­ viral etiology, having responded quickly to symp­ nic, and five of them were under 16 years tomatic therapy. No other drugs had been taken, and of age. The various hematological param­ there was no exposure to toxins. There was no family history of anemia. eters and clinical diagnoses of these seven Upon admission, the patient’s temperature was patients are portrayed in table III. 100.2° F and pulse rate was 120 per min. Except for pallor, this well nourished, active child’s physical examination was normal. Laboratory examinations Discussion included: urinalysis = normal; direct Coomb’s test = negative; stools for occult blood = negative; osmotic fragility = normal; serum iron, 157 /j.g per dl; iron Failure of the bone marrow to produce binding capacity, 332 ¡xg per dl; haptoglobin, 81 mg erythrocytes, granulocytes, and thrombo­ per dl (normal, 60 to 270), and red cell glueose-6- phosphate dehydrogenase, 5.7 IU per g Hb (normal, cytes with resulting pancytopenia is des­ 5 to 9). Cultures of urine, blood, throat, and stool ignated “.” Various de­ were either negative or contained normal flora. A grees of this condition are encountered in chest x-ray was normal. A bone marrow from the iliac crest on the second hospital day, when the reticulo­ clinical practice, extending from the clas­ cyte count was 0.2 percent, was 60 percent cellular sical aplastic anemia with severe general­ with a myeloid :erythroid (M:E) ratio of 3:1. Nor­ ized marrow hypocellularity and marked moblastic erythroid elements of all stages of matura­ tion were present, although pronormoblasts and peripheral pancytopenia to less profound basophilic normoblasts appeared increased. Stain- hypoplastic conditions associated with cy- able hemosiderin was slightly increased. Lacking topenias of lesser degree. evidence of , these findings were inter­ Marrow suppression has been ascribed preted as a signal of marrow recovery, suggesting that reticulocytosis would soon follow. to a wide variety of etiologies,2 ranging The patient was observed in the hospital for eight from foreign substances (chemicals, tox­ days with the first evidence of reticulocytosis occur­ ring on the fourth hospital day. The only treatment ins, and drugs) to infectious agents (pri­ consisted of 100 ml of packed red cells on the fourth marily bacterial and viral) to associated day. His hematological parameters are portrayed in neoplasia (thymoma, preleukemic states). table II. On the day of discharge, the patient’s hemo­ globin was 9.8 g per dl and hematocrit was 29.6 The largest single category, however, re­ percent. One month later, the hemoglobin was 12 g mains the idiopathic cases. per dl, hematocrit, 36 percent, and reticulocytes, 1.8 It is quite probable that viral infections percent, while at the one year follow-up, the hemo­ globin was 14 g per dl and the hematocrit, 40 will be increasingly incriminated in many percent. of the cases that are now regarded as idiopathic. is one form of viral illness which has been implicated Results of Survey of Reticulocyte Counts not only in complete marrow apla­ in Viral Diseases sia,3,9,15,16 but also in transient red cell Of the 52 patients with neutropenia, re­ aplasia.17 Prior to 1955, this form of infec­ view of clinical and laboratory data al­ tion was not considered to be of etiologic lowed a diagnosis of uncomplicated and importance in aplastic anemia. However, untreated viral disease in 35 of them. The since that time numerous case reports in­ remaining 17 neutropenic patients were volving type A, type B,5,14 and non A and excluded, since they were frequently re­ non B8 viral hepatitis have been doc­ ceiving drug therapy which might umented. Although Coomb’s negative he­ have been myelosuppressive. Addition­ molytic forms of anemia have been associ­ ally, their inflammatory processes ap­ ated with viral hepatitis,18 the anemia is 198 BIEMER AND TAYLOR

TA BLE III

Hematological Parameters and Clinical Diagnoses of Seven Reticulocytopenic Patients with Viral Disorders

RBC Hctf Platelets Days Age million Hgb* Per- thousand R.$ WBC N.G.% L.fl Since Patient Sex Yrs /cmm gm/dl cent /cmm /cim /cmm /cim /cmm Onset Clinical Diagnoses

