The Jurnal f ALLERGY and CLINICAL IMMUNOLOGY VOLUME 51 NUMBER 2 The effect f alternate-day prednisne n the white bld cunt in children with chrnic asthma H. Cha, M.D., and A. Gilbert, M.T. Denver, Cl. Children requiring alternate-day sterid therapy fr chrnic a~thma were exandned t establish changes that might ccur in the ttal and differential leukcyte vaunts n the day-n amd the day-ff predni~ue. It was fund that the majrity shwed n ttal cunt changes n either day, and the ttals were nt dse.dependent. Marked changes in the differential, independent f the dse abve 5 rag., were nted. Crtiesterids have been said t have significant effects n the quality as well as the quantity f the leukeytes. Pituitary adrencrtictrpic hrmne (ACTH) evkes a leukcyte respnse in man and animals2 Dugherty and White 2 have shwn that ACTH injected in varius mammals prduces an abslute lymphpenia prvided the adrenal crtex is intact. Daughaday, Williams, and Daland ~ have shwn similar respnses in man, indicating that a single intramuscular injectin f ACTH will result in an abslute and relative plymrphnuclear leukeytsis and a lymphpenia als relative and abslute. Esinpenia was als bserved. Hudsn/ experimenting with guinea pigs, suggested that the reductin f esinphils was prbably due t lack f discharge f the esinphils frm the bne marrw under the influence f crticsterids. Nwell, ~ using culture techniques, indicated that prednislne apparently prevented the lympheytes frm underging mitsis withut interfering with mitsis itself. It is therefre clear that the use f crticsterids in any frm is likely t Fr~am the Children's Asthma Research Institute and Hspital. Received fr publicatin Aug. 4~ 1972. Reprint requests t: H. Chai, M.D., Directr f Hspital Services, C.A.R.LH., 341 W. 19th Ave., Denver, Cl. 824. Yl. 51, N. 2, pp. 65-7
66 Chai and Gilbert J. ALLERGY CLIN. IMMUNOL. FEBRUARY 1973 TABLE I. Sterid dsage* Ttal 48 hur dse N. f subjects 2.5-5 rag. 15 1-15 nag. 17 2-3 mg. 21 35-45 mg. 11 5-6 rag. 8 65 rag. 1 8 rag. 1 *Taken as a ttal dse~ 8: A.M. every 48 hurs; range r 2.5 t 8 rag. TABLE II. Variability and range in ttal white cell cunt Day-n sterids: 8 hurs after administratin f ttal dse Day-ff sterids: 24 hurs after administratin f ttal dse Day-n 9,675 Range 5,-17~55 Day-ff 1,153 Range 4,85-18, TABLE Ill. Cellular distributin I Per cent Type f cell Day-n I Day-ff Segmented cells 82.2 46.5 Lympheytes 15.8 46. Esinphils 1.1 5. Mneytes.1 2. Basphils.3.2 have a prfund effect n the cell distributin and perhaps the ttal number f circulating leukcytes. Children suffering frm chrnic sterid-dependent asthma, wh require lngterm crticsterids, present a special prblem. They are subject t cncurrent illness in n less degree than their nrmal peers. Cnsequently, it becmes f paramunt imprtance t knw what effect their maintenance sterid therapy has n the quantity and quality f the white cells if this labratry prcedure is t have any meaning in the diagnsis f cmplicating pathlgy, especially the ccurrence f infectin. Even mre s is it necessary t knw what effect sterids have when administered n an alternate-day basis (the ttal dse being given at 8: A.~. every 48 hurs). PROCEDURE Seventy-fur subjects tk part in the study. There were 26 females and 48 males. Their age range varied frm 6 t 15 years. They were all chrnic, perennial asthmatics wh had been n an alternate-day regimen f crtiesterid therapy fr many mnths prir t this study. All the cunts were perfrmed by the same technician in rder t avid any pssible bias that might have been present if different technicians had dne the cunting and the differential. All cunts were perfrmed between 2: and 3: P.~. n the day-n and day-ff sterids. This was dne t avid any pssible circadian effects r any changes that culd pssibly be accunted fr because f fd ingestin r any ther variable that might be timerelated. The prednisne (which was the sterid administered t all children) was given at 8:
