Om P Sharma1 Bronchoalveolar Lavage ( BAL) and Tropical Lung Disease

Abstract developed world and the vast tropical and subtropical The advent of fiberoptic bronchoscopy permitted bron- land masses have not had benefit of BAL analysis. choalveolar (BAL) to become an easily performed well- Although many investigators have reported the range -tolerated diagnostic and investigative tool. The tech- and cellular content of Bal fluid in normal individu- nique has opened up a helpful new window to the lungs. als, the usefulness of such an evaluation in tropical Changes in the quantity and pattern of BAL fluid and lung diseases is over due. analysis of cells, cytokines have enabled us to broaden our understanding of respiratory and multisystem dis- Key-words: Bronchoalveolar lavage (BAL), Parag- orders. For obvious reasons of cost and availability he onimiasis, tropical eosinophilia, leptospirosis, technique, to a large extent, has remained limited to the Bronchial Lavage (BAL) in Tropical Lung Disease

In tropical medicine, perhaps more than any ticed in rural areas of Asia and Africa, with other medical specialty, a complete history little or no laboratory tests and radiological and physical examination are of paramount facilities, medical acumen is the only tool used importance. In an average outpatient depart- in establishing the correct diagnosis. In a ment, 20-40% of patients come with respi- poor country chest x-ray films are expensive; ratory complaints; whereas, 20-30% of hos- a single chest x-ray film may cost as much as pital medical admissions are for disorders much more the entire health budget for a affecting the lungs. When medicine is prac- year for four people. Even when a few of

1 MD, DTM&H, FRCP Professor of Medicine Keck School of Medicine Los Angeles, California Correspondence: Roomll-900 LAC+USC Medical Center Keck School of Medicine 1200 North State Los Angeles CA, 90033 Email: [email protected]

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the modern diagnostic technologies are read- among HlV-infected individuals, many pa- ily available, the clinician should learn to use tients with other chronic respiratory illness- them with discretion. It is neither helpful nor es suffer from unwarranted lengthy thera- economical to obtain a chest x-ray in order peutic trial of anti-tuberculosis drugs. In to demonstrate what can clearly be deduct- South Africa as many as half of the patients ed from history and physical examination considered “unresponsive pulmonary tuber- including e.g., pulmonary consolidation, pleu- culosis”, seen in a tuberculosis hospital, did ral effusion, sputum-positive tuberculosis. not have tuberculosis; the correct diagnoses Bronchoalveolar lavage (BAL) is a basic tech- included non-tuberculous bronchiectasis, nique used to collect cells and non-cellular lung abscess, congenital cystic lung, hydatid material from the surface of the respiratory disease, sarcoidosis, and foreign bodies. Di- tree. Although various conduits have been agnosis of tuberculosis is confirmed by spu- used to obtain BAL samples, the fiberoptic tum examination. Typically 10,000 organisms bronchoscope is the most common. Since per ml of sputum are needed for smear pos- its introduction in the 1970, particularly in itivity. Bronchoscopic examinations includ- the developed countries, BAL has become an ing washings, brushings, and biopsy speci- important tool for diagnosing, assessing ac- mens establish the diagnosis in 5S-96& tivity, and monitoring a large number of pul- (average rate of 725). In a study of 1734 monary diseases1. The instrument is expen- patients who had bronchoscopy and bron- sive, but each procedure can be performed chial cultures 8.3% had tuberculosis; amongst with minimal expense. BAL and brushing can those who with tuberculosis, 82.6% had pos- identify acid-fast bacilli in sputum-negative pa- itive bronchial cultures. The positive BAL tients, Pneumocystis carinii, fungi, parasites, cultures was the only means of diagnosis in and foreign-body particles. Although, a phy- 44% of the patients2 Transbronchial biopsy sician can quite readily learn the procedure increases the diagnostic yield by identifying after a period of instruction by an expert, the caseating granulomas4,5,6. value of BAL is limited by the quality of lab- oratory facilities2. BAL is useful in the follow- (b) Melioidosis ing tropical lung diseases. Melioidosis is caused by Burkholderia pseu- domallei, a gram-negative aerobe and facul- tative anaerobe that occurs in muddy water 1. Bacterial infection and soil in the endemic áreas in Vietnam, Cambodia, Laos, Thailand, the Philippines, (a)Tuberculosis índia, Malaysia and Australia. It causes both More than 8 million new cases of tubercu- acute and chronic, un-resolving pneumonia, losis occur each year, nearly 95% are in de- particularly affecting the upper lobes. The veloping countries. The acquired immune infection may remain dormant and reactivate deficiency syndrome (AIDS) epidemic has only during periods of stress and immuno- had a major impact on the incidence and clin- -suppression, particularly the HlV-infection. ical manifestations of tuberculosis. Because Tuberculosis, fungai diseases, lung cancer, tuberculosis is common disease, especially and paragonimiasis are in the differential di-

