Vincent W. Ing The Etiology and Management of SUMMARY SOMMAIRE Leukopenia is an abnormal reduction of La leucopenie est une diminution anormale de la quantite de leucocytes circulants, affectant surtout circulating white blood cells, especially the les . On confond souvent le terme granulocytes. The term leukopenia is often leucopenie avec neutropenie. La neutropenie peut used interchangeably with . It soit reduire la production efficace des globules may result from reduced production of white blancs, soit augmenter leur utilisation et leur blood cells or increased utilization and destruction, ou les deux. Infection, medicaments, tumeur maligne, megaloblastose, hyperplenisme et destruction, or both. Infection, drugs, immunoneutropenie sont responsables de la plupart malignancy, megaloblastosis, hypersplenism des cas de neutropenie. La neutropenie primaire est and immunoneutropenia are responsible for tres rare. Parfois, surtout chez les enfants, la most cases of neutropenia. Primary neutropenie primaire est hereditaire et associee a neutropenia is very rare. Sometimes, d'autres anomalies congenitales. Le principale particularly in children, primary neutropenia menace engendree par la neutroperue est le risque d'infection. Le traitement requiert l'identification de is hereditary and may be associated with la cause et une therapie antimicrobienne, surtout en other developmental defects. The major presence d'une infection systemique grave. danger of neutropenia is the risk of infection. Management requires identification of the cause and effective antimicrobial therapy, especially when serious systemic infection is present. (Can Fam Physician 1984; 30:1835-1839.). 1111 millin

Dr. Ing is an assistant professor in more serious deficit. The lowest nor- have less phagocytic and bactericidal the Department of Medicine at mal concentration of neutrophils is activity. Their rate of mobilization to Dalhousie University, Halifax, and about 1,500-1,800 per mm3. ' This sites of inflammation is also less effi- an attending physician at the minimum number may vary among cient.4 Halifax Infirmary and Victoria different ethnic groups; lower neutro- General Hospital, Halifax, NS. phil counts have been recorded for Kinetics Reprint requests to: Suite 635, 5991 blacks in the U.S. and Africa.2' 3 In normal adults, granulocyte pro- Spring Garden Rd., Halifax, NS. There is a rough correlation be- duction5 takes place primarily in the B3H 1Y6. tween the degree of neutropenia and bone marrow. The life history of the the risk of bacterial infection. An ab- granulocytes can be separated into solute count of 500-1,000 per mm3 is bone marrow, blood and tissue T EUKOPENIA IS an absolute re- associated with moderately increased phases. In the bone marrow phase, Lduction in circulating white blood risk. A count below 500 per mm:3 the myeloblasts, promyelocytes and cells below the lower limit of normal (i.e., ) that persists for myelocytes (progeny of the commit- values. Technically, it includes neu- more than a few days, is invariably ted stem cell CFU), constitute the mi- trophils, and even lympho- associated with serious infection. totic compartment. They are all cap- cytes. In clinical practice, it is practi- The risk of infection may be modi- a bl e o f c e I d i v i s i o n s . cally synonymous with neutropenia. fied considerably by the presence of Metamyelocytes, band and segmented Agranulocytosis implies a much monocytosis. In general, monocytes neutropils, all incapable of cell divi-

CAN. FAM. PHYSICIAN Vol. 30: SEPTEMBER 1984 1 835 sions, constitute the maturations peripheral blood. The best example is ably. Neutropenia may be an inciden- storage compartment. The size of this the myeloid maturation defect due to tal finding or overshadowed by other compartment is about seven to 13 vitamin B12 deficiency. Megaloblas- clinical disturbances. It is essential to times that of the peripheral blood tosis is a common feature, along with elicit a careful history, with specific pool. It has been estimated to be be- significant elevation of serum lactic reference to drugs, exposure to toxic tween five and 9 x 109 cells/kg Bwt.5 dehydrogenase.8 compounds, possible genetic predis- In the peripheral blood pool, the gran- position, nutritional state and signifi- ulocytes establish an efficient equilib- Type 3: cant constitutional symptoms, such as rium between the circulating blood Reduced granulocyte survival fever and weight loss. Physical exam- granulocyte pool (CGP) and the mar- An acceleration in the consumption ination should be performed with ginal granulocyte pool (MGP). In an of granulocytes in the peripheral keen attention to lymphadenopathy, emergency, rapid reinforcement of blood stimulates an increase in the ef- spleen and liver evidence suggesting CGP can be achieved within a short fective granulocytopoiesis. 