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Lung infiltrations as a complication of PAS treatment
Tubercle, Lond., (1958), 39, I69
Lung Infiltrations as a Complication of PA_S Treatment By A. M. H O L M B O E flora the Department of Lung Diseases, Rikshospitalet, Oslo Since PAS was introduced in the therapy of tuberculosis ten years ago, the drug has become known for its side-effects, which m a y be very unpleasant for the patient and sometimes'even of a serious nature. M a n y of these are apparently typical allergic reactions. T h e y generally appear when the drug has been used for some weeks, manifesting themselves through rising temperature, exanthemata, reactions of the mucous membranes or serious anaphylactic s h o c k - a n d they are usually accompanied by eosinophilia. I t is also well known that allergic reactions of various kinds m a y cause radiographic lung shadows. I n the transitory lung infiltrations first described by Loeftter in 1936 , the accompanying eosinophilia suggests an allergic m e c h a n i s m - and infiltrations of this kind have in fact been observed several times as a complication to treatment with various drugs, for instance penicillin and iodine (Falk and Newcomer, I949; Usher, I951 ). Transitory lung infiltrations resulting from PAS treatment were described for the first time by Morandi and his colleagues in 1951. Since then, as far as the author has been able to discover only 6 established cases have been published (Warring and Howlett, 1952 ; Cuthbert, 1954; T u c h m a n , 1954; Atwell and Prior, 1955; Paine, 1955). In 4 additional cases PAS was regarded as the most probable aetiological factor, but in these cases the patients had received other drugs at the same time, and for some reason or other no provocative test with PAS had been performed. In the majority of the previously described cases the lung infiltrations had appeared one to four weeks after the PAS treatment had been started. I n one case (Cuthbert, I954) , however, the symptoms did not a p p e a r until the treatment had lasted for eight weeks. In all the cases there was a rising temperature and eosinophilia (6-26 per cent), and most of the patients also showed other signs of hypersensitivity to PAS, partly from the gastro-intestinal tract, partly as skin itching, e.xanthemata, conjunctivitis and ill-defined myalgic pains. In all the cases described, there was a complete radiographic disappearance of the lung infiltrations one to two weeks after PAS treatment had been stopped. I t is obviously important to be aware of this complication of PAS treatment, since the infiltrations otherwise m a y easily be misinterpreted as spread of the tuberculosis. One case, recently observed in the Department of Lung Diseases, Rikshospitalet, Oslo, will be described, because it differs in certain aspects from cases previously published.
Case Report The patient, a woman aged 32 years, was admitted to the Department of Lung Diseases, Rikshospitalet, on June 18, 1956. Apart from diabetes mellitus, diagnosed in 1953 and since then well controlled on insulin and diet, she had had no previous illnesses of importance. She was Pirquet positive after BeG-vacclnation in 195o and had passed mass-radiography in 195o and screening in February i956, both with negative lung findings. From March 1956 she began to feel tired, and in May she bechme feverish and had a productive cough with purulent sputum. A chest x-ray disclosed a lesion with an egg-sized cavity in the right lower lobe. The ESR was elevated, and tubercle bacilli were found in the sputum shortly after her admissiori. O
~7 o
TUBERCI.E
L
Fie. x. - Lung fields after tile first episode of fever, joint pains and transient shadows, with the tuberculous lesions in tile right middle zone.
Fro. 2 . - F r e s h opacities following a further short period o f treatment with PAS.
