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Blood studies in allergy
T
HE blood respo~Isr following t Ire I rial ingest ion of a sulfonamide drug has beerr stutlictl in tlrrw eases of known sulfonamide scnsitivity. Total and diffewnt iwl lertcocyte connt,s ww made prior to :111d at frequent, inter+\-als for as long as as ton days following the oral administrat,ion of a test dose. A white blood cell diluting tluid consisting of phlosirw a11t1 llletllyl~wc blue diwolved in equal parts propylene gl\-co1 and water’-‘: was cniployed. This technique ljcrmits the countin, m cl~aml~~~ differentiation of eosinophiles, pal\-n~o~~~lioririclr;lr and nion0nuclcar lcrrcocytcs, in the same specimen ul~on which t Irtl total leucocyte count is detcrwined. illld 200 cells Differential counts oi’ 100 ~11s iri the wuntin g cllamlJw fro111 the M7right stairrcd film WOI’(’r)rird(a at ~a(*lr ol)scrvat ion. The total numl~er of cosinophilcs was dctcrmincd 1)~ w~urtiny tlrcl cosin staining cells in tlio rnlcd iitw 01’ ow side of tlw conntillg clianilwi* (i.e., in 9 squares n~ultiplicd hy 22.2 to obtain the nirmhcr 1~~7 writ imetcr of blood) and as a rcsnlt of the tliflcrcntial count ol’ 100 ~11s in the chamber and 200 ~11s of’ tlrcl sl;rirrctl film. Thcrc is U~irs()rrto IJelievr that the counting clr;r~rrl~~~I~lrrri~lrrc affords iI rrjo~*(~irccrlratc nrethotl of enumerating eosinopliilw t llali lllat OlJtililld from the clifTerc~ntia1 count of the stained film.’ IZecor~ls ol’ the temperai uw, ~~ulsc,and blood pressure were secured at each observation; in two of the cases vital capa&y determinations w(~w also made. (‘.\Sl’,>
1
CASE I.--,%. A.! il ~l’il~lll~ltC? llIll*SC’, aged 55 years, lrad Iwen subject to intermittent att,acks of rhinitis and nasal obstruction sinw 1925, rccurrent right maxillary sirrr~s in fcction since 1928, and lj~orrchi;rl asthrnil since 1938. The typical and fwqncntly wpcatetl course of’ events in recent years which had started with irrr allergic rhinitis, WIS follomt~d within a few da,ys 1)~ inl’cction of tllv right antrum and asthma. Var*iorrs t,ypes of treatment, including a siil~niii~~oiisr*cwction, nasal poIypectoni~-, dust avoidance, dietary rrtarr;r~~~rrrCrrI,illltO~C~lOllS vnccinr. tllld forcigri protein therapy lliltl failc>d to rclicw htr symptoms. Because her acute attacks of astlrrrra \VC’RJ~ISWI~IJ-~)rcw~Icd 1)~ :I “cold” and sinus infwtion, it was assumed that an infwtion was tlrtb cause of her astllnlil, and sc‘vcl*;ll cpisotlcs wcl’c tl*rwtccl with snlfonaniitl~~ With furtlici~ olwtwt ion it I)ecanic evident that her aciitch drugs.
*From Medical
the Allergy School. This
Clinic. study
Urpartment was Anancrd
of
Internal Medicine. in mitt by Parke,
L’niversity Davis and
of Michig:in (‘ompany.
1s
THl5
.JOGRN.\I,
01“
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symptoms had corresponded to the grass or ragweed pollen seasons 01 had been associated with house dust csposurc, altIlougli she consistentl) showed negative cutaneous and intracutaneous skin reactions to thcst~ as well as to all other test antigens. Specific pollen 1~~poscnsitizatioI~ during the 1943 seasons produced marked relief and avoided the coml)licat,ing sinus infection previously present at that time of the yxr. IhlSl hyposensitization since November, 1943, has rcsnlted in a definite diminution in her winter rhinitis and asthma. Her first sulfonamide therapy was reeeivcd Jan. 20, 1942, at, the time of a purulent sinus infection associated with I~ronchial asthma. Sulfadiazine, 3 Gm., was taken daily for a week without an apprccG~l-Aechange in her sinus infection or asthma. Sulfat~hiazolc, 3 Om. daily, was started immediately following and continued in this dose for thrcr weeks. ITcr symptoms subsided during the third week. The second course of sulfathiazol(~, 3 (im. daily, was piyycribcd under similar circumstunccs in .Jlme, 1942. By the end of the srcond day there &as improvement in the sinus infection and asthma. The drug was continued for a wok; at the end of this time she was symptom fret, and tllclre had l)ccll 110 rariation fl~0111 I~olYWll in the tOti lcllcOc~\-tc COlmt. Another Ilout of rhinitis tlcrclopcd in mid-August, 19-R Collowed I)>, 1)ain in the right maxillary sin1ls rcpion on ,1ugust 22, and 2lSt hlllil on August 31. Rulfatliiazolc, 3 (ini. dail)-, was started Scptcmher 1. On the third day (after 9 Cini. of tIic> drug) the total wliitc cell count, dropped to 3,200 cells per cubic millimeter, and the drug was immcdiat+- stropped. There were apparently no symptoms related to the The rhinitis and as1 hma continued for another three medication. wreks. She returned Dec. 20, 1942, with a rccurrencc of symptoms and rcqucstcd another trial of sulfathiazole. The note regarding her previous ncutropenia had been misfiled in her record and thi’s fact, was not apI)reciated as the drug was prescribed for the fourth time, 1 Gm., being given at 5 :00 P.M. Lassitude and malaise developed two hours later and were followed by chills and a progressive temperature elevation. Cpon admission to the hospital at 10 :15 I’X. she complained of nausea, severe headache, and generalized aching. The admission white hlootl caount,was 2,800. The temperat,urc reached a maximum of 102.4” F. IS) Inorning the leurocyte count was 5,300, and all symptoms had sul)sidcd cxcel)t for residual fatigucl. It is of interest. that there was a distinct improvement in the rhinitis and asthma for a week following this w action. The latter then gradually rct,urnetl in its formrr severity. on C)ctobcr 2, 1943, she rolunteercd t,o take 1 Gin. of sulfat~hiazolc. The clinical observations arid hlootl counts are rrcordctl in TaI)Ie J. (‘cllular changes in ahsolute vnlues arc rcpr1~scntc~dyraphically in ( ‘harls 1 and 2. I<‘roy a fasting pre-ingestion level of 8,800 cells per cubic millimeters tllcx white connt. fell to 3,550 at the end of the fi1.H 110llr ;tnd rcachrd a
