Bronchoalveolar lavages in two patients with miliary tuberculosis have

shown lymphocytic alveolitis. A 6-month regimen with an initial intensive 2-

month phase resulted in remarkable clinical and radiographic improvement

in both. However, bronchoalveolar lavage following treatment has shown

that there was a persistence of lymphocytic alveolitis, though with reduced

intensity. The significance of the persisting alveolitis, despite treatment, is

not known at present. There is also a suggestion that compartment-alisation

of lymphocytes may occur in miliary tuberculosis of the lung

Jawahar, M S

Prabhakar, R

Reetha, A M

Vijayan, V K

NIRT Institutional Repository

Indian J Chest Dis & All SciVol. 32 No. 1 pp 49-53 (1990)PERSISTING ALVEOLITIS IN MILIARY TUBERCULOSISDESPITE TREATMENT WITH SHORT-COURSECHEMOTHERAPYV.K. Vijayan, M.S. Jawahar, A.M. Reetha and R PrabhakarCardio-Pulmonary Medicine Unit, Tuberculosis Research Centre, (ICMR), MadrasBronchoalveolar lavages in two patients with miliary tuberculosis haveshown lymphocytic alveolitis. A 6-month regimen with an initial intensive 2-month phase resulted in remarkable clinical and radiographic improvementin both. However, bronchoalveolar lavage following treatment has shownthat there was a persistence of lymphocytic alveolitis, though with reducedintensity. The significance of the persisting alveolitis, despite treatment, isnot known at present. There is also a suggestion that compartment-alisationof lymphocytes may occur in miliary tuberculosis of the lung.Miliary disease of the lung due to Mycobacterium tuberculosis poses diagnostic as well astherapeutic problems because of the radiographic similarity with diffuse lung diseases andalso due to the seriousness of the disease. Miliary tuberculosis is essentially an interstitiallung disease and studies have reported lymphocytic alveolitis1 at the diagnostic stage inthese patients. Availability of potent chemotherapeutic agents2 has made it possible to treatthis condition successfully. Bronchoalveolar lavage (BAL) studies were carried out in 2patients with radiological and bacteriological evidence of miliary tuberculosis, in order tostudy the response of the alveolitis to treatment with intensive short course chemotherapy.Case ReportsCase 1. A 24-year-old female patient complained of dyspnoea, cough, chest pain and feverof one week duration. She was a housewife, denied any previous illness or history oftuberculosis in the family, and was a non-smoker. On physical examination, she hadCorrespondence : Dr V.K. Vijayan, Cardio-Pulmonary Medicine Unit. Tuberculosis ResearchCentre, (ICMR), Spur Tank Road, Madras-600 031.4950 Alveolitis in miliary tuberculosisTable. BAL in miliary tuberculosisPretreatment Post-treatment (6 months)Total cells  M  L  N  E(x106/100ml) % % % %Total cells M LCase 1 51.3 17 82 0 1 22.8 62 37 1 0Case 2 48.9 25 75 0 0 21.8 25   66        6   3M = Macrophages; L = Lymphocytes; N = Neutrophils; E = Eosinophilsdyspnoea at rest, respiratory rate was 40/min, pulse rate 144/min, temperature 99 °F andblood pressure 100/70 mmHg. Fine rales were heard in both lung bases. Mantoux test with1 TU PPD was 15 mm. Total leucocyte count was 11000 cells/mm3 with differentials aspolymorphs 81%, lymphocytes 17% and eosinophils 2%. There were albumin (+), 2-4 puscells and occasional RBCs/HPF in urine and stool did not show any ova or cyst. Skiagramchest revealed diffuse miliary shadows in both lung fieldsespecially in the mid and lowerzones. Two sputa examined by fluorescent microscopy were negative for AFB Pulmonaryfunctions could not be done because of breathlessness, Blood gas studies showed a pH7.53, PaO2 42.4 mmHg, PaCO2 25.1 mmHg and HCO3 +20.9 mmol/l. Bronchoalveolarlavage3 using flexible fibreoptic bronchoscope showed an increase in cellularity in the lowerrespiratory tract (51.3 x 106/100 ml of the lavage fluid), with 82% lymphocytes, confirmingthe presence of lymphocytic alveolitis. The patient was provisionally diagnosed to besuffering from miliary tuberculosis based on clinical, radiological and lavage findings.She was prescribed injection streptomycin 0.75 g, isoniazid 300 mg, rifampicin 450 mg,pyrazinamide 1 g and ethambutol 600 mg daily for the first 2 months, followed byrifampicin 450 mg and isoniazid 300 mg daily for the next 4 months. Meanwhile, thesputum, urine and lavage culture results were reported