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Local treatment of aspergilloma of the lung with a paste containing nystatin or amphotericin B
184
Tubercle, Lond., (1970), 51, 184
LOCAL
TREATMENT OF ASPERGILLOMA OF THE LUNG CONTAINING NYSTATIN OR AMPHOTERICIN
WITH A PASTE B
By PAWELKRAK~WKA,KAZIMIERZTRACZYK,JERZYWALCZAK,HALINAHALWEG, ZQFIA ELSNER,LILIA PAWLICKA From the National Institute of Tuberculosis and the Pharmaceutical Institute, Warsaw, Poland
SUMMARY In order to increase the fungicidal effect of nystatin or amphotericin B in topical treatment of pulmonary aspergilloma, a paste containing these drugs was used. The paste was administered by means of intracavitary needling and instillation. Five to 18 needlings were applied in each case. Ten patients with 12 aspergillomas were treated with nystatin and ten patients were treated with amphotericin B. In all patients treated with nystatin the fungi disappeared from the sputum; during treatment five patients expectorated plugs composed of fungi. Nine patients had haemoptysis before treatment; in six of them haemoptysis stopped during treatment, and in three it diminished. In three patients aspergilloma disappeared and in three it regressed on radiographs. Ten patients were treated with the paste containing amphotericin B. In seven, fungi disappeared from the sputum. Three patients expectorated plugs. Cessation of haemoptysis was observed in six cases. The aspergilloma regressed in five cases. In two early cases with thickening of the cavity wall due to the development of the fungi on its inner surface, the regression was remarkably prompt.
Afin d’augmenter l’effet fongicide de la nystatine et de l’amphotericine B dans le traitement de l’aspergillome pulmonaire - sujet d’actualite - on utilise une substance contenant ces drogues. Ce medicament est administre par ponction et instillation intravitaire. Cinq a 18 ponctions ont et6 faites dans chaque cas. Dix malades totalisant 13 aspergillomes ont CtCtrait& avec la nystatine et dix avec l’amphotericine B. Chez tous les malades trait& avec la nystatine, l’aspergillus ne put Ctre retrouve dans l’expectoration. Durant le traitement, cinq malades expectorerent des agrtgats contenant le champignon. Neuf malades ont eu des hemoptysies avant le traitement; chez six d’entre eux les hemoptysies ont cesst au tours du traitement, et pour trois autres, elles ont diminut d’intensite. Pour trois malades l’aspergillome fut gueri, et pour trois autres, les signes radioscopiques regresskent. Dix malades ont CtCtrait& avec le medicament contenant l’amphothicine B. Pour sept d’entre eux, l’aspergillus a disparu de l’expectoration. Trois malades ont expectore des agregats contenant le champignon. Les hemoptysies ont disparu dans six cas, l’aspergillome a regress6 dans cinq. Pour deux cas, pris tout au debut, avec Cpaississement de la paroi
185
TREATMENT OF ASPERGILLOMA cavitaire dO au developpement quablement rapide.
du champignon
a la surface interne,
la regression
fut remar-
RESUMEN Se us6 una pasta que contenia nystatina o anfotericina B para el tratamiento local de aspergilomas pulmonares. La pasta se aplico por medio de punciones intracavitarias. En cada case se efectuaron de 5 a 18 punciones. Diez pacientes con dote aspergilomas fueron tratados con nystatina y diez pacientes fueron tratados con anfotericina B. En todos 10s pacientes tratados con nystatina 10s hongos desaparecieron de1 esputo; durante el tratamiento cinco enfermos eliminaron moldes compuestos por hongos. Nueve pacientes tenian hemoptisis antes de1 tratamiento; en seis de ellos la hemoptisis desaparecio con el tratamiento, y en 10s otros tres, disminuyo. En tres pacientes desaparecio el aspergiloma y otros tres hubo una reduction radiografica. Diez pacientes fueron tratados con la pasta que contenia anfotericina B. Los hongos desaparecieron de 10s esputos en siete cases. Tres pacientes expectoraron moldes. La hemoptisis cedio en seis cases. Los aspergilomas retrocedieron en cinco cases. En dos cases recientes, con engrosamiento de la pared cavitaria debido al desarrollo de1 hongo en su interior, la regresion fuC llamativamente rapida.
ZUSAMMENFASSUNG Urn die fungicide Wirkung von Nystatin oder Amphotericin B bei der Lokalbehandlung der Lungenaspergillose zu steigern, wurde eine diese Medikamente enthaltende Paste verwendet. Die Paste wurde durch Kavernenpunktion und Installation appliziert. Im Einzelfall wurden fiinf bis 18 Punktionen vorgenommen. Zehn Patienten mit 12 Aspergillomen wurden mit Nystatin behandelt, zehn weitere mit Amphotericin B. Bei allen mit Nystatin behandelten Kranken verschwanden die Erreger aus dem Sputum. Unter der Behandlung expektorierten fiinf Patienten Klumpen von zusammengeballten Pilzen. Neun Patienten hatten vor der Behandlung Hamoptysen; bei sechs von ihnen kam die Blutung unter der Behandlung zum Stehen, bei drei wurde sie geringer. Das Aspergillom verschwand in drei Fallen und bildete sich in drei weiteren rijntgenologisch zuriick. Zehn Patienten wurden mit der Amphotericin B enthaltenden Paste behandelt. Die Erreger verschwanden bei sieben aus dem Sputum. Drei Patienten expektorierten Klumpen. Aufhijren der Blutung wurde in sechs Fallen beobachtet. Das Aspergillom bildete sich in fiinf Fallen zuriick. In zwei Friihfallen mit Verdickung der Kavernenwand infolge Ansiedlung der Pilze auf der inneren Oberflache ging die Rtickbildung bemerkenswert schnell vonstatten. Introduction Aspergilloma of the lung is a frequent cause of haemoptysis, which is sometimes so profuse that it may be fatal. An aspergilloma can reach a giant size and, occasionally, can undergo purulent infection. Therefore, whenever possible, an aspergilloma should be resected surgically. However, in the majority of cases surgical treatment is not feasible; it is precluded because of respiratory insufficiency due to chronic tuberculosis or emphysema, car pulmonale, the age of the patient, or bilateral aspergillomas. In the authors’ material including 120 cases of aspergilloma, only 32 patients were operated on and in 88 surgical treatment was contraindicated.