9 Neutro- a multiple system disease or malign- time by a preferential shift from the penia develops when the depletion ancy. In dealing with a case of mild MGP. The granulocytes circulate in rate exceeds the production rate. The and asymptomatic neutropenia, it is the peripheral blood for about ten bone marrow is hypercellular, with reasonable to postpone all investiga- hours before making an unidirected increased myeloid immaturity. Leuko- tions for one to two weeks and repeat entry into the tissue phase. cyte reserve pools are reduced. The the hemogram to assure that neutro- turnover rate is markedly increased, penia is not an artifact produced by Functional Classification and the neutrophil survival is shor- electronic counters. Other causes of Of tened. This condition may be due to spurious neutropenia include clump- Neutropenia ing in the presence of paraproteine- Neutropenia may result from re- leukocyte antibody or toxin,10 hy- peractivity of the reticuloendothelial mia, and counts done on aged blood. duced effective production of white However, symptomatic neutropenia, blood cells, increased utilization or system or excess splenic sequestra- tion. agranulocytosis and pancytopenia de- destruction, or all of these.6 7 Re- serve prompt attention. duced delivery of mature neutrophils Type 4: The laboratory investigations from the bone marrow may be related Combination granulocytopenia needed to identify the cause of neutro- to reduced myeloid proliferation in penia include complete blood counts, the marrow or ineffective granulocy- This is probably the mechanism which most commonly produces neu- bone marrow aspiration and trephine topoiesis. The major mechanisms for biopsy, liver function tests and lactic an excessive loss of neutrophils from tropenia. The best example is acute with sepsis. The effective dehydrogenase. Studies pertaining to the peripheral blood are: accelerated granulocyte kinetics and turnover, migration into the tissue in association granulocytopoiesis is severely re- stricted to begin with, and sepsis fur- ability of phagocytosis and migration with infection or inflammation; re- are usually feasible only in granulo- duced survival due to a maturation de- ther promotes excessive peripheral de- struction of granulocytes. cyte research centres. Indeed, in most fect, increased reticuloendothelial sys- cases, these studies are not essential tem (RES) activity or cell damage by for the clinical diagnosis of neutro- leucotoxin, or an abnormal transient Type 5: Pseudoneutropenia penia. In specific cases, marrow gran- or prolonged shift into the marginal ulocyte reserves can be assessed by pool. Pseudoneutropeniall is an apparent using 200 mg of intravenous hydro- Type 1: neutropenia, resulting from a shift in cortisol and measuring the peak neu- Reduced production equilibrium towards the marginal trophil concentration in three to four with myeloid hypoplasia granulocyte pool. Occasionally, an in- hours. 12 crease in the size of the bone marrow In clinical practice, most cases of Myeloid proliferation is sup- storage pool, due to an impaired re- neutropenia can be accounted for by pressed, resulting in shrinkage of the lease of marrow neutrophils, may also several pathologic entities. These in- marrow storage pool. The neutrophil be responsible. The total granulocyte clude infection, drugs, malignancy, survival is relatively unaffected. pool remains normal. Leukocyte ki- hypersplenism, megaloblastosis and However, the total turnover is re- netics are unaffected. Pseudoneutro- immunoneutropenia. duced. Biopsy of the bone marrow penia usually is transient in associa- may -demonstrate fibrosis, dysplasia, tion with virema, hypersensitivity Infection leukemia or malignant cell infiltra- state or splenic and hepatic conges- acute viral or rick- tion, and other morphologic aberra- tion. It also may occur in familial or Many systemic tions, in addition to bone marrow hy- chronic form. ettsial infections produce neutropenia. poplasia. The characteristic pattern is that which occurs with infectious hepa- Type 2: Clinical Approach titis 13 or mononucleosis. 14 Leuko- Ineffective granulocytopoiesis To Neutropenia penia develops during the first two Intramedullary death of myeloid Neutropenia may be present as an days and may persist for three to precursors is a dominant feature. De- isolated hematologic abnormality or seven days, a time which corresponds spite an apparent marrow myeloid hy- in association with anemia and/or to the period of acute viremia and perplasia, the storage pool is reduced, thrombocytopenia. The mode of clini- virally-induced leukocyte damage re- and fewer cells are released into the cal presentation may vary consider- sulting in excessive peripheral mar-