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aching Chills, rllinorrllcn, nausea Vomiting, diarrhea Chills, nausea, diarrhea Rewro 1,ackaclw Ih-owsy, cdrcmelp fatigued Generalized sownrss Residual fatigue, lyeakness Residual I’atigue, xeakners Residual fatigue, weakness Residual fatigue, weakness Moderate fatigue, weakness Moderate fatigue, weakness Moderate fatigue, weakness Moderate fatigue, weakness Slight fatigue, n-eakness Slight fatigue, weakness Ease of fatigue Ease of fatigue
Malaise,
\liltl
Chart
l.-Case
1.
(A. 12.1 ing’ the
The cellular ingestion of
responw 1 Gm. of
ant1 clinical sulfathic+mlc.
observations
follow-
An alxxdutc diniinl~tion in lyiii~~l~o~~yt~~s clevelo~m~ shortly after tlic pranulocytes began to shift to the lefft and increase in number. IiYlllphopenia, reaching a minimum of 3 67 cells per cubic centimeter at six
kAKDOI,PH
A\i\D
HAWLIN(;
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IN
AI,IXHC;Y
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hours, continued for the following four hours; a relative diminution in lymphocytes persisted for two days. These changes are also illustrated in Chart 2. A reduction of the eosinophilcs was noted at one and one-half hours: one hour later thy had disappeared from the periphrra.1 circulation (i.e., no eosinophiles were observed in the entire ruled and unruled areas of the t,wo sides of the ronnting chamber). They remained depressed for twent,y-four hours, a period corresponding t,o the elevations of the temperature and pnlsc. The blood pressure did not show a significant or constant chance.
Chart Aim and thiaaole.
Z.-Case counting
1. (A. rhamber
A.)
Comparison of the differential techniques following the ingestion
counts by the stained of 1 Gm. of sulfa-
Two additional cases wrc studied from this viewpoint incidental to observations in evaluating the significance of bronchial asthma developing during sulfonamide therapy. Detailed histories of these cases have been presented elsewhere.” CASE 2.-F. F., male, aged 40 gears, with a ncgat,ive past and family history of allergic disease, developed his initial attack of bronchial
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AS'D SYXP~XS
DIFFERENI*IAL
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examination examination exa,mination
negative negative neaative
REX ARKS
SIXFATIIIAZOLE
Chest examination negative Chest examination ne&ive Coughing after vital capacity Coughing, drowsiness Coughing, heavy chest Coughing, chest c%iimination nrgxtive Dyspneic, Ales in chest Moderately severe asthma severe asthma - Modrratelv Slights cyanosis -Whcczine less, coucrh._ productive _ Wheezing less; c~n~gh productive R5lrs only after vital eapneitp Moderateh severe asthma” Mild as&a Chest examinntirm negative Chest examination negative Slight coughing, few rbles in chest* Slight cwqliing, fern r%lrs in rhwt” Chest examination negative Chest examination negative Chest examination negative Chest examina.ti~n negative Chest examination negative, discharged negntirc -. Chest examination --
_
chest Chest _ Chest
--
-i-
OF 2 GM.
RANDOLPH
AND
RAWLING
:
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AIJ,ERC;P
asthma on the seventh day of sulfathiazole therapy (combined nasal installation and oral administration). He remained in severe status asthmaticus for three days, his asthma. persisting for seven days. After he had been symptom-free for a week he submitted to the ingestion of 2 Gm. of sulfathiazole at 9 :00 r2.M., October 5, 1943. He developed a severe attack of ast,hma as evidenced by his record of symptom#s and vital capacity as shown in Table II and Chart 3. From this data it will be noted that he did not develop a striking change in his total leucocytc count as in the preceding ca#se,the most marked variation occurring in the eosinophile determinations. After a temporary elevation one hour following ingestion, the eosinophiles diminished to 4 per cent at four r hours, corresponding t,o the peak of his asthma symptoms. They remained at low levels during the attack, following which they showed a surprising elevation reaching approximately 30 per cent of the differential count at the end of twenty-four hours, then persist,ed at high A slight increase in young levels throughout the period of observation. myeloid ~11s also occurred in this case.
i”.““U ____ 2,000
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2,500 2,000 iii?
,’ I~NACZILSi
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,r ‘41
1,500 l*ooo
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act. Chart
I4 I
3.-&x
5 2.
(F. F.) Cellular response lowing the ingestion of 2
I and Gm.
6 vital capacity of sulfathiazole.