186
KRAK6WKA
AND
OTHERS
Non-surgical treatment has not been widely used. Intravenous administration of amphotericin B has not given satisfactory results. Numerous attempts at topical treatment have been made and occasional cases published. Nystatin in suspension (Bergmann, 1959) or amphotericin B (Brouet and others, 1964; Migubres, Paczuszynski & Esteve,) have been instilled by intracavitary needlings. Amphotericin B has also been injected into the trachea by direct puncture (Ikemoto, 1965). Ramirez, (1964) instilled amphotericin B and sodium iodide by a catheter left in place near the orifice of the bronchus of the diseased pulmonary lobe. Adelson and Malcolm (1968) applied direct intracavitary instillation of sodium iodide solution via a catheter inserted percutaneously and left in the aspergilloma cavity for 40 days. In a previous study a suspension of nystatin was injected by syringe and needle into the aspergilloma cavity. Cure was achieved in three out of 11 patients, the number of needlings ranging from 14 to 83 (Krakowka and others, 1963; 1965). To increase and prolong the effect of the drugs and thus reduce the number and frequency of intracavitary needlings, nystatin was administered in a thick suspension (paste) of sulphathiazol and Lipiodol Ultra-fluid. In some cases the suspension remained in the cavity for about two weeks, but usually it was expectorated within 24 hours (Krakowka and others, 1967). The present study deals with topical treatment with a paste containing nystatin or amphotericin B administered by intracavitary needling. The paste was prepared according to Friedel’s experience with paste containing antituberculosis drugs, isoniazid, streptomycin, or tebethion. Friedel (1963) administered it through a cardiac catheter at bronchoscopy. The advantage of the paste lies in its semi-fluid consistency. It is fluid at 45°C solidifies at body temperature and remains in the cavity for a long time (Voigt and Weiss, 1960); the effect of the incorporated drugs is thus prolonged. Methods Before treatment, routine anteroposterior and lateral radiograms and tomograms were taken in each case. At least four cultures of the sputum on Sabouraud’s agar for A.fumigutus were made and the colony count was graded (see Table I). Precipitating antibodies against A. fumigatus filtrates were determined by the use of double diffusion technique in agar gel according to Ouchterlony. In patients treated with amphotericin B, urinalysis, blood urea and creatinine were determined every two weeks. In all patients examinations of blood coagulation were done before endocavitary treatment, in order to avoid bleeding associated with a disturbance of coagulation. In the first period of this study the paste containing nystatin was used, and in the second the paste containing amphotericin B. Both pastes were prepared at the Pharmaceutical Institute, Warsaw. The drug was suspended under aseptic conditions in lipophilic gel with 24% of a liquid contrast medium (Lipiodol Ultrafluid). Lipophilic gel vehicle contains a mixture of high fatty acids with wax or paraffin; it is commonly used as a vehicle for suppositories in pharmacy. It had a melting point of 46°C and solidification point of 37°C; it is liquid at 40 to 5O”C, and solidifies at body temperature. The physicochemical properties of this paste make it suitable for intracavitary administration. The composition of the paste is as follows : amphotericin B1 500 mg. or nystatin2 45OOOOOu, vehicle 76 ml., Lipiodol Ultra-fluid3 24 ml. Lipiodol Ultra-fluid is added to visualize whether the paste is injected into the cavity and to determine the time it remains there. The paste was examined in vitro by two methods: (1) Antifungal activity: Spores of A. fumigatus were added to the paste, stored at 37°C for various periods of time, and then inoculated on Czapek’s agar. It was found that the paste with nystatin in concentration of 45,000~ per ml. completely 1 Fungizone intravenous, Squibb p Mycostatin, Squibb 8 Lipiodol Ultra-fluid,
Guerbert
TREATMENT
187
OF ASPERGILLOMA
TABLEI.-RESULTS OF INTRACAVITARYTREATMENT OF ASPERGILLOMA WITH NYSTATIN-CONTAININGPASTE
Number
case aspergillomas
Growth of A. fumigatust
Haemoptysis* before
j treatment
after treatment
+__i
I. 2. 3. 4. 5. 6. I. 8. 9.
10.
