Original Article PYRAZINAMIDE THERAPY AND SEVERITY OF HAEMOPTYSIS. 2 Clotting Time 4.87 ± 1.46 Min. 3 Prothrombin Time ± Sec.

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1 Original Article 79 PYRAZINAMIDE THERAPY AND SEVERITY OF HAEMOPTYSIS N.K. Jain 1, Sudip Banerjee 2, S.P. Agnihotri 3, S. Koolwaal 4, N. Joshi 4 and Shubhranshu 2 (Original receied on ; Reised ersion receied on ; Accepted on ) Summary: Background: Pyrazinamide (PZA) has been known to adersely affect the haemostatic mechanisms in our body. Aim: This study aims to find out whether PZA has any influence on the course of haemoptysis. Methods: One hundred and six patients of actie pulmonary tuberculosis and haemoptysis, haing normal baseline coagulators profile, were included in this prospectie study. One half of them were gien PZA containing anti-tuberculosis regimens (PZA group) and the other half were prescribed non-pza containing regimens (non-pza group). They were managed conseratiely and followed up for a period of 7 days. Results: Blood loss during therapy was moderate to massie in amount in majority (56.61%) of patients in the PZA group as compared to non-pza group (35.84 %). Though the mean duration of haemoptysis was almost similar in both the groups (3.98 days in the PZA group ersus 4.12 days in the non-pza group), but in patients in whom haemoptysis lasted for more than 3 days, in the non-pza group, majority (62.50 %) had minimal blood loss as compared to the PZA group (48.27 %). Concusion: Although PZA does not alter the mean duration of haemoptysis but omission of PZA can significantly reduce blood loss during therapy. [Indian J Tuberc 2005; 52:79-83] Key words: Haemoptysis, Haemostatic mechanisms INTRODUCTION It has been mentioned in a few reports in literature that pyrazinamide therapy upsets the haemostatic balance in the body. The mechanisms cited for the aboe phenomenon are increased prothrombin time, decreased platelet count and decreased platelet aggregation and adhesieness 1-4. Fatal cases of haemoptysis during PZA therapy hae been reported, but the aboe findings were incidental 3. The present study was conducted with the aim to find out whether PZA has any influence on the course of haemoptysis in patients with actie PTB. MATERIAL AND METHODS This prospectie single blind randomised clinical trial included 106 patients of actie pulmonary tuberculosis (PTB) presenting with haemoptysis. The inclusion criteria of these patients were: (a) minimal to moderate lesion on chest X-ray (b) haing normal baseline coagulation profile (bleeding time, clotting time, prothrombin time, serum calcium and platelet count) (c) haing no other systemic disease or immunosuppressie condition All the patients were subjected to a detailed clinical history, physical examination and inestigations which included a chest X-ray, Table 1: Base line coagulation profile of the patients in the PZA group Name of the Test Mean Value ± S.D. 1 Bleeding Time 3.92 ± 1.10 Min. 2 Clotting Time 4.87 ± 1.46 Min. 3 Prothrombin Time ± Sec. 4 Serum Calcium 9.35 ± 1.45 mg/ dl 5 Platelet Count 3.14 ± Lacs/µ L 1. Done by Duke s method (1912) 2. Done by method of Lee & White (1913) 3. Determined by Quick s one stage method (1966) 4. Done by Clark & Collip s method (1925) 5. Done by method of Brecher 7 Crinkite (1950) 1. Professor & Head of the Department 2. Postgraduate Student 3. Associate Professor 4. Assistant Professor Department of Chest Diseases and Tuberculosis, SMS Medical College, Jaipur. Correspondence: Dr. N.K. Jain, A-123, Subhash Nagar Shopping Centre, Jaipur (Rajasthan) jainkdr@yahoo.co.in

