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Role of itraconazole in the management of aspergillosis in treated patients of pulmonary tuberculosis Gupta P R, Vyas A, Meena R C, Khangarot S, Kanoongo D, Jain S - Lung India
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ORIGINAL ARTICLE
Year : 2005  |  Volume : 22  |  Issue : 3  |  Page : 81-85 Table of Contents   

Role of itraconazole in the management of aspergillosis in treated patients of pulmonary tuberculosis


Department of Chest & TB & Deptt. of Microbiology, SMS Medical College, Jaipur., India

Correspondence Address:
P R Gupta
A-66, Subhash Nagar Shopping Centre, Jaipur-302 016.
India
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   Abstract  

Sputum/ bronchial washings of 445 patients with residual tubercular cavitation were subjected to smear and culture examination to isolate fungi. Patients suffering from aspergillosis were put on oral itraconazole daily for 6 months and monitored clinicoradiologically during and after therapy.
About half of the patients of aspergilloma and 85% of the patients of chronic necrotizing pulmonary aspergillosis improved by 3 months of therapy. Nausea and headache observed during therapy in 8 and 4 patients respectively were mild and self limiting. Relapses were seen in 8 out of the 37 patients who had completed 6 months therapy and available for follow-up.

Keywords: Aspergillosis, Aspergilloma, Chronic necrotizing pulmonary aspergillosis.


How to cite this article:
Gupta P R, Vyas A, Meena R C, Khangarot S, Kanoongo D, Jain S. Role of itraconazole in the management of aspergillosis in treated patients of pulmonary tuberculosis. Lung India 2005;22:81-5

How to cite this URL:
Gupta P R, Vyas A, Meena R C, Khangarot S, Kanoongo D, Jain S. Role of itraconazole in the management of aspergillosis in treated patients of pulmonary tuberculosis. Lung India [serial online] 2005 [cited 2014 Mar 7];22:81-5. Available from: http://www.lungindia.com/text.asp?2005/22/3/81/44449


   Introduction   Top


Successful chemotherapy of tuberculosis has led to survival of many patients with persistent residual lesions in the lung. These residual lesions, more particularly the cavitary lesions, are prone to fungal super-infections. These fungi, especially Aspergilli may germinate in situ, causing noninvasive ball like lesions (Aspergilloma) [1],[2] or become locally invasive causing persistent symptoms in patients with little or no immuno-suppression. The latter has been described and named as a separate entity i.e. chronic necrotizing pulmonary aspergillosis. [3] The treatment and clinical outcome of these ailments are not well defined. Itraconeazole is a relatively new triazole antifungal agent with low toxicity and good tissue penetration. It has been shown to be effective in patients with aspergillus infection [4],[6] and when used for prolonged periods, was found to eradicate the organisms. [7] Experience with the drug, however, is very limited.

The present study was undertaken to further define these issues.


   Material & Methods   Top


Treated patients of pulmonary tuberculosis presenting with persistent cough, haemoptysis and/ or well defined ball like lesions in their chest skiagrams were further evaluated at the Hospital for Chest Diseases & TB, Jaipur.

Inclusion criteria for the purpose of the study were as under:

  1. Residual cavitary disease of > 2.5 mm diameter.
  2. Sputum smear negative for AFB on three consecutive days.
  3. Poor clinico-radiological response to appropriate antibiotic therapy for at least 7 days (as based on clinical and microbiological investigations).


Exclusion criteria were as under :

  1. Alcoholics and HIV positive patients.
  2. Presence of coexisting diseases like diabetes mellitus, chronic renal failure and chronic liver failure.
  3. Patients on immunosuppressive drugs and/or steroids.


Sputa of the study patients were examined on KOH's mount for two consecutive days for the presence of fungi. It was also sent for culture to isolate fungi, if any. Where the patient did not expectorate, the smear and culture examinations were done on bronchial washings obtained through fiberoptic bronchoscopy.

Aspergillosis was diagnosed as under:

Aspergilloma : Presence of one or more round opacity/opacities inside a preexisting cavity/cavities in the lung and isolation of aspergilli in the sputum/ bronchial wash specimen in the absence of any other fungus, mycobacteria and/or other bacteria.

Chronic necrotizing pulmonary aspergillosis: Persistent presence of respiratory and constitutional symptoms, thickening of wall of a preexisting cavity/ cavities in the lung and isolation of aspergilli in the sputum/bronchial wash specimen in the absence of any other fungus, mycobacteria and/or other bacteria.

All the patients suffering from aspergilloma and chronic necrotizing pulmonary aspergillosis were treated with a single dose oral itraconazole 200 mg daily along with symptomatic treatment as and when required. The course of the therapy was monitored clinically and radiologically every month for three consecutive months and at the end of 6 months. Patients not responding by 3 months were subjected to bronchoscopy to rule out any other complicating pathology.


   Observations   Top


A total of 520 patients were evaluated between January, 2000 to October, 2003. Of them, 61 patients left and 14 died during the period of intake. This left 445 patients for inclusion in the study. Sputa could be obtained in 426 patients. In the remaining 19 patients, the mycological examinations were done on bronchial washings obtained through fiberoptic bronchoscopy.