9 determinations
19110 fol-
CME 3.-M. M., female, aged 34 years, with a past history of atopic dermatitis, allergic rhinitis, and bronchial asthma, developed manifestations of sensitivity to sulfadiazine during the course of pneumonia in 1942. A year later 0.5 Gm. of sulfadiazine was taken during an upper respiratory infection and was followed by headache, a generalized rash, and an attack of bronchial asthma for the first time in three years. After the lapse of another year, the same dose was repeated experimentally on Feb. 5, 1944. Although not followed by clinical asthma,
THE
JOURXL~I.
01’
CI-
S3.LA30NOI
f
AI,I.ERGT
RANDOLPH
AND
RAWLING
:
BLOOD
STUDIES
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25
ALLERGY
she developed a diminution in her vital capacity, severe headache, and general malaise. As may be observed from Table III and Chart 4, the total white count dropped precipitously immediately after the drug and then became elevated coincident with the appearance of young myeloid There also occurred an early diminucells in the peripheral circulation. tion of cosinophiles followed by a delayed relative cosinophilia.
Chart
4.-Case
3. (M. following
M.) the
Cellular ingestion
response of 0.5
and vital capacity Gm. of sulfadiazine.
determinations
DISCIJSSION
It is evident from widespread usage that, a.lthough the majority of individuals tolerate the sulfonamide drugs, others develop unmistakable symptoms of intolerance despite similarities in regard to the clinical It is difficult to inindications, dosage, and duration of treat,ment. terpret the clinical evidence of intolerance occurring during the first course of therapy. It is open to debate whether the underlying mechanism of intolerance developin g during the initial course of t,herapy is due to a chemical poisoning or specific sensitization. However, the immediate and dramatic response which occurs when the drug is again given can be explained only upon the basis of a true allergic reaction. We do not consider t,he occurrence of crystalluria in this discussion. The usual delay in the onset of symptoms during the first course of therapy may possibly be attributed to accumulative quantit,ative chemical effects. However, the fact that these reactions of int,olerance most commonly appear during the second week of treatment suggests that some qualitative variation has occurred in t,he reactivity of the host as the result of a period of exposure. A situation is presented which contains the requirements for the development of an antigen-antibody Benzene ring cont,aining drugs are known to be pophenomenon. tentially antigenic, the time relationship from the initial exposure to
26
THE
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Hagethe development of symptoms would permit antibody production. man and Blake6 pointed out the similarities in the circumstances preceding the onset, of clinical symptoms of intolerance to sulfonamides and the production of the delayed type of serum sickness. A period of approximately ten days is essential for the development, of clinical evidence of sensitivity in both conditions. Furthermore, certain clinical reactions to sulfonamides, such as drug fever, may become evident wit,h resumption of therapy after a lapse of ten days from the time of the initial dose.: This observation is compatible with the presented thesis and is not readily explained on the basis of a “toxic” effect of the drug in the sense of a quantitative chemical poisoning. Once This analogy to serum sickness may be carried a st,ep further. serum sensitivity has been established in the host, a repeated antigcnic exposure calls forth an accelera.tcd type of serum sickness. Similarly, in a patient, with a past history of clinical intolerance to a specific sulfonamide, a repeated dose may produce a sharp reaction. The severit,y of this reaction, as in the serum response, appears to depend upon the degree of sensitivity t>xisting at, the time and to a less extent upon the size of the dose received, although more violent reactions tend to follow the administration of larger doses. Case 1 (A. A.) may be t,aken as an example of the altered rea,ctivity developing from repeated exposures to sulfathiazole. Two courses of therapy were received without evidence of clinical intolerance or variation in the hematological response. The third course was tolerated clinically, but the patient developed a neut,ropenia on the third day. The fourth and fifth attempt,s to prescribe the drug were immediately followed by a severe neutropenia. and a violent, constitutional reaction after single doses. Several features of this case are unusual and instructive. It is significant that her previously existing bronchial asthma cleared immediately after the ingestion of the trial dose and that she remained asthma-free for a period of one week. The subsidence of previous allergic symptoms during the period of a second and different allergic response is not an uncommon clinical finding. The prompt occurrence of neutropenia in The deassociation with severe constit3utional symptoms was striking. velopment of a leucocytosis followin g the neutropenia, dependent in its early stages, at least, upon the presence of many young myeloid forms in the circulation is a feature of the drug reaction which has not been emphasized. Although early attention has been called to the leucocytosis occurring during the course of sulfanilamide therapy, this response from a trial dose in a known react,ing patient was first, carefully studied by Schlesinger and Rlitchell.8 They reported a leucocytosis with an increase in polymorphonuclears within a few hours after the trial administra,tion of a test dose in patients reacting unfavorably to a previous Course of sulfanilamide therapy. The leucocytosis was often associated
RANDOLPH
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STUDIES
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27