S 22 REVISTA PORTUGUESA DE PNEUMOLOGIA Vol XIII Suplemento 2 Outubro 2007 Bronchoalveolar Lavage ( BAL) and Tropical Lung Disease Om P Sharma agnosis. Bronchoscopic biopsy, brushing and (d) Brucellosis BAL provide material for culture and tissue Brucella melitensis has a worldwide distri- to definitely rule out tuberculosis, cancer, and bution but found predominantly in Midddle other granulomatous diseases7,8,9. Eastern and Mediterranean countries. The infection is acquired by ingestion ,inhalation, (c)Leptospirosis and by skin. Pulmonary infections occur af- Leptospirosis is a re-emerging tropical dis- ter ingestion of the bacteria with resulting ease with large epidemics all around the septicemia and pulmonary involvement. Pul- world. The disease, caused by a spirochete monar findings include cough, pleuritic chest of the genus Leptospira, has the clinical spec- pain, and fever. Miliary infiltrate, nodules, trum that ranges from sub-clinical benign ill- consolidation, hilar adenopathy, and pleural ness to fatal respiratory failure. The disease effusion have all been reported . The organ- has two classical forms of presentation: ic- ism has been isolated from sputum; howev- teric and anicteric. The anicteric form is com- er, there is no clear role for bronchoscopy3. mon, benign, and self-limiting; whereas, the icteric form tents to be multisystem wit a mortality rate of 15% or more. Hemoptysis, 2. Fungal infection the main pulmonary symptom, varies from a blood-tinged sputum to a fatal massive al- (a)Cryptococcosis veolar hemorrhage. The radiographic pattern Cryptococcus neoformans is a fungal infec- is similar to that of alveolar hemorrhage tion acquired by inhalation of the organism caused by other conditions. Alveolar bleed- commonly found in pigeon droppings and ing, due to diffuse capillary damage, is present in geographic areas that support growth of in almost ali the case with signs of pulmo- the red river gum tree (sub-Saharan Africa, nary involvement and in 70% of those with- Southern California). Most pulmonary infec- out any pulmonary signs. Serology with tions are asymptomatic and self-limiting in macro- or microscopic agglutination is the immuno-competent host. The disease may most common way of diagnosing leptospiro- be difficult to diagnose because fungal smears sis. A four-fold increase in titers between and cultures of expectorated sputum are paired sera is accepted in confirming the positive in less than 25% of patients. In current case. Detection of specific IgM an- immuno-compromised hosts the diagnosis tibodies by ELISA is more sensitive than the of cryptococcosis can be made in more than detection of agglutinating antibodies. The 90 % of patients. Transbronchial biopsies definitive diagnosis depends on fmding Lept- are diagnostic in less than 35%, cultures of ospira in blood, cerebrospinal fluid, or BAL BAL fluid are positive in 60-90% of patients. fluid cultures. Leptospira can also be detect- Cytologic studies of BAL fluid demonstrates ed by dark-field examination of bronchoal- the organism in 36-62% of the cases. The veolar lavage fluid. PCR methods have been latex agglutination assay for cryptococcal applied to rapid detection of Leptospira antigen is highly sensitive and may be present DNA in specimens of serum, urine, CSF and in more than 90% of immunosuppressed aqueous humor10, 11,12. patients with pulmonary cryptococcosis13,14,15.

