I34 TH E BRITISH J O U R N A L OF TUBERCULOSIS

ON THE OCCURRENCE OF EOSINOPHILIA IN TUBERCULOSIS TREATED WITH ANTIBIOTICS

A PRELIMINARY OBSERVATION

BY JOHN READ

From the Thoracic Unit of the Royal Princc Alfrcd Hospital, Sydney

THE occurrence of sidc-effccts during antibiotic treatmcnt of tubcrculosis is now wcll rccognised. Thcsc undcsirable reactions arc most common with para-amino-salicylic acid (P.A.S.), Icss frequcnt with streptomycin, and rare with isoniazid in ordinary doscs. Thcy occurrcd in 7, 3 and I per ccnt. rcspcctivcly of paticnts rccciving cach drug (as part of combincd thcrapy) in a rcccnt largc survey. (U.S. Public Hcalth Service, 1954. )

The spccific action of strcptomycin on thc cighth cranial ncrve was quite soon rccogniscd as a toxic cffcct. An allergic reaction in the form of skin eruptions with or without fever was rccordcd as early as 1948, both in paticnts rcceiving strcptomycin and in thcir attendants who handlcd it (Stringfcllow, 1948; Crofton, i953. )

Cuthbert (1954) has described a case of Loeffier's syndrome in a patient receiving streptomycin and P.A.S. for pulmonary tuberculosis.

The toxic effects of isoniazid are few, and are confined largely to the central and peripheral nervous system. No instances of hypersensitivity seem to have been recorded.

P.A.S. has deservedly the most sinister reputation of the three. A number of recent reports have appeared on its toxic manifestations, including one case of fatal allergic reaction (Steininger, Klopfenstein and Woodruff, I954). Dixon (i954) has reviewed the subject of P.A.S. ' toxicity,' and from the literature has summarised 26 cases of jaundice following its administration. This jaundice was associated with pyrexia and skin rashes and most patients had a consider- able eosinophil leucocytosis in their peripheral blood. The author regarded this feature as being of diagnostic importance in the picture of P.A.S. hepatitis. Warring and Howlett (1952), in reviewing the same problem, differentiate " toxic " and " allergic " rcactions to P.A.S. Toxic reactions are mostly limited to the gastro-intestinal tract, whilst under the heading of allergy they list acute drug fever and skin rashes, headache, burning eyes, lachrymation and conjunctival injection, transient lymphadenopathy, angioneurotic ccdema, anaphylactic shock, spasmodic cough and wheezing, jaundice, granulopenia, and a reaction rescmbling infectious mononucleosis.

It may be seen that an eosinophilia is associated with many of these hyper- sensitivity reactions to streptomycin and P.A.S. This paper offers details of a group of patients suffering from tuberculosis and treated by various anti- biotic combinations who devcloped an eosinophilia without any other allergic manifestations.

(Received for publication aVovember o3, 1954.)

AND DISEASES OF T H E CHEST 135

The possibility of this occurrence was raised during the study of a patient who had a gross overt allergic reaction to both streptomycin and P.A.S.

Mrs. E.S., aged 34, had long-standing pulmonary tuberculosis with more recent apical cavitation. Her leucocyte count was normal. Following four weeks' treatment with streptomycin, i gm. twice weekly, and sodium P.A.S., 12 gm. daily, she suddenly developed a temperature of lO2 ° F., loin pain, frequency of micturition, and bleeding per vaginam. The cause was not detected and the drugs were continued for a further week, when her temperature had reached lO5 ° F., she was vomiting, her liver and spleen were palpable, and she had developed a rash. This rash proceeded to an exfoliative dermatitis. Her eosinophil count reached 14,ooo per c.mm. ( + 5 per cent. of 31,ooo white cells). Cortisone, 35 ° mgm. over four days, proved dramatic therapy, com- pletely abolishing her symptoms and signs and probably saving her life.

