å¡ CASE REPORT å¡

Pulmonary Infiltration and Eosinophilia Associated with Sulfasalazine Therapy for Ulcerative Colitis: A Case Report and Review of Literature Susumu Yamakado, Yutaka Yoshida, Takashi Yamada, Teruyuki Kishida, Masafumi Kobayashi and Takeo Nomura We report a 52-yr-old man with ulcerative colitis who developed sulfasalazine-induced pulmonary infiltration with eosinophilia (PIE syndrome), which resolved completely after withdrawal of this drug. Desensitization to sulfasalazine was successful, and allowed the patient to receive this drug without recurrence of the pulmonary toxicity. This is the first case of the sulfasalazine-induced PIE syndrome in Japan; a review of the world literature found no previousMedicine cases of successful desensitization following sulfasalazine-induced PIE syndrome. (Internal 31: 108- 113, 1992) Key words: PIE syndrome, desensitization

Introduction

inflammatory bowel disease on September 28, 1988. On admission, his body temperature was 38.0°C and pulse Sulfasalazine, a therapeutic agent widely used for was 84/min, and tenderness was observed in the umbilical inflammatory bowel disease, frequently causes such side region with watery and bloody diarrhea. Laboratory effects as nausea and vomiting, skin rashes, fever, head data on admission revealed a mild leukocytosis with ache, blood dyscrasias, and hepatic dysfunction. Pul a normal differential, an elevated C-reactive protein monary infiltration and eosinophilia (PIE syndrome) due (CRP), and hypoalbuminemia indicating his malnu to sulfasalazine have rarely been reported. We recently tritional state (Table 1). enema and total colono A double-contrast barium encountered a patient who developed PIE syndrome scopic examination revealed multiple ulcers, pseudo after the start of sulfasalazine therapy. Desensitization polyps, edema of the colonic mucosa and submucosal to sulfasalazine was successful, and therapy could be bleeding, which were consistent with moderately active restarted without recurrence of the PIE syndrome. ulcerative colitis (Figs. 1, 2). Chest roentgenogram on Case Report admission showed no abnormalities. Blood and sputum A 52-yr-old male nonsmoker developed diarrhea Aculture diagnosis of ulcerative colitis wasnegative. made on the basis for bacteria and fungi were and melena for several days in July 1988. He consulted a of the clinical symptoms together with the barium enema medical college hospital, but no abnormalities were found and colonoscopic findings. Treatment with sulfasalazine in blood tests or stool examination. He was later admitted (3.0g/day) was initiated on October 3 with total par to another medical college hospital for an operation due enteral nutrition for the first 2wk. No other medication to finger trauma in August 1988. After this hospitali was prescribed. Fever and melena subsided immediately zation, bloody diarrhea with tenesmus and abdominal and diarrhea disappeared in a month. White blood cell pain appeared again. Oral antidiarrheal agents were count and CRP were normalized. Remission of ulcerative He wasbut thenhisreferred to our hospital and withfever suspected given, symptoms continued developed. colitis was confirmed by colonoscopy on November 8 (Fig. 3). About 30 days after the initiation of sulfasalazine From The Third Department of Internal Medicine, Nippon Medical School, Tokyo Received for publication October ll, 1990; Accepted for publication May 13, 1991 Reprint requests should be addressed to Susumu Yamakado, MD, The Third Department of Internal Medicine, Nippon Medical School Sendagi, Bunkyo-ku, Tokyo 113, Japan 108

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Sulfasalazine-induced Table 1.

Laboratory

Findings

W B C 9 ,5 0 0 /m m j (S ta b 10 , S e g 5 9 , E o , 6 , M on 5 ,L ym 20% ) R B C 4 3 1 x 10 4 /m m 3 H b. H t. P it .

12 .6 g /d l 3 9 .8 % 30 .5 x 10 4 /m m 3

G O T G PT LD H A LP y -G T P C ho i TG TP A lb y -g1

19 IU /1 14 IU /1 2 8 2 IU /1 1 15 I U /1 13 I U /1 ll l m g /d l 8 5 m g /d l 5 .9 g /d l 1 .9 g /d l 1 .5 g /d l

PIE Syndrome

on Admission BU N C re a t . U A N a K C 1

7 .0 m g /d l 0 .9 m g /d l 5 .7 m g /d l 1 3 6 m E q /l 4 .O m E q /l 1 0 2 m E q /l

CR P E SR

I O .l m g /d l 6 m m /h

U rin a ly sis P ro te in G lu c o s e U ro b ilin o g e n O cc u lt b lo o d

((((+

F eces O cc u lt b lo o d

(3 + )

) ) ) )

Pit., platelet; Choi., cholesterol; T.G., triglyceride; T.P., total protein; Great., creatinine; U.A., uric acid. Fig. 2. Colonoscopic view of the sigmoid colon on admission demonstrating granular appearance with variable sized ulcerations and no normal appearing mucosa.

