Document 5kdjVzgZKpb6LJRVEpyjkwmOz

FILE NAME: Talc (TALC) DATE: 1996 DOC#: TALC174 DOCUMENT DESCRIPTION: Journal Article - Atypical Mycobacteriosis as a Complication of Talc Pneumoconiosis C- Eur Resptr J, 1996, 9, 1757-1759 DOI 10 1183/09031936 96 09081757 Printed in UK - ali rights reserved dsspY'tf&rx X V<rf. ^-.jyJ^P-n-S^ Copyright <-bHS Journals Ltd 199 European Respiratory Journal ISSN 0903 - 1936 CASE REPORT Atypical mycobacteriosis as a complication of talc pneumoconiosis C. De Coster*, J.M. Verstraeten**, P. Dumortier*, P. De Vuyst* Atypical mwobactei msis as a complication of talc pneumoconiosis C De Costei, J M Verstraeten, P Dumoitiei, P De Vuyst ERS tournais Ltd 199b ABSTRACT: A 57 year old man, receiving compensation for talc pneumoconiosis since 1977, was' admitted to hospital for the first time in 1987, with symptoms of weight loss, fever, dyspnoea and productive cough. A chest roentgenogram showed bilateral cavitation. Two years later, Mycobacterium xenopi was found in sputum cultures. Despite specific oral antibiotherapv, the patient's health deteriorated and he died in 1990. To the best of our knowledge, this is the first reported case of an association of talcosis with a M. xenopi pneumonia. The relative timing of the two diseases sug gests that talc pneumoconiosis predisposed to the infection by M. xenopi. Em Respti J , 996, 9, 1757-1759 'Chest Dept, F.tasme Univcisiry Hospital, Universit Libre de iruselles Brussels '"' Akademisch Ziehen luis Sint Vincentius Ghent, Belgium Coircspondence P De Vuyst Chesi Seivae Erasme Inn crsity Hospital S08 lout, tie Lenmk B-1070 Bius-els Belgium K eyw oids Atypical mycobacteria talc pneumoconiosis Received September 19 199s Accepted altei levision Pebi uars 20 iOyo Case report The patient, born in 1932, worked as a talc miller horn 1969 until 1980 m a Belgian factoiy. The raw material was imported mainly irom Montana, US (Yellowstone). Talc was crushed without addition ol other mateiials and seived as a high giade talc lor pharmaceutical puiposes. The patient had never previously been exposed to other mineials ie g, silica, asbestos) and had a smoking his tory of 35 pack-years. In 1977, the diagnosis of talc pneu moconiosis was made, essentially on the basis of a chest radiograph. In 1983, chest radiographs showed a progiession of the small opacities (graded q/q 2/2 according to a) the International Laboui Office (ILO) classification) and the appearance of a laige opacity in the tight tippet lobe (graded A) (fig la) The results of pulinonaiy function tests at that time were as follows foictd vital capacity (FVC) 2.7 L (65% of predicted), lorcec cxpiratoiy vol ume (FEVi) 2.3 L (73% pied); total lung capacity (TI.C) 5.2 L (91% pied); and transfer factor of the lung lot caihon monoxide (73.,CO) 61% pred. A oronchoah eolar lavage (BAL) performed in 1983 showed abundant talc particles, talc bodies and traces of trem ilite [11 Quart/ was not detected m the BAL fluid, but due to the con siderable amount of talc panicles, tince1- of quarL/ could have remained undetected by this method b) big 1 - a) Chest radiograph m 1983 showing bilaieial rounded opacities and a large opacity in the right uppet loix 1987. showing piogrcssion of the lesions with cavitations ol both uppei lobes b- Q ium uiihograph m 1758 C. DE COSTER ET At. In 1987, at the age of 55 yrs, the patient was admit ted to the hospital with symptoms of fever, dyspnoea and purulent sputum. Theic was also a significant weight loss (38 kg body weight for 1.65 m). Chest radiographs showed a progression of the large opacity in the right uppei lobe and cavitations of both upper lobes, predominating m the left uppei lobe (fig lb). Pulmonary function tests showed a deterioration of the spirometric values: FVC 