After treatment for one m o n t h with streptomycin and isoniazid, both given daily, regression of tbe lesion and shrinking of tile cavity was observed. The ESR fell, and the patient became afebrile. Nevertheless, because she had diabetes and the lung lesions were localized to a small area, a lung resection was planned after treatment with isoniazid and PAS for another two months. After a few weeks' treatment with isoniazid and PAS however, the patient presented new s)anptoms, which forced us to postpone tile planned resection for some time. In August she started complaining o f migrating pains ifi her joints, localized to her right shoulder-joint for the iqrst two weeks, then moving to her knee-joints, ankles, left wrist and right jaw. The E S R rose again from 3 8 to 78 ram., in I hour, but there was no rise o f temperature, no exanthem, no eosinophilia and the antistreptolysin titre was normal. Nothing abnormaI was found on examination of the joints, including x-ray examination of tile shoulders. Withdrawal of isoniazid and PAS for five days resulted in no improvement of the symptoms, and the treatment was therefore resumed. A routine chest x-ray on October 19, when the patient had suffered from her joifit-symptoms for about one month, showed further regression of the lesion and cavity in the right lower lobe, but new shadows had now appeared in the apico-posterior segment and in the lingula of the left upper lobe. A n x-ray a few days later also disclosed a new opacity in the right upper lobe. It seemed unlikely that the tuberculosis had spread during treatment which had already led to regression of the original lesions. However, we dared not entirely exclude such a possibility in a diabetic woman. Therefore, after having tried penicillin and tetracycline without effect, we started her on isoniazid and streptomycin again from October 3, considering this the most effective combination of antibiotics against tuberculosis. Her general condition improved within a short time. The new shadows disappeared after a few weeks (Fig. t) and the joint-pains also vanished. During a week's leave of absence before the planned resection the patient again h a d isoniazid and PAS and returned to the ward on November x I in a very bad condition, and again complaining o f joint-pains. She stated that her temperature had risen and she had felt distinctly ill the day after getting home. An x-ray disclosed new extensive opacities in both lungs, especially on the right side (Fig. ~). There was no eosinophilia this time either, but our suspicion of an allergic reaction towards PAS was now so strong that this drug was immediately replaced by streptomycin. Her general condition again promptly improved, the temperature became normal, the ESR fell, and the shadows in the lungs disappeared in the course o f a few weeks. Tile planned resection o f the apical segment of the right lower lobe was performed on December 4, without any complications. An x-ray six weeks after the operation showed only ordinary post-operative' cbanges without new lung shadows (Fig. 3). Before and after the operation the patient had received isoniazid and streptomycin~ but as it was considered important for the future treatment to prove a possible PAS allergy, a provocative test was now performed with the consent of the patient. After only two days of taking PAS, 6 g. on the first day
PAS SENSITIVITY
I7I
,me
nt=-~k_
I
Fro. 3- - j~fter resection o f the apical segment of the right lower lobe.
and 12 g. on tile second, her temperature rose, she felt ill, and an x-ray again disclosed a n e w opacity in the right lung. The ESR rose from I6 mm. to 45 mm., but there was still no eosinoplfilia. Tile subjective symptoms quickly disappeared after stopping PAS and an x-ray a week later showed definite regression. This last test proved with certainty that the transitory lung infiltrations and probably her joint pains as well, were due to hypersensitivity to PAS. An extraordinary feature in our case was that the patient did not hax'e eoslnophilia at any time and that her temperature did not rise until very late in the course of her illness. On the other h a n d she had a pronounced rise of the ESR on each occasion, while in the previously published cases the ESR either had not been mentioned or had been described as normal.
Summar~
A case is reported of allergic lung infiltrations arising during treatment of pulmonary tuberculosis. PAS was suspected to be the cause and the suspicion was later verified by a provocative test. The transitory lung infiltrations were accompanied by migrating joint pains and a rising ESR, but unlike the other published reports, there was at no stage any eosinophilia. References Atwell, R . J . , and Prior, J. A. (x955) Ann. intern. ~Ied., 42, I9o. Cuthbert, R . J . (]954) Brit. reed. J., ii, 398. Falk, M. S., and Newcomer, V. D. (1949) J. Amer. reed. Ass., xlz, 21. Loeftler, W. (x936) Schweiz. reed. |Vschr., 66, xo69. Morandi, L., Ochsner, H., and Neuenschwander, A. (x95x) Schweiz. reed. |Vschr., 8~, 13oz, Paine, D. (I955) Arch. intern. Med., 96, 768. Tuchman, H. (x954) Amer. Rev. Tuberc., 70, I7t. Usher, B. (195x) Canad. reed. Ass. J . , 64, 67. Warring, ,,Fz C . , J r . , and HQwlett, K. S., Jr. (z95~) Amer. Rev. Tuber¢., 65, 235.