VOLUME 51 Effect f alternate-day prednisne n white bld cunt 67 NUMBER 2 TOTAL WBC OF DAY ON/DAY OFF STEROIDS 18 I f i f I f I' I I I I I I [ I I qd 17 16 15 14 12 m e-,e=. II.~ I 9 m! 8 I 7 6 5 4 8 5mrn ( IOmgrnl2.5mgrn(12~1151 T m,i 17.5rag 2mgm I 25 I 3 135 I 4 ('~L_421Srl,lg ml4s lsl~s t 6 (65('~(~mJl~m rngm. prednisne every 48 hurs FIG. 1. Distributin f the ttal white cell cunt (all cells) n the day-n and day-ff prednisne (57 children). ~.~. as a ttal dse fr the succeeding 48 hurs, the dse level being determined by degree f asthma cntrl achieved in the face f full activity. The initial day-n cunt thus allwed 6 t 7 hurs fr any sterid effects t becme apparent. The next cunt was dne 24 hurs after the day-n ctmt, each subject having thus received n further sterids fr 24 hurs prir t the secnd cunt. All subjects were n ral brnchdilatrs, and these remained unchanged n either the day-n r the day-ff. If the changes nted were due t such medicatins, they shuld have been the same n either day. N stat medicatins (epinephrine~ isprterenl, rectal r intravenus aminphylline) were given fr 24 hurs prir t the bld cunt n either day. All children were clinically free f asthma r any ther pathlgy when the cunts were clne. RESULTS The number f subjects at varius increments f prednisne are nted in Table I. Fifty-three subjects were n 3 mg., r less every ther day, 11 were in the 35 t 45 mg. range, and 8 were between 5 and 6 mg.; 2 subjects were at higher dses. Ttal white cell cunt The variability and range in ttal white cell cunt are shwn in Table II. It will be nted that there was essentially n difference between ttal white cell cunts n either day, in the majrity f subjects bth the day-n and day-ff having almst the same range. It is f interest t nte that 52 f the subjects ~7.6 per cent) shwed a variatin in ttal cunts f 3, r less, half f them being n different t within 1, cells. Thirteen subjects (2.3 per cent) had an
68 Chai and Gilbert J. ALLERGY CLIN. IMMUNOL. FEBRUARY 1973 1% DISTRIBUTION OF WHITE BLOOD CELLS DAY -OFF 1 II It I I I I I I II I I I 9% 8% Plys 9 Lymphs 7% 6% 5% 4% 3% 2% 9 "- 9 G ~ 9 9 DO 9 O(: OQ~149 9 9 ~ 9 9 9 9 ~) 9 13 ~ 9 9 O e QOB e 9 9 =9 ~ 9 9 9 ~ 9 9 9 9 9 9 9 O 9 O 9 9 9 9 DO 9. D D 9 O 9 O 9 ~ ~ 9 ~149 9 e 1% % 2s~Q~l ~mg~ t IOm~m III I~ Itl 2.~m 12sl 3 13514 I,1451,l~16lfle.~m 9 12.5 mgm 17.Smgm 42.5mgm ]' TSOmgm L65mgm mgm. prednisne every 48 hurs FIG. 2. Distributin f the plyrnrphnucler leukcytes and lymphcytes n day.ff sterids (74 children). increase f mre than 3, n the day-n when cmpared t the day-ff, while 9 had an increase abve 3, n the day-ff when cmpared t the day-n. Fig. 1 illustrates the individual variatin in 57 f the children in relatin t ttal dse (17 subjects were mitted fr the sake f clarity, but all shw the same distributin). There is n evidence that the ttal cunt is dependent n the prednisne dsage. Cellular distributin The distributin f cells, hwever, shws a marked change n the day-n when cmpared t the day-ff sterids. Table III utlines the changes nted in the varius leukcyte types. The plymrphnuelear leukcytes shw a marked increase that is bth abslute and relative, accmpanied by an equally marked decrease in lymphcytes that is als relative and abslute. Examinatin f Figs. 2 and 3 (which graphically display the plymrphnuclear leukcyte and lymphcyte percentages n the day-ff and day-n, respectively) indicates that in large part the change ccurs t the maximal degree at dsage levels f 1 mg., r greater, every ther day. There is a tendency fr the differences between the 2 cell systems t apprach that fund n the day-ff at 5 rag. and less. The esinphil cunts shw the expected drp n the day-n, and it was f interest t nte the same ehange in the mncytes. Basphils apparently shwed n differences, but the very small numbers f these cells make this interpretatin pen t questin.