with the production of a rash and constitutional symptoms. They did not note the presence of an initial neutropenia in counts performed at hourly intervals a.fter ingestion and did not comment on the presence of young myeloid forms in the blood during the induced reaction. So-called “ leucemoid reactions ’ ’ have been reported in patients receiving sulfonamide therapy, counts reaching as high as 100,000 cells per millimeter of blood. These reactions occurred after continued sulfonamide therapy and were usually associated with hemolytic anemia. In this case the erythroc-te count or hemoglobin determination did not vary from the preingestion normal during or following the reaction. There was no clinical evidence of a hcmolytic phenomenon although fragility and other special studies were not done. The cellular response in this patient, was not limited to t,he myeloid cells as evidenced by the absolute diminution in the number of eosinophiles and lymphocytes. There was a definite correlation between the period of eosinopenia and the constitutional symptoms as measured by elevations in the temperature and pulse. It is well known that eosinophiles tend to diminish in the peripheral circulation during the height of acute allergic sympt,oms and reappear with the subsidence of sympt,oms. The lymphopenia, reaching a. low point, six hours after ingestion and persisting at low levels for several hours is a further striking reaction which, as far as we know, has not been described as part of the drug allergic response. The question might be raised as to whether the lymphocytes a.re reduced relatively as a result of the marked myeloid reaction. The degree of lymphopenia in this case suggest,s some additional mechanism. This case also illustrates the point that the total white cell count performed with the standard acetic acid diluent in the absence of a differential count might fail to detect a major blood response to a. sensitizing drug. For instance, six hours after the ingestion of sulfathiazole the total leucocyte count was normal (7,850), although the film differential count reveals that 66 per cent of the cells were young myeloid forms and that there was an absolute diminution from previous levels of both the lymphocytes and eosinophiles. However, this abnormality was readily detected by performin, w the total leucocyte count with the propylene glycol aqueous diluent. The superiority of the latter diluting fluid in comparison with the standard acetic diluent has been reported elsewhere.’ Furthermore, assuming that a, differential count had been performed at six hours with either the counting chamber or film technique, and that the sulfona,mide drug had been prescribed in the presence of a severe infection, the shift to the left as well as the other blood changes could readily have been ascribed to the presence of the infection rather than as a result of the drug administration. It becomes apparent that the early cellular changes resulting from sulfonamide therapy, especially after repeated doses, must be carefully differentiated from those result-
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OF
ALLERGY
ing from an infection. A single blood count, during the course of a drug reaction may be misinterpreted; the true picture may not become evident unless repeated blood determinations are made. The nearly identical contours of the differential counts as determined from the stained film and the counting chamber techniques attests to the This agreement. is notereliability of the proplvlene glycol method. worthy in that the variations within the differential count were correctly appraised from the counting chamber determinations performed immediately and completed prior to obtainin, (p the results of the film differential count. In Case 2, t,he patient (F. F.) failed to show the sharp neutropenia after trial ingestion of sulfathiazole as in the first case. Nevertheless, the total leucocyte count dropped slightly and there was a diminution in the eosinophiles. The delayed po’streactive eosinophilia remained the most significant cellular reaction in this case; this high value, approximately 30 per cent, might possibly be explained on the fact t,hat the patient had a moderate eosinophilia prior to ingestion. As far as we are aware, changes of this magnitude in the number of eosinophiles dnring the course of and following a sulfonamide reaction have not previously been reported. A reaction of the same general pat,tern was observed in the third patient (M. &I.) although the cellular changes were evident, to a less striking degree than in the preceding cases. Perhaps a less: marked degree of sensitivity existed at the tirnr of the t,est dose; also a smaller trial do&e was administ,ered. There is the additional fact that sulfadiazine may be a less potent sensitizin g agent than sulfathiazole, clinical observations tend to support this view. It is of more than passing interest that of these three cases of bronchial asthma, the trial dose of a sulfonamide drug resulted in the prompt, temporary improvement of the bronchial asthma in one instance, the production of a severe asthmatic paroxysm in another, and a slightly diminished vital capacity suggestive of a minimal bronchial spasm in the t,hird. SUMMARY
1. The trial ingestion of a specific sulfonamide drug in three asthmatics known to be clinically drug sensitive resultled in an initial diminution in total leucocytes and eosinophiles; this was followed by an increase in leucocytes due, in part, to the presence of young myeloid cells. 2. After the constitutional symptoms: had subsided, the eosinophiles either returned to the preingestion count or showed a definite increase above that level. 3. The clinical and hematological response in these cases supports the thesis that an allergic mechanism is responsible for the described reactions.
RANDOLPH
AND
RAWLING:
BLOOD
STUDIES
IN
ALLERGY
29
REFERENCES 1. Randolah. T. G.: Enumeration and Differentiation of Leucocvtes in the Counting Chamber with Propylene Glycol-Aqueous Stains, Proc. Sot. Exper. Biol. & Med. 52: 20, 1943. 2. Randolph, T. G.: Blood Studies in Allergy. 1. The Direct Counting Chamber Determinations of Eosinophils by Propylene Glycol-Aqueous Stains, J. ALLERGY 15: 59, 1944. 3. Randolph, T. G.: Differentiation of Leucocvtes in the Counting ‘Chamber by Propylene Glycol-Aqueous Stains; A Screen for the Detection of Major Bloob Abnormality, Am. J. Clin. Path., Technical Section 8: 48, 1944. 4. Randolph, T. G., and Stanton, C. L.: A Comparison of the Counting Chamber and Film Methods of Enumerating Eosinonhils. To be nublished. 5. Ra.ndolph, T. CT., and Rattling, F. F. AT: Bron&ial Asthma ai a Manifestation of Sulfonamide Sensitivity, J. A. M. A. 126: 166, 1944. 6. Hageman, P. O., and Blake, F. Cr.: A Specific Febrile Reaction to Sulfanilimide, Drug Ferer, J. A. M. A. 109: 642, 137. Febrile Reactions Accompanying Read7. Lyons, R. H., and Balberor, H. J.: ministration of Sulfathiazolc, .J. A. M. A. 118: 955, 1942. 8. Schlesinger, E. R., and Mitchell, IV. I,.: Sulfanilimide Eruption, A Study of Patients with the Morbilliform Rash and of their Subsequent Reactions, Am. J. Dis. Child. 56: 1256, 1938.