as positive for M. tuberculosis pre-treatment and the organisms were sensitive to streptomycin, isoniazid, rifampicin andethambutol. Sputa became negative for M. tuberculosis by culture at 1st month oftreatment. During the entire period of her 6 months chemotherapy, she had missedtreatment only for a total of 16 days and she continues to be negative for M. tuberculosis byculture in sputum at the end of 6 and 12 months. She had also shown remarkable clinicaland radiological improvement following the treatment. Pulmonary function tests at the endof treatment revealed a mild restrictive ventilatory defect (TLC% predicted 83%, RV%predicted 78%, FRC% predicted 83.4%) and diffusion defect (TLCO% predicted 76%).Arterial blood gases were normal (pH 7.4, PaO2 104.2 mmHg and PaCO2 35.2 mmHg).There was a reduction in total cells (22.8 x 106/100 ml) and lymphocytes (37%) in BALfluid following treatment (Table).Case 2. A 45-year-old female patient was evaluated for cough, dyspnoea, chest pain andfever of 3 months duration. She was a housewife and non-smoker. She also denied anyV.K. Vijayan et al 51previous illness or family history of tuberculosis. On physical examination, pulse rate was92/min, respiratory rate 28/min, temperature 98.2 °F and BP 90/60 mmHg. There were noabnormal signs on auscultation. Mantoux with 1 TU PPD was 19 mm, and total leucocytecount was 10400/mm3 with differentials as polymorphs 77%, lymphocytes 15% andeosinophils 8%. Urine and stool examinations were within normal limits. Skiagram chestshowed miliary shadows in both lung fields. Out of a total of 6 sputa, one was positive forAFB by fluorescent microscopy. BAL showed that the total cells were 48.9 x 106/100 mland lymphocytes were 75%, confirming the presence of lymphocytic alveolitis in thispatient as well. She was given injection streptomycin 0.75 g, isoniazid 400 mg, rifampicin450 mg and pyrazinamide 1.5 g thrice weekly for the first two months followed bystreptomycin 0.75 g, isoniazid 600 mg and rifampicin 450 mg twice-weekly for the next 4months. However, streptomycin was terminated at the end of 5th month due to giddiness.Her pre-treatment sputa and lavage cultures became positive for M. tuberculosis and theorganisms were sensitive to streptomycin, isoniazid and rifampicin. Sputa became negativefor M. tuberculosis by culture at 1st month of treatment. She had missed only one doseduring the entire 6 months period of chemotherapy. She had also shown remarkableclinical and radiographic improvement following treatment and sputa continued to benegative for M. tuberculosis by culture at 6 and 12 months. BAL at 6 months had shownthat total cells were 21.8 x 106/100 ml and lymphocytes were 66% (Table). Pulmonaryfunction tests revealed that there was diffusion defect (TLCO% predicted 59.4%), withnormal lung volumes.DiscussionClinical trials in tuberculous meningitis: pulmonary tuberculosis2, spinal tuberculosis5and tuberculosis of lymphnodes6 had shown that treatment with potent bactericidal andsterilising drugs for 6-9 months is adequate for remarkable therapeutic response. Thoughno controlled clinical trials in miliary tuberculosis of the lung have been reported, thehighly satisfactory clinical response and complete radiographic resolution of the lesions inour patients suggest that 6 months treatment may be adequate for a bacteriologicalresponse in these patients.Lymphocytic alveolitis in miliary tuberculosis prior to treatment has previously beenreported1. Since the mean lymphocytes in BALF in our normal subjects3 were 21 (SE ±4%), the patients with lymphocytes > 31% in BAL fluid was classified as havinglymphocytic alveolitis. The persistence of lymphocytic alveolitis with reduced intensity inour patients even after treatment with potent chemotherapeutic regimen requires furtherindepth study. Will the alveolitis subside spontaneously as time passes or will it produce anydeleterious effects on the lung parenchyma? Long term follow-up of such patients areessential to answer these questions. As it has been shown that lymphocytic alveolitis cancause lung injury and fibrosis in sarcoidosis and hypersensitivity pneumonitis7, there is apossibility that alveolitis observed in miliary tuberculosis patients, despite treatment, maycause injury to lung parenchyma. In addition, the finding of reduced transfer factor at 652 Alveolitis in miliary tuberculosismonth in