2 80 N. K. JAIN ET AL Table 2: Base line coagulation profile of the patients in the non-pza group Name of the Test Bleeding Time Clotting Time Prothrombin Time Serum Calcium Platelet Count Mean Value ± S.D ± 1.09 Min ± Min ± 0.82 Sec ± mg/ dl 2.51 ± Lacs/µ L sputum smear for Acid Fast Bacilli by Ziehl Neelsen Stain / fungal hyphae / (Grams stain), Routine blood counts (Hemoglobin, total leucocyte counts, differential leucocyte count, ESR), lier function test (SGOT, SGPT, total bilirubin, alkaline phosphatase), Kidney function tests (serum urea, creatinine), baseline coagulation profile (bleeding time, clotting time, prothrombin time, serum calcium and platelet count) and ELISA test for detecting HIV infection. The patients were diided into two groups; one half of them receied PZA containing anti-tuberculosis regimens (PZA group) and the other half receied non-pza containing regimens (non-pza group). The anti-tubercular regimens gien to the two groups were as follows: PZA group non-pza group Fresh cases HERZ HER Defaulter/ relapse cases SHERZ SHER Multi drugresistant cases KHEZQPEd KHEQPEd Other than anti-tuberculosis drugs (ATD), the management was conseratie and consisted of bed rest, a codeine containing cough suppressant, a common antibiotic, intraenous adrenochrome monosemicarbazone and supportie treatment in the form of oxygen, blood transfusion and sedaties / anxiolytics as and when required. The patients were followed up for a period of 7 days and were assessed for a) Blood loss during therapy Each patient was proided a 500 ml calibrated transparent plastic container for spitting the expectorated blood. The amount of blood loss was monitored and recorded by the nursing staff on duty and was cross-checked by the Table 3: Blood loss during therapy in the two groups RESULTS Group PZA Non PZA P alue & Significance Blood Loss During Therapy Minimal Moderate Massie (43.40%) (43.40%) (13.20%) (64.15%) (24.53%) (11.32%) P < 0.05 P > 0.5 χ 2 = χ 2 = 0.4 S P > 0.1, χ 2 = 0.79 S = Significant, = Not Significant

3 PYRAZINAMIDE AND HAEMOPTYSIS 81 Table 4: Duration of Haemoptysis in the two groups Group PZA Non PZA P alue & Significance = Not Significant Duration of Haemoptysis (days) 3 > (45.3%) (54.7%) (39.62%) (60.38%) P > 0.5 χ 2 = Mean Duration (days ± S.D.) 3.98 ± ± 1.95 Table 5: Blood loss during therapy after 3 days in the two groups Group PZA Non PZA P alue & Significance = Not Significant, NA = Not Applicable Blood Loss During Therapy Minimal Moderate Massie (48.27%) (44.83%) (6.9%) (62.5%) (34.38%) (3.12%) χ 2 = 0.95 NA NA emergency doctors (who were different from the clinical inestigators) eery 12 hours b) Duration of haemoptysis Blood loss during therapy was classified as: Minimal: Blood streaking of sputum to 20 ml of blood loss per day. Moderate: Any amount more than minimal but less than massie Massie: Blood loss > 600 ml in 48 hrs Or Any amount that is threatening to life (Crocco et al, 1968) RESULTS Blood loss during therapy was moderate to massie in amount in 30 patients (56.60 %) in the PZA group as compared to 19 patients in the non-pza group (35.84 %). Massie haemoptysis was also more common in the PZA