* Haemoptysis:
before
in
+
I
+
+
t
i-
+1-+ +
+
+
-+
7
+
+-
t A+
-t
+ q- + !- profuse and frequent - + profuse, infrequent scanty and frequent +’ scanty, infrequent + none
_~
!_
L
/
4 +-+ t-
1
after treatment
i treatment
T-
_
Radiographic appearance of aspergilloma after treatment
~ I Disappearance No change No change No change Regression Regression No change Regression Disappearance of aspergilloma in the left lung: new aspergilloma in the right lung. Disappearance
t Growth of A. fumigatus: + + + - i- exceedingly abundant: innumerable colonies ./. :. + f abundant: more than 20 colonies +. 1~moderate: 10 to 20 colonies .,. _I_ scarce: 4 to 10 colonies very scarce: 1 to 3 col. -1 no growth
the growth of A.,fumigatus after four days. The paste with amphotericin B, 5 mg per ml, inhibited inhibited the growth of A. fumigatus after only 30 minutes. (2) Determination of diffusion of the drug incorporated in the paste into the medium. Wells of a diameter of 9 mm. were cut in Czapek’s agar inoculated with spores of A. fumigatus, and were then filled with one of the pastes. It was found that the paste with nystatin, 45OOOu per ml., did not produce zones of inhibition; the paste with amphotericin B, 5 mg. per ml., gave zones of growth inhibition of about 20 mm. in diameter. It was also established that the amphotericin B-containing paste could be stored at 4°C for about two months without any significant loss of its activity (Halweg and others, in preparation). The paste is injected into the aspergilloma-containing cavity by puncture of the chest wall under fluoroscopic control. The patient is in the prone position on the x-ray table. The puncture is made after careful localization of the cavity, usually in the interscapular area. A needle, 10 cm. long and 1.2 mm. in diameter, with a stillette, is used. It is tightly connected to a syringe. Free aspiration of air indicates that the needle has entered the cavity. Several ml. of 2% xylocaine are instilled in the cavity to suppress the cough reflex. The paste is heated to 50°C and poured into the syringe previously stoppered with a special butt; until injection, the syringe is kept in a water bath of 50°C. After the initial resistance is overcome the paste passes freely through the needle. At body temperature the paste solidifies. Usually 5 ml. of the paste are injected every seven to ten days; sometimes the intervals between punctures are longer, up to three weeks. These longer intervals are made necessary because of either haemoptysis or stagnation of the paste in the cavity.
188
KRAK6WKA
AND
OTHERS
Results of treatment with nystatin-containing
paste
Ten patients with 12 aspergillomas were treated with nystatin-containing paste. Two of them had bilateral aspergillomas. The size of the cavities ranged from three to 10 cm. in diameter. The number of needlings varied from five to 18. The number of ineffective needlings was small, not exceeding 5 per cent; they were due to technical difficulties in entering small cavities, or aspiration of blood instead of air, or haemoptysis following the needling. The observation period after the intracavitary treatment had been completed varied from 2 to 18 months. Five patients started to expectorate plugs during intracavitary treatment. Before treatment nine patients had recurrent haemoptysis, in two of them it was life-threatening. In six patients, the treatment resulted in cessasion of haemoptysis, and in three, only blood-streaked sputum occasionally appeared (Table I). In three patients fungus balls disappeared 2, 11, and 14 months respectively after the completion of treatment. In three patients, fungus balls diminished considerably. In the remaining four patients no change was apparent on radiographs (Table I). In one case, a new aspergilloma in the contralateral lung developed. In all treated patients cultures of the sputum became negative after treatment (Table I). In two cases, cultures of surgical specimens were negative, although direct microscopic examination revealed fragments of mycelium. Precipitin tests with filtrates of cultures of A. fumigatus were positive initially in all cases. In two cases, they became less intensive after the completion of treatment.
TABLEII.-RESULTS OFINTRACAVITARYTREATMENTOFASPERGILLOMA WITH AMPHOTERICIN B-CONTAININGPASTE
Case
Number of aspergillomas
Growth of A. fumigatust
HaemoptysiP before treatment
after treatment
11. 12.
1 1
++++
+
13. 14. 15.
1 1 1
+++ ++ +
+
16. 17. 18. 19. 20.
1 1 1 1 1
++++ ++++ + + -t
* Haemoptysis:
before treatment
+
after treatment
+++
+ ++++ -
+ -t + + profuse and frequent profuse, infrequent +++ scanty and frequent i+ scanty, infrequent + none
+ + + + +
(
+ + t + +
+-I-
-
t +++++
-
+++++ ++ + +++
I +
Radiographic appearance of aspergilloma after treatment
L
-
+
-
Disintegration of aspergilloma New aspergilloma in the contralateral lung No change Regression Almost complete evacuation of aspergilloma-containing cavity No change Regression Regression No change Regression
t Growth of A. fumigatus: + -k + + + exceedingly abundant: innumerable colonies abundant: more than 20 + -k -t + colonies moderate : 10 to 20 colonies +++ scarce : 4 to 10 colonies +i very scarce : 1 to 3 colonies + no growth
TREATMENT
OF
ASPERGILLOMA
189
Results of treatment with amphotericin B-containing paste
Ten patients were treated with amphotericin B-containing paste. In eight cases the aspergilloma had the typical radiographic appearance of a round or oval shadow with air crescent, and in the other two cases the cavity wall was thickened as a result of the development of fungi. The number of needlings in each case varied from four to nine. The follow-up after the completion of treatment was from one to six months. The needlings, as in the previous group, were repeated every one to two weeks, sometimes every three weeks. Three patients started to expectorate plugs of mycelium under local treatment. Ten patients had haemoptysis before treatment; in six of them it disappeared after treatment (Table II). Aspergilloma regressed in five cases. In two of them there was thickening of the cavity wall owing to development of the fungi; the fungal masses separated from the wall and fell into the cavity lumen and, finally, disappeared almost completely within three to four months. One of these patients died: at necropsy remnants of the fungi were found in the cavity, but cultures were negative, although before treatment on numerous occasions abundant growth of A. fumigutus had been obtained from the sputum (Figs. 1,2,3,4). Before treatment cultures of the sputum were positive for A. fumigatus in all patients. In three patients cultures were still positive after treatment, but in one of them this could be explained by the development of a new aspergilloma in the contralateral lung (Table II). In all patients precipitin tests with filtrates of A. fumigatus cultures prior to the treatment were positive and remained so during the observation period. Neither abnormalities in the urine nor increase of blood urea and of serum creatinine were observed. Discussion
The above study shows that the paste containing either nystatin or amphotericin B has fungicidal effects. The therapeutic results of both pastes were satisfactory. In two early cases in which fungi grew on the inner wall of the cavity before the development of a typical fungus ball, the therapeutic results were prompt. This shows the necessity of early diagnosis of fungus invasion of a cavity, as well as of early treatment. It is probable that the therapeutic effect depends first of all on the antifungal action of the drugs incorporated in the paste, as shown by the in vitro experiments. However, the effect of the paste itself cannot be excluded: it covers the surface of the fungus ball and thus impairs air supply. But the prompt disappearance of the fungi from the sputum of the patients would suggest an effect of the drugs rather than that of the paste itself. The effect of intracavitary treatment with a paste containing either nystatin or amphotericin B was assessed on the basis of the following: expectoration of plugs composed of fungi; cessation of haemoptysis; disappearance or regression of the aspergilloma on radiographs; negative cultures of sputum for A. jiimigatus; decrease of precipitin reactions. The full assessment of the majority of the above criteria, except cultures of sputum, requires a long time. The value of sputum culture, however, is limited. Aspergillomas too small to be seen on radiographs can co-exist with those easily visualized; and tiny aspergillomas can be the cause of persistently positive cultures. On the other hand, cultures of the sputum gives a relatively rapid answer. It was, therefore used for determining the frequency of intracavitary needlings in order to obtain the best fungicidal effect. It was done in eight patients with abundant growth on numerous occasions before treatment. Of the six treated with nystatin, in four the cultures became negative after one, one, two and three intracavitary needlings, and in two after five and seven needhngs. Two patients were treated with amphoteritin B; in both the cultures became negative after two and four needlings respectively. In one further case in which a new aspergilloma appeared in the contralateral lung, the abundance of growth was unchanged.