Fig. 1. Double contrast film of descending colon demon strating diffuse granularity with symmetric narrowing and lossFig. 3. Colonoscopic view of the descending colon on remission of haustra. demonstrating inflammatory polyps, disappearance of ulcerations and dry appearing mucosa. therapy, however he complained of a productive cough culture was negative again, but a chest roentgenogram and slight fever. Laboratory examination revealed leuko revealed diffuse infiltrative opacities involving both cytosis with eosinophilia (2,700/mm3). Numerous eosino upper lung fields and the left lower lobe (Fig. 5). Pul philserythrocyte frequently contained 3 or rate 4 nuclear lobes in (Fig. The sedimentation was 90mm the4). monary function tests revealed no restrictive or obstruc first hour and the CRP was 5.0mg/dl, although these tive patterns. The lymphocyte stimulation test was tests had returned to normal 2wk previously. Sputum negative for sulfasalazine. Bronchoscopic examination Internal

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109

Yamakado et al consent because sulfasalazine was useful for maintenance therapy and this patient had impaired glucose tolerance. The dose of sulfasalazine was increased slowly over 10wk as folows: 5 mg/day, lOmg/day, 20mg/day, 50mg/ day, lOOmg/day, 250mg/day, 500mg/day, 750mg/day, 500mg b.i.d., and 500mg t.i.d. A remission ofulcerative colitis was obtained about 2 months after reinitiation of sulfasalazine. There was no recurrence of the PIE syndrome after the desensitization of sulfasalazine. Discussion Ulcerative colitis is generally recognized to be associ ated with various extra-intestinal complications. Pul monary vasculitis, suppurative bronchiectasis (1), and bronchial epithelial change (2) have been reported in Fig. 4. Peripheral eosinophils at the time of the occurrence of PIE patients with ulcerative colitis. Therefore, these other syndrome (x400). lesions must be considered in patients with ulcerative colitis. The differential diagnosis was made easily in ,this case by the rapid improvement seen after discontinuation Sulfasalazine-induced pulmonary disease is unusual of sulfasalazine. despite the frequent use of this drug for inflammatory bowel disease. This patient had the typical features of the most characteristic form of sulfasalazine-induced pulmonary toxicity, "PIE syndrome," which is still rate; only 12 cases have been reported including the present case (3-13) (Table 2). The clinical picture is character ized by cough, dyspnea, fever, bilateral lung infiltrates, and peripheral eosinophilia of over 1,000/mm3. The average age of these patients was 43.8 yr, which is higher than usual for inflammatory bowel disease patients. Ten were male, and only 2 were female. The dose of sulfa salazine ranged from 1.0 to 6.0 g/day, and was over 3.0g/ day in most cases. The average period of administration Fig. 5. Chest roentgenogram at the time of development of the PIE syndrome demonstrating diffuse infiltrative opacities in was 9.0wk, except in 2 cases where the PIE syndrome developed after a very long period of therapy. The both the upper lung field and the left lower lobe. Sulfasalazine is metabolized 5-aminosalicylic prognosis of this syndrome isinto generally good, and acid the was not performed because of the patient's refusal. and sulfapyridine, and either of these metabolities may symptoms quickly were resolved when sulfasalazine was A presumptive diagnosis of the PIE syndrome was discontinued produced the in PIE allsyndrome except one byfatal a mechanism case (9). that remains made from the physical examination findings, laboratory unknown. Probably the mechanism is, as suggested in an data, chest roentgenogram, and negative culture results. Sulfasalazine was discontinued on December 7, 1988, editorial by Gell and Coombs, a type I or type III hypersensitivity reaction (14). The percentage of periph and oral tranilast (300 mg/day) was given. Over the next 6 days, a dramatic improvement was observed. Cough eral eosinophils with three-lobed nuclei was increased in this patient (23% vs 10.5 ± 1.9% in 10 healthy controls), and dyspnea subsided, and the fever was resolved. A chest roentgenogram obtained 2 wk later was clear except for linear infiltrates in the left lower lobe. The peripheral eosinophilia was also improved. He left the hospital on He had a relapse of ulcerative colitis a month after December 13, 1988. discharge from the hospital. Accordingly, we tried de sensitization to sulfasalazine with the patient's informed 110

and eosinophils with four-lobed nuclei, which are never observed in healthy controls, were also detected. These hyperactive and hypermature eosinophils may be pro In Japan, recorded of PIE syndrome are duced by most various stimuli,cases like eosinophil chemotactic due to in unknown (76.9%), factor the PIE causes syndrome (15). followed by mycosis (19.4%) and parasitism (1.9%) (16). Only ll cases have Internal