4 82 N. K. JAIN ET AL group (13.20 %) as compared to the non-pza group (11.32 %). The statistical difference between the two groups haing minimal and moderate haemoptysis was significant [χ 2 = for 1 df, 0.02<P<0.05] (Table 3). Howeer, more patients in the non-pza group were obsered to hae haemoptysis lasting for greater than 3 days (n = 32, %) as compared to the PZA group ( n = 29, 54.7 %). The obsered mean duration of haemoptysis was also slightly more in the non-pza group (4.11 ± 1.95 days) as compared to the PZA group (3.98 ± 2.2 days). The difference, howeer, was not statistically significant [χ 2 = 0.34 for 1 df, P > 0.5] (Table 4). Blood loss during therapy after 3 days was seen to be more seere in the PZA group as compared to the non-pza group: majority of the patients in the PZA group had moderate to massie haemoptysis (n = 15, 51.73%), whereas majority of the patients in the non- PZA group had minimal haemoptysis (n = 20, 62.5 %) after 3 days, the statistical difference between the two groups was, howeer, not significant [χ 2 = 0.95, 0.1<P<0.5] (Table 5). DISCUSSION In the early days of introduction of PZA, efficacy of PZA was inestigated in 60 tubercular cases by allotting them chemotherapy with different regimens incorporating PZA [namely PZA mono therapy, streptomycin + PZA and PAS + PZA] 4. Fatal haemoptysis was found to be an unusual aderse effect in % cases belonging to all the 3 groups. PZA was suggested as the possible culprit but were unable to put forward any explanation for the aboe phenomenon. Later, a few clinical inestigators highlighted the property of PZA causing derangement of the haemostatic mechanisms in the body. PZA use is associated with increased prothrombin time, decreased platelet count, platelet aggregation and adhesieness 1-3. A few cases of fatal haemoptysis associated with PZA therapy hae been reported in literature, but those cases had haemoptysis as an incidental finding, while being treated with PZA containing antitubercular regimen. No study could be found in the literature, which has compared PZA containing ersus non-pza containing ATD regimens in cases of haemoptysis. In our study, the seerity of haemoptysis was seen to be more with PZA containing regimens as compared to non-pza regimens. The possible cause of the aboe finding is the derangement of the haemostatic mechanism by pyrazinamide. Howeer, the mean duration of haemoptysis in the two groups of patients were almost the same (3.98 ± 2.2 days in the PZA group s 4.11 ± 1.95 days in the non-pza group). We are unable to put forward an explanation for this phenomenon. Perhaps studies with longer follow up period will be able to answer this question in the future. The findings of our study can be utilized by temporarily withholding PZA from the antitubercular regimen during the period of actie haemoptysis. This would decrease the seerity of haemoptysis and hence mortality due to this threatening symptom. Howeer, further studies are required on this subject to answer the following unanswered questions: a) Out of the different mechanisms by which pyrazinamide alters the haemostatic balance, which one is chiefly responsible for causation of haemoptysis? b) After temporary withholding of pyrazinamide during the period of actie haemoptysis, how quickly after cessation of haemoptysis can we reintroduce it, so that it will not cause recurrence of haemoptysis? REFERENCES 1. Krashner L. Tr. Twelfth Conference on the Chemotherapy of Tuberculosis, Veterans Administration, 341, Zorini AO, Spma G and De Simoni GE. Clinical and

5 PYRAZINAMIDE AND HAEMOPTYSIS 83 biological inestigations on the new antituberculosis drugs (pyrazinamide and cycloserine). Dis of Chest 1958; 34: Sharma TN, Jain NK, Kumar P, et al. Alterations in haemostatic mechanism during pyrazinamide therapy. Indian J Tuberc 1982; 29 (2): Potter BP, Chang SF. Experience with pyrazinamide. Dis of Chest 1955; 27: 44. Statement about ownership and other particulars of the as per Form IV under Rule 8 of the Registration of Newspapers (Central) Rules Place of Publication : New Delhi 2. Periodicity of Publication : Quarterly, published in the months of January, April, July and October 3. Printer s name, nationality : Sri S.C. Goyal, Indian; New Delhi Publisher s name, nationality : Sri S.C. Goyal, Indian; New Delhi Editor s name, nationality : Dr. S.P. Agarwal, Indian; New Delhi Name and adress of indiiduals Secretary General, who own the newspaper and partners; Tuberculosis Association of India, or shareholders holding more than one percent of the total capital New Delhi I, Sri S.C. Goyal, Secretary General of the Tuberculosis Association of India, New Delhi , hereby declare that the particulars gien aboe are true to the best of my knowledge and belief. S.C. Goyal On behalf of the Tuberculosis Association of India

6 84 PRE-TEST COUELLING FOR HIV With the uprising HIV epidemic in the country, it has become imperatie for eery physician to acquire knowledge and skills for HIV counselling comprising general post-test and HIV-positie patient counselling. The guidelines for pretest counselling are: Put the person at ease; establish personal rapport. Explain in layman s language what HIV is, how it occurs, any wrong perceptions that may be current, and its consequences (a possibility of progression to AIDS). Explain the benefits of HIV testing -medical as well as sociological. Detail the steps of HIV testing, the significance of positie or negatie result, the margin of error in the test being offered and whether it is for screening or confirmation. Stress that a positie result does not mean AIDS or een a prediction that it must occur, sooner or later. Discuss at length the confidentiality issue and its implications. Frankly answer doubts and fears; who all shall be informed by the person concerned, if the test is positie. Explain explicitly the meaning and implications of giing written informed consent, the right to refuse the test and the potential consequences of refusal, especially for the spouse and family. Assure that medical help will be extended, een if the test is refused. Allow adequate time for pondering oer the situation and making the decision in faour of the test. Published by the Tuberculosis Association of India in the interest of public health (Adapted and extracted from NACO Guidelines)