our patients is also significant. Immunological investigations using BAL coupledwith long term clinical and pulmonary function studies are required to unravel the mystery.If there is a possibility that these patients might develop interstitial fibrosis, the role ofsteroids in the management of miliary disease of the lung due to M. tuberculosis has to becritically evaluated, as it had been shown recently that anti-tuberculosis chemotherapyshould be initially supplemented with steroids in patients with tuberculous constrictivepericarditis,8 if there are no contra-indications. Another interesting finding in these patientsis the occurrence of relative lymphopenia in peripheral blood, as opposed to lymphocytosisin BAL fluid, suggesting that there may be compartmentalisation of lymphocytes in miliarytuberculosis. An increased number of helper/inducer T-lymphocytes at sites ofinvolvement had been previously reported in tuberculous pleural effusion9, tuberculoidleprosy10, pulmonary sarcoidosis11, rheumatoid arthritis12 and hypersensitivitypneumonitis13. It had been demonstrated in tuberculous pleural effusion that pleural T-lymphocytes, but not blood T-lymphocytes, released gamma interferon when exposed toPPD14, suggesting that the immune response is also compartmentalised in tuberculouspleurisy. The observation of increased lymphocytes in BAL fluid and a simultaneousdecrease in lymphocytes in periphera1 brood in our patients warrants further extensiveimmunological studies in miliary tuberculosis.References1.2.3.4.5.6.7.8.Kalra L, Verma K, Pande JN, Guleria JS. Diagnostic significance of broncho-alveolar lavagefluid analysis in bilateral diffuse lung disease. Indian J Med Res 1984; 79 : 697-707.Fox W. Whither short course chemotherapy? Br J Dis Chest 1981; 75 : 331-357.Pinkston P, Vijayan VK, Nutman TB et al. Acute tropical pulmonary eosinophilia :Characterisation of the lower respiratory tract inflammation and its response to therapy. JClin Invest 1987; 80 : 216-225.Phuapradit P, Vejjajiva A. Treatment of tuberculous meningitis : Role of short coursechemotherapy. J Medicine 1987; 62 (New Series) : 249-258.A controlled trial of short course regimens of chemotherapy in patients receiving ambulatorytreatment or undergoing radical surgery for tuberculosis of the spine. An Indian Council ofMedical Research/British Medical Research Council Working Party Study in Madras. Indian JTub 1989; 36 (Suppl) : 1-21.British Thoracic Society. Short course chemotherapy for tuberculosis of lymph nodes : Acontrolled trial. Br Med J 1985; 290 : 1106-08.Crystal RG, Bitterman PB, Rennard RI, Hance AJ, Keogh BA. Interstitial lung disease ofunknown cause. Disorders characterised by chronic inflammation of the lower respiratorytract. N Engl J Med 1984; 310 : 154-166 and 235-244.Strang JIG, Kakaza HH, Gibson DG, Girling DJ, Nunn AJ, Fox W. Controlled trial ofprednisolone adjuvant in treatment of tuberculous constrictive pericarditis. Lancet 1987; 2 :1418-22.VK Vijayan et al 539. Rossi GA, Balbi B, Manca F. Tuberculous pleural effusion : Evidence for selective presenceof PPD-specific T-lymphocytes at site of inflammation in the early phase of infection. Am RevRespir Dis 1987; 136 : 575-579.10. Van Voorhis WC, Kaplen G, Nunes Samo E et al. The cutaneous infiltrates of leprosy.Cellular characteristics and the predominant T-cell phenotypes. N Engl J Med 1982, 307 :1593-97.11. Hunninghake GW, Crystal RG. Pulmonary sarcoidosis : A disease mediated by excess helperT-lymphocyte activity at sites of disease activity. N Engl J Med 1981; 305 : 429-34.12. Janossy G, Duke O, Poulter LW, Panavi G, Bofill M, Gold Stem G. Rheumatoid arthritis : Adisease of T-lymphocyte/macrophage immunoregulation. Lancet 1981; 2 : 839-42.13. Costabel U, Bross KJ, Maxen J, Matthys H. T-lymphocytosis in bronchoalveolar lavage fluidof hypersensitivity pneumonitis. Changes in profile of T-cell subsets during the course of thedisease. Chest 1984; 85 : 514-22.14. Shimokata K, Kawachi H, Kishimoto H, Maeda F, Ito Y. Local cellular immunity intuberculous pleurisy. Am Rev Respir Dis 1982; 126 : 822-24.

Persistng alveolitis in miliary tuberculosis despite treatment with short-course chemotherapy

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Persistng alveolitis in miliary tuberculosis despite treatment with short-course chemotherapy

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