Case Report Ind. J Tub., 2001, 48, 97 ASYMPTOMATIC APLASTIC ANAEMIA IN A PATIENT RECEIVING ANTI-TUBERCULOSIS TREATMENT Anil K. Agarwal, Inder Mohan Chugh, Chandramani Punjabi, Sumita Dewan* and Ashok Shah (Received on 25.9.2000, Revised Version received on 15.2.2001, Accepted on 22.2.2001) Summary: Blood dyscrasias with anti-tuberculosis drugs are known but rarely encountered and even less thought of. We describe a patient who developed pancytopenia due to aplastic anaemia of moderate severity which was diagnosed after 7 months of therapy. This was thought to be an idiosyncratic response to Streptomycin. A 6 month clinical follow-up after cessation of therapy revealed that the blood counts continued to remain depressed, but she was totally asymptomatic. Subsequently, we were informed that the patient had an uncomplicated normal vaginal delivery 2 years after stopping therapy. INTRODUCTION Blood dyscrasias induced by anti-tuberculosis drugs are known but are rarely encountered. A wide range of haematological abnormalities has been reported with these drugs. However, the physician rarely suspects this serious complication which can have fatal consequences. Aplastic anaemia is a hyporegenerative bone marrow disorder characterised pathologically by a reduction in the amount of haemopocitic bone marrow and pancytopenia1. Drugs are often indicted as a major cause of acquired aplastic anaemia. We describe a patient who developed pancytopenia due to aplaslic anaemia of moderate severity while receiving anti-tuberculosis therapy, probably caused by an idiosyncratic reaction to Streptomycin. Although her total leucocytic and platelet counts were still depressed 6 months after cessation of drugs, the patient was asymptomatic. This case report was prompted by the rarity of such reports in the literature. CASE REPORT A 25-year-old female was referred to our Institute for re-evaluation of anti-tuberculosis therapy (ATT) initiated 3 months before presentation. Five months prior to referral, she had developed high grade continuous fever of acute onset for which she consulted a general practitioner. She was administered various courses of antibiotics and symptomatic treatment but with no relief. A borderline positive Widal test resulted in suspicion of typhoid fever for which she received a course of Ofloxacin but without relief. The patient did not receive Chloramphenicol. Two months later, she experienced loss of appetite along with generalised weakness and was then admitted in a nursing home. A chest roentgenogram showed right side plcural effusion which was confirmed on computed tomography (CT) of thorax. The CT also revealed enlarged right hilar and carinal lymph nodes. Based on her radiological profile, she was diagnosed as a case of pulmonary tuberculosis with pleural effusion and was started on an antituberculosis regimen comprising Rifampicin 450 mg, Isoniazid 300 mg, Pyrazinamide 1500 mg and Ethambutol 800 mg once daily. Ten days after initiation of ATT, she developed jaundice and her liver function tests were deranged. Rifampicin and Pyraziaamide were stopped and Streptomycin 0.75g once daily intramuscularly was added to Isoniazid and Ethambutol. Oral Prednisolone was also added which was gradually tapered off. However, pleural tap was not done. Six weeks subsequent to rescheduling of the ATT, she felt better and her symptoms gradually disappeared. She was still on the three drugs (Streptomycin, Isoniazid and Ethambutol) when she reported to us. Physical examination revealed a pale young female of average built in no acute distress. There was no clubbing, cyanosis or any significant lymphadenopathy. Diaphragmatic excursion was decreased on the right side. Percussion note was dull Department ot Respiratory Medicine, Vallabhbhai Patel Chest Institute, University of Delhi. Delhi and *Haematologist, Department ot Medicine. Safdarjung Hospital, New Delhi Correspondence :Dr. Ashok Shah M.D., Department of Respiratory Medicine. Vallahhbhai Patel Chest Institute. University oi Delhi. P.O. Box 2101. Delhi-110007 98 ANIL K. AGARWAL ET AL and 202 KAU/dL respectively. The liver function on the right infrascapular and infraaxillary regions tests were within normal limits when she reported to Breath sounds were decreased in the same areas with us and it continued to remain so. Other investigations no adventitious sounds. No other abnormality was which included serum proteins, serum calcium blood detected. sugar, stool