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1992)

Sulfasalazine-induced Table 2.

Reported

PIE Syndrome

Cases of Sulfasalazine-induced

PIE Syndrome

S u lfa sa laz in e A u th o r (y e a r )

A ge (y r)

S ex

D o se (g /d a y )

J o n e s '& M a lo n e (1 9 7 2 )

36

F

4 .0

T o d d & D y er (1 9 7 9 )

58

M

C o n sta n tin id is (1 9 7 6 )

23

B e rlin e r e t a 1 (1 9 8 0 )

D u ra tio n (w e e k s )

S y m p to m s

C h e st X -ra y

E o sin . (/m m 3)

10

C ou gh , d y sp n e a

1 ,0 9 0

1 .5 - 3 .0

12

F

?

104

40

F

2 .0 - 4 .0

6

W ang et a1 (1 9 8 4 )

88

M

2 .0

4

D y sp n e a , c o u gh , fe v e r D y sp n e a , c o u gh , w e ig h t lo ss C ou gh , fe v e r, ra sh F ever, m a la ise

L t . lu n g , R t. u p p e r lo b e in f. B il. co n fl u n t o p a citie s B il. so ft in f.

Y a ffe & K o r elitz (1 9 8 3 )

43

M

4 .0

5

B a illie (1 9 8 4 )

57

M

4 .0

3

C a zz a d o ri e t a1 ( 19 8 5 ) S u lliv a n ( 19 8 7 )

26

M

3 .0

28

40

M

2 .0

8

Jo rd an & C o w an ( 19 8 8 ) S ch e rp e n iss e e t a 1 ( 19 8 8 )

26

M

1 .0

3 12

36

M

6 .0

6

P re se n t ca se ( 19 8 9 )

52

M

3 .0

8

C ou gh , fe v e r , an o re x ia D y sp n e a , o rth o p nea C h e st p a in , fe v e r M a la ise , fe v e r , cou gh D y sp n e a , fe v e r D y sp n e a , cou gh

C o ugh , fe v e r

H isto i.

5 ,5 9 0

1 ,0 0 8

P e rip h e ra l lu n g in f.

1 ,2 0 0

L t.L u ng , R t. u p p e r lo b e in f. B il. u p p er lo b e in f.

2 ,8 0 0

In ters titia l c h a n g e

1 ,8 0 7

A c u te & c h ro n ic in f.

B il. p e rip h er al & b as al in f . B il. in f. o p a citie s B il. u p p e r lo b e in f .

1 ,7 2 8

1 ,5 0 0

B ro n c h io litis o b lite r an ce

C o lla p se

2 ,7 0 9

C o n so lid a tio n R t. m id . lo b e

B il. la te r al R t.u pper lo b e d e n se o p a citie s B il. u p p e r lo b e in f . L t. lo w e r lo b e in f.

1 ,8 6 4

1 ,1 0 0

3 ,19 8

B iL , b ila te ral; in f., in fi ltra tio n ; R t ., rig h t; L t, le ft ; - , n o t d e scrib e d ; E o sin ., e o sin o p h il; H isto l., h isto lo g y .

been described in the literature as being drug-induced, with anti-inflammatory agents, antibiotics, a contrast material, anti-arrhythmic agent, and gold salt being involved (17-27)agents (Tablethat 3).have been specifically Two etiological related to the PIE syndrome are parasitic infestation and allergic reactions. In contrast to the decreasing role of parasitism as a cause of the PIE syndrome, drugs and enviromental hazards have recently become more signif Desensitization to sulfasalazine has been attempted icant (28). for various hypersensitivity reactions, including skin rashes, fever, nausea and vomiting, headache, alopecia, joint pain, facial edema, and hemolysis (9, ll, 29-35). The overall success rate is reported to be better than 77%, but for eosinophilic pneumonia, Sullivan (ll) Internal