1836 CAN. FAM. PHYSICIAN Vol. 30: SEPTEMBER 1984 gination and utilization. Atypical lym- cell production. cases of acute leukemia, neutropenia phocytes are often observed during Idiosyncratic reactions: These'6 17 might be the only abnormality discov- the same period. Toxic cytoplasmic tend to be more prevalent among ered on a routine hemogram. The pres- granulation and Dohle bodies fre- women, the elderly, or patients with a sence of a frank leukoerythroblastic quently appear in the neutropenia strong history of allergies. In general, picture in the absence of significant phase. Usually, the granulocyte count idiosyncratic reactions can be divided splenomegaly should arouse serious returns by the tenth to the fourteenth into two categories-slow or delayed suspicion of bone marrow infiltration day. Other infectious diseases often onset and abrupt onset neutropenia. by tumor cells. associated with neutropenia include The phenothiazine derivatives are rubella, smallpox, chickenpox and implicated more frequently in the eti- Hypersplenism measles .15 ology of slow onset neutropenia than Leukopenia occurs with splenome- Agranulocytosis may occur in asso- any other drug. 18 This adverse reac- galy in many diseases, such as cirrho- ciation with an overwhelming infec- tion is dose dependent, rarely occur- sis with portal hypertension, lym- tion in a previously healthy individ- ring within two weeks or after 90 phoma, and Felty's ual. Mild to moderate cases of days of drug administration. At times, syndrome. The usual picture is a mod- neutropenia are often associated with agranulocytosis may appear. Not in- est reduction of all blood elements. bacillary dysentery, typhoid and para- frequently, however, the neutrophil The bone marrow cellularity is often typhoid- fever and , al- concentration may stabilize at a re- increased with normal maturation se- though the responsible mechanism is duced level or may even return quence. The survival of neutrophils is, poorly understood. towards normal when the drug con- however, shortened. tinues to be administered. The bone Drugs marrow is aplastic or hypoplastic Megaloblastosis Due to the frequent use of multiple when neutropenia has developed. It is This pathologic process20 should be drugs, it can be difficult to identify believed that bone marrow suppres- seriously entertained in the presence of the responsible drug. Often, the clini- sion is due to drug inhibition of DNA poor nutritional state, anorexia, alco- cian is forced to made an educated synthesis. 18 holism, senility, neurological deficits, guess, based upon his analysis of the In some cases, abrupt onset neutro- and chronic diarrhea. In most cases, patient's drug record and the temporal penia rapidly follows repeated or in- pancytopenia is present, although iso- relationship of the drugs to the onset termittent exposure to a drug. The lated neutropenia might be the present- of neutropenia, as well as upon his mechanism is often unclear but is pre- ing hematological abnormality. Labo- knowledge of the pharmacological ac- sumed to be immunologically me- ratory abnormalities that might tion and side effects of the drugs in diated. Drug-hapten antibody reac- provide clues to this process include question. In addition, the disease for tion17 has been proposed as a cause in high MCV, the presence of hyperseg- which the drugs are used may well some situations. and mented neutrophils, oval macrocytes, contribute to the development of neu- monocytosis may be present, along and high lactic dehydrogenase. The tropenia. with bone marrow myeloid hyperpla- common etiologic deficiency is folic Two categories of drug-induced sia. Following the cessation of drug acid, due either to nutritional defi- neutropenia have been recognized. therapy, bone marrow function re- ciency or a drug (e.g., phenytoin)21 These are predictable reactions and covers in a few days. Occasionally, which interferes with its metabolism. idiosyncratic