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(b)Histoplasmosis clude fever, dry cough and dyspnea. Diag- It is a common fungal infection with a broad nosis is established by nebulized sputm and spectrum of pulmonary manifestations rang- BAL fluid examination. %. Both silver stains ing from acute pneumonitis, disseminated and direct fluorescent antibody test are use- military disease, extensive calcifications, fibro- fiil for detecting the organism. Transbron- sing mediastinitis, and cavitations. Serologic chial lung biopsy may be utilized if the B AL tests may be useful, but BAL and biopsy are examination is negative and the diagnosis is more sensitive and easily available. In patient in question.. Bronchoscopic examinations with disseminated disease, particularly in have a sensitivity of 55-919. AIDS patients, detection of Histoplasma an- tigen in urine by enzyme immunoassay is a sensitive and specific test. Bronchoscopy es- 3. Parasites (Table I) tablished the diagnosis in 71 of 469 patients with histoplasmosis. In 11% of these, bron- (a) Amebiasis choscopy was the only diagnostic method16,17. Entamoeba histolytica infests approximate- ly 10% of the world’s population. It is the (c) Coccidioidomycosis third leading parasitic cause of death world- Caused by Coccidioides immitis, this fugal wide. 90% of patients are asymptomatic; 10 infection has numerous pulmonary manifes- % have amoebic colitis. Other organs, par- tations, but most patients do not require any ticularly the liver, lung, and CNS are involved treatment. Two skin antigens, coccidioidin in 2-20% of patients. The different forms and spherulin are available. Skin tests are of pleuro-pulmonary amebiasis include: most beneficial in patients who are not from the endemic areas, but have recently travelled (i) Hematogenous pulmonary involvement through the endemic area, and have symp- without hepatic abscess. toms consistent with acute clinical syndrome (ii) Independent hepatic and pulmonary in- with erythema nodosum and pulmonary infil- volvement trates. BAL and a transbronchial lung biopsy (iii) Direct extension of the liver abscess into may show typical coci spherules clinching the the lung pleura or pericardium. Most pa- diagnosis particularly in imunosuppressed tients with pulmonary disease have neg- patients with diffuse lung disease. BAL fluid ative stool studies. Sputum examination should always be sent for cytology (Papani- or B AL may demonstrate trophozoites colaou stain), fungal stains (KOH, silver and establish the diagnosis; role of B AL stain) and culture18. is limited (20) The sensitivity of pleural fluid test is less than 10%. Serologic di- (d) Pneumocystis jiroveci (carinii) agnosis with ELISA is useful. Is a common cause of severe pneumonia among immunosuppressed patients both in (b) Schistosomiasis tropical and temperate countries. The epi- Schistosomiasis, also called bilharziasis, is one demiology of the disease has changed with of the most prevalent infectious diseases in the HIV epidemic. Common symptoms in- the world. It is endemic in more than 70 de-

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Table 1. Pulmonary symptoms caused by common parasites

Species Cough Wheezing Dyspnea Pnurmonitis Hemoptysis Chronic

Ascaris +++ +++ ++ +++ + –

Hookworm +++ +++ ++ ++ – –

Strongyloides +++ +++ ++ +++ – –

Visceral larva migrans +++ +++ ++ ++ – –

Pneumocystis +++ + +++ +++ – –

Toxoplasma + – +++ +++ – –

Entameba histolytica ++ – +++ +++ – –

Filaria ++ ++ ++ ++ – –

Schistosoma ++ – ++ ++ – –

Paragonimus ++ + ++ ++ +++ +++

Echinococcus – – – – ++ +++

– Usually absent; ++++ Key symptom veloping countries. The most prevalent area tosome infection in man, lung can be in- is Africa. The number of people affected is volved. Early and late pulmonary Schisto- more than 200 million. Although the lungs somiasis are two different types of disease are not an end organ in the life cycle of schis- with different clinical and radiological man-

Table 1I. Acute and chronic pulmonary schistosomiasis

Features Acute pulmonary disease Chronic pulmonary disease

Onset after exposure Weeks (4-8) Years

Population at risk Non-immune (travelers) Immune (living in endemic areas)