The results of smear examination (KOH's mount) are shown in [Table 1]. Sixty patients showed septate hyphae. Another 12 patients showed septate hyphae along with pseudohyphae and budding yeasts. Only pseudohyphae and budding yeasts were seen in 55 patients.

On fungal culture, more than one fungus was isolated in 28 of the samples. These included aspergilli and candida in 15, aspergilli and other fungi in 5 and other fungi along with candida in 9 patients [Table 2].

Clinico-radiological features of the patients isolating fungi are shown in [Table 3]. Majority of the patients had more than one symptom. Clinicoradiological manifestations in patients showing presence of aspergilli alone were similar to those demonstrating aspergilli along with other fungi. Mean age of the patients and duration of disease were higher in patients exhibiting aspergilli as compared to candida (p<0.001) and other fungi (p<0.05). Mycetomas were seen more frequently in patients exhibiting aspergilli as compared to other fungi (p<0.05).

The co-relation of symptoms with the type of disease is shown in [Table 4]. Majority of patients suffering from aspergilloma presented with haemoptysis and/or cough. Eight patients were asymptomatic. Most patients suffering from chronic necrotizing pulmonary aspergillosis had multiple symptoms but haemoptysis was less common in them.

[Table 5] shows the results of chemotherapy in patients suffering from aspergillosis at the end of 3 months of itraconazole therapy. Bronchoscopy in non responders was essentially within normal limits.

Nausea and headache were the only adverse reactions and were reported by 8 and 4 out of 88 patients receiving itraconazole therapy respectively. All these symptoms were mild and self limiting.

Only 55 out of the 61 responders were available for analysis at the end of 6 months. The remaining 6 patients were lost to follow up. All the responders continued to do well at the end of 6 months also.

Of the 55 responders, 37 patients are available for follow up after 3 to 23 months of stopping chemotherapy. Eight had relapsed by then.


   Discussion   Top


Fungi were isolated in a total of 189 out of the 445 treated patients of pulmonary tuberculosis (42.5%) in this study. This is no more than that found in a study on patients of chronic non tubercular respiratory disorders where fungi could be isolated in 67 out of the 106 patients. [8]

Aspergilli were isolated in 113 patients out of the 445 patients studied (28%). Aspergilli were the only fungi in 94 of the patients but in the remaining 19 patients aspergilli were isolated along with Candida and/or other fungi. A research committee of British Tuberculosis Association found aspergillus precipitins in 134 out of 544 patients with tuberculosis (25%). [9]

Although, the age, sex, duration of illness and clinico radiological features of the 19 patients showing aspergilli along with other fungi were similar to the 94 patients showing aspergilli only, they were not considered fit for further study since the role of other fungi i.e. Penicillum, Curvilleria and Alterneria in causation of disease, if any, could not be ruled out in contrast to candida. The contribution of the latter in causation of respiratory pathology is considered equivocal. Indeed, 3 and 10 patients not isolating any of the aspergilli but isolating other fungi presented with aspergilloma and chronic necrotizing pulmonary aspergillosis-like picture respectively.

In other 8 and 2 patients presenting with aspergilloma and chronic necrotizing pulmonary aspergillosis-like picture respectively, none of the fungi could be isolated. These patients were also not considered fit for further study as serology could not be done in them to prove aspergillosis for want of facilities. It is well known that aspergilli may not be isolated in proven cases of aspergillomas. Thus, in a review of 9 separate studies on aspergilloma, positive sputum cultures were seen in 58% of the patients. [10] A research committee of British Thoracic Association [9] reported 5 patients with mycetomas without precipitins.

After these exclusions, we could diagnose aspergilloma in 43 and chronic necrotizing pulmonary aspergillosis in 45 patients, out of the total 445 patients studied. Research committee of British Thoracic Association [9] detected aspergillomas in 64 (5 with negative serology) out of the 544 patients studied. It could detect 19 other patients where the precipitin test was highly positive but the radiological picture was less typical. These patients showed recent radiographic fluctuations, thickening of the cavity wall and pleural thickening. In all probabilities, these were the cases of chronic necrotizing pulmonary aspergillosis. This assessment of aspergillosis in these prospective studies may be an underestimation of the problem as the frequency of aspergillosis was much higher in an autopsy study where aspergilli were isolated from tissues in 11 out of the 15 patients having residual tubercular cavitary lesion. [11]

Most patients of aspergilloma presented with haemoptysis with or without cough. However, 8 patients were asymptomatic. Sputum, fever and anorexia were uncommon in these patients. Aspergillomas are known to have a highly varied presentation ranging from asymptomatic stable to progressive radiological opacity/opacities, from mild to intractable haemoptysis and/or from gradual regression to spontaneous lysis. [12],[13] Review of 9 separate studies on aspergilloma revealed that haemoptysis was the predominant symptom in 74% of the patients. Haemoptysis was seen in 70% of patients with aspergilloma in the present study.