HE blood respo~Isr following t Ire I rial ingest ion of a sulfonamide drug has beerr stutlictl in tlrrw eases of known sulfonamide scnsitivity. Total and diffewnt iwl lertcocyte connt,s ww made prior to :111d at frequent, inter+\-als for as long as as ton days following the oral administrat,ion of a test dose. A white blood cell diluting tluid consisting of phlosirw a11t1 llletllyl~wc blue diwolved in equal parts propylene gl\-co1 and water’-‘: was cniployed. This technique ljcrmits the countin, m cl~aml~~~ differentiation of eosinophiles, pal\-n~o~~~lioririclr;lr and nion0nuclcar lcrrcocytcs, in the same specimen ul~on which t Irtl total leucocyte count is detcrwined. illld 200 cells Differential counts oi’ 100 ~11s iri the wuntin g cllamlJw fro111 the M7right stairrcd film WOI’(’r)rird(a at ~a(*lr ol)scrvat ion. The total numl~er of cosinophilcs was dctcrmincd 1)~ w~urtiny tlrcl cosin staining cells in tlio rnlcd iitw 01’ ow side of tlw conntillg clianilwi* (i.e., in 9 squares n~ultiplicd hy 22.2 to obtain the nirmhcr 1~~7 writ imetcr of blood) and as a rcsnlt of the tliflcrcntial count ol’ 100 ~11s in the chamber and 200 ~11s of’ tlrcl sl;rirrctl film. Thcrc is U~irs()rrto IJelievr that the counting clr;r~rrl~~~I~lrrri~lrrc affords iI rrjo~*(~irccrlratc nrethotl of enumerating eosinopliilw t llali lllat OlJtililld from the clifTerc~ntia1 count of the stained film.’ IZecor~ls ol’ the temperai uw, ~~ulsc,and blood pressure were secured at each observation; in two of the cases vital capa&y determinations w(~w also made. (‘.\Sl’,>
1
CASE I.--,%. A.! il ~l’il~lll~ltC? llIll*SC’, aged 55 years, lrad Iwen subject to intermittent att,acks of rhinitis and nasal obstruction sinw 1925, rccurrent right maxillary sirrr~s in fcction since 1928, and lj~orrchi;rl asthrnil since 1938. The typical and fwqncntly wpcatetl course of’ events in recent years which had started with irrr allergic rhinitis, WIS follomt~d within a few da,ys 1)~ inl’cction of tllv right antrum and asthma. Var*iorrs t,ypes of treatment, including a siil~niii~~oiisr*cwction, nasal poIypectoni~-, dust avoidance, dietary rrtarr;r~~~rrrCrrI,illltO~C~lOllS vnccinr. tllld forcigri protein therapy lliltl failc>d to rclicw htr symptoms. Because her acute attacks of astlrrrra \VC’RJ~ISWI~IJ-~)rcw~Icd 1)~ :I “cold” and sinus infwtion, it was assumed that an infwtion was tlrtb cause of her astllnlil, and sc‘vcl*;ll cpisotlcs wcl’c tl*rwtccl with snlfonaniitl~~ With furtlici~ olwtwt ion it I)ecanic evident that her aciitch drugs.
*From Medical
the Allergy School. This
Clinic. study
Urpartment was Anancrd
of
Internal Medicine. in mitt by Parke,
L’niversity Davis and
of Michig:in (‘ompany.
1s
THl5
.JOGRN.\I,
01“
.\I,I.ICRGT
symptoms had corresponded to the grass or ragweed pollen seasons 01 had been associated with house dust csposurc, altIlougli she consistentl) showed negative cutaneous and intracutaneous skin reactions to thcst~ as well as to all other test antigens. Specific pollen 1~~poscnsitizatioI~ during the 1943 seasons produced marked relief and avoided the coml)licat,ing sinus infection previously present at that time of the yxr. IhlSl hyposensitization since November, 1943, has rcsnlted in a definite diminution in her winter rhinitis and asthma. Her first sulfonamide therapy was reeeivcd Jan. 20, 1942, at, the time of a purulent sinus infection associated with I~ronchial asthma. Sulfadiazine, 3 Gm., was taken daily for a week without an apprccG~l-Aechange in her sinus infection or asthma. Sulfat~hiazolc, 3 Om. daily, was started immediately following and continued in this dose for thrcr weeks. ITcr symptoms subsided during the third week. The second course of sulfathiazol(~, 3 (im. daily, was piyycribcd under similar circumstunccs in .Jlme, 1942. By the end of the srcond day there &as improvement in the sinus infection and asthma. The drug was continued for a wok; at the end of this time she was symptom fret, and tllclre had l)ccll 110 rariation fl~0111 I~olYWll in the tOti lcllcOc~\-tc COlmt. Another Ilout of rhinitis tlcrclopcd in mid-August, 19-R Collowed I)>, 1)ain in the right maxillary sin1ls rcpion on ,1ugust 22, and 2lSt hlllil on August 31. Rulfatliiazolc, 3 (ini. dail)-, was started Scptcmher 1. On the third day (after 9 Cini. of tIic> drug) the total wliitc cell count, dropped to 3,200 cells per cubic millimeter, and the drug was immcdiat+- stropped. There were apparently no symptoms related to the The rhinitis and as1 hma continued for another three medication. wreks. She returned Dec. 20, 1942, with a rccurrencc of symptoms and rcqucstcd another trial of sulfathiazole. The note regarding her previous ncutropenia had been misfiled in her record and thi’s fact, was not apI)reciated as the drug was prescribed for the fourth time, 1 Gm., being given at 5 :00 P.M. Lassitude and malaise developed two hours later and were followed by chills and a progressive temperature elevation. Cpon admission to the hospital at 10 :15 I’X. she complained of nausea, severe headache, and generalized aching. The admission white hlootl caount,was 2,800. The temperat,urc reached a maximum of 102.4” F. IS) Inorning the leurocyte count was 5,300, and all symptoms had sul)sidcd cxcel)t for residual fatigucl. It is of interest. that there was a distinct improvement in the rhinitis and asthma for a week following this w action. The latter then gradually rct,urnetl in its formrr severity. on C)ctobcr 2, 1943, she rolunteercd t,o take 1 Gin. of sulfat~hiazolc. The clinical observations arid hlootl counts are rrcordctl in TaI)Ie J. (‘cllular changes in ahsolute vnlues arc rcpr1~scntc~dyraphically in ( ‘harls 1 and 2. I<‘roy a fasting pre-ingestion level of 8,800 cells per cubic millimeters tllcx white connt. fell to 3,550 at the end of the fi1.H 110llr ;tnd rcachrd a