Pathogenesis Immune-complex disease Glanuloma formation

Clinical features Cough, fever, eosinophilia Dyspnea, cor-pulmonale

Chest x-ray Nodules, infiltrates Pulmonary hypertension

Diagnosis Ova in stools and urine Ova in stools, urine, lung biopsy tissue

Serology Helpful Unhelpful

Treatment Praziquental, Arthemeter Arthemeter

Outcome Good Only partially reversible

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ifestations (Table II).The usefulness of bron- of 100 cases bronchoscopy showed patho- choscopy and tissue biopsy has never been logical changes in 70%26. assessed, but they are unlikely to be of help due t ransom distribution of the granulo- (e) Strongyloidiasis mas. There are case reports in which open Strongyloides stercoralis is nematode infec- lung biopsy established the diagnosis but this tion has a worldwide distribution. Africa has in recommended21,22. the prevalence rates of 10-50%. Humans are infected through skin penetration by filari- (c) Paragonimiasis form larvae during contact with contaminat- Paragonimiasis is a helminthic zoonosis ed soil. Acute infection is characterized by caused by a lung fluke of the genus Parag- eosinophilia, cough, fever, and pulmonary onimus. Human disease is caused by inges- infiltrates and may be confused with tropi- tion of undercooked crabs and crayfish in- cal pulmonary eosinophilia. Chronic Strong- fected metacercarial larvae. Although found yloidiasis causes cough, dyspnea, and wheez- in Africa and Latin America, paragonimiasis ing. Disseminated (hyperinfection) occurs is endemic in Korea, Thailand, Laos, the predominantly in immunosuppressed or de- Philippines, China, and Japan. It is mainly a bilited patients. In these cases eosinophilia disease of the young. Ninety percent of pa- is absent. The sensitivity of stool examina- tients have the blood stained coffee-colored, tion is only 27-73%. The larvae, eggs, and rusty sputum. The physical examination is adult worms can be noted in wet prepara- usually unremarkable. The diagnosis is es- tions, Gram stain, and Papanicoalou stain of tablished by low-power microscopic identi- sputum. B AL, bronchial brushings, and fication of telltale opperculated eggs in transbronchial biopsy have been used27, 28. morning sputum examination, pleural fluid and stool. Bronchoscopy is more sensitive than routine sputum examination. Broncho- 4. Pulmonary eosinophilia (PIE) alveolar lavage and post-bronchoscopy speci- syndrome mens provide higher yield of organisms23,24,25. The association of pulmonary infiltrates and blood eosinophilia is recognized as pulmonary (d) Echinococcosis or Hydatid Cyst eosinophilia or pulmonary infiltration with disease eosinophilia (PIE) syndrome. PIE results from Echinococcosis is found in all those coun- the introduction of foreign material into the tries where humans have close contact with human body by different routes: ingestion, in- dogs and sheep. The disease is acquired by fection, inhalation, skin contacts, and vaginal ingestion of parasite eggs, which after pene- absorption. The parasitic causes of PIE are trating the intestinal wall gain an entry in to Filaria, Strongyloides, Schistosoma, Ascaris, the liver and lungs. Most cases are asympto- Trichnella, Ancyclostoma, and Paragonimus matic and are detected on a routine chest x- spp. The pulmonary infiltrates occur during -ray film. The diagnosis can be established larval mugration through the lungs and are usu- by finding protoscolices, hooklets or mem- ally transitory. B AL during the stage may re- brane in the sputum or B AL fluid. In a study veal eosinophils as well as larval parasites29.

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5. Tropical pulmonary eosinophilia References Can cause cough, wheezing, dyspnea, fever, night sweats, weight loss, fatigue, peripheral 1. King T. Interstitial Lung Disease in Text Book of Bron- eosinophilia, and diffuse miliary or nodular choscopy (Eds) Steven H. Feinsilver and Alan M. Fein. Williams and Wilkins, Balti- pulmonary infiltrates. The disease occurs more, USA 1995: 185-220 predominantly in males, with a male: female 2. Lamb C, Lederman E, Crum N. Bronchoscopy: Diag- ratio of 4:l, mainly in ages of 15 to 40 years. nosis and Interventional Approach in Tropical Pulmo- It is caused by immunologic hyper-responsi- nary Diseases in Tropical Lung disease, Second Edition veness to fllarial parasites and is prevalent in (Editor) Om P. Sharma. Taylor and Francis, New York, fïlarial endemic areas of the world, especial- NY 2006:95-116 ly South Eat Asia and South Pacific Islands. 3. Baughman R, Dohn M, Loudon R, Frame P. Bron- choscopy with bronchoalveolar lavage in tuberculosis and In many countries including India the ef- fungai infections. Chest 1991; 99; 92-97 fícient control of filariasis has drastically re- 4. Jett J, Corteze D, Dines D. The value of bronchosco- duced the incidence of tropical eosinophilia. py in the diagnosis of mycobacterial disease: A fíve-year experience. Chest 1981; 80: 575-578 5. Stenson W, Arnada C, Bevelaque F. Transbronchial Tropical granulomas bioposy cultures in pulmonary tuberculosis. Chest 1983; 83:883-884 In the tropics there are numerous causes of 6. Palenque E, Amor F, Bernaldo de-Quiros JC. Compa- pulmonary granulomas ranging from live rep- rison of bronchial washing, brushing and biopsy for di- licating intracellular organisms (bacteria, my- agnosis of pulmonary tuberculosis. Eur J Clin Microbiol cobacteria, fungi, viruses) to non-replicating 1987; 6: 191-193 metazoans (helminths) to inanimate substanc- 7. Thummakul T, Wilde H. Tantawichien T. Melioidosis, es (metais, chemical agents) and organic (ani- an environmental and occupational hazard in Thailand. mal and plant proteins) antigens. Parasitic Mil Med 1999; 164: 658-662 8. Khoo K, Cheng S, Tan Y. Endobronchial mass in a causes of lung granulomas are visceral leish- patient with Burkholderia pseudomallei infection. Ann maniasis (kalazar), metazoan tissue parasites Acad Med (sing) 2000; 29: 108-109 such as Tríchnella spp., nematodes such as 9. Bouvy J, Degener J, Stinjen C, Gallee M, van der Berg Ascasis luimbricoides, Toxacara canis and B. Septic melioidosis after a visit to Southeast Ásia. Eur trematodes such as Schistosoma mansoni30,31. J Clin Microbiol 1986; 5: 655-656 10. Bethlem E, Carvalho C.Pulmonary Leptospirosis. In Tropical Lung Disease. Second Edition (Ed) Om P. Shar- ma. Taylor and Francis, New York,NY 2006:431-454 Conclusion 11. Paganin F, GauzereB, Lugagne N, Blanc P, Robin X. The spectrum of tropical lung disease is vast. Bronchoalveolar lavage in rapid diagnosis of leptospiro- It is a significant cause of morbidity and sis. Lancet 1996; 347: 1483-1484 mortality in the developing countries. Most 12. Martinez -Garcia M. Pulmonary involvement in leptos- of theses illnesses are preventable if appro- pirosis. Eur J Clin Microbiol InfectDis 2000; 19:471-474 priate clinical and laboratory tools are avail- 13. Aberg J, Mundy J, Pwoderly W. Pulmonary crypto- able. Social upheavals, economic failures and coccosis in patients without HIV infection. Chest 1999; 115: 737-074 political crusades have destroyed the infra- 14. Saag M, Graybill J, Larsen R. et ai: Practice guidelines structure needed to provide the most basic for the treatment of cryptococcal disease. Clin Infect medical necessity. Dis 2000; 30: 710-718

