Leading Article

Ind. J Tub., 2002,49, 125

ACUTE LUNG INJURY IN MILIARY TUBERCULOSIS

Ashish Bhalla1, M. Mahapatra1, Ram Singh2 and Sanjay DCruz1

(Received on 11.4.2001, Accepted on 12.1.2002)

Summary :Miliary tuberculosis is a serious disease associated with various complications such as acute lung injury in the form of adult respiratory distress syndrome (ARDS). The risk of developing ARDS in such cases is minimal but it is invariably fatal. Early recognition of ARDS and institution of definitive therapy is of obvious importance. Early initiation of steroids along with anti-tuberculosis therapy could save many lives. Key words: Miliary tuberculosis, Acute lung injury, ARDS _______________

INTRODUCTION
Acute lung injury has been defined as a syndrome of inflammation and increased pulmonary permeability associated with a constellation of clinical, radiological and physiological abnormalities which cannot be explained by left atrial or pulmonary capillary hypertension. Adult respiratory distress syndrome (ARDS) is the most severe form of acute lung injury. It is said to occur when the ratio of partial pressure of oxygen to the fraction of inspired oxygen is < or = 200 regardless of how much positive end expiratory pressure is, bilateral lung infiltrates on chest X-ray and pulmonary artery occlusion pressure of < or = 18 mm Hg or no clinical evidence of left atrial pressure on the basis of clinical data or investigations. Severe and diffuse alveolar capillary involvement is associated with a variety of disorders1-3 and carries risk of mortality ranging from 40-60%4,5. However, the initial pulmonary insult is difficult to recognize. Identification of the primary cause of respiratory distress is vital for the initiation of appropriate therapy. Tuberculosis is a potentially curable but uncommon cause of adult respiratory distress syndrome (ARDS), and is associated with very high mortality4-7. Godfine et al described the presence of

respiratory failure in patients with miliary tuberculosis for the first time in 19698. Subsequently, Agarwal et al9 described this complication in patients with pulmonary tuberculosis. In the last three decades, an increasing number of cases of ARDS has been reported in patients with pulmonary as well as miliary tuberculosis from Japan, China, France, USA and India.4-6, 10-14 Most of such data are in the form of sporadic case reports. The largest series reported from India is from All India Institute of Medical Sciences (AIIMS) in which 6 cases of ARDS in HIV negative tuberculosis cases were noted over a 12 year period, indicating the relative rarity of this complication in tuberculosis4. Development of ARDS in tuberculosis after initiation of therapy is rarer. Skurnaki and colleagues in their study of 10 patients have reported one patient developing respiratory distress and disseminated intra-vascular coagulation one day after initiation of 15 anti -tuberculosis therapy .

PATHO-PHYSIOLOGY
Varying degrees of hypoxemia and alveolar arterial oxygen gradient, reflecting inequalities of ventilation, perfusion and impaired diffusion of

1. Senior Lecturer 2. Reader Department of Medicine, Government Medical College and Hospital, Sector 32, Chandigarh Correspondence: Dr. Ashish Bhalla, 1032, Sector 24-B, Chandigarh email : ashishbhalla@id.eth.net

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oxygen has been reported in early miliary tuberculosis16. Signs of ARDS are commonly met with in autopsy studies in patients with miliary tuberculosis17. In untreated miliary tuberculosis, injury to the alveolar capillary membrane appears to result from intense and widespread perifocal inflammatory reaction, interstitial granulomatous inflammation, and obliterative endarteritis16. Initially, the local vascularity is increased and later, alveoli are filled with dense exudative material. Ultimately, the air spaces may be replaced by caseating granulomas. The exact mechanism of ARDS in both pulmonary and miliary tuberculosis is not known. Various theories implicate massive release of mycobacteria into the pulmonary circulation resulting in widespread inflammatory reaction, infiltration and obliterative endarteritis 5,16 . Other postulated mechanisms include volume overload, embolization of platelets, fibrin aggregates in pulmonary capillaries resulting in endothelial damage and leukocyte activation resulting in increased vascular permeability18. Later, the alveoli are filled with exudative material leading to the clinical manifestations of ARDS. On the molecular level, Lipoarabinomannan, a component of mycobacterial cell wall, has been thought to act similar to lipopolysaccharides in Gram negative sepsis so as to activate macrophages. The activated macrophages release tumor narcosis factor alpha (TNF-) and interleukin 1. These activated macrophages are key to causation of endothelial lung injury as shown in flow diagram below6,19. The endothelial cells also are made more susceptible to the toxic effects of TNF- by Mycobacterium tuberculosis. Lipoarabinomannan activates macrophages Release of TNF - and IL-1 Endothelial damage Acute lung injury Indian Journal of Tuberculosis

CLINICAL FEATURES
Majority of the patients present with subacute or chronic febrile illness. Initial presentation with an acute onset of breathlessness is rare. In miliary tuberculosis patients, most of the times there is mild dyspnoea which gradually worsens. It is uncommon to find acute dyspnoea at initiation of therapy. Systemic examination in these patients may be unremarkable but mild hepatomegaly, minimal jaundice and choroid tubercles suggest a diagnosis of miliary tuberculosis. Early diagnosis of miliary tuberculosis is difficult because viral pneumonias presenting with respiratory distress too may have a similar clinical presentation and X-ray picture. Only careful clinical history taking may give a clue of miliary tuberculosis.