reactions. however, the neutropenia may be irre- Vitamin B12 deficiency results in an Predictable reactions: If given in versible. In specific situations, gene- identical pathological state. sufficient doses, the drugs in this cat- tic abnormality might predispose a pa- tient to a drug reaction. The increased Immunoneutropenia22 egory will consistently cause neutro- Neutropenia is present in over 50% penia. The best examples are cancer incidence of adverse effects with sul- fasalazine in individuals who are slow of patients with disseminated chemotherapeutic agents. They act .23 The of cir- mainly by interfering with cell pro- acetylators is an example of such gen- erythematosus presence etic susceptibility. 19 culating leukoagglutinins, in conjunc- duction, either by directly injuring the tion with splenomegaly, can often be stem cell or mitotic compartment of The drugs that most clinicians rec- ognize as being associated with neu- demonstrated. Seldom is immunoneu- the bone marrow, or by slowing cell to increase the division by blocking DNA strand du- tropenia include phenothiazine, diure- tropenia severe enough tics, antithyroid agents, nonsteroidal patient's susceptibility to infection. plication, interfering with the purine Leukocyte auto-antibodies have also or pyrimiditle metabolism, disrupting anti-inflammatory agents, certain anti- biotics and analgesics. We must rec- been associated with other connected the microtubules of the mitotic spin- tissue such as rheumatoid ar- dle, or interfering with RNA forma- ognize that all drugs have the poten- diseases, tial to induce an idiosyncratic thritis and Felty's syndrome. Rarely, tion and the translation and transcrip- in an idio- tion granulocytopenia. auto-antibodies may occur processes. The neutropenia- is pathic form, similar to the way in dose-related. There is usually a delay anemia before neutropenia appears. The Malignancy which autoimmune hemolytic length of the delay is related to the Neutropenia may be associated with or thrombocytopenia appear. size of marrow neutrophil reserve. In all hematological or non-hematologi- a previously healthy marrow, a delay cal malignancies. In most cases, there Uncommon neutropenis disorders24' 25 of eight to 14 days can be expected, is clear evidence of disturbance of all Pediatric: Several clinical syn- even after complete suppression of bone marrow elements. In selected dromes have been associated with neu-

CAN. FAM. PHYSICIAN Vol. 30: SEPTEMBER 1984 1 837 tropenia. Some are transmitted as an represent redistribution of granulo- agents are continued until the results of autosomal recessive or dominant trait. cytes within various compartments. blood cultures and sensitivity tests are Others appear to be sex-linked reces- known, at which time the antimicro- sive disorders. The bone marrow cel- Management bial program may be readjusted if nec- lularity varies among these syn- essary. The antibiotics should be con- dromes, indicating that several The treatment30 of neutropenia de- tinued for at least three days after the mechanisms are responsible for the pends on its etiology, severity and the patient has become afebrile. When granulocytopenia. Many of these neu- estimated risk. In situations where the there is obvious clinical deterioration tropenic patients also demonstrate etiological factor can be identified and or persistent fever after seven days of other developmental disorders (i.e., rectified (e.g., drugs, folic acid defi- antimicrobial therapy, the clinician thymic aplasia, B cell dysfunction, or ciency), treatment should be instituted must completely reassess the patient, bone growth abnormalities). The risk without delay. The risk of infection keeping in mind the possibility of an of infection varies greatly. Even depends upon a complex interrelation- opportunistic infection or abscess. among those with recurrent bouts of ship of lymphocytes, neutrophils and In selective cases, specific diagnos- infection, life can be lengthened signi- , cellular and circulating tic measures such as open lung biopsy ficantly with aggressive antibiotic immunological defense, along with or bronchoscopy may be required, in therapy. physical barriers which normally pro- addition to blood cultures. When no Adult: Benign familial neutro- vide protection against infecting orga- concrete evidence of the etiological penia26 is transmitted as an autosomal nisms. Any qualitative or quantitative agent can be secured, a trial of ampho- dominant trait. Affected patients are defect in one of these