1.4 L (35% pred): FEV 0 6 L (21% pred); residual volume (RV) 4.0 L (190% pred); and 7L.CO 11% pred. The sedimentation late reached 107 rnm-h'1 and the white blood cell count 7xl0l) cells-L1). Aitenal blood gas examination disclo sed severe hypoxaemia (arterial oxygen tension (Pa.O,) 4 9 kPa (37 mmHg)) Sputum smears for bacteria and acid-fast bacilli were negative. Clavulanic acid + amoxy cillin had no effect on the fever but the patient recov ered aftei antibiotic treatment of 10 days duration with co-trimoxazole. In 1988, the patient was once moie admitted because of fevei and chest pain. A chest radiograph showed a "hydroaenc level" in the right upper lobe. Blood cultures wcie negative and theie weie no pathogens detected m the sputum. Oial antibiotherapy with co-tnmoxazole was administrated for 3 days, followed by cefuroxime One year later, he was again admitted to the hospital with the same symptoms, chest radiographs showing a progres sion of the cavitary lesions. At that tune, the sputum cultuie yielded 20 colonies of Mycobartei turn xenopi hut was negative for Mycobactenum tuberculosis. Oral rifampicin, 600 m g-day1, and isoniazid (INH), 300 m g-day1, were initiated. However, because M. xenopi was resistant to INH, it was replaced by ofloxacin (400 mg d a y 1). Four months later, the patient was admitted for the last lime because his condition had deteriorated. He develo ped severe renal failure, anaemia, leucocytosis and shock. Despite intensive care, the patient died a few days later Discussion The fust penod (1977-1987) of this patient's disease is dominated by the diagnosis and the compensation tot talc pneumoconiosis ("occupational" period). The second is dominated by mycobacterial infection leading to death (1987-1990) ("infectious" period). Knowing the diagno sis of M xenopi infection, it is difficult to define its exact onset. On the ladiogiaph fiom 1983, it is possible that the right uppei lobe opacity already corresponds to an infectious process. Nevertheless, the discussion will con sider two phases m the patient's evolution: the talc pneu moconiosis and the M xenopi infection, and the possible lelationship between them. Talc pneumoconiosis in an uncommon pneumoconio sis, which classically requires a long duration of expo sure to a high concentration of dust [2, 3], Cigarette smoke appeals to increase the risk of developing this disease. In the present case, the piolonged exposure to high lev els of lespirable talc paitides, together with the presence of diffuse, bilateial, small, rounded opacities on chest radiogiaphs is compatible with the diagnosis of talcosis [2, 3] BAL confirmed the retention of a very high con centration of talc pai tides. The clinical and radiological data were compatible with previous descuptions of pneu moconiosis in talc-exposed workers, so that ro lung biop sies were taken The Belgian Occupational Disease Fund agreed to lecognizc and compensate this di .ease Large opacities are also dcscnbed in talcosis. and the abnormalities m the right upper lobe on the chest ladiograph from 1983 were also consideied as a pait of the pneumoconiosis However, the fact that thn lesion was unilateral should have been considered as atypical This underscores the problem of differential diagrosis of lung opacities appearing in pneumoconitmc subjt cts, usually considered as comotic masses without any <omplemenlary investigations. Furthermoie, there was a cleai pro gression of the bilateral small opacities. No prior exposuie to other mineral dust had been detected, and even if a few tremolite asbestos fibres weie found in BAL, there were no evident signs of asbestosis (no pleural plaques oi thickening, no evidence of interstitial fibrosis) The fact that the asbestos type was tiemolite