190
KRAK6WKA
AND
OTHERS
FIG. 1
FIG. l-Case 15. ‘Destroyed’ lung with a cavity. Bacteriological quiescence FIG. 2-Case 15. Decrease of the cavity resulting from the development
FIG. 3 FIG. 3-Case
15. Separation
topical treatment.
was obtained byl:chemotherapy. of fungi on its inner wall.
FIG. 4.
of the fungal masses with the paste from the cavity wall into the lumen during FIG. 4-Case 15. Evacuation of the cavity: remnants of aspergilloma at the bottom of the cavity. Four months after the start of topicai treatment.
TREATMENT
OF ASPERGILLOMA
191
The present study suggests that four to seven needlings can be sufficient to obtain fungicidal effect; but the number given should depend on the results of culture of the sputum in each case. Prompt disappearance of fungi from the sputum indicates a fungicidal effect of the paste. This was confirmed by the examination of pulmonary resection and necropsy specimens from patients previously given topical treatment. The present clinical study does not indicate which of the two drugs used is of greater benefit. In half the cases haemoptysis, sometimes profuse but never life-threatening, occurred immediately after the intracavitary needling and instillation of the paste. It usually stopped within one to three hours and only occasionally lasted for two to three days. In a few cases slight fever occurred after needling and lasted for one to three days. If too large an amount of the paste was injected it was expectorated, but the remnants of the paste were sometimes seen even a few weeks after injection. In none of the patients included in the present study did a pneumothorax occur. In two patients in our previous series a small pneumothorax had occurred without, however, clinical signs and the lung promptly re-expanded Blood urea and creatinine did not show any abnormalities during amphotericin B administration. It may be concluded that this method of intracavitary treatment of pulmonary aspergilloma is safe and the results are encouraging. REFERENCES ADELSON, H. T. & MALCOLM, J. A. (1968). Endocavitary treatment of pulmonary mycetomas. American Review of Respiratory Diseases, 98,U. BERGMANN, L. (1959). Aspergillom und Lungentuberkulose. Tuberkulosearzt, 13,763. BROUET, G., LION, F., DEMANGE, J. & NEVO~, P. (1964). Traitement local de l’aspergillome pulmonaire par injections transpariktales d’amphottricine B. Journal Francais de Medecine et Chirurgie Thoraciques. 18,789. FRIEDEL, H. (1963). Die endobronchiale Plombierung der Kaverne. Beitriige zur Klinik der Tuberkulose, 127,251. HALWEG, H., ELSNER, Z., MICHALSKA-TRENKNER, E. & KRAK~WKA, P. Antifungic properties of the paste containing nystatin or amphotericin B. In preparation. TKEMOTO,H. (1965). Treatment of pulmonary aspergilloma with amphotericin B. Archives of Internal Medicine, 115, 598. KRAK~WKA, P., CHODKOWSKA, S., HALWEG, H. & PAWLICKA, L. (1963). Own experience in the treatment and proGruzlica, 31, 1113. gnosis of pulmonary aspergilloma. KRAK~WKA, P., CHODKOWSKA, S., HALWEG, H., & PAWLICKA, L. (1965). Treatment of pulmonary aspergilloma. Proceedings of the International Symposium on Medical Mycology, Warszawa, 1963, PZWL, 249. KRAK~WKA, P., SZYMCZYK, E., CISZEK, J. & HALWEG, H. (1967). Topical treatment of aspergillomas with prolonged action nystatin: preliminary communication. Polish Medical Journal, 6, 1217. KRAK~WKA, P., SZYMCZYK, E., CISZEK, J. & HALWEG, H. (1967). Topical treatment of pulmonary aspergillomas with nystatin prolongatum (preliminary report). Gruzlica, 3547. MIGU~RES, J., PACZUSZYNSKI, H. & ESTBVE, R. (1965). Aspergillome pulmonaire en apparence primitif, trait6 avec succts par injections trans-thoraciques d’amphotkricine B. Journal Frangais de MPdecine et Chirurgie Thoraciques, 19,59. RAMIREZ, R. J. (1964). Pulmonary aspergilloma: endobronchial treatment. New England Journal of Medicine, 271, 1281. VOIGT, R. & WEISS, F. (1960). Entwicklung von Fiillmassen zur endocavitgren Behandlung der Lungentuberkulose. Arzneimittel Forschung, 10,650.
