Candidal CEsophagitis

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47

Miconazole Treatment in Candidal CEsophagitis by Dr H Verhaegen (Department of Internal Medicine, St Bartholomeus Hospital, Merksem, Belgium)

CEsophageal candidiasis develops in about one per cent of patients undergoing cancer chemotherapy, and also is most prevalent in patients with hmmatologic malignant conditions. It is defined as an infection of the cesophagus in which the organism in a mycelial phase has invaded the mucosa with resulting destructive changes. Pathologic changes secondary to candidal infection of the cesophagus include marked mucosal inflammation, erosion, ulcerations, whitish plaque-like material and pseudomembranes and pseudotumour formations. Invasion of the aesophagus by candida has been described in association with several diseases: diabetes mellitus, carcinoma (especially in patients treated with cytostatics) and malnutrition. It is also found in patients treated with antibiotics or corticosteroids. In these diseases the underlying immunological abnormalities are responsible for the higher susceptibility to infection with candida. For this reason, the response to therapy will depend on the degree and kind of immunological disturbances which are present. The two drugs most commonly used in treating oesophageal candidosis are oral nystatin and intravenous amphotericin B. There are no adequate control studies comparing the two drugs and in most studies no immunological investigation has been done in order to elucidate their underlying defects. In a series of 13 patients described by Holt (1968), nystatin was effective only in those patients who did not have underlying hmematological abnormalities. Jensen et al. (1964), treating cancer patients, found nystatin ineffective, while a satisfactory improvement was found in 19 out of 23 patients treated with amphotericin B. Table I Patient details Age Patient I 2 3 4 5 6 7

Sex M F M M F F F

(years) Associated disease 67 Polyarthrosis - coxarthrosis 79 Diabetes mellitus - hiatus hernia 52 Achalasia esphagi 77 Pneumonia (antibiotics) atherosclerosis 70 Gastric cancer 68 57

Ur2mia-anwmia Gastric cancer

Dr H Verhaegen

Summarizing the results of different studies it appears that oral nystatin is ineffective in certain patients, whereas the more effective amphotericin B has many toxic side-effects. These considerations led us to investigate the immunological status of patients with candidal cesophagitis and to treat them with a new drug, miconazole, which seems to be effective against candida, and which is devoid of serious sideeffects. Materials and Methods The diagnosis of cesophageal candidosis was made by means of cesophagoscopy, biopsy and cultures of the cesophagus in 7 patients. In all patients, cesophagoscopy was repeated one to four times for evaluation of therapeutic efficacy. The ages and associated diseases of the patients are given in Table 1. An immunologic evaluation was performed (Table 2) and included: immunoglobulins IgA, IgG, IgM; total heemolytic complement C3, C4; granulocyte chemotaxis in vitro; phagocytosis of candida by polymorphonuclear leukocytes (PMN); myeloperoxidase staining; spontaneous and stimulated NBT tests and delayed skin tests to candida, PPD and mumps. The treatment schedule with miconazole is given in Table 3. Miconazole was given in intravenous infusion in glucose over a period of 30-60 minutes. Routine laboratory tests were performed before treatment and at regular intervals in all the patients treated. The following tests were performed: himoglobin, hiematocrit, red blood cell, white blood cell and differential count; BUN, FBS, creatinine; serum electrolytes, SGOT and SGPT; uric acid, serum proteins and electrophoresis; LDH and yGT, and urine analysis.

48 Proc. roy. Soc. Med. Volume 70 1977 Supplement I

Table 2 Immunological evaluation Granulocyte Patient I 2 3 4 5 6 7

IgA t t N N N N N N

IgG t N N N N N N

IgM Complement N t t N N X N t t N 1 N N t

Chemotaxis Phagocytosis Killing N N N N N N N N N N N 4 N N N N N

-

Cell-mediated reaction to Candida N ;

; ; N 4

Table 3 Treatment schedule of miconazole Improvement (days after treatment) Patient 1 2 3

Daily dose (mg) 600 2 x 400 600 600 600 600

600 4

600 600 600

5 6 7

600 600 600

Complete normalization at

.esophagoscopy Duration 7 days 6 days 7 days 7 days 5 days/week for 4 weeks 3 days/week for I week 1 day/week 2 days/week for 4 weeks 1 day/week for 8 weeks

Subjective 3

Oesophagoscopy (time after treatment) 1 month

10

28 2 months

7

8

28

3 3 3

7 14 14

3 months

Results of Immunologic Evaluation The results of the immunological evaluations are summarized in Table 2. In the first patient a very high level of IgA was found with a moderate elevation of IgG. On immunoelectrophoresis these elevations were not monoclonal. The total z hwmolytic complement was elevated in 6 patients and abnormally low in one patient. This suggests complement activation and/or consumption. With the in vitro chemotaxis it was found that the cells of one patient had an abnormally low C.; response to a chemotactic stimulus, while the E serum of this patient generated a normal chemo- z tactic stimulus. A pathological response was found in one patient in the in vitro phagocytosis of Candida albicans by his PMNs which was impaired in autologous serum (mean number of candida/PMN: 1/90) as compared with the ofCandida albicans by phagocytosis in normal AB serum (mean number Fig 1 In vitro phagocytosis leukocytes of a patient with oral of candida/PMN: 4/28).,As shown in Fig 1, the polymorphonuclear and cesophageal candidiasis in autologous serum (A) in vitro phagocytosis of Candida albicans by and AB serum (B) and by polymorphonuclear normal PMNs was impaired in the patient's leukocytes ofa healthy subject incubated in autologous serum and could not be restored by addition of serum (C); AB serum (D); autologous serum HBSS V 1/1, E), patient's serum (F); patient's seruml autologous serum. After inactivation of the (VI autologous serum (VI V, 1/1, G) andpatient's serum patient's serum for 30 minutes at 56°C, the inactivatedfor 30 minutes at 56'C/autologous serum phagocytosis inhibiting activity disappeared. In (V/V, 1/1, H)

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The evaluation of therapy in the other 3 patients was more difficult. The symptoms of dysphagia were not so pronounced, but the underlying pathology was very severe (2 cases of gastric cancer and one case of urnmia). Nevertheless a subjective improvement was obtained after 3 days and control cesophagoscopy after 7-14 days showed a major improvement.