sugiests a pos sible geological contamination of talc [1] It is actually admitted that M xenopi cai be patho genic for humans and lead to severe disease, but lung dis eases due to this mycobacteiial species aie nut Undeilying pre-existmg pulmonary diseases, such as pulmonaiy tubeiculosis, chronic bronchitis, emphysema, bronchiectasis, interstitial pulmonary fibrosis, lung caicinorua and saicoidosis, are predisposing factors for.W xenom infection [4 6|. Diagnostic oitcna exist foi identifying pulmonais disease where M xenopi is considered to be a pathogen, including repeated positive cultures, an abnormal chest roentgenogram consistent with mycobacterial infection, and absence of other pathogens m the sputum (4, 6) Various radiographic manifestations of M xinopi infec tion are described from multiple nodular shadows Lo cavi tary lesions [7], The clinical and radiological evolution of our patient since 1987 is consistent with a chronic lung infection by mycobacteria. M xenopi was found twice in sputum cultures, whereas M tubeit ulosis was never detected and could be excluded Theiefore, accord ing to mycobdctcnological and loentgenogiaphic eiitcria, it is obvious that the patient died fiom destructive lung infection by M xenopi Theie arc only a tew cases described in the hteiature in which lung disease caused by M xenopi led to death [4, 5, 7) As far as we know, this is the first case icpoit of the association of talc pneumoconiosis and lung infection by M xenopi Even if the succession of these iwo uncom mon diseases in an individual case could be purely coin cidental, this seems unlikely, and several clues suggest that the presence of talcosis predisposed to the secondary infection by M xenopi A parallel situation occurs m sili cosis, another pneumoconiosis which is a well-known predisposing condition for tuberculosis or even nonlubeiculous mycobacterial disease [8, 9| The met eased susceptibility to these othei diseases could bt explained by impaired function of macrophages due to silica ]1(). 11J. Alveolar macrophages are important m the defence against mycobacteria, not only through their phagocytic and bactericidal activities, but also through the amplifi cation of the host defence by the release oi cytokines (inteileukin-l|3 (IL-ip) and tumour necrosis fuctot-u (TNF-a)) [12]. In the case of talc pneumoconiosis, in which macrophages are ovei loaded by talc pai tide-, it t . conceivable that these activities can be lnipaucd ATYPICAL MYC OB ACTERIOSIS IN TALC PNEUMOCONIOSIS 1759 In conclusion, this case study suggests that lung infec tion by mycobacteria, at least M xenopi, can complicate talc pneumoconiosis. In such a situation, it should be considered as a part of the occupational disease and com pensated as well. References 1 De Vuyst P, Dumortier P, Lophonte P, Vande Weyer R, Yeinault JC. Mmeralogtcal analysis of bronchoalveolar lavage in talc pneumoconiosis. Eur J Resptr Dis 1987, 70. 150-156. 2 Lophonte P, Fabie J, Foitune JP, Pincemm J, Delaude A. Les silicatoses pulmonaires Poumon Coeui 1978; 3' 193-201 3 hr Parkes WE, ed. Occupational Lung Disoiders. 2nd edn London, Butteiwoiths, 1982, Chaptei 9, pp 296 -310. 4 Smith MJ, Citron KM Clinical review of pulmonary disease caused by Mvtobaitamm xenopi. Thoiin 1983, 38 373 377 5 Banks J, Hunter AM, Campbell 1A Jenkins PA Smuh AP Pulmonary mlection with Myi abac teuum xenopi review ol uealment and response 1not ax 1984 39 376-382 6 Wolinsky E Nontubeiculous m>cob<aeua and asso ciated diseases Am Re\ Respu Dis 1971, 119 107-179 7 Simoi AE, Salit IE, Vellend H The iole ol M\t obai lenwn xenopi m human disease Am Rev Respu Dis 19X7, 129 435-438 8 Moigan E J Silicosis and lubeiculosis Clusr 1970 77 202-203 9 Smdei DE The relationship between tuberculosis and silicosis