Tubercle, Lond., (1970), 51, 184
LOCAL
TREATMENT OF ASPERGILLOMA OF THE LUNG CONTAINING NYSTATIN OR AMPHOTERICIN
WITH A PASTE B
By PAWELKRAK~WKA,KAZIMIERZTRACZYK,JERZYWALCZAK,HALINAHALWEG, ZQFIA ELSNER,LILIA PAWLICKA From the National Institute of Tuberculosis and the Pharmaceutical Institute, Warsaw, Poland
SUMMARY In order to increase the fungicidal effect of nystatin or amphotericin B in topical treatment of pulmonary aspergilloma, a paste containing these drugs was used. The paste was administered by means of intracavitary needling and instillation. Five to 18 needlings were applied in each case. Ten patients with 12 aspergillomas were treated with nystatin and ten patients were treated with amphotericin B. In all patients treated with nystatin the fungi disappeared from the sputum; during treatment five patients expectorated plugs composed of fungi. Nine patients had haemoptysis before treatment; in six of them haemoptysis stopped during treatment, and in three it diminished. In three patients aspergilloma disappeared and in three it regressed on radiographs. Ten patients were treated with the paste containing amphotericin B. In seven, fungi disappeared from the sputum. Three patients expectorated plugs. Cessation of haemoptysis was observed in six cases. The aspergilloma regressed in five cases. In two early cases with thickening of the cavity wall due to the development of the fungi on its inner surface, the regression was remarkably prompt.
Afin d’augmenter l’effet fongicide de la nystatine et de l’amphotericine B dans le traitement de l’aspergillome pulmonaire - sujet d’actualite - on utilise une substance contenant ces drogues. Ce medicament est administre par ponction et instillation intravitaire. Cinq a 18 ponctions ont et6 faites dans chaque cas. Dix malades totalisant 13 aspergillomes ont CtCtrait& avec la nystatine et dix avec l’amphotericine B. Chez tous les malades trait& avec la nystatine, l’aspergillus ne put Ctre retrouve dans l’expectoration. Durant le traitement, cinq malades expectorerent des agrtgats contenant le champignon. Neuf malades ont eu des hemoptysies avant le traitement; chez six d’entre eux les hemoptysies ont cesst au tours du traitement, et pour trois autres, elles ont diminut d’intensite. Pour trois malades l’aspergillome fut gueri, et pour trois autres, les signes radioscopiques regresskent. Dix malades ont CtCtrait& avec le medicament contenant l’amphothicine B. Pour sept d’entre eux, l’aspergillus a disparu de l’expectoration. Trois malades ont expectore des agregats contenant le champignon. Les hemoptysies ont disparu dans six cas, l’aspergillome a regress6 dans cinq. Pour deux cas, pris tout au debut, avec Cpaississement de la paroi
185
TREATMENT OF ASPERGILLOMA cavitaire dO au developpement quablement rapide.
du champignon
a la surface interne,
la regression
fut remar-
RESUMEN Se us6 una pasta que contenia nystatina o anfotericina B para el tratamiento local de aspergilomas pulmonares. La pasta se aplico por medio de punciones intracavitarias. En cada case se efectuaron de 5 a 18 punciones. Diez pacientes con dote aspergilomas fueron tratados con nystatina y diez pacientes fueron tratados con anfotericina B. En todos 10s pacientes tratados con nystatina 10s hongos desaparecieron de1 esputo; durante el tratamiento cinco enfermos eliminaron moldes compuestos por hongos. Nueve pacientes tenian hemoptisis antes de1 tratamiento; en seis de ellos la hemoptisis desaparecio con el tratamiento, y en 10s otros tres, disminuyo. En tres pacientes desaparecio el aspergiloma y otros tres hubo una reduction radiografica. Diez pacientes fueron tratados con la pasta que contenia anfotericina B. Los hongos desaparecieron de 10s esputos en siete cases. Tres pacientes expectoraron moldes. La hemoptisis cedio en seis cases. Los aspergilomas retrocedieron en cinco cases. En dos cases recientes, con engrosamiento de la pared cavitaria debido al desarrollo de1 hongo en su interior, la regresion fuC llamativamente rapida.
ZUSAMMENFASSUNG Urn die fungicide Wirkung von Nystatin oder Amphotericin B bei der Lokalbehandlung der Lungenaspergillose zu steigern, wurde eine diese Medikamente enthaltende Paste verwendet. Die Paste wurde durch Kavernenpunktion und Installation appliziert. Im Einzelfall wurden fiinf bis 18 Punktionen vorgenommen. Zehn Patienten mit 12 Aspergillomen wurden mit Nystatin behandelt, zehn weitere mit Amphotericin B. Bei allen mit Nystatin behandelten Kranken verschwanden die Erreger aus dem Sputum. Unter der Behandlung expektorierten fiinf Patienten Klumpen von zusammengeballten Pilzen. Neun Patienten hatten vor der Behandlung Hamoptysen; bei sechs von ihnen kam die Blutung unter der Behandlung zum Stehen, bei drei wurde sie geringer. Das Aspergillom verschwand in drei Fallen und bildete sich in drei weiteren rijntgenologisch zuriick. Zehn Patienten wurden mit der Amphotericin B enthaltenden Paste behandelt. Die Erreger verschwanden bei sieben aus dem Sputum. Drei Patienten expektorierten Klumpen. Aufhijren der Blutung wurde in sechs Fallen beobachtet. Das Aspergillom bildete sich in fiinf Fallen zuriick. In zwei Friihfallen mit Verdickung der Kavernenwand infolge Ansiedlung der Pilze auf der inneren Oberflache ging die Rtickbildung bemerkenswert schnell vonstatten. Introduction Aspergilloma of the lung is a frequent cause of haemoptysis, which is sometimes so profuse that it may be fatal. An aspergilloma can reach a giant size and, occasionally, can undergo purulent infection. Therefore, whenever possible, an aspergilloma should be resected surgically. However, in the majority of cases surgical treatment is not feasible; it is precluded because of respiratory insufficiency due to chronic tuberculosis or emphysema, car pulmonale, the age of the patient, or bilateral aspergillomas. In the authors’ material including 120 cases of aspergilloma, only 32 patients were operated on and in 88 surgical treatment was contraindicated.