INVESTIGATIONS
It is important to demonstrate acid fast bacilli or granulomatous tissue in tuberculosis patients developing ARDS. It is common to have negative sputum for acid fast bacilli (AFB) and negative tuberculin test. Various studies have shown sputum smear positivity varying between 20-40%20-22 and a few patients may show AFB positivity after initiation of steroid therapy. Tuberculin test may also be negative in as many as 30-60% patients20-22. X-ray chest may or may not be helpful. The initial X-ray picture usually shows presence of reticulo-nodular shadows indicative of miliary tuberculosis. These X-ray findings may also suggest an alternative diagnosis of conditions like sarcoidosis, hypersensitivity pneumonitis, pneumoconiosis, pulmonary metastases or amyloidosis. Good history taking and clinical examination will help in differential diagnosis. Later, in the course of illness, there is coalescence of pulmonary infiltrates and pulmonary opacification which manifests, clinically, as respiratory distress. High resolution CT scan (HRCT) of chest

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may be helpful when diagnosis of miliary tuberculosis is in doubt :diffuse, small, nodular densities measuring upto 3 mm on HRCT may help in establishing a diagnosis of miliary tuberculosis in suspected cases23, 24. However, similar findings may be seen in various other conditions like pulmonary metastases, sarcoidosis, hypersensitivity pneumonitis and pneumoconiosis23-26. Patients with dyspnoea might show presence of ground glass opacities of variable extent and distribution on HRCT26. Broncho-alveolar lavage(BAL) and transbronchial lung biopsy (TBLB) may be helpful in making an early diagnosis of miliary tuberculosis27. Early TBLB in patients developing ARDS, in whom the diagnosis of miliary tuberculosis is suspected, may be of help in confirming the diagnosis1,28. ELISA test for detection of tuberculous antigen has not been found to be helpful. PCR is a promising test but its role for establishing the diagnosis of tuberculosis in such patients still needs exploration4,29. A strong clinical suspicion on the basis of history and a suggestive X-ray / CT scan help in establishing the diagnosis of miliary tuberculosis in suspected cases when they present as ARDS.

ventilation for ARDS patients. All precautions such as strict asepsis and barrier nursing should be taken to avoid super-added infections. Most of the times, it is the nosocomial infections and their complications which cause death in ARDS patients. A careful watch kept on the vital parameters and an early weaning system will help in achieving a good outcome in such patients. Reversal of acute perifocal inflammation, as judged by improvement in X-ray picture, may be observed in miliary tuberculosis within 72 hours of the initiation of definitive therapy 31. Complete resolution of X-ray abnormalities has been reported to occur as early as within 9 days of initiation of ATT31. Diffusing capacities may improve rapidly and return to normal in as short a period as three weeks32; however, some changes usually persist for months16. X-ray changes suggestive of ARDS might persist for even upto a few months after complete clinical resolution has occurred.Therefore, patients with miliary tuberculosis should be recognised early and carefully watched for ventilatory dysfunction during the course of their illness and when ATT is initiated. The risk of developing ARDS in such cases is 33 minimal .

REFERENCES
1. Ashburg DG, Bigelow DB,Petty TL et al: Acute respiratory distress in adults. Lancet, 1967, 2, 319 Petty TL, Ashburg DG: The adult respiratory distress syndrome, clinical features, factors influencing the prognosis and principles of management. Chest, 1971, 60, 233 Sutton FD, Hudson LD, Petty TL: Recognition and management of the adult respiratory distress syndrome. Chest, 1974;,66 (suppl),34 Mohan A, Sharma SK, Pande JN: Adult respiratory distress syndrome in miliary tuberculosis: a twelve year experience. Indian J Chest Dis Allied Sci, 1996, 38, 157 Piqueras AR, Marruecos L, Artigas A, Rodrigues C: Miliary tuberculosis and adult respiratory distress syndrome. Intensive Care Med, 1987, 13, 175 Penner C, Roberts D, Kunimoto D, Manfreda J, Long R: Tuberculosis as a primary cause of respiratory failure requiring ventilation. Am J Respir Crit Care Med, 1995, 151. 867 Homan W, Harman E, Braun NMT et al: Miliary tuberculosis presenting as acute respiratory failure. Chest, 1975, 67, 366

MANAGEMENT
The two interventions useful in reducing pulmonary injury are specific antimicrobial therapy and non-specific anti-inflammatory therapy (corticosteroids). Steroids added to treatment with anti-tuberculosis drugs have shown promising results in such patients. Though ATT, as such, can not be expected to reverse the capillary damage, the supportive therapy with ventilation and steroids may be life saving. Steroid therapy appears to be effective in reducing systemic toxicity and intensity of inflammatory exudative pulmonary response10-14, 30, 31. Supportive therapy, in the form of good care in an intensive care unit, is as essential as

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