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failed to achieve desensitization to sulfasalazine, and therefore used azodisalicylate (Olsalazine) to control the colitis and pulmonary problem. In the light of the experi ence with the present case, we suggest that desensitization to sulfasalazine is initially attempted for PIE syndrome In the present case, of course careful follow-up is induced by this drug. necessary so as to detect the recurrence of PIE syndrome or any other side effects in the future. Scherpenisse et al (13) reported the use of Olsalazine for a patient with Crohn's disease and sulfasalazine-induced eosinophilic pneumonia. For the patients in whom desensitization to sulfasalazine fails, this new 5-aminosalicylic acid com pound (Olsalazine) may prove to be a useful alternative. Ill

Yamakado et al Table 3.

1) N itro fu ra n to in 2 ) S a licy la te s B ro m o v a le ry l u re a N o n fu ra m in

4 ) P ro p y lio d o n e 5 ) D -P e n ic illa m in e 6 ) G o ld sa lt 7 ) R ifam p icin Im ip ra m in e H C l 8 ) C e fo tia m H C l 9 ) M in o m y c in 1 0 ) M e x ile tin e H C l l l ) S e rra p e ta se

Isenberg Jl, Goldstein H, Koran A, et al. Pulmonary vasculitis an uncommon complication of ulcerative colitis. N Engl J Med 279: 1376,

2)

1968.

Kraft SC, Earle RH, Roesler M, et al. Unexplained bronchopulmonary disease with inflammatory bowel disease. Arch Intern Med 136:

454,

1976.

3)

Jones

4)

Thorax 27: 713, 1972. Todd TF, Dyer NH. Sulphasalazine

GR, Malone DNS. Sulphasalazine

induced lung.

lung disease.

Med J Aust

1: 570,

1976.

5) 6) 7)

Constantinidis KA. Eosinophilic pneumonia; An unusual side effect of therapy with salicylazosulfapyridine (letter to editor) Chest 70: 315, 1976. Berliner S, Neeman A, Shoenfeld Y, et al. Salazopyrin-induced eosinophilic pneumonia. Respiration 39: 119, 1980. Wang KK, Bowyer BA, Schroeder KW, et al. Pulmonary infiltrates and eosinophilia associated with sulfasalazine. Mayo Clin Proc

8) 9) 10) ll)

59:

343,

1984.

Yaffe BH, Korelitz BI. Sulfasalazine Pneumonitis. AmJ Gastroenterol 78: 493, 1984. Baillie MB. Sulfasalazine and pulmonary infiltrates. Am J Gastroenterol 79: 77, 1984. Cazzadori A, Braggio P, Bontempini L. Salazopyrin-induced eosinophilic pneumonia. Respiration 47: 158, 1985. Sullivan SN. Sulfasalazine lung. J Clin Gastroenterol 10: 218, 1987.

12) 13)

14)

Jordan A, Corwan RE. Reversible pulmonary disease and eosinophilia with sulphasalazine. J R Soc Med 81: 233, 1988. Scherpenisse J, Valk VD, Bosch VD, et al. Olsalazine as an alternative therapy in a patient with sulfasalazine-induced eosinophilic pneumonia. J Clin Gastroenterol 10: 218, 1988. Editorial. Sulphasalazine-induced lung disease. Lancet ii: 504, 1974.

112

E o sin . (% )

Ig E

51

F

12

3 ,2 0 0 U /m l

19 69 50

F F F

13 56 29

2 ,9 9 2 U /m l 2 ,2 9 9 U /m l

30

M

ll

61

M

t

19 4 IU /m l t

42

F

33

N o rm al

50

F

t

77

M

37

F

34

59

M

T

54

M

t

51

M

t

-, not described.

References 1)

Sex

K . K aw ai (19 7 5 ) T . M a tsu sh im a

| , increased;

PIE Syndrome in Japan

A ge (y r)

(19 8 1) J . K ih a ra (19 8 4 ) K . F uku da (19 8 4 ) S . H ay a sh i (19 8 5 ) Y . T a k ig u ch i ( 19 8 5 ) A . K in o sh ita (1 9 8 5 ) M . Trie (1 9 8 7 ) S . M o rita (1 9 8 7 ) K . T a k a m izu (1 9 8 7 ) T . I gish i (1 9 8 8 )

3 ) N a lid ix ic a cid

eosinophil;

Cases of Drug-induced

F ir st a u th o r (y r)