186
KRAK6WKA
AND
OTHERS
Non-surgical treatment has not been widely used. Intravenous administration of amphotericin B has not given satisfactory results. Numerous attempts at topical treatment have been made and occasional cases published. Nystatin in suspension (Bergmann, 1959) or amphotericin B (Brouet and others, 1964; Migubres, Paczuszynski & Esteve,) have been instilled by intracavitary needlings. Amphotericin B has also been injected into the trachea by direct puncture (Ikemoto, 1965). Ramirez, (1964) instilled amphotericin B and sodium iodide by a catheter left in place near the orifice of the bronchus of the diseased pulmonary lobe. Adelson and Malcolm (1968) applied direct intracavitary instillation of sodium iodide solution via a catheter inserted percutaneously and left in the aspergilloma cavity for 40 days. In a previous study a suspension of nystatin was injected by syringe and needle into the aspergilloma cavity. Cure was achieved in three out of 11 patients, the number of needlings ranging from 14 to 83 (Krakowka and others, 1963; 1965). To increase and prolong the effect of the drugs and thus reduce the number and frequency of intracavitary needlings, nystatin was administered in a thick suspension (paste) of sulphathiazol and Lipiodol Ultra-fluid. In some cases the suspension remained in the cavity for about two weeks, but usually it was expectorated within 24 hours (Krakowka and others, 1967). The present study deals with topical treatment with a paste containing nystatin or amphotericin B administered by intracavitary needling. The paste was prepared according to Friedel’s experience with paste containing antituberculosis drugs, isoniazid, streptomycin, or tebethion. Friedel (1963) administered it through a cardiac catheter at bronchoscopy. The advantage of the paste lies in its semi-fluid consistency. It is fluid at 45°C solidifies at body temperature and remains in the cavity for a long time (Voigt and Weiss, 1960); the effect of the incorporated drugs is thus prolonged. Methods Before treatment, routine anteroposterior and lateral radiograms and tomograms were taken in each case. At least four cultures of the sputum on Sabouraud’s agar for A.fumigutus were made and the colony count was graded (see Table I). Precipitating antibodies against A. fumigatus filtrates were determined by the use of double diffusion technique in agar gel according to Ouchterlony. In patients treated with amphotericin B, urinalysis, blood urea and creatinine were determined every two weeks. In all patients examinations of blood coagulation were done before endocavitary treatment, in order to avoid bleeding associated with a disturbance of coagulation. In the first period of this study the paste containing nystatin was used, and in the second the paste containing amphotericin B. Both pastes were prepared at the Pharmaceutical Institute, Warsaw. The drug was suspended under aseptic conditions in lipophilic gel with 24% of a liquid contrast medium (Lipiodol Ultrafluid). Lipophilic gel vehicle contains a mixture of high fatty acids with wax or paraffin; it is commonly used as a vehicle for suppositories in pharmacy. It had a melting point of 46°C and solidification point of 37°C; it is liquid at 40 to 5O”C, and solidifies at body temperature. The physicochemical properties of this paste make it suitable for intracavitary administration. The composition of the paste is as follows : amphotericin B1 500 mg. or nystatin2 45OOOOOu, vehicle 76 ml., Lipiodol Ultra-fluid3 24 ml. Lipiodol Ultra-fluid is added to visualize whether the paste is injected into the cavity and to determine the time it remains there. The paste was examined in vitro by two methods: (1) Antifungal activity: Spores of A. fumigatus were added to the paste, stored at 37°C for various periods of time, and then inoculated on Czapek’s agar. It was found that the paste with nystatin in concentration of 45,000~ per ml. completely 1 Fungizone intravenous, Squibb p Mycostatin, Squibb 8 Lipiodol Ultra-fluid,
Guerbert
TREATMENT
187
OF ASPERGILLOMA
TABLEI.-RESULTS OF INTRACAVITARYTREATMENT OF ASPERGILLOMA WITH NYSTATIN-CONTAININGPASTE
Number
case aspergillomas
Growth of A. fumigatust
Haemoptysis* before
j treatment
after treatment
+__i
I. 2. 3. 4. 5. 6. I. 8. 9.
10.
