Tuberculosis in Refugees from Southeast Asia

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-~lilliE CHEST editorials ---=-

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VOLUME 82 I NUMBER 2 I AUGUST, 1982

Histamine Receptors in the Lung The precise pathogenesis of asthma remains elu · sive. It is clearly multifactoral; the patient who wheezes only after a viral infection is different from the wheezing child with a strong family history of asthma, or from the factory worker who develops wheezing after exposure to wood dust. Furthermore, development of effective pharmacotherapy has been multifaceted. The major concentration in recent years has been on more effective use of methylxanthines and steroids, as well as the use of more specific beta-adrenergic agents. Although therapy with antihistamines has long been known to have some effect on airflow obstruction in asthma, antihistamines have not attained a prominent role in our understanding of the pathophysiology or treatment of this disorder. Recent work by a number of investigators has revived interest in the role of antihistamines in asthma. Animal and in vitro human studies have demonstrated the presence of H, and H2 receptors in the lung through the use of specific receptor antagonists. 1•2 In this issue of Chest (see page 143), Schachter and colleagues provide clinical evidence for the presence of H2 receptors in asthmatic patients, confirming recent work by Nathan et al. 3 The exact relationship between pulmonary H, and H2 receptors remains unclear. It appears that H, receptors have a predominant bronchoconstrictive effect, while H2 receptors modulate bronchodilatation. The effect of H, receptors is usually dominant, but the problem is one of balance. That is, there may be a block or deficiency of H 2 receptors in asthmatic patients rather than a greater number of H, receptors. Also, the effective proportion of each receptor probably varies in the same patient in different clinical settings. The work of Schachter and colleagues supports this concept as they were unable to demonstrate H2 mediated bronchodilatation in normal subjects. Animal studies have shown conversion of some H2 receptors to H, receptors during hypersensitization, 4 but it is not yet known if this happens in man. One's receptor status is therefore not likely to be a static defect, but intimately tied to the clinical setting. This interplay must be further defined before

this new information can be applied clinically. Although probably not useful in every asthmatic patient, therapy directed at histamine receptors has great promise for selected individuals. We may be able to exploit the relationship of H, and H2 receptors much as we have for beta, and beta2 adrenergic receptors. For example, H2 agonist aerosols may provide useful bronchodilatation. Specific H 1 antagonists may be useful in certain patients and are already being tested in clinical trials. Whether or not the information provided by Schachter and colleagues leads to new clinically therapeutic agents, this line of investigation will certainly improve our understanding of the pathophysiology of asthma. ]ames R. Myers, M.D. Providence, Rhode Island Providence VA Medical Center, Brown University. REFERENCES

Chand N. Distribution and classification of airway histamine receptors : The physiological significance of histamine H 2 -receptors. Advanced Pharm Chemother 1980; 17:10-31 2 Dunlop LS, Smith AP. The effect of histamine antagonists or antigen-induced contractions of sensitized human bronchus in vitro. Br J Pharmacal 1977; 59 :475 3 Nathan RA, Segall N, Schocket AL. A comparison of the actions of H 1 and H 2 antihistamines on histamine-induced bronchoconstriction and cutaneous wheal response in asthmatic patients.] Allerg Clin Immunol 1981; 67 : 17177 4 Chand N, Altura BM . Distribution of histamine receptor in mammalian airway smooth muscle cells. Cell Bioi 1979; 83 :237 (suppl)

Tuberculosis in Refugees from Southeast Asia Approximately 500,000 refugees from Southeast Asia have been admitted into the United States since 1975. Tuberculosis is prevalent in this population, and as such, has been a source of overrea~ tion in some areas of high resettlement density. Tuberculosis can represent a differential diagnosis CHEST I 82 I 2 I AUGUST, 1982