D rug

Eosin.,

Reported

Kihara J, Kino T, Furue M, et al. Nuclear hypersegmentation of pulmonary eosinophils in eosinophilic pneumonia. Nippon Kyobu Shikkan Gakkai Zasshi 26: 31, 1988 (in Japanese with English abstract).A, Nakazawa T. PIE syndrome, in: Allergic Pulmonary Umeeda Disease. Kobayashi S, Murao M, Eds. Nankodo, Tokyo, 1986, p.127. Kawai K, Hasegawa M, Aoyagi A, et al. A case of pneumonia with eosinophilia caused by Nitrofurantoin. (Abstr) Nippon Kyobu Shikkan Gakkai Zasshi 13: 736, 1975 (in Japanese). Matsushima T, Hara H, Yagi S. Three cases of PIE syndrome, probably due to drugs. Nippon Kyobu Rinsho 40: 85, 1981 (in Japanese with English abstract). Hayashi S, Hirose N, Ikeda T, et al. A case of prolonged pulmonary eosinophilia caused by D-penicillamin. Nippon Kyobu Shikkan Gakkai Zasshi 23: 479, 1985 (in Japanese with English abstract). Fukuda K, Mon N, Kino N, et al. A case of pulmonary emphy sema with PIE syndrome caused by Propyliodone. (Abstr) Nippon Kyobu Shikkan Gakkai Zasshi 22: 352, 1984 (in Japanese). Kihara J, Nishimura K, Mon M, et al. A case of probably drug induced PIE syndrome that ECF was detected in BAL material and serum. (Abstr) Nippon Kyobu Shikkan Gakkai Zasshi 22: 352, 1984 (in Japanese). Kinoshita A, Nagasawa M, Koga H, et al. A case of PIE syn drome caused by Rifampicin and Imipramine HC1. (Abstr) Nippo Kyobu Shikkan Gakkai Zasshi 23: 1389, 1985 (in Japanese). Takiguchi Y, Hashizume T, Shinozaki K, et al. A case of "Gold lung" showing PIE syndrome. (Abstr) Nippon Kyobu Shikkan Gakkai Zasshi 23: 1389, 1985 (in Japanese). Irie M, Tejima H, Togawa H, et al. A case of PIE syndrome caused by Cefotiam HC1. (Abstr) Nippon Naika Gakkai Zasshi 76: 459, 1987 (in Japanese). Morita S, Mitanijima T, Matsuda Y. A case of PIE syndrome Internal

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Sulfasalazine-induced PIE Syndrome caused by Minomycin. (Abstr) Nippon Kyobu Shikkan Gakkai 1981. Zasshi 31) Taffet 25: SL, 940,Das 1987 KM. (in Desensitization Japanese). of patients with inflammatory 26) bowel Takamizu diseaseK, to Nagata sulfasalazine. M, Kasaoka Am J Med K, et 73: al. A 520, case 1982. of PIE syndrome 32) Taffet caused SL, DasbyKM. Mexiletine Sulfasalazine-adverse HC1. (Abstr) Nippon effects and Kyobu desensit ShikkanDig Gakkai Zasshi 1987 (in Japanese). ization. Dis Sci 28: 25: 833,941, 1983. 27) Purdy 33) Igishi T, BH, Taiga Philips H, Shigeshiro DM, Summers K, etRW. al. ADesensitization case of PIE syndrome for sul caused by Serrapeptase. Nippon Naika Gakkai Zasshi 77: fasalazine skin rash. Ann(Abstr) Int Med 100: 512, 1984. 118,Korelitz 34) 1988 (inBI, Japanese). Present DH, Rubin PH, et al. Desensitization to 28) Mayock RL, Lozzo RV. The eosinophilic pneumonia, in: Pul-' sulfasalazine after hypersensitivity reactions in patients with monary Diseasebowel and Disorders. Fishman AP, Ed. McGraw-Hill inflammatory disease. J Clin Gastroenterol 6: 27, 1984. Book 35) Chiba Company, M, Murata Philadelphia, M, Iizuka2nd M, ed. et al. Vol Desensitization 1. 1986, p. 683. to salicylazo 29) Higenbottom T, Cochrane Clark TJH, et al. Bronchial sulfapyridine (Salazopyrin) in aGM, patient with ulcerative colitis. disease in Nippon Shokakibyo ulcerative Gakkai colitis. Thorax Zasshi 83: 34: 113, 581, 1986 1980.(in Japanese). 30) Holdsworth CD. Sulphasalazine desensitization. Lancet 282: 110,

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