* Haemoptysis:
before
in
+
I
+
+
t
i-
+1-+ +
+
+
-+
7
+
+-
t A+
-t
+ q- + !- profuse and frequent - + profuse, infrequent scanty and frequent +’ scanty, infrequent + none
_~
!_
L
/
4 +-+ t-
1
after treatment
i treatment
T-
_
Radiographic appearance of aspergilloma after treatment
~ I Disappearance No change No change No change Regression Regression No change Regression Disappearance of aspergilloma in the left lung: new aspergilloma in the right lung. Disappearance
t Growth of A. fumigatus: + + + - i- exceedingly abundant: innumerable colonies ./. :. + f abundant: more than 20 colonies +. 1~moderate: 10 to 20 colonies .,. _I_ scarce: 4 to 10 colonies very scarce: 1 to 3 col. -1 no growth
the growth of A.,fumigatus after four days. The paste with amphotericin B, 5 mg per ml, inhibited inhibited the growth of A. fumigatus after only 30 minutes. (2) Determination of diffusion of the drug incorporated in the paste into the medium. Wells of a diameter of 9 mm. were cut in Czapek’s agar inoculated with spores of A. fumigatus, and were then filled with one of the pastes. It was found that the paste with nystatin, 45OOOu per ml., did not produce zones of inhibition; the paste with amphotericin B, 5 mg. per ml., gave zones of growth inhibition of about 20 mm. in diameter. It was also established that the amphotericin B-containing paste could be stored at 4°C for about two months without any significant loss of its activity (Halweg and others, in preparation). The paste is injected into the aspergilloma-containing cavity by puncture of the chest wall under fluoroscopic control. The patient is in the prone position on the x-ray table. The puncture is made after careful localization of the cavity, usually in the interscapular area. A needle, 10 cm. long and 1.2 mm. in diameter, with a stillette, is used. It is tightly connected to a syringe. Free aspiration of air indicates that the needle has entered the cavity. Several ml. of 2% xylocaine are instilled in the cavity to suppress the cough reflex. The paste is heated to 50°C and poured into the syringe previously stoppered with a special butt; until injection, the syringe is kept in a water bath of 50°C. After the initial resistance is overcome the paste passes freely through the needle. At body temperature the paste solidifies. Usually 5 ml. of the paste are injected every seven to ten days; sometimes the intervals between punctures are longer, up to three weeks. These longer intervals are made necessary because of either haemoptysis or stagnation of the paste in the cavity.
188
KRAK6WKA
AND
OTHERS
Results of treatment with nystatin-containing
paste
Ten patients with 12 aspergillomas were treated with nystatin-containing paste. Two of them had bilateral aspergillomas. The size of the cavities ranged from three to 10 cm. in diameter. The number of needlings varied from five to 18. The number of ineffective needlings was small, not exceeding 5 per cent; they were due to technical difficulties in entering small cavities, or aspiration of blood instead of air, or haemoptysis following the needling. The observation period after the intracavitary treatment had been completed varied from 2 to 18 months. Five patients started to expectorate plugs during intracavitary treatment. Before treatment nine patients had recurrent haemoptysis, in two of them it was life-threatening. In six patients, the treatment resulted in cessasion of haemoptysis, and in three, only blood-streaked sputum occasionally appeared (Table I). In three patients fungus balls disappeared 2, 11, and 14 months respectively after the completion of treatment. In three patients, fungus balls diminished considerably. In the remaining four patients no change was apparent on radiographs (Table I). In one case, a new aspergilloma in the contralateral lung developed. In all treated patients cultures of the sputum became negative after treatment (Table I). In two cases, cultures of surgical specimens were negative, although direct microscopic examination revealed fragments of mycelium. Precipitin tests with filtrates of cultures of A. fumigatus were positive initially in all cases. In two cases, they became less intensive after the completion of treatment.
TABLEII.-RESULTS OFINTRACAVITARYTREATMENTOFASPERGILLOMA WITH AMPHOTERICIN B-CONTAININGPASTE
Case
Number of aspergillomas
Growth of A. fumigatust
HaemoptysiP before treatment
after treatment
11. 12.
1 1
++++
+
13. 14. 15.
1 1 1
+++ ++ +
+
16. 17. 18. 19. 20.
1 1 1 1 1
++++ ++++ + + -t
* Haemoptysis:
before treatment
+
after treatment
+++
+ ++++ -
+ -t + + profuse and frequent profuse, infrequent +++ scanty and frequent i+ scanty, infrequent + none
+ + + + +
(
+ + t + +
+-I-
-
t +++++
-
+++++ ++ + +++
I +
Radiographic appearance of aspergilloma after treatment
L
-
+
-
Disintegration of aspergilloma New aspergilloma in the contralateral lung No change Regression Almost complete evacuation of aspergilloma-containing cavity No change Regression Regression No change Regression
t Growth of A. fumigatus: + -k + + + exceedingly abundant: innumerable colonies abundant: more than 20 + -k -t + colonies moderate : 10 to 20 colonies +++ scarce : 4 to 10 colonies +i very scarce : 1 to 3 colonies + no growth
TREATMENT
OF
ASPERGILLOMA
189
Results of treatment with amphotericin B-containing paste
Ten patients were treated with amphotericin B-containing paste. In eight cases the aspergilloma had the typical radiographic appearance of a round or oval shadow with air crescent, and in the other two cases the cavity wall was thickened as a result of the development of fungi. The number of needlings in each case varied from four to nine. The follow-up after the completion of treatment was from one to six months. The needlings, as in the previous group, were repeated every one to two weeks, sometimes every three weeks. Three patients started to expectorate plugs of mycelium under local treatment. Ten patients had haemoptysis before treatment; in six of them it disappeared after treatment (Table II). Aspergilloma regressed in five cases. In two of them there was thickening of the cavity wall owing to development of the fungi; the fungal masses separated from the wall and fell into the cavity lumen and, finally, disappeared almost completely within three to four months. One of these patients died: at necropsy remnants of the fungi were found in the cavity, but cultures were negative, although before treatment on numerous occasions abundant growth of A. fumigutus had been obtained from the sputum (Figs. 1,2,3,4). Before treatment cultures of the sputum were positive for A. fumigatus in all patients. In three patients cultures were still positive after treatment, but in one of them this could be explained by the development of a new aspergilloma in the contralateral lung (Table II). In all patients precipitin tests with filtrates of A. fumigatus cultures prior to the treatment were positive and remained so during the observation period. Neither abnormalities in the urine nor increase of blood urea and of serum creatinine were observed. Discussion
The above study shows that the paste containing either nystatin or amphotericin B has fungicidal effects. The therapeutic results of both pastes were satisfactory. In two early cases in which fungi grew on the inner wall of the cavity before the development of a typical fungus ball, the therapeutic results were prompt. This shows the necessity of early diagnosis of fungus invasion of a cavity, as well as of early treatment. It is probable that the therapeutic effect depends first of all on the antifungal action of the drugs incorporated in the paste, as shown by the in vitro experiments. However, the effect of the paste itself cannot be excluded: it covers the surface of the fungus ball and thus impairs air supply. But the prompt disappearance of the fungi from the sputum of the patients would suggest an effect of the drugs rather than that of the paste itself. The effect of intracavitary treatment with a paste containing either nystatin or amphotericin B was assessed on the basis of the following: expectoration of plugs composed of fungi; cessation of haemoptysis; disappearance or regression of the aspergilloma on radiographs; negative cultures of sputum for A. jiimigatus; decrease of precipitin reactions. The full assessment of the majority of the above criteria, except cultures of sputum, requires a long time. The value of sputum culture, however, is limited. Aspergillomas too small to be seen on radiographs can co-exist with those easily visualized; and tiny aspergillomas can be the cause of persistently positive cultures. On the other hand, cultures of the sputum gives a relatively rapid answer. It was, therefore used for determining the frequency of intracavitary needlings in order to obtain the best fungicidal effect. It was done in eight patients with abundant growth on numerous occasions before treatment. Of the six treated with nystatin, in four the cultures became negative after one, one, two and three intracavitary needlings, and in two after five and seven needhngs. Two patients were treated with amphoteritin B; in both the cultures became negative after two and four needlings respectively. In one further case in which a new aspergilloma appeared in the contralateral lung, the abundance of growth was unchanged.