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aching Chills, rllinorrllcn, nausea Vomiting, diarrhea Chills, nausea, diarrhea Rewro 1,ackaclw Ih-owsy, cdrcmelp fatigued Generalized sownrss Residual fatigue, lyeakness Residual I’atigue, xeakners Residual fatigue, weakness Residual fatigue, weakness Moderate fatigue, weakness Moderate fatigue, weakness Moderate fatigue, weakness Moderate fatigue, weakness Slight fatigue, n-eakness Slight fatigue, weakness Ease of fatigue Ease of fatigue
Malaise,
\liltl
Chart
l.-Case
1.
(A. 12.1 ing’ the
The cellular ingestion of
responw 1 Gm. of
ant1 clinical sulfathic+mlc.
observations
follow-
An alxxdutc diniinl~tion in lyiii~~l~o~~yt~~s clevelo~m~ shortly after tlic pranulocytes began to shift to the lefft and increase in number. IiYlllphopenia, reaching a minimum of 3 67 cells per cubic centimeter at six
kAKDOI,PH
A\i\D
HAWLIN(;
:
BLOOD
STCDIES
IN
AI,IXHC;Y
21
hours, continued for the following four hours; a relative diminution in lymphocytes persisted for two days. These changes are also illustrated in Chart 2. A reduction of the eosinophilcs was noted at one and one-half hours: one hour later thy had disappeared from the periphrra.1 circulation (i.e., no eosinophiles were observed in the entire ruled and unruled areas of the t,wo sides of the ronnting chamber). They remained depressed for twent,y-four hours, a period corresponding t,o the elevations of the temperature and pnlsc. The blood pressure did not show a significant or constant chance.
Chart Aim and thiaaole.
Z.-Case counting
1. (A. rhamber
A.)
Comparison of the differential techniques following the ingestion
counts by the stained of 1 Gm. of sulfa-
Two additional cases wrc studied from this viewpoint incidental to observations in evaluating the significance of bronchial asthma developing during sulfonamide therapy. Detailed histories of these cases have been presented elsewhere.” CASE 2.-F. F., male, aged 40 gears, with a ncgat,ive past and family history of allergic disease, developed his initial attack of bronchial
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RESPO~E
29 29 2.3
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examination examination exa,mination
negative negative neaative
REX ARKS
SIXFATIIIAZOLE
Chest examination negative Chest examination ne&ive Coughing after vital capacity Coughing, drowsiness Coughing, heavy chest Coughing, chest c%iimination nrgxtive Dyspneic, Ales in chest Moderately severe asthma severe asthma - Modrratelv Slights cyanosis -Whcczine less, coucrh._ productive _ Wheezing less; c~n~gh productive R5lrs only after vital eapneitp Moderateh severe asthma” Mild as&a Chest examinntirm negative Chest examination negative Slight coughing, few rbles in chest* Slight cwqliing, fern r%lrs in rhwt” Chest examination negative Chest examination negative Chest examination negative Chest examina.ti~n negative Chest examination negative, discharged negntirc -. Chest examination --
_
chest Chest _ Chest
--
-i-
OF 2 GM.
RANDOLPH
AND
RAWLING
:
BLOOD
STUDIES
IN
23
AIJ,ERC;P
asthma on the seventh day of sulfathiazole therapy (combined nasal installation and oral administration). He remained in severe status asthmaticus for three days, his asthma. persisting for seven days. After he had been symptom-free for a week he submitted to the ingestion of 2 Gm. of sulfathiazole at 9 :00 r2.M., October 5, 1943. He developed a severe attack of ast,hma as evidenced by his record of symptom#s and vital capacity as shown in Table II and Chart 3. From this data it will be noted that he did not develop a striking change in his total leucocytc count as in the preceding ca#se,the most marked variation occurring in the eosinophile determinations. After a temporary elevation one hour following ingestion, the eosinophiles diminished to 4 per cent at four r hours, corresponding t,o the peak of his asthma symptoms. They remained at low levels during the attack, following which they showed a surprising elevation reaching approximately 30 per cent of the differential count at the end of twenty-four hours, then persist,ed at high A slight increase in young levels throughout the period of observation. myeloid ~11s also occurred in this case.
i”.““U ____ 2,000
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2,500 2,000 iii?
,’ I~NACZILSi
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act. Chart
I4 I
3.-&x
5 2.
(F. F.) Cellular response lowing the ingestion of 2
I and Gm.