At the end of 3 months of therapy, 20 out of the 43 patients (49%) with aspergilloma had clinical as well as radiological response to itraconazole, 2 other patients showed clinical response with stable radiological lesions. Major part of this response should be attributed to the drug as spontaneous lysis is seen in only about 10% of the patients. [12],[13] Further, none of the patients showed progression. This modest response was achieved without causing any major adverse effect. Compared to this, surgical treatment of aspergilloma is reportedly associated with high morbidity and mortality. [14]

As many as 38 out of the 45 patients (85%) with chronic necrotizing pulmonary aspergillosis had a favourable clinico-radiological response in the present study. Several workers have also reported good response with itraconazole therapy in patients with chronic necrotizing pulmonary aspergillosis. [15],[16]

Besides the better clinico-radiological response, defaults were also less common in patients with chronic necrotizing pulmonary aspergillosis as compared to aspergilloma. This favourable response rate with itraconazole therapy in patients with chronic necrotizing pulmonary aspergillosis as compared to aspergilloma was also noted by Dupont. [17] The poor response in patients with aspergilloma is possibly due to poor penetration of the drug. Further, 3 months of therapy may not be adequate to assess the response of therapy in patients with aspergilloma. In one study on 9 patients, 2 patients showed a late response (after 1 year) to itraconazole. [1]

The overall response was better in our study as compared to that in the study by Dupont. [17] This difference was possibly due to the fact that the duration of therapy in our study was at least 3 months as compared to as short as 1 week in some of his patients. [17]

Relapse rates after stopping therapy in the responders was high in the present study i.e. 8 out of the 37 responders available for analysis after 3 to 23 months of follow up had relapsed. Thus even 6 months of itraconazole therapy was possibly not adequate. A British Thoracic and Tuberculosis Association report also suggested that prolonged therapy was needed to prevent relapses in these patients. [1]

 
   References   Top

1. British Thoracic and Tuberculosis Association Report: Aspergilloma and residual tuberculosis cavities: The result of a resurvey. Tubercle 1970; 51:227-245.  Back to cited text no. 1    
2. Kawamura S, Maesaki S, Tomono K et al. Clinical evaluation of 61 patients with pulmonary aspergilloma. Intern Med 2000; 39: 209-212.  Back to cited text no. 2    
3. Binder RE, Faling LJ, Pugatch RD, Mahasean C, Snider GL. Chronic Necrotizing Pulmonary Aspergillosis: A Discrete Clinical Entity. Medicine 1982; 61: 109-124.  Back to cited text no. 3    
4. De Beule K, De Doncker P, Cauwenbergh G et al. The treatment of aspergillosis and aspergilloma with itraconazole, clinical results of an open international study (1982-87) Mycoses 1988; 31: 476-485.  Back to cited text no. 4    
5. Elliott JA, Milne LJR, Cumming D. Chronic necrotizing aspergillosis treated with itraconazole. Thorax 1989; 44: 820-821.  Back to cited text no. 5    
6. Armstrong RH. Chronic necrotising aspergillosis and its treatment with itraconazole-a case report. Aust NZ J Med 1990; 19:670.  Back to cited text no. 6    
7. Barnes M, Burdon J, Harris Alan. Itraconazole for pulmonary mycetoma. Med J Aust 1991; 154:150.  Back to cited text no. 7    
8. Afzal M. Occurrence of fungi in sputum of patients with chronic respiratory disorders. Ind. J. Chest Dis. & All. Sci. 1980; 22: 188-189.  Back to cited text no. 8    
9. Research Committee of the British Tuberculosis Association. Aspergillus in persistent lung cavities after tuberculosis. Tubercle. Lond. 1968; 49:1.  Back to cited text no. 9    
10. Glimp RA, Bayer AS. Pulmonary aspergilloma. Diagnostic and therapeutic considerations. Arch Intern Med 1983; 143: 303-308.  Back to cited text no. 10    
11. Kawabata Y, Iwai K. Tuberculosis sequelae: pathological findings. Kekkaku. 1990 ; 65:839-45.  Back to cited text no. 11    
12. Hammerman KJ, Christianson CS, Huntington Ione, Hurst GA, Zelman M, Tosh FE. Spontaneous lysis of aspergillomata. Chest 1973; 64: 697-699.  Back to cited text no. 12    
13. Gefter WB. The spectrum of pulmonary aspergillosis. J Thorac Imaging 1992; 7: 56-74.  Back to cited text no. 13  [PUBMED]  
14. Regnard JF, Icard P, Nicolosi M et al. Aspergilloma: a series of 89 surgical cases. Ann Thorac Surg 2000; 69: 898-903.  Back to cited text no. 14    
15. Caras WE, Pluss JL. Chronic necrotizing pulmonary aspergillosis: pathologic outcome after itraconazole therapy. Mayo Clin Proc 1996; 71 : 25-30.  Back to cited text no. 15  [PUBMED]  
16. Saraceno JL, Phelps DT, Ferro TJ et al. Chronic necrotizing aspergillosis: approach to management. Chest 1997; 112: 541-548.  Back to cited text no. 16    
17. Dupont B. Itraconazole therapy in aspergillosis : Study in 49 patients. Journal of the American Academy of Dermatology 1990; 23: 607-614.  Back to cited text no. 17  [PUBMED]  



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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