factors may pre- tericin, ketoconazole or even a syste- often healthy, showing moderate dispose the patient to infection. mic antiviral agent, is appropriate. monocytosis and eosinophilia. Bone When neutropenia is severe and pro- Although the effectiveness of granulo- marrow studies are usually unremark- longed (e.g., in cases of acute leuke- cyte transfusion has been well estab- able. In recent years, the definition of mia), a major problem is recognizing lished, in general it should be consid- this syndrome has been broadened to the infection. Due to the paucity of ered only when there is fulminant include several large ethnic groups neutrophils, purulent exudates are infection and the response to antibiot- with genetically determined neutro- scanty and clinical signs may be mini- ics has been suboptimal. Granulocyte penia. mal. Other significant factors promote transfusion on a prophylactic basis is With non-familial chronic idio- infection. In addition to quantitative not recommended, in view of the risk pathic neutropenia27 the bone marrow deficiency of neutrophils, their bac- of cytomegalovirus infection.32 is normal or moderately hypercellular tericidal activity is often diminished. In cases of chronic neutropenia, and contains no segmented neutro- In addition to their myelosuppressive bacterial infections are usually a less phils. In general, the risk of infection activity, antineoplastic drugs also have serious problem. In specific situations is not significant. A modest monocy- deleterious impact on functions such where the etiologic factor is primarily tosis is usually present. as cytotoxicity mediated by leuko- hypersplenism or immunoneutropenia, Chronic hypoplastic neutropenia28 cytes. It has been demonstrated that splenectomy may be beneficial. is a rare disorder with significant mar- doxorubicin, vincristine and other row suppression and a high risk of bac- such drugs can decrease leukocyte- terial infection recurring. There is no mediated, antibody-dependent cellular Prophylaxis of infection hereditary pattern. Some patients have cytotoxicity (ADCC) and natural killer Different measures have been an associated thymic disorder or hypo- cytotoxicity (NKC) against viral in- studied, with the intention of either re- gammaglobulinemia. Absolute mono- fected target cells.31 Mechanical bar- ducing bacterial infection or promot- cytosis is unusual. riers, which represent an important ing granulocyte functions. Reverse Some cases of cyclic neutropenia29 limiting factor to colonization and in- isolation, which was quite popular for appear to be transmitted as an autoso- fection, frequently are disrupted by many years, has been found to have no mal dominant trait, while others have well intentioned but iatrogenic mea- specific value. The efficacy of a germ- no significant hereditary basis. The sures (e.g., oropharyngeal and gas- free protective environment, espe- usual history is that at intervals of trointestinal ulcerations due to cancer cially when used with prophylactic an- every two or three weeks patients dem- chemotherapy, urethral catheterization tibiotics, has been established. onstrate fever lasting for several days, and indwelling venous catheters). However, due to its prohibitive cost as well as neutropenia which lasts for Treating such a complicated case re- and the psychological impact on the three or four days. Studies indicate quires intense nursing care and con- patient, it is seldom used.30 Prophy- the disorder may be the result of peri- stant and keen observation for the lactic antibiotic programs have re- odic stem cell failure. 35 slightest evidence of infection. If fever mained controversial. In our centre, Pseudoneutropenia is another type or tangible evidence of infection de- Septra DS tablets, one bid are used of adult neutropenia. Acute cases of velops, suitable blood, urine and only for compromised patients, such neutropenia hSave occasionally been throat cultures should be obtained, and as those with acute leukemia who are observed in association with anaphy- then antibiotics must be given, unless undergoing induction chemotherapy. laxis, leukophoresis or hemodialysis. there is an obvious noninfectious Androgen therapy combined with When neutrophils adhere to the filter, cause. To provide adequate bacterici- small doses of corticosteroid for three they release a labile factor which in- dal coverage, combination antibiotics to four months has achieved moderate duces vascular margination. Chronic should be used. Most centres use an but unpredictable success in promoting forms may be present with prolonged aminoglycoside plus antipseudomonal production in cases of nonmalignant malnutrition. The neutropenia might penicillin or cephalosporin. These myeloid hypoplasia. Recently, lithium