Lung Infiltrations as a Complication of PA_S Treatment By A. M. H O L M B O E flora the Department of Lung Diseases, Rikshospitalet, Oslo Since PAS was introduced in the therapy of tuberculosis ten years ago, the drug has become known for its side-effects, which m a y be very unpleasant for the patient and sometimes'even of a serious nature. M a n y of these are apparently typical allergic reactions. T h e y generally appear when the drug has been used for some weeks, manifesting themselves through rising temperature, exanthemata, reactions of the mucous membranes or serious anaphylactic s h o c k - a n d they are usually accompanied by eosinophilia. I t is also well known that allergic reactions of various kinds m a y cause radiographic lung shadows. I n the transitory lung infiltrations first described by Loeftter in 1936 , the accompanying eosinophilia suggests an allergic m e c h a n i s m - and infiltrations of this kind have in fact been observed several times as a complication to treatment with various drugs, for instance penicillin and iodine (Falk and Newcomer, I949; Usher, I951 ). Transitory lung infiltrations resulting from PAS treatment were described for the first time by Morandi and his colleagues in 1951. Since then, as far as the author has been able to discover only 6 established cases have been published (Warring and Howlett, 1952 ; Cuthbert, 1954; T u c h m a n , 1954; Atwell and Prior, 1955; Paine, 1955). In 4 additional cases PAS was regarded as the most probable aetiological factor, but in these cases the patients had received other drugs at the same time, and for some reason or other no provocative test with PAS had been performed. In the majority of the previously described cases the lung infiltrations had appeared one to four weeks after the PAS treatment had been started. I n one case (Cuthbert, I954) , however, the symptoms did not a p p e a r until the treatment had lasted for eight weeks. In all the cases there was a rising temperature and eosinophilia (6-26 per cent), and most of the patients also showed other signs of hypersensitivity to PAS, partly from the gastro-intestinal tract, partly as skin itching, e.xanthemata, conjunctivitis and ill-defined myalgic pains. In all the cases described, there was a complete radiographic disappearance of the lung infiltrations one to two weeks after PAS treatment had been stopped. I t is obviously important to be aware of this complication of PAS treatment, since the infiltrations otherwise m a y easily be misinterpreted as spread of the tuberculosis. One case, recently observed in the Department of Lung Diseases, Rikshospitalet, Oslo, will be described, because it differs in certain aspects from cases previously published.
Case Report The patient, a woman aged 32 years, was admitted to the Department of Lung Diseases, Rikshospitalet, on June 18, 1956. Apart from diabetes mellitus, diagnosed in 1953 and since then well controlled on insulin and diet, she had had no previous illnesses of importance. She was Pirquet positive after BeG-vacclnation in 195o and had passed mass-radiography in 195o and screening in February i956, both with negative lung findings. From March 1956 she began to feel tired, and in May she bechme feverish and had a productive cough with purulent sputum. A chest x-ray disclosed a lesion with an egg-sized cavity in the right lower lobe. The ESR was elevated, and tubercle bacilli were found in the sputum shortly after her admissiori. O
~7 o
TUBERCI.E
L
Fie. x. - Lung fields after tile first episode of fever, joint pains and transient shadows, with the tuberculous lesions in tile right middle zone.
Fro. 2 . - F r e s h opacities following a further short period o f treatment with PAS.