VOLUME 51 Effect f alternate-day prednisne n white bld cunt 69 NUMBER 2 1% i " 9% 8% 7'/ 6% 5% c3 4% + ~ 9 9 3% 9 2%, 9 9 1%.. + %i >..Smgm I Q DISTRIBUTION OF WHITE BLOOD CELLS DAY- ON 5mgm I IT II " 1 I I I [ I Zl I... ~l -- cl ~ 13 cl 1:1 (2 D Ol:ll:l I:1 I:1 CI ~~ ~1:11~ a~ I:l~ i:1 -- 1:1 i:1 i:1 i:1 t21 ~ i:1 _ I ~ Plys Lymphs 9 9 9 9 9 9 9 Illa 9 9 41 O II 9 9 9 9 9 Oq 9 O 9 9 9 O 9 9 41 9 9 Of 19149 ~ 9 9 9 Q 9 11 k il I,re,,,, ill I, I ++ + 12.5 mgm. 42.Smgm J 5mgm L65mgm mgm. prednisne every 48 hurs FIG. 3. Distributin f plymrphnuclear leukcytes and lymphcytes n day-n sterids (74 children). COMMENT In general terms this study has demnstrated that in these subjects the majrity have shwn n significant change in the ttal white cell cunt n matter what the dse level f prednisne was (within the 2.5 mg. t 8 mg. range). This finding is cntrary t the accepted view that crticsterids affect the ttal white cell cunt. The fact that 13 subjects did shw significant increases n the d~+y-n is cunterbalanced by 9 subjects wh shwed very similar changes n the day-ff and hence reflect individual respnses f a minrity f the children. It is highly unlikely that these changes are due t cell destructin r increased prductin, althugh the underlying mechanisms were nt studied. Lymphcytes are destryed by crticsterids in certain animals but nt in man. The rapid changes nted (24 hurs in this study but prbably far sner, as changes in esinphils ccur within 3 hurs) indicate a prbable hmestatic mechanism that mbilizes plymrphnuclear leukcytes frm the strage cmpartment in the micrcirculatin and causes emigratin f lymphcytes int reticulendthelial strage sites. The decrease in esinphils may be based n a prlngatin f mitsis and retentin in the bne marrw, and hence reduced entry f such cells int the circulatin as well as remval t strage sites utside the circulatin2 Whatever the mechanisms invlved, the findings in this study indicate that it is essential t establish a baseline cunt and distributin f the leukcytes in all children wh are likely t be n prlnged alternate-day prednisne therapy fr' asthma (and prbably fr any disease that requires similar therapy) if crn-
7 Chai and Gilbert J. ALLERGY CLIN. IMMUNOL. FEBRUARY 1973 plicating pathlgic prcesses develp that require a white bld cell cunt and differential as an imprtant facet f diagnsis. Baseline cunts shuld be dne during a quiescent phase f the illness fr which sterids are being given, as well as in the absence f any ther cmplicating pathlgic prcess, f which infectin is likely t be the mst imprtant. It is true that the majrity f subjects in this study shwed n changes in ttal cunt, but the real differences nted in a sizable minrity (32.4 per cent) indicates that each child must have individual baseline and differential cunts perfrmed. REFERENCES 1 Wintrbe, M. M. : Clinical hematlgy, Philadelphia, 1967, Lea & Febiger. 9. Dugherty, T. F., and White, A.: Influence f hrmnes n lymphid tissue structure and functin, Endcrinlgy 35: 1, 1944. 3 Daughaday, W. H., Williams. R. H., and Daland, G. A. : The effect f endcrinpathies n the bld, Bld 3: 1342, 1948. 4 Hudsn, G. : The marrw reserve f esinphils, Br. J. Haematl. 1: 122~ 1964. Nwell, P. C.: Inhibitin f human leukcyte mitsis by prednislne in vitr, Cancer Res. 21" 1518, 19~}1.