Test doses of streptomycin and P.A.S. showed that she was sensitive to both drugs. She was slowly and uneventfully desensitised to streptomycin and continued on combined therapy with streptomycin and isoniazid to lobectomy

t w o months later. Though she had no recurrence of her allergic symptoms, her eosinophil count remained high, up to 2,5oo per c.mm. (35 per cent. of 7,1oo white cells). After lobectomy with removal of all radiologically obvious disease, her eosinophil count, as expected, fell to zero in the immediate post- operative period. I t then became elevated again but only moderately so (700 to 1,3oo per c.mm.). When the drugs were finally suspended her leucocyte count returned to no rma l

This chance observation led to a more careful search for an eosinophilia without symptoms in other patients, in the hope of detecting " subclinical a l le rgy" and avoiding similar mishaps. Accordingly, serial leucocyte counts were performed on all patients who remained in hospital for at least one month after commencing treatment (a minority of those given antibiotics). At first, when an eosinophilia was detected, a careful watch was kept for signs or symptoms of allergy, but these failed to appear. We soon realised that we were seeing a number of patients with a symptomless eosinophilia, and that, despite continued antiobiotic treatment, they were remaining quite symptomless, though the eosinophilia persisted.

Over a period of eight months, 36 consecutive patients with tuberculosis who remained in hospital for at least one month have had leucocyte counts performed after commencing t reatment with various combinations of strepto- mycin, P.A.S. and isoniazid. Those patients admitted because of an overt allergic reaction have been omitted. Of these 36 patients, no less than I o have developed an eosinophil count above normal limits, and none of these has subsequently shown any other allergic manifestations. Details of these io patients are given in the accompanying table.

Whitby and Britton (1953) regard 400 eosinophils per c.mm. as the upper limit of normality. Since our figures are not the result of direct eosinophil counts, we have set a rather more stringent standard of 500 per c.mm. Even so, several cases with counts just over this figure have been omitted.

The statement " eosinophilia first seen " is only relative, as some patients may have had the phenomenon for a month or more without having a leucocyte count performed. Similarly, it has not been possible to obtain leucocyte

I36 THE BRITISH JOURNAL OF TUBERCULOSIS

counts, say six months, after commenc ing t reatment , so tha t the possibility o f a late eosinophil react ion in still more patients canno t be ruled out.

I t will be seen that the eosinophilic reaction has occurred in patients on each possible combina t ion o f the three antibiotics. S t rep tomycin is the c o m m o n factor in all patients, at least for a time, bu t one pa t ien t cont inued to have a marked eosinophilia on a r~gime of P.A.S. and isoniazid, months after cessation o f s t reptomycin therapy.

The " course unknown " group represents patients sent to sanatoria, who have had no allergic reactions, bu t in w h o m no recent leucocyte counts are available.

T h e first pa t ient of the table is wor th considering in more detail. She was a Polish woman , aged 38, with r ight upper lobe cavitat ion and a positive sputum. He r leucocyte count on admission to hospital was within no rma l limits, and there was no family or personal history or allergy. She was t reated o n I gm.

TABLE I

Eosinophilia Maximum Follow-up Course of the No. Disease Treatment first seen eosinophil without eosinophilia

count* ill-effects

I Pulmonary SP 3,68o 8 months Persisted (see text) PH 3 months (39)

2 Pulmonary SP 2 months 2,300 6 months Persisted (I9)

3 Pulmonary SPH (D) I month 1,265 I month Unknown Laryngeal (I I) Intestinal

4 Pulmonary SH i month i, i oo 3 months Fell, but not to normal

5 Pulmonary SP I month I, x oo 6 months Fell to normal (~o)

6 Pulmonary SP 6 weeks 1025 4 months Fell, but not to normal (I6)

7 Pulmonary SP 2 months 975 3 months Unknown (7)

8 Bronchial SP IO weeks 82o 2 months Unknown (9)

9 Meningitis SH (D) ~ weeks 1,875 3 months Persistent (I6)

IO Meningitis SPH (D) 4 months 640 3 months Unknown (9)

S: Streptomycin, I gin. twice weekly; or (D) daily. P: P.A.S. (sodium salt), I2 gin, daily. H: Isoniazid, 2o0 mgm. daily; 300 mgm. daily for meningitis. * The eosinophils are expressed as cells per c.mm. Percentage of total white cells is given

in brackets.