examination, etc. did not show any abnormality. Tuberculin test with 1 TU did not show LABORATORY INVESTIGATIONS any induration. Tests for human immunodeficiency virus (HIV) were also negative. Repeated direct Haematological investigations, done on smear stains for acid fast bacilli were also negative presentation, showed haemoglobin 9.2 g/dL with and the culture did not grow Mycobacterium total leucocyte count 4000/mm’ and differential leucocyte count: 82% neutrophils, 16% lymphocytes tuberculosis. and 2% eosinophils. The platelet count was 3,49,0007 CLINICAL COURSE mm1 and peripheral blood smear showed neutrophilia along With anisocytosis and microcytosis. Her urine The patient improved clinically with ATT and examination was within normal limits. A review of her symptoms gradually disappeared. Prednisolone her haemogram over the preceding 5 months (Table was tapered off and stopped 2 weeks after presenting 1) revealed that at the time of initiation of ATT her to us. Anti-tuberculosis therapy comprising 1 total leucocyte count was 6150/mm and haemoglobin Streptomycin, Isoniazid and Ethambutol was was 5.4 g/dL for which she received 3 units of blood continued. Rifampicin and Pyrazinamide were transition which raised the haemoglobin level. Liver introduced 6 weeks later and Streptomycin was function tests done when she developed jaundice withdrawn 3 weeks later(Figure 1). A chest showed serum bilirubin of 3.21 mg/dL with SCOT, roentgenogram done at the time of presentation had SGPT and alkaline phosphatase 115 IU/L, 135 ITj/L shown minimal right side pleural effusion, confirmed on ultrasonography, which subsequently disappeared. Haemogram done at the end of the seventh month of therapy showed a sharp decline in the total leucocyte and platelet counts. ATT was stopped forthwith. A bone marrow aspiration (Figure 2) revealed moderately hypocellular marrow with severe megaloblastic changes. There were no ring sideroblasts in the bone marrow. A chest roentgenogram as well as CT thorax done after stopping ATT were read as normal. The patient remained asymptomatic but her total leucocyte and platelet counts continued to remain depressed even 6 months after cessation of ATT with no untoward effects. Although the patient was lost to clinical follow up after 6 months, yet we were informed that she had an uncomplicated normal vaginal delivery 2 years after stopping therapy. DISCUSSION Blood dyscrasias comprise 10% of the total number of drug induced adverse effects and account tor approximately 40% of fatal reactions related to drug administration2. Although blood dyscrasias are known to occur with ATT, the adverse effect is not a 25-year-old female, APLASTIC ANAEMIA DURING ANTI-TUBERCULOSIS TREATMENT 99 Table 1: Showing duration and combination of anti-tuberculosis therapy along with haemotological profile 17/3/97 25/3/97 5/4/97 15/4/97 Hb 24/5/97 12/6/97 14/10/97 20/10/97 9/12/97 20/1/98 11/4/98 5.4 6.3 9.9 10.3 8.7 9.2 10.2 10.7 TLC 6150 6200 7050 15300 9450 4000 1800 2000 DLC P73L20 P70L28 P62L35 P83L14 P75L24 P82L16 P69L26 - P73L23 P87L1 1 EOM2 EOM3 E2M1 E1MO E2MO E4M1 - E3M 1 E2M2 PCV 22% - - - 28.4% 29.4% - 28.8% 3.3% ESR - - 90 120 - 35 49 Platelets - - - - 349 116 110 12.1 3100 10.1 2400 11.8 3490 55 - 194 186 Hb : hameoglobin, P: polymorphonuclear cells, L: lymphocytes, E:eosinophils, M : monocytes to aplastic anaemia. Although the total leucocyte An idiosyncratic response to a drug is not dose count (TLC) had fallen to 4000/cu.mm after 3 related. Although it can be seen with the first dose, months of Streptomycin, Isoniazid and Ethambutol, it seems to occur when patient is exposed to the drug the platelet count was still normal. However, a sharp on more than one occasion and during prolonged decline in both the parameters was observed after 7 therapy4. The symptoms may sometimes not manifest months of ATT, by which time Streptomycin was for weeks or months. There is currently no evidence withdrawn and Rifampicin and Pyrazinamide added to account for a mechanism regarding the for 12 weeks. Standard text books1-3 state that the idiosyncratic response to any drug1. This makes it peripheral blood counts usually return to normal after difficult to investigate adverse drug reactions withdrawal of the offending drug but, in our case, ascribed to idiosyncracy2. the counts remained depressed even 6 months after cessation of therapy, and the patient remained Aplastic anaemia is an uncommon occurrence