1 838 CAN. FAM. PHYSICIAN Vol. 30: SEPTEMBER 1984 carbonate has been discovered to en- 14. Cantow Kostinas JE: Studies in WF, c I~~~ hance proliferation of human granulo- . IV. Changes in cytic colonies in vitro. In some the granulocyte series. Am J Clin Pathol Brief Prescribing Information. centres, lithium carbonate 900 mg per 1966; 46:43-47. RYNACROMW SOLUTION. (Sodium Cromoglycate 2% 15. Murdock JM, Smith CC: Hematologi- w/v Nasal Metered Dose Mist) day is used during induction chemoth- cal aspects of systemic diseases: Infection. THERAPEUTIC CLASSIFICATION. Seasonal Rhinitis erapy in acute leukemia.33 In my expe- Clin Haematol 1972; 1:619-644. Prophylaxis rience, however, its effects have been 16. Palva IP, Mustala 00: Drug induced ACTION: In the immediate allergic reaction (Type I) agranulocytosis with special reference to the union of antigen with reaginic antibody leads rather unimpressive. to the formation and release of spasmogens and other aminophenazone, I. Adults. Acta Med mediators of the anaphylactic reaction. Sodium Scand 1970; 187:109-115. cromoglycate appears to block a step in the chain of Bone marrow transplantation 17. Pisciotta A V: Drug induced leucopenia events triggered by this union.This property accounts and aplastic anemia. Clin Pharmacol Ther for the prophylactic rather than symptomatic approach In recent years, allogeneic bone 1971; 12:13-43. to the management of seasonal rhinitis. marrow transplantation has become an 18. Kinross-Wright J: The current status of Sodium cromoglycate has no antihistaminic, anti- established modality for the treatment phenothiazines. JAMA 1967; 200:461- inflammatory or decongestant activity. 464. INDICATIONS: Prophylaxis of seasonal rhinitis. of aplastic anemia, CONTRAINDICATIONS: Hypersensitivity to com- states and acute leukemia.34 By restor- 19. Shroder H, Evans DAP: Acetylator ponents of Rynacrom '. phenotype and adverse effects ofsulfasala- WARNINGS: The number of sprays to be administered ing the normal hematological func- zine in healthy, subjects. Gut 1972; 13:278- per day should be specified to the patient. Regular tion, the bone marrow graft represents 284. dosage is important - treatment must not be discon- an indirect adjuvant measure in the 20. Megaloblastic leukopenia, editorial. N tinued abruptly, especially when benefit has been Engl J Med 1967; 227:50. obtained. management of infection. It takes sev- 21. Flexner JM, Hartman RC: Megalo- PRECAUTIONS: The experience in patients with nasal eral weeks for the donor's graft to be- polyps is limited and therefore these patients should blastic anemia associated with anticonvul- be carefully observed while undergoing treatment. come firmly established. Until then, sant drugs. Am J Med 1960; 28:386-396. Possible immunologic changes resulting in reactions the recipient is at great risk of serious 22. Boxer LA, Greenberg MS, Boxer GTJ such as polymyositis, pneumonitis and heart failure, and sometimes even fatal infection. i et al: Autoinmnune neutropenia. N Engl J urticaria and anaphylaxis, have been reported and are Med 1975; 293:748-753. being actively investigated. 23. Mowat AG: Connection tissue disease. Clinical experience in children under 5 years of age is References Clin Haetnatol 1972; 1:573-594. limited. Kauder Mauer AM: De- During clinical use there have been, to date, no reports 1. Zacharski LR, Elvebac k LR, Linman 24. Wriedt K, E, of adverse effects on the mother or the fetus which JW: Leucocyte counts in healthy adults. fective myelopoiesis in congenital neutro- could be ascribed to the use of sodium cromoglycate. Am J Clin Pathol 1971; 56:148-150. penia. N Engl J Med 1970; 283:1072- Nevertheless, as with all medications, caution must 2. Broun GO Jr, Herbig FK, Hamilton JR: /077. be exercised during pregnancy. Leukopenia in Negroes. N Engl J Med 25. Parnmlev RJ, Ogawta M, Darby CP, et ADVERSE REACTIONS: Occasionally slight irritation of 1966; 275:1410-1413. al: Congenital neutr-openia: Neutrophil the nasal mucosa may occur. Cases of erythema, urti- with abnior-mal matur-ation. caria or maculo- papular rash have been reported and 3. Shaper AG, Lewis P: Genetic neutro- proliferation these have cleared within a few days on withdrawal of penia in people of African origin. Lancet Blood 1975; 46:723-733. the drug. Occasional headache, sneezing, cough and 1971; 2:1023-1024. 