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problem for the U.S.-trained physician not familiar with other tropical lung diseases. Prior BCG vaccination and high prevalence of "primary" INH resistance further compound the picture. The prevalence among refugees is high for all stages of tuberculosis. 1·2 Approximately 60 percent of the refugees have a positive Mantoux skin test; 1 to 2 percent have active tuberculosis (abnormal See page 168 for discussion of paragonimiasis in SE Asian refugees

findings on chest films, acid-fast bacilli in the sputum); and 5 to 6 percent have inactive TB (stable chest films and negative findings on sputum study for acid-fast bacilli). Prior BCG vaccination accounts for some but not all of the patients with a positive skin test. Compared to the general population, the prevalence of active tuberculosis in the refugees is roughly 100 times greater. Diagnosis established by screening for tuberculosis at the refugee camps is not always reliable. Chest films consistently are of poor quality, and sometimes are mislabeled in terms of patients identity. Other tropical diseases (melioidosis, ascariasis, paragonimiasis, hooi:-worm infection, tropical eosinophilia, etc) should be included in the differential diagnosis of a refugee with pulmonary tuberculosis. Among these, paragonimiasis with its chronic hemoptysis, lung infiltrations, and pleural effusion3·8 deserves special consideration, since it can closely resemble tuberculosis. However, concern about paragonimiasis should never over-shadow that for TB. As a rule, paragonimiasis is a disease of low morbidity and mortality. It can never be a contagious disease in the United States because of the complex life cycle of the parasite. Moreover, with the potential coexistence of the two diseases, the documented diagnosis of paragonimiasis cannot rule out tuberculosis in a refugee from SE Asia. Current guidelines for INH chemoprophylaxis defined by the joint ATS I CDC recommendation 7 should apply to the refugees, regardless of prior BCG vaccination. The rationale for such a policy is manifold. First, INH chemoprophylaxis is safe when properly monitored. Second, protection from BCG vaccination is at best controversial. Finally, with borderline accommodations at the refugee camps, exposure to patients with active tuberculosis is almost unavoidable. Rifampin chemoprophylaxis has been proposed for people exposed to patients with INH-resistant tuberculosis.8 • 10 However, the prevalence of INH resistance among the refugees, although high, is not considered sufficient justification for a systematic 134

application of rifampin chemoprophylaxis to this population. It is unfortunate that BCG vaccination for prevention of tuberculosis is still practiced in many refugee camps, sometimes on the eve of the refugee's departure for the United States. There is no justification for this practice, and the U.S. health officials should take firm action to put an end to this approach to tuberculosis prevention. Primary resistance to INH among the refugee patients with active tuberculosis ranges from 10 to 30 percent;1·2•5 resistance to ethambutal ( EMB) and rifampin is negligible. Our experience over the last several years with triple drug therapy ( INH 300 mg, rifampin 600 mg and EMB 15 mg/kg daily dose) as initial treatment for SE Asian patients with active tuberculosis has been highly satisfactory. As a rule, cavities close, sputum conversion occurs and clinical status improves over four to six weeks of treatment, even in those who turn out to have resistance to INH. This result points to the high effectiveness of rifampin; it may also suggest the potency of EMB as a third antituberculosis drug in a triple-drug regimen for the population under consideration. Recent therapy based upon the dual bacteriocidal concept11·12 would recommend a four-drug regimen ( capreomycin, rifampin, INH and PZA), or at least a triple-drug regimen with PZA ( INH, rifampin and PZA) as initial therapy for patients with potential INH resistance. From our observation, we believe that triple drug therapy with EMB ( INH, rifampin and EMB at 15 mg/kg) deserves a fair reevaluation, at least in the population under consideration. However, EMB at high dose (25 mg/kg) should not be tried again, considering the severe optic neuritis observed in many refugees subjected to this treatment overseas prior to their arrival in the United States. Low zinc levels in the blood have been speculated to be the reason for the frequency of this complication in refugees.13·14 The risks of spreading tuberculosis from the refugee patient are not significant. Contagiousness of tuberculosis stems from poor compliance and transient life style of patients with active disease. Clearly, this is not the case with the refugee patient whose compliance, as a rule, is more than satisfactory, and whose location is listed in several federal and local registries. Tuberculosis in the refugee from SE Asia is a well-defined problem with a predicted end Unfortunately, for political reasons and/or budgetary strategies of agencies concerned, the issue of refugee tuberculosis has periodically reached the front page headlines of lay press, inflated to a "crisis" proportion. Probably, one should add an extra guideline to tuberculosis control procedures-that Editorial•

is, that human suffering and disease should never be used for political leverage and expediency.