CK F 30 4.13 12.7 37.7 142 12,399 2,700 2,025 459 1 Viral pharyngitis LM F 1.3 3.87 11.2 31.6 126 3,870 3,000 960 1,980 3 Viral pharyngitis ML F 39 3.62 11.5 33.3 128 3,620 7,000 910 5,810 10 Hepatitis due to infectious mono­ nucleosis DL F 13 4.56 13.0 38.9 241 13,680 3,500 2,170 1,155 1 Chicken pox TMM 9 4.74 13.4 40.3 177 9,480 3,900 897 2,262 2 Acute gastro­ enteritis DM M 16 5.03 15.3 46.3 134 20,120 2,700 2,133 459 2 KB M 24 4.36 10.9 32.5 295 21,800 4,600 644 3,450 3 Viral

♦Hemoglobin fHematocrit ^Reticulocytes §Neutrophilic granulocytes ^Lymphocytes accounted for more commonly on the ba­ been documented in many other forms of sis of marrow suppression as reflected by hemolytic anemia as well.6,7,12 low reticulocyte counts. Complete mar­ Further data linking viral illness and row failure as found in viral hepatitis erythroid cell line suppression has been is associated with a predominantly adult compiled by Alter and Nathan.1 Approxi­ male population during the recovery mately 60 cases have been reported of phase of the hepatitis.3'15,16 It is unrelated transient erythroblastopenia in children, to the severity of the hepatitis and has a all of whom have suffered some form of survival rate of only 12 to 15 percent.15 viral illness two weeks to two months A similar although less frequent associ­ prior to the development of pallor. All ation of bone marrow suppression has of these patients were between the ages been noted in . of one month and six years and all Although hemolytic anemia is more fre­ presented with anemia and reticulocyto- quently observed, aplastic anemia has penia. Subsequent bone marrow exam­ manifested itself via granulocytopenia, inations showed erythroid hypoplasia. thrombocytopenia, and, least commonly, Prognosis, however, was excellent with pancytopenia.10,13,19 Van Doornik et al be­ patients recovering usually within one to lieve that infection with Epstein Barr vi­ two months and often with no treatment. rus should be added to the list of possible The two cases which are the subject of causes of aplastic anemia.19 this report serve to illustrate further the The unique suppression of the eryth- association between viral illness and the roid cell line in association with infec­ depression of erythropoiesis with result­ tious diseases, particularly viral illnesses, ant anemia. While only one of our cases has been observed for many years in the appears to be pure red cell hypoplasia, so-called “aplastic crises” of a variety the other exhibiting granuloctyopenia as of congenital hemolytic anemias. Obvi­ well, there is no question that the princi­ ously, in these types of anemia, a small pal clinical manifestations were related to hiatus in red cell production can quickly anemia. Furthermore, since these two result in significant anemia. The most cases appeared at our hospital within a common forms of hemolytic anemia that relatively short period of time, the authors have been associated with such crises are suggested that virus-induced suppression congenital spherocytic anemia and sickle of erythropoiesis as particularly mani­ cell disease, although similar crises have fested by reticulocytopenia might be RETICULOCYTOPENIA IN VIRAL ILLNESS 199 drome of hepatitis and aplastic anaemia. Brit. J. more common than is generally appreci­ Haematol. 27:345-355, 1974. ated. That this is a fact is substantiated by 4. As t e r , R. H.: Disorders ofhemostasis-quantita- our study of 35 cases in which seven or 20 tive platelet disorders. Hematology. Williams, W. J., Beutler, E., Ersler, A. J., and Rundles, R. percent of the patients were found to have W., eds. New York, McGraw-Hill Book Co., reticulocytopenia. 