Am Rev Respu Dis 1978, 118 455-460 10 Lowne DB What goes wrong with the mauophage m silicosis' Eui J Respu Dis 1982, 63 80-182 11. Wallace RJ, O'Brien R, Glassroth J, Raleigh J, Dutt A Diagnosis and Uealment ol disease caused by nontubei culous mycobacteua (ATS official statement) Am A'<> Resptr Dis 1990, 142 940-953 J2 Rom NW, Zhang Y The using tide ol tubeuulosis and llte human hosl response to Myt obaaei run mbeii ulosis I Lob Clin Med 1993, 121 737-741 CT^ The New England Journal of Medicine R CCOI'jLS o 1 tin ( a s s a c l v u s c t t s t j p u p i ' al . H o s p i t a l Weekly Clinicopa-tholojyical Exercises F O U N D E D BY R I C H A R D C CABO' l R j blri E Sc u l l y , M D , Editor E u g i n l J M ar k, M D , Associate Editor Wi i i i a m F M c N l l i y , M D , Associate Editor S ai i i H E r f i i n g , L ucy D P i i i i i m , and Si ACM M El I l.NDLR, A ssistant Editai * ditional bilateral nodules. There was no hilar or me diastinal lymphadenopathy A thoracic computed to mographic (CT) scan (Fig. 2) revealed a spiculated mass in the periphery o f the right upper lobe and multiple smaller nodules, 2 to 5 mm m diameter, in the lower lung zones. Microscopical examination of a specimen from a needle-aspiration biopsy o f the mass in the right upper lobe was reported to show adenocarcinoma. The patient's cough improved, but slight exertional dyspnea persisted. He came to this hospital. The patient was retired from a job in a rubber plant, Case 21-1999 PRESENTATION OE CASE A 69-year-old man was admitted to the hospital be cause of the radiologic finding o f pulmonary nodules. The patient had been well until several weeks ear lier, when a cough, fever, and dyspnea developed. A thoracic radiograph obtained at another hospital 11 days before admission (Fig. 1) showed an irregular nodule, 2 bv 1.5 cm, in the right upper lobe and ad- J Figure 1. Posteroanterior Radiograph of the Chest Showing an Irregular Nodule in the Periphery of the Right Upper Lobe. B Figure 2. A CT Scan through the Right Upper Lobe (Panel A) Showing an Irregular Nodule, and a CT Scan through the Low er Lung Zones (Panel B) Showing Multiple Nodules, 2 to 5 mm in Diameter. 182 July 15, 1999 Downloaded from www nejm.org at HHS LIBRARIES CONSORTIUM on April 12, 2006 Copyright 1999 Massachusetts Medical Society All rights reserved CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL T a b l e 1. H lm a io u iw c , and Bio o n C hem ical V alues V ar iable Heinarocrit {%) Mean corpuscular volume (un3) While cell count (per mm3) Platelet count (per mm3) Sodium (m inol/laer) Potassium (mmol/hter) Chloiuie (mmol/hter) Caibon dioxide (m m ol/htei) Uiea nitrogen Cieatmme Glucose V alue 379 92 6,900 245,000 142 5 3 102 301 Normal Normal Normal T able 2. R e s u l t s o f P u l m o n a r y - F u n c t i o n T e s i s V a r ia b le * R esult value (% o f predicted) FEV, (litas) Vital capacity (liters) FEV) vtl il capacity Flow iace at 50% o f vital capacity (liters/scc) Maximal bieathing capacity (lirers/min) Total lung capacity (hteis) Residual volume (liters) Residual volume total lung capacity Airway resistance (cm o f water/Iiter/sec) Specific conductance (liteis/sec/cin ot water Single-breath carbon monoxide diffusing capacity (m l/m m /m m Hg) Carbon monoxide diflusmg constant (ml/imn/nim Ilg) Oxygen saturation (%) 1 49, 1 64f (49) 2 51, 2 75f (64) 0 59 (76)$ 1 04 (23) 52 (49) 9 8 (176) 7 29 (324) 0 74 (180) 1 28 0 0971 16 0 (6 7 ) 4 4 (96) 9 9 U, 9 7 * * *FEV, denotes forced cxpiratoiy volume in one second t'Hus value was obtained after the patient had inhaled a bronchodil tror medication The value was based on the first measuiements o f FEV, ind vital capacity The predicted range is 0 8 to 2 4 cm o f water per litei per second JThe