6 vital capacity of sulfathiazole.
9 determinations
19110 fol-
CME 3.-M. M., female, aged 34 years, with a past history of atopic dermatitis, allergic rhinitis, and bronchial asthma, developed manifestations of sensitivity to sulfadiazine during the course of pneumonia in 1942. A year later 0.5 Gm. of sulfadiazine was taken during an upper respiratory infection and was followed by headache, a generalized rash, and an attack of bronchial asthma for the first time in three years. After the lapse of another year, the same dose was repeated experimentally on Feb. 5, 1944. Although not followed by clinical asthma,
THE
JOURXL~I.
01’
CI-
S3.LA30NOI
f
AI,I.ERGT
RANDOLPH
AND
RAWLING
:
BLOOD
STUDIES
IN
25
ALLERGY
she developed a diminution in her vital capacity, severe headache, and general malaise. As may be observed from Table III and Chart 4, the total white count dropped precipitously immediately after the drug and then became elevated coincident with the appearance of young myeloid There also occurred an early diminucells in the peripheral circulation. tion of cosinophiles followed by a delayed relative cosinophilia.
Chart
4.-Case
3. (M. following
M.) the
Cellular ingestion
response of 0.5
and vital capacity Gm. of sulfadiazine.
determinations
DISCIJSSION
It is evident from widespread usage that, a.lthough the majority of individuals tolerate the sulfonamide drugs, others develop unmistakable symptoms of intolerance despite similarities in regard to the clinical It is difficult to inindications, dosage, and duration of treat,ment. terpret the clinical evidence of intolerance occurring during the first course of therapy. It is open to debate whether the underlying mechanism of intolerance developin g during the initial course of t,herapy is due to a chemical poisoning or specific sensitization. However, the immediate and dramatic response which occurs when the drug is again given can be explained only upon the basis of a true allergic reaction. We do not consider t,he occurrence of crystalluria in this discussion. The usual delay in the onset of symptoms during the first course of therapy may possibly be attributed to accumulative quantit,ative chemical effects. However, the fact that these reactions of int,olerance most commonly appear during the second week of treatment suggests that some qualitative variation has occurred in t,he reactivity of the host as the result of a period of exposure. A situation is presented which contains the requirements for the development of an antigen-antibody Benzene ring cont,aining drugs are known to be pophenomenon. tentially antigenic, the time relationship from the initial exposure to
26
THE
JOURNAL
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Hagethe development of symptoms would permit antibody production. man and Blake6 pointed out the similarities in the circumstances preceding the onset, of clinical symptoms of intolerance to sulfonamides and the production of the delayed type of serum sickness. A period of approximately ten days is essential for the development, of clinical evidence of sensitivity in both conditions. Furthermore, certain clinical reactions to sulfonamides, such as drug fever, may become evident wit,h resumption of therapy after a lapse of ten days from the time of the initial dose.: This observation is compatible with the presented thesis and is not readily explained on the basis of a “toxic” effect of the drug in the sense of a quantitative chemical poisoning. Once This analogy to serum sickness may be carried a st,ep further. serum sensitivity has been established in the host, a repeated antigcnic exposure calls forth an accelera.tcd type of serum sickness. Similarly, in a patient, with a past history of clinical intolerance to a specific sulfonamide, a repeated dose may produce a sharp reaction. The severit,y of this reaction, as in the serum response, appears to depend upon the degree of sensitivity t>xisting at, the time and to a less extent upon the size of the dose received, although more violent reactions tend to follow the administration of larger doses. Case 1 (A. A.) may be t,aken as an example of the altered rea,ctivity developing from repeated exposures to sulfathiazole. Two courses of therapy were received without evidence of clinical intolerance or variation in the hematological response. The third course was tolerated clinically, but the patient developed a neut,ropenia on the third day. The fourth and fifth attempt,s to prescribe the drug were immediately followed by a severe neutropenia. and a violent, constitutional reaction after single doses. Several features of this case are unusual and instructive. It is significant that her previously existing bronchial asthma cleared immediately after the ingestion of the trial dose and that she remained asthma-free for a period of one week. The subsidence of previous allergic symptoms during the period of a second and different allergic response is not an uncommon clinical finding. The prompt occurrence of neutropenia in The deassociation with severe constit3utional symptoms was striking. velopment of a leucocytosis followin g the neutropenia, dependent in its early stages, at least, upon the presence of many young myeloid forms in the circulation is a feature of the drug reaction which has not been emphasized. Although early attention has been called to the leucocytosis occurring during the course of sulfanilamide therapy, this response from a trial dose in a known react,ing patient was first, carefully studied by Schlesinger and Rlitchell.8 They reported a leucocytosis with an increase in polymorphonuclears within a few hours after the trial administra,tion of a test dose in patients reacting unfavorably to a previous Course of sulfanilamide therapy. The leucocytosis was often associated