AND DISEASES OF T H E C H E S T I37

of streptomycin twice weekly and I2 gm. of sodium P.A.S. daily, and showed steady improvement. Three months later she was found by chance to have a leucocyte count of 4,6oo with 23 p e r cent. eosinophils. Serial white cell counts showed a persistent marked eosinophilia, with a max imum of 3,680 eosinophils per c.mm. (39 per cent. of 7,9oo white cells). After five months she was changed to an isoniazid-P.A.S, combinat ion and the phenomenon persisted. After nine months a segmental resection of her residual disease was performed. Her eosinophil count fell abruptly immediately after operation, as might have been expected. I t remained within normal limits for five weeks and then rose again (P.A.S. and isoniazid having been continued throughout) .

Comment Gill (I94o), from a perusal of the continental literature, stated that eosino-

philia occurs in tuberculosis under the following circumstances:

(a) Following the diagnostic or therapeutic injection of tuberculin. This is known as the Michaelow reaction.

(b) In tuberculous lymphadenitis. (c) Complicating artificial pneumothorax therapy. (d) Complicating gold therapy. (e) Occurring spontaneously in pu lmonary tuberculosis.

Nevertheless, eosinophilia arising spontaneously must be exceedingly rare. No patient has been admit ted to the beds of this unit in the past year with untreated tuberculosis and an eosinophil leucocytosis. However, eosinophilia in association with other manifestations o f allergy to antibiotics has been commonly seen in recent years.

The present report indicates that eosinophilia is quite frequent as an isolated finding in cases of tuberculosis treated with antibiotics; it has occurred in Io out of 36 unselected patients. The eosinophil count may reach quite high levels, but the higher counts carry on greater risk of overt allergic reactions. These latter reactions occur " out of the blue," and serial white cell counts seem to be of no help in anticipating them.

The high eosinophil count may persist (or even increase) for months, it may fall, or it may return to normal, but, as emphasised, it does not, in our experience, presage true drug sensitivity reactions.

S u m m a r y A well-marked eosinophil leucocytosis developed in IO out of 36 patients

with tuberculosis while under t rea tment with antibiotics, unaccompanied by any of the associated hypersensitivity reactions recorded in the literature.

Though some of these patients have been followed for six months or more, no allergic symptoms have developed. The eosinophilia is not a danger signal.

I t is suggested that the phenomenon will be found to be quite common.

Grateful acknowledgments are due to Dr. Cotter Harvey and Dr. H. M. Rennie for much valuable advice and encouragement in the preparation of this paper.

I38 T H E B R I T I S H J O U R N A L O F T U B E R C U L O S I S

REFERENCES CROFTO~, J. (x953): Brit. Med. 3 , 2, IOI4. CUTHBERT, R. J. (I954): Brit. Med. J. , 2, 398. Dixon, W. M. (I954): Brit. 07. Tuberc., 48, xo2. GXLL, A. M. (I94O): Brit. Med. 07., 2, 22o. STEININOER, W. J., KLOPFENSTE, IN, M. D., and WOODRUFF, C. E. (I954): Amer. Rev. Tuberc.,

69, 45 x. STRI~OI~.LLOW, C. (I948): Brit. Med. o7., 2, 387 • UNrrED STAT~S PUBLIC HEALT~ SERVIC~ (1954): Amer. Rev: Tubere., 69, x. W.~a~iNo, F. C., and HOWL~TT, K. S. (x95~): Amer. Rev. Tuberc., 65, 235. WnrrBx, and BRITTON (1953): " Disorders of the Blood." Seventh Edit., p. 94.