After treatment for one m o n t h with streptomycin and isoniazid, both given daily, regression of tbe lesion and shrinking of tile cavity was observed. The ESR fell, and the patient became afebrile. Nevertheless, because she had diabetes and the lung lesions were localized to a small area, a lung resection was planned after treatment with isoniazid and PAS for another two months. After a few weeks' treatment with isoniazid and PAS however, the patient presented new s)anptoms, which forced us to postpone tile planned resection for some time. In August she started complaining o f migrating pains ifi her joints, localized to her right shoulder-joint for the iqrst two weeks, then moving to her knee-joints, ankles, left wrist and right jaw. The E S R rose again from 3 8 to 78 ram., in I hour, but there was no rise o f temperature, no exanthem, no eosinophilia and the antistreptolysin titre was normal. Nothing abnormaI was found on examination of the joints, including x-ray examination of tile shoulders. Withdrawal of isoniazid and PAS for five days resulted in no improvement of the symptoms, and the treatment was therefore resumed. A routine chest x-ray on October 19, when the patient had suffered from her joifit-symptoms for about one month, showed further regression of the lesion and cavity in the right lower lobe, but new shadows had now appeared in the apico-posterior segment and in the lingula of the left upper lobe. A n x-ray a few days later also disclosed a new opacity in the right upper lobe. It seemed unlikely that the tuberculosis had spread during treatment which had already led to regression of the original lesions. However, we dared not entirely exclude such a possibility in a diabetic woman. Therefore, after having tried penicillin and tetracycline without effect, we started her on isoniazid and streptomycin again from October 3, considering this the most effective combination of antibiotics against tuberculosis. Her general condition improved within a short time. The new shadows disappeared after a few weeks (Fig. t) and the joint-pains also vanished. During a week's leave of absence before the planned resection the patient again h a d isoniazid and PAS and returned to the ward on November x I in a very bad condition, and again complaining o f joint-pains. She stated that her temperature had risen and she had felt distinctly ill the day after getting home. An x-ray disclosed new extensive opacities in both lungs, especially on the right side (Fig. ~). There was no eosinophilia this time either, but our suspicion of an allergic reaction towards PAS was now so strong that this drug was immediately replaced by streptomycin. Her general condition again promptly improved, the temperature became normal, the ESR fell, and the shadows in the lungs disappeared in the course o f a few weeks. Tile planned resection o f the apical segment of the right lower lobe was performed on December 4, without any complications. An x-ray six weeks after the operation showed only ordinary post-operative' cbanges without new lung shadows (Fig. 3). Before and after the operation the patient had received isoniazid and streptomycin~ but as it was considered important for the future treatment to prove a possible PAS allergy, a provocative test was now performed with the consent of the patient. After only two days of taking PAS, 6 g. on the first day
PAS SENSITIVITY
I7I
,me
nt=-~k_
I
Fro. 3- - j~fter resection o f the apical segment of the right lower lobe.
and 12 g. on tile second, her temperature rose, she felt ill, and an x-ray again disclosed a n e w opacity in the right lung. The ESR rose from I6 mm. to 45 mm., but there was still no eosinoplfilia. Tile subjective symptoms quickly disappeared after stopping PAS and an x-ray a week later showed definite regression. This last test proved with certainty that the transitory lung infiltrations and probably her joint pains as well, were due to hypersensitivity to PAS. An extraordinary feature in our case was that the patient did not hax'e eoslnophilia at any time and that her temperature did not rise until very late in the course of her illness. On the other h a n d she had a pronounced rise of the ESR on each occasion, while in the previously published cases the ESR either had not been mentioned or had been described as normal.
Summar~
A case is reported of allergic lung infiltrations arising during treatment of pulmonary tuberculosis. PAS was suspected to be the cause and the suspicion was later verified by a provocative test. The transitory lung infiltrations were accompanied by migrating joint pains and a rising ESR, but unlike the other published reports, there was at no stage any eosinophilia. References Atwell, R . J . , and Prior, J. A. (x955) Ann. intern. ~Ied., 42, I9o. Cuthbert, R . J . (]954) Brit. reed. J., ii, 398. Falk, M. S., and Newcomer, V. D. (1949) J. Amer. reed. Ass., xlz, 21. Loeftler, W. (x936) Schweiz. reed. |Vschr., 66, xo69. Morandi, L., Ochsner, H., and Neuenschwander, A. (x95x) Schweiz. reed. |Vschr., 8~, 13oz, Paine, D. (I955) Arch. intern. Med., 96, 768. Tuchman, H. (x954) Amer. Rev. Tuberc., 70, I7t. Usher, B. (195x) Canad. reed. Ass. J . , 64, 67. Warring, ,,Fz C . , J r . , and HQwlett, K. S., Jr. (z95~) Amer. Rev. Tuber¢., 65, 235.