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with the production of a rash and constitutional symptoms. They did not note the presence of an initial neutropenia in counts performed at hourly intervals a.fter ingestion and did not comment on the presence of young myeloid forms in the blood during the induced reaction. So-called “ leucemoid reactions ’ ’ have been reported in patients receiving sulfonamide therapy, counts reaching as high as 100,000 cells per millimeter of blood. These reactions occurred after continued sulfonamide therapy and were usually associated with hemolytic anemia. In this case the erythroc-te count or hemoglobin determination did not vary from the preingestion normal during or following the reaction. There was no clinical evidence of a hcmolytic phenomenon although fragility and other special studies were not done. The cellular response in this patient, was not limited to t,he myeloid cells as evidenced by the absolute diminution in the number of eosinophiles and lymphocytes. There was a definite correlation between the period of eosinopenia and the constitutional symptoms as measured by elevations in the temperature and pulse. It is well known that eosinophiles tend to diminish in the peripheral circulation during the height of acute allergic sympt,oms and reappear with the subsidence of sympt,oms. The lymphopenia, reaching a. low point, six hours after ingestion and persisting at low levels for several hours is a further striking reaction which, as far as we know, has not been described as part of the drug allergic response. The question might be raised as to whether the lymphocytes a.re reduced relatively as a result of the marked myeloid reaction. The degree of lymphopenia in this case suggest,s some additional mechanism. This case also illustrates the point that the total white cell count performed with the standard acetic acid diluent in the absence of a differential count might fail to detect a major blood response to a. sensitizing drug. For instance, six hours after the ingestion of sulfathiazole the total leucocyte count was normal (7,850), although the film differential count reveals that 66 per cent of the cells were young myeloid forms and that there was an absolute diminution from previous levels of both the lymphocytes and eosinophiles. However, this abnormality was readily detected by performin, w the total leucocyte count with the propylene glycol aqueous diluent. The superiority of the latter diluting fluid in comparison with the standard acetic diluent has been reported elsewhere.’ Furthermore, assuming that a, differential count had been performed at six hours with either the counting chamber or film technique, and that the sulfona,mide drug had been prescribed in the presence of a severe infection, the shift to the left as well as the other blood changes could readily have been ascribed to the presence of the infection rather than as a result of the drug administration. It becomes apparent that the early cellular changes resulting from sulfonamide therapy, especially after repeated doses, must be carefully differentiated from those result-
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ing from an infection. A single blood count, during the course of a drug reaction may be misinterpreted; the true picture may not become evident unless repeated blood determinations are made. The nearly identical contours of the differential counts as determined from the stained film and the counting chamber techniques attests to the This agreement. is notereliability of the proplvlene glycol method. worthy in that the variations within the differential count were correctly appraised from the counting chamber determinations performed immediately and completed prior to obtainin, (p the results of the film differential count. In Case 2, t,he patient (F. F.) failed to show the sharp neutropenia after trial ingestion of sulfathiazole as in the first case. Nevertheless, the total leucocyte count dropped slightly and there was a diminution in the eosinophiles. The delayed po’streactive eosinophilia remained the most significant cellular reaction in this case; this high value, approximately 30 per cent, might possibly be explained on the fact t,hat the patient had a moderate eosinophilia prior to ingestion. As far as we are aware, changes of this magnitude in the number of eosinophiles dnring the course of and following a sulfonamide reaction have not previously been reported. A reaction of the same general pat,tern was observed in the third patient (M. &I.) although the cellular changes were evident, to a less striking degree than in the preceding cases. Perhaps a less: marked degree of sensitivity existed at the tirnr of the t,est dose; also a smaller trial do&e was administ,ered. There is the additional fact that sulfadiazine may be a less potent sensitizin g agent than sulfathiazole, clinical observations tend to support this view. It is of more than passing interest that of these three cases of bronchial asthma, the trial dose of a sulfonamide drug resulted in the prompt, temporary improvement of the bronchial asthma in one instance, the production of a severe asthmatic paroxysm in another, and a slightly diminished vital capacity suggestive of a minimal bronchial spasm in the t,hird. SUMMARY
1. The trial ingestion of a specific sulfonamide drug in three asthmatics known to be clinically drug sensitive resultled in an initial diminution in total leucocytes and eosinophiles; this was followed by an increase in leucocytes due, in part, to the presence of young myeloid cells. 2. After the constitutional symptoms: had subsided, the eosinophiles either returned to the preingestion count or showed a definite increase above that level. 3. The clinical and hematological response in these cases supports the thesis that an allergic mechanism is responsible for the described reactions.
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REFERENCES 1. Randolah. T. G.: Enumeration and Differentiation of Leucocvtes in the Counting Chamber with Propylene Glycol-Aqueous Stains, Proc. Sot. Exper. Biol. & Med. 52: 20, 1943. 2. Randolph, T. G.: Blood Studies in Allergy. 1. The Direct Counting Chamber Determinations of Eosinophils by Propylene Glycol-Aqueous Stains, J. ALLERGY 15: 59, 1944. 3. Randolph, T. G.: Differentiation of Leucocvtes in the Counting ‘Chamber by Propylene Glycol-Aqueous Stains; A Screen for the Detection of Major Bloob Abnormality, Am. J. Clin. Path., Technical Section 8: 48, 1944. 4. Randolph, T. G., and Stanton, C. L.: A Comparison of the Counting Chamber and Film Methods of Enumerating Eosinonhils. To be nublished. 5. Ra.ndolph, T. CT., and Rattling, F. F. AT: Bron&ial Asthma ai a Manifestation of Sulfonamide Sensitivity, J. A. M. A. 126: 166, 1944. 6. Hageman, P. O., and Blake, F. Cr.: A Specific Febrile Reaction to Sulfanilimide, Drug Ferer, J. A. M. A. 109: 642, 137. Febrile Reactions Accompanying Read7. Lyons, R. H., and Balberor, H. J.: ministration of Sulfathiazolc, .J. A. M. A. 118: 955, 1942. 8. Schlesinger, E. R., and Mitchell, IV. I,.: Sulfanilimide Eruption, A Study of Patients with the Morbilliform Rash and of their Subsequent Reactions, Am. J. Dis. Child. 56: 1256, 1938.