Vu-Dinh Minh, M.D.; Thomas]. Prendergast, M.D.; and Paul Engle, M.D., Orange, California Department of Medicine, University of California, Irvine, and Orange County Public Health Department, Santa Ana. Re,mt requests: Dr. Minh, Pulmonary Division, UCI Medical Center, 101 City Drive, Orange, California 92668 REFERENCES

1 Center for Disease Control. Update on refugee health status. Morbidity and Mortality Weekly Rep 1975; 24: 267-68 2 Center for Disease Control. Health status on Indochinese refugees. Morbidity and Mortality Weekly Rep 1979; 28:385-98 3 Mayer GJ. Pulmonary paragonimiasis. J Pediatr 1979; 95:75-6 4 Minh VD, Engle P, Greenwood JR, Prendergast TJ, Salness K, Sinclair R. Pleural paragonimiasis in a S.E. Asian refugee. Am Rev Respir Dis 1981; 124:186-88 5 Coleman DL, Root RK. Pulmonary Infections in S.E. Asian refugees. Clin Chest Med 1981; 2 :133-43 6 American Thoracic Society. Preventive therapy of tuberculosis infection. A statement by an Ad Hoc Committee. Am Rev Respir Dis 1974; 110:371 7 Preventive treatment of tuberculosis: A joint statement of the American National Tuberculosis and Respiratory Disease Association and the Center for Disease Control. Am Rev Respir Dis 1971; 104:460-65 8 Fairshter RD, Randazzo GP, Garlin J. Failure of INH chemoprophylaxis after exposure to INH-resistant tuberculosis. Am Rev Re~pir Dis 1975; 112:37-42 9 Koplan JP, Farer LS. Choice of preventive treatment for isoniazid-resistant tuberculous infection. JAMA 1980; 224:2736-40 10 Glassroth J, Robins AG, Snider DE Jr. Tuberculosis in the 1980's. N Eng! J Med 1980; 302:1441-50 11 Dutt AK, Stead WW. Chemotherapy' of tuberculosis for the 1980's. Clin Chest Med 1980; 1:243-52 12 Grosset J. Bacteriologic basis of short course chemotherapy for tuberculosis. Clin Chest Med 1980; 1:231-42 13 Wong EK, Leopold IH. Zinc deficiency and visual dysfunction. Metabolic and Pedmtr Ophthalrnol 1979; 1: 1-4 14 Wong EK. Personal communication

Case Reports of Untoward Drug Reactions, Adverse Events, and Rare Diseases The problem is a shortage of page space. Only a small number of the case reports submitted to scientific medical periodicals can be accepted for publication. Most editorial boards attach the highest priority to reports of clinical investigations in a consecutive series of patients. Editorial responsibility for publication of data from clinical trials and other multiple subject studies limits space for single case

studies. This shortage of page space grows more serious as the volume of excellent research increases throughout the world. Although we recognize the educational merits of a carefully described case study, the Editorial Board members of this periodical can justify publication of case reports only if these data establish new principles or modify cu"ently accepted concepts. There is no longer room for the description of the "sixth case" of a new syndrome, and we experience a similar inability to publish every report of adverse drug reactions. Problems related to documentation of case reports come at a particularly inopportune time in the historic development of pharmacologic management of diseases. There is current stress on prophylactic administration of drugs to reduce the risks of degenerative diseases in high risk patient populations. Oliver1 noted that the emphasis must be shifted away from analyzing shortterm toxic effects of drugs toward identification of unexpected adverse reactions occurring after years of drug administration. He reported that potentially serious adverse effects from such agents as practolol administered after myocardial infarction, the lipid lowering drug clofibrate, and the use of bendroflumethiazide for therapy of hypertension, appeared several years after the continued administration of the drugs. Where will the clinician obtain information about the short- and longterm potential risks of therapy if medical periodicals cannot publish all reports of toxic effects of new pharmacologic agents? Currently, the practitioner can report his observations to the Food and Drug Administration or to the manufacturer. A short 13-element form for reporting a potential adverse reaction is attached periodically to the Food and Drug Bulletin which is sent to most health professionals. This form can be sent to the Adverse Drug Reaction Monitoring Program, Department of Drug Experience, the Food and Drug Administration, Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857. Isolated reports of hepatic toxic reactions to the drug ticrynafen (from clinicians all over the country) provided enough information for the Food and Drug Administration to identify clearly the risks attendant to such therapy and the drug was withdrawn from the United States market. In other instances, reports submitted directly to the manufacturer have provided the necessary data for evaluation of potentially serious side effects. The United States Pharmacopeia Convention, Inc has devised a method that incorporates convenient mailing forms for reporting problems with medical devices. All data returned to the USP are rushed to the FDA and the manufacturer. Mass mailings of these conCHEST I 82 I 2 I AUGUST, 1882

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