26. Cutting HO, Lang JE: Familial benign unpleasant taste in the mouth have been reported. 4. Baehner RL, Johnston RB Jr: chronic neutropenia. Ann Intern Med Eosinophilic pneumonia has been reported rarely. function in children neutropenia and 1964; 61:876-887. SYMPTOMS AND TREATMENT OF OVERDOSAGE: wtith 27. Kyle RA, Linman TW: Chronic idio- There have been no reported cases in humans of over- chronic infection. Blood 1972; 40:31-41. dosage of the drug. Symptomatic treatment is 5. Wintrobe MM, et al: Leucocyte kinetics pathic neutropenia: Newly recognised en- tity? N Engl J Med 1968; 279:1015-1019. suggested should overdosage occur. and function, in Clinical Hematology, ed DOSAGE AND ADMINISTRATION: It is recommended 8. Philadelphia, Lea & Febiger, 1981; 28. Spaet JH, Damnashek W: Chronic hypo- that treatment be instituted prior to the time at which pp 208-218. plastic neutropenia. Am J Med 1952; the seasonal symptoms normally occur, and continued 6. Kauder E, Mauer AM: Neutropenia of 13:35-45. throughout the season. childhood. J Pediatr 1966; 69:147-151. 29. Guerry D, Dalo DC, Omnine M et al: Dosage for both adults and children over 5 years 7. Finch SC: Granulocyte disorders- Studies on the mechanism of human cyclic of age: neutr-openia. Blood 1972; 40:951. Initial Treatment: One mist into each nostril 6 times benign, quantitative abnormalities of gran- daily. One mist deliversapproximately 0.13 mL (2.6 mg) ulocvtes, in Williams WJ (ed): Hemato- 30. Bodev GP, Bolivar R, Fainstein V: In- of sodium cromoglycate 2% solution. logy, ed 2. New York, McGraw-Hill, 1977, fectious coomplicaitions in leukemia pa- Maintenance Therapy: When adequate response has pp 717-734. tients. Semnin Hematol 1982; 19:193-220. been obtained, the frequency of inhalations may be 8. Emerson PM, Wilkinson JJ: Lac tate de- 31. Bolivatr R, Kohl S, Pickering LK: Ef- reduced to one spray or mist to each nostril every 8 to hydrogenase in diagnosis and assessment fect ofantineoplastic dr-ugs on antibody de- 12 hours. of response to treatment of megaloblastic pendent cellular cytotoxicity mediated by Concomitant Therapy: Other rhinitis therapy should human leukocytes against herpes simplex be used as required. anemia. Br J Haemnatol 1966; 12:678- Withdrawal of Rynacrom Therapy: Patients should 688. virus infected target cells. Cancer 1980; be warned against suddenly discontinuing therapy 9. Greenberg MS, Zangor B, Wong H: 46:1555-1561. when symptoms have been partially or completely- Studies in granulocvXtopenic subjects. 32. Winston DJ, Ho WG, Howell CL: Cv- controlled by_Rynacrom. Blood 1967; 30:891-892. tomegalovirus associated with leucocite As the action of Rynacrom is essentially preventative, 10. Tullis JL: Prevalence, nature and iden- transfusion. Ann Intern Med 1980; 93:671- continuity of therapy is important in patients who have 675. gained benefit. tification of leucocyte antibodies. N Engl J If for any reason Rynacrom is withdrawn, a suggested Med 1958; 258:569-578. 33. Stein R, Flexner JM, Graiber LE: Lith- regimen for withdrawal is to reduce the Rynacrom 11. Deinard AS, Page AR: A studv of ium and granulocvtopenia during induc- dosage gradually over a period of one week. It should steroid-induced in a patient tion therapy of acute myelogenous leuke- be borne in mind that symptoms of rhinitis may recur with chronic benign neutropenia of child- mnia. Blood 1979; 54:636-641. when Rynacrom is discontinued. hood. Br J Haematol 1974; 28:333-345. 34. Santos GW, Kaizer H: Bone marrowv AVAILABILITY: Rynacrom Solution Nasal Metered Dose Mist (sodium cromoglycate 2% w/v): is supplied 12. Dale DC: Comparison of agents pro- transplantation in acute leukemia. Semin in a high density polyethylene bottle with a pump to be ducing a neutrophilic leucocytosis in man. Hematol 1983; 19:227-239. attached to the bottle.The bottle contains not less than J Clin Invest 1975; 56:808-813. 35. Weeden PL, Robinett B, Grahaon TC, 26 mL (or not less than 13 mL) of solution. The pump 13. Nagaraju M, Weitzmnan S, Baumann G: et al: Canine : A stein delivers approximately 2.6 mg of sodium cromoglycate cell defect. 1974; (0.13 mL of the 2% w/v solution) per mist. Benzal- Viral hepatitis and agranulocvtosis. Am I J C/in InvRest 53.950- konium chloride (0.01%) is added asan antimicrobial. Dig 1973; 18.247-252. 956. Store below 30°C. Protect from direct sunlight. *Sample Size.

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