190
KRAK6WKA
AND
OTHERS
FIG. 1
FIG. l-Case 15. ‘Destroyed’ lung with a cavity. Bacteriological quiescence FIG. 2-Case 15. Decrease of the cavity resulting from the development
FIG. 3 FIG. 3-Case
15. Separation
topical treatment.
was obtained byl:chemotherapy. of fungi on its inner wall.
FIG. 4.
of the fungal masses with the paste from the cavity wall into the lumen during FIG. 4-Case 15. Evacuation of the cavity: remnants of aspergilloma at the bottom of the cavity. Four months after the start of topicai treatment.
TREATMENT
OF ASPERGILLOMA
191
The present study suggests that four to seven needlings can be sufficient to obtain fungicidal effect; but the number given should depend on the results of culture of the sputum in each case. Prompt disappearance of fungi from the sputum indicates a fungicidal effect of the paste. This was confirmed by the examination of pulmonary resection and necropsy specimens from patients previously given topical treatment. The present clinical study does not indicate which of the two drugs used is of greater benefit. In half the cases haemoptysis, sometimes profuse but never life-threatening, occurred immediately after the intracavitary needling and instillation of the paste. It usually stopped within one to three hours and only occasionally lasted for two to three days. In a few cases slight fever occurred after needling and lasted for one to three days. If too large an amount of the paste was injected it was expectorated, but the remnants of the paste were sometimes seen even a few weeks after injection. In none of the patients included in the present study did a pneumothorax occur. In two patients in our previous series a small pneumothorax had occurred without, however, clinical signs and the lung promptly re-expanded Blood urea and creatinine did not show any abnormalities during amphotericin B administration. It may be concluded that this method of intracavitary treatment of pulmonary aspergilloma is safe and the results are encouraging. REFERENCES ADELSON, H. T. & MALCOLM, J. A. (1968). Endocavitary treatment of pulmonary mycetomas. American Review of Respiratory Diseases, 98,U. BERGMANN, L. (1959). Aspergillom und Lungentuberkulose. Tuberkulosearzt, 13,763. BROUET, G., LION, F., DEMANGE, J. & NEVO~, P. (1964). Traitement local de l’aspergillome pulmonaire par injections transpariktales d’amphottricine B. Journal Francais de Medecine et Chirurgie Thoraciques. 18,789. FRIEDEL, H. (1963). Die endobronchiale Plombierung der Kaverne. Beitriige zur Klinik der Tuberkulose, 127,251. HALWEG, H., ELSNER, Z., MICHALSKA-TRENKNER, E. & KRAK~WKA, P. Antifungic properties of the paste containing nystatin or amphotericin B. In preparation. TKEMOTO,H. (1965). Treatment of pulmonary aspergilloma with amphotericin B. Archives of Internal Medicine, 115, 598. KRAK~WKA, P., CHODKOWSKA, S., HALWEG, H. & PAWLICKA, L. (1963). Own experience in the treatment and proGruzlica, 31, 1113. gnosis of pulmonary aspergilloma. KRAK~WKA, P., CHODKOWSKA, S., HALWEG, H., & PAWLICKA, L. (1965). Treatment of pulmonary aspergilloma. Proceedings of the International Symposium on Medical Mycology, Warszawa, 1963, PZWL, 249. KRAK~WKA, P., SZYMCZYK, E., CISZEK, J. & HALWEG, H. (1967). Topical treatment of aspergillomas with prolonged action nystatin: preliminary communication. Polish Medical Journal, 6, 1217. KRAK~WKA, P., SZYMCZYK, E., CISZEK, J. & HALWEG, H. (1967). Topical treatment of pulmonary aspergillomas with nystatin prolongatum (preliminary report). Gruzlica, 3547. MIGU~RES, J., PACZUSZYNSKI, H. & ESTBVE, R. (1965). Aspergillome pulmonaire en apparence primitif, trait6 avec succts par injections trans-thoraciques d’amphotkricine B. Journal Frangais de MPdecine et Chirurgie Thoraciques, 19,59. RAMIREZ, R. J. (1964). Pulmonary aspergilloma: endobronchial treatment. New England Journal of Medicine, 271, 1281. VOIGT, R. & WEISS, F. (1960). Entwicklung von Fiillmassen zur endocavitgren Behandlung der Lungentuberkulose. Arzneimittel Forschung, 10,650.