asymptomatic. This led us to think that it may have with ATT. In a study of 108 patients with aplastic been caused by an idiosyncratic reaction to anaemia, only three (2.8%) were found to be taking Figure 2: Bone marrow aspiration showing hypocellular marrow fragments and a few haemopoeitic cells (Leishmen’s stain x 40) Streptomycin, since this drug has been incriminated earlier. ATT2. Williams et aP reported three cases of aplastic anaemia occurring in association with ATT. All the three patients died of haemorrhage secondary to thrombocytopenia, consistent with an irreversible damage of the bone marrow. The patients were on different combinations of Streptomycin, Thioacetazone, Isoniazid, Para-aminosalicylic acid and Dimethylcarbazine. Deyke and Wallace’1, reported two cases of aplastic anaemia when using Streptomycin injections alone, on the 79th and 95* days of treatment. Of the two patients, one died 19 days after detection while for the other patient, the recovery was doubtful. Our patient, however, underwent an uneventful pregnancy, with a successful outcome, 24 months after cessation of ATT. An earlier review7 had incriminated Para-aminosalicylic acid and Streptomycin as causative agents for aplastic anaemia. We presume that the idiosyncratic reaction, in our patient, was due to Streptomycin even though he had also Isoniazid and Ethambutol. Although 100 ANII, K. AGARWAL KT AL aplastic anaemia due to Streptomycin alone6 and ACKNOWLEDGEMENT Isoniazid in combination with other drugs2’”1 has been The authors are grateful to Dr. Desh Deepak documented, Isoniazid as the sole cause of aplastic for composing Figure 1 and Table I. anaemia is yet to be reported. The possibility of Ethambutol being the offending agent also remains open, but to OUR knowledge, there are no reports in REFERENCES the literature implicating Ethambutol as a cause of 1. Firkin F, Chesterman C, Penington D, Rush B, (eds) De aplastic anaemia. Blood dyscrasias,, as a complication of tuberculosis, are also known8. Pancytopenia is most commonly associated with the disseminated forms of the disease but is best known to occur with miliary tuberculosis7. Pancytopenia due to hemophagocytic syndrome as a presentation of tuberculosis has also been recordedy. This syndrome is characterized by fever, hepatosplenomegaly, pancytopenia and proliferation of histiocytes with erythrophagocytosis, and is thought to be due to immune dysregulation secondary to tuberculosis. It is estimated that annually over 8 million people develop active tuberculosis and aproximately 2.9 million patients die of the disease10. Considering the number of patients who are taking ATT at any particular time and the number of patients who are initiated on ATT in a year, there remains an immense potential for the occurrence of blood dyscrasias. The physicians should remain alert to the fact that these may be caused by the disease itself or with drugs when on ATT. Early detection of blood dyscrasias along with early intervention could hopefully lead to reduction in morbidity and mortality. Gruchy’s Clinical Haematology in Medical Practice: 5”‘ ed.; Delhi: Oxford University Press; 1989; I 19 2. Holdiness MR. A review of blood dyscrasias induced by the anti-tuberculosis drugs. Tubercle 1987; 68:301 3. Williams DM. Pancytopenia, aplastic anemia, and pure red cell aplasia. In: Lee GR, Bithell TC, Foerster J. Athens JW, Lukens JN, (eds). Wintrobe’s Clinical Hematology; 9’” cd; Vol.1. Philadelphia: Lea & Febiger; 1993; 913 4. Klaassen CD. Principles of toxicology and treatment of poisoning. In Hardman JG. Oilman AG, Limbird LE, (ed) Goodman and Oilman’s The pharmacological basis of therapeutics. 9”‘ ed. New York: McGraw-Hill; 1996; 63 5. Williams CKO. Aderoju EA. Adenle AD, Sekoni G. Esan GJF. Aplastic anaemia associated with anti-tuberculosis chemotherapy. Ada Hoc-mat 1982; 68:329 6. Deyke VF, Wallace JB. Development of aplastic anemia during the use of streptomycin. JAMA 1948; 136:1098 7. Cameron SJ. Tuberculosis and the blood - A special relationship? Tubercle 1974; 55:55 8. Goldenberg AS. Hematologjc abnormalities and mycobacterial infections. In Rom WN, Garay SM,(ed) Tuberculosis. Boston: Little, Brown and Company; 1996; 645 9. Basu S, Mohan H, Malhotra H. Pancytopenia due to hemophagocytic syndrome as the presenting manifestation of tuberculosis. JAP! 2000; 48: 845 10. Malm AS, McAdam KPWJ. Escalating threat from tuberculosis: The third epidemic. Thorax 1995; 5()(Suppl I):S37