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15. Malabonga V, Basti J, Kamholtz S. Utility of bron- 24. Sharma O. A man who loved drunken crabs: A case choscopic sampling techniques for cryptococcal disea- of pulmonary paragonimiasis. Chest 1989; 95: 670-672 ses in AIDS. Chest 1991; 99: 370-372 25. Scacewater R. Just another hemoptysis or a fluke? 16. Prechter G, Prakash U. Bronchoscopy in the diagno- MissouriMed2001;98: 515-516 sis of histoplasmosis. Chest 1989; 95: 1033-1036 26. Gottstein B, Reichen J. Hydatd Lung Diseases. In 17. Cortese D, Prakash. Bronchoscopy in Pulmonary In- Tropical Lung Disease. Second Edition (Ed) Om P. Shar- fections. Chapter 14, Bronchoscopy. Raven Press Ltd ma. Taylor & Francis Group, New York, NY 2006:327- New York, 1994: 188-198 -350 18. Sarosi G. Rapid diagnostic evaluation of bronchial 27. Woodring J, Halfhill H, Reed J. Pulmonary strongyloi- washings in patients with suspected coccidioidomycois. diasis: clinicai and imaging features. Am J Roentgenol Semin Respir Infect 2001; 164:238-241 1994; 162: 537-54 20. Sanchez A, Wilcox A, Sharma O. Pleuropulmonary ame- 28. Wehner J, Kirsch C. Pulmonary Manifestations of biasis. In Tropical Lung Disease, Second Edition (Ed) Om P. strongyloidiasis. Semin Respir Infect 19097; 12: 122-129 Sharma. Taylor and Francis, New York, NY 2006, 281-293 29. Vijayan V. Immunopathogenesis and Treatment of 21. Schwartz E. Lung involvement in Schistosomiasis. In Eosinophilic Lung Disease in the Tropics. In Tropical Tropical Lung Disease. Second Edition (Ed) Om P. Shar- Lung Diseae. Second Edition. (Ed) Om P. Sharma. Taylor ma. Taylor and Francis. New York, NY 2006: 351-365 & Francis Group, New York, NY 2006;195-239\ 22. Davidson B. the “lung shift” in treated schistosomi- 30. Vucinic V, Sharma O. Tropical Granulomas: Diagno- asis. Bronchoalveolar lavage evidence of eosinophilic sis. In Tropical Lung disease. pneumonia. Chest 1986; 89: 455-457 Second Edition.(Ed) Om P. Sharma. Taylor & Francis 23. Mukae H, Taniguchi H, Matsumoto N, liboshi H, Group. New York, NY 2006:173-193 Ashitani J, Matsukura S, Nawa Y. Clinicoradiologic fea- 31. Slotar D, Escalante P, Jones B.Pulmonary manifesta- tures of pleuropulmonay Paragonimus westermani on tions of HIV/AIDS in the tropics. Clin Chest Med 2002; Kyusu Island, Japan. Chest 2001; 120: 514-520 23: 355-367

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