predicted value is more tlian 0 1 2 litei per second per centimeter ot water ||This value was obtained while the patient was breathing ambient an at rest **T h is value was obtained after rhe patient had walked for three mmures where he had been exposed to talc for 28 years. There was no history o f exposure to asbestos He had smoked two cigarettes daily for six years He re sided in Arizona and was physically act ve. His med ications were metoprolol, quinapril, and tciazosin There was no history o f sputum production, wheez ing, hemoptysis, chest pain, tuberculosis or expo sure to it, coccidioidomycosis, weight loss, or a ma lignant tumor. The temperature was 3 6 .8 C , the pulse was 67, and the respirations were 20 The hi nod pressure was 1 2 0 /8 5 mm Hg. On examination, the patient was a slim man who appeared well. The lungs were clear except for a few rhonchi on the right side. Laboratory tests were performed (Table 1). An electrocardiogram revealed a sinus bradycardia at a rate o f 50, with nonspecific ST-segment and T-wave abnormalities The results o f pulmonarv-function studies performed at the other hospital are shown in Table 2. A diagnostic procedure was performed. DIFFERENTIAL DIAGNOSIS D r . S imon D. S pivack*: This panent had an ill-defined respiratory illness characterized by fever, cough, and dyspnea. Since his cough improved with out any known treatment, one can rule out the com mon acute, bilateral, bacterial pneumonias, such as those due to Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae, particular ly in the absence o f known exposure to these organ isms. If the patient was immunocompromised, how ever, a lung biopsy would be needed to rule out these infections. Systemic immunocompromise, such as that caused by the T-ccll deficiency associated with lymphoma, infection with the human nnmunodefi ciency virus (H IV ), and use o f corticosteroids or cy closporine; the B-cell deficiency associated with mul tiple myeloma; neutrophil deficiency; or the combined deficiencies that may follow an allogene c bone matrow transplantation, predisposes a host to infections with particular sets of organisms, depending on the critical elements o f the host's defense that are lack ing. Since this patient had no apparent risk factors for disseminated tuberculosis or pneumocystis pneu monia, these diagnoses are unlikely. May we review the radiographic findings5 D r . J o -Annf. O. S hepard The chest film (Fig 1) obtained before admission shows an irregular nod ulc, 2 by 1.5 cm, in the right uppei lobe, as well as smaller bilateral nodules. The C T scan (Fig. 2) shows the irregular nodule in the posterior segment of the *Attending physician, Pulmonary ami Criticil Caic M cJiun c, Albans Medical Center, associate professoi, Albany Medic.il Colli gc, icscauh ph\ sician, New York State Dep.utment ot Health, Division oi Himnn loxicol ogv and Molecular Epidemiology -- all in Albany Volume 341 Numb, l 3 183 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12, 2006 Copyright 1999 Massachusetts Medical Society All rights reserved The New England Journal of Medicine right upper lobe and numerous bilateral nodules, 2 to 5 mm in diameter, in the lower lung zones No lymphadenopathy or pleural plaques were visible. D r . S p i v a c k : Since the patient had radiographi cally stable disease without treatment over a period o f at least 11 days, we can rule out acute bacterial processes, such as those attributable to Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneu moniae, and oral anaerobes. In the absence o f a his tory o f exposure and without a report o f positive re sults o f skin tests with purified protein derivative, localized Mycobacterium tuberculosis infection is un likely. There is no clinical evidence