1977, pp. 1322-1323. The specific mechanisms by which the 5. Ca sc ia t o , D. A., Kl e in , C. A., Ka p l o w it z , N., and SCOTT, J. L.: Aplastic anemia associated marrow and, in particular the erythroid with type B viral hepatitis. Arch. Intern. Med. cell line, is depressed in viral illnesses are 138:1557-1558, 1978. unclear. While it is probable that a variety 6. C h a r n e y , E. and M il l e r , G.: Reticulocytope­ nia in . Amer. J. Dis. Child. of viruses may cause marrow depression, i07:450-455, 1964. it is uncertain whether or not their manner 7. C o n k l in , G. T., G e o r g e , J. N., and Se a r s, D. of action is similar in all cases. Certain A.: Transient erythroid aplasia in hemolytic anemia: a review of the literature with two case clinical presentations, such as those in our reports. Tex. Rep. Biol. Med.32:391^111,1974. series of the seven reticulocytopenic pa­ 8. F ir k in , F. C., N ic h o l s , K., and W h e l a n , G.: tients, suggest a sudden and direct action Transient myeloid and erythroid aplasia associ­ against the marrow. Whether or not this ated with infectious hepatitis. Brit. Med. J. 2:1534, 1978. could represent a direct cellular or chro­ 9. H a g l e r , L., Pa s t o r e , R. A., and Be r g in , J.J.: mosomal insult wrought by a virus, or a Aplastic anemia following viral hepatitis: re­ port of two fatal cases and literature review. toxin resulting from a virus-induced meta­ Medicine 54:139-164, 1975. bolic pathway interruption, is only specu­ 10. Ja in , S. and Sh e r l o c k , S.: Infectious mononu­ lative. Other clinical settings, i.e., those cleosis with jaundice, anaemia and enceph­ described in our two case reports, suggest alopathy. Brit. Med. J. 3:138-139, 1975. 11. Ko e n ig , H. M., Lig h t s e y , A. L., N e l s o n , P. L., a more indirect, time-consuming process G r is w o l d , W. R., and D ia m o n d , L. K.: Inhibi­ such as the slow buildup of an immuno­ tion of erythroid colony formation by immuno­ logic surge or the gradual replication of globulin G (IgG) from patients with transient erythroblastopenia of childhood (TEC). Blood an altered virus exhibiting a hematode- 52(Suppl.):207, 1978. pressive potential.9,11 12. Ma n n , J. R., C o t t e r , K. P., Wa l k e r , R. A., Bir g , G. W. G., and St u a r t , J.: Anaemic crisis In any event, despite the lack of un­ in sickle cell disease. J. Clin. Path. 28:341-344, animity regarding mechanisms, it appears 1975. that viral depression of bone marrow 13. Mir , M. A. and D e l a m o r e , I. W.: Aplastic anaemia complicating infectious mononucleo­ hematopoietic elements is a well substan­ sis. Scand. J. Haematol. Ji:314-318, 1973. tiated phenomenon. Moreover, particular 14. Nak a m u ra , S., Sa t o , T., T o sh iy u k i, M., and depression of the erythroid precursors may YASUSHI, S.: Viral and aplastic ane­ occur, sometimes resulting only in a pe­ mia. Tohoku. J. Exp. Med. Ji6:101-102, 1975. 15. P e t e r s , P. J., D a v ie s, B., and C h e n , S. T.: ripheral reticulocytopenia but occasion­ aplastic anemia: a serious complication of viral ally yielding marrow erythroblastopenia hepatitis. W. Va. Med. J. 72:61-63, 1976. and anemia. Finally, it is possible that 16. Sa m a n ta ra y , S. K., J o h n so n , S., and T ik u , M. L.: Viral hepatitis-aplastic anemia syndrome; a common and frequently trivial or subclin- case report and review of literature. J. Assoc. ical viral infections may be responsible Physicians India 22:777-780, 1974. 17. Se a r s , D. A., G e o r g e , J. N., and G o l d , M. S.: for many cases of marrow depression that Transient red blood cell aplasia in association are currently regarded as idiopathic in with viral hepatitis. Arch. Intern. Med. 135: nature. 1585-1589, 1975. 18. Va n d e r h o f f , J. A. and Am e n t , M. E.: Severe Coombs negative hemolytic anemia in hepatitis References B. West. J. Med. i25:228-230, 1976. 19. Van D o o r n ik , M. C., Van ’T Ve e r -Ko r t h o f , E. T., and Wie r e n g a , H.: Fatal aplastic 1. Al t e r , B. P. and N a t h a n , D. G.: Red cell anaemia complicating infectious mononucleo­ aplasia in children. Arch. Dis. Child. 54:263- sis. Scand. J. Haematol. 20:52-56, 1978. 267, 1979. 20. W y n g a a r d en , J. B.: Normal laboratory values 2. Al t e r , B. P., P o t t e r , N. U., and F r e d e r ic k , of clinical importance. Cecil Textbook of Medi­ P. L.: Classification and aetiology of the aplastic cine, vol. 2. Beeson, P. B., McDermott, W., and anaemias. Clin. 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