Fig 2 Patient 4. X-ray appearance before treatment shows narrowing of the ersophagus

Side-effects ofTherapy During miconazole infusion one patient experienced nausea; no other side-effects were seen. Routine laboratory examinations were performed in each patient before treatment, after one week of therapy and at monthly intervals during and at the end of therapy. The total doses administered to each patient are given in Table 4. No change was seen in the various laboratory tests.

the indirect tests for evaluation of destruction of Discussion Candida albicans, no disturbances were found in A good clinical response was obtained in all our patients treated with miconazole. In most studies our group of patients. To evaluate cell-mediated immunity, skin tests the evaluation of therapy has been based on were performed. A negative delayed hyper- clinical grounds. In our experience the patients' subjective sensitivity reaction to candida was found in 5 complaints disappear soon after treatment, but patients. control cesophagoscopy still shows residual cesophagitis. An effective control of the theraEvaluation of Therapy Dysphagia with regurgitation of food was very peutic efficacy of a drug can therefore be based pronounced in the first 4 patients (Table 3). In only on repeated cesophagoscopy. In our study these cases, the cesophagoscope could not pass complete normalization of the oesophagus could be observed in 3 patients. the lower part of the cesophagus (Fig 2). The results of treatment also depend on the A clear clinical improvement was seen after 3-10 days of therapy with miconazole. In these clinical status of the patient, the associated cases, the relief of symptoms was easily detect- pathology and the underlying immunologic able, since before therapy they were unable to disturbances. These factors must be considered take solid foods. In 3 of them cesophagoscopy was in evaluating the response to therapy. The imrepeated after one month; a major improvement provement after miconazole therapy was spectacuof the lesions was seen in 2 and complete normali- lar in the patient who had only a phagocytosis zation could be observed by cesophagoscopy in 3 disturbance, despite the fact that his dysphagia of them after respectively one, two and three was of 3 years' duration and the cesophageal months (Figs 3-8 on colour plate II, facing p 40). involvement very pronounced at cesophagoscopy. The other patient refused control cesophagoscopy The improvement after therapy was less marked in an elderly woman with long standing diabetes but was clinically free of symptoms. mellitus, paracesophageal hernia, extreme atherosclerosis and disturbed cell-mediated immunity. Table 4 In short, we can conclude from the data on this Side-effects small number of patients that miconazole seems to be a safe and effective drug in the treatment of Tota intra- Side-effects of treatment venous dose candidal cesophagitis. Patient 1 2 3 4 5

6 7

(mg) 13200 18000 16800 9600 3600 9000 9000

Subjective

Objective'

0 0 0 nausea 0 0 0

no change no change no change no change no change no change no change

'Routine hematology, liver function tests, BUN, creatinine, uric acid, blood sugar and electrolytes, urine analysis

Summary Seven patients with candidal cesophagitis were treated for up to 8 weeks with an intravenous infusion of miconazole, usually 600 mg given over a period of 30-60 minutes with a frequency depending upon the individual patient. As well as oesophagoscopy, biopsy and culture to estab-

50 Proc. roy. Soc. Med. Volume 70 1977 Supplement I lish the clinical course of the disease, a series of immunological investigations were performed, to assess the involvement of the patients' immune mechanisms, together with a whole battery of laboratory investigations to assess their response to the drug. A subjective improvement was observed in all patients after periods varying from 3 to 10 days and objective improvements were observed by cesophagoscopy by 5 of the patients in periods of one to four weeks. The same procedure showed 3 patients to have become completely normal after periods of one to three months. Apart from one instance of nausea, no other side-effects and no abnormal laboratory results were seen. It is suggested that the results of treatment depend on the clinical status of the patient, the associated pathology and the underlying immunological disturbance. REFERENCES Holt J M (1968) Gut 9, 227 Jensen C R, Senderup A, Thompson J B & Bickel J (1964) Acta medica Scandinavica 175,455

Dr Verhaegen said that in all patients they had done skin tests with PPD, with candida at different dosages, and mumps streptokinase and streptodornase. In some patients they had done blast transformation tests and in others only controlled skin tests. The patient with achalasia of the cesophagus, for example, after treatment and after complete normalization, still had negative skin tests for candida. Dr R Negroni (Buenos Aires) wished to know the reason for the increase of the complement level. Dr Verhaegen thought there was an activation of complement. He had seen normalization of the total hemolytic complement in all the patients except in one who had a very low level and who was still at a low level after treatment. He thought it was a result, not a cause. Activation of complement was seen in other infectious diseases although he did not know the full reason. Dr R Negroni (Buenos Aires) said he had found this activation of the complement in aspergillosis of the lung, but did not know the reason either. Dr Verhaegen suggested that the complement factors are produced by macrophages, so that if the macrophages were activated, there was an activation of such factors. Dr R Negroni (Buenos Aires) said he would like to ask the opinion of the mycologists on the use of serology as an aid to the diagnosis of deep-

DISCUSSION

seated candidal infections.

Dr H Thulin (Aarhus) asked Dr Verhaegen to enlarge on his investigations into cellular immunity. Had Dr Verhaegen followed the phases before and after the treatment.

Professor Vanbreuseghem (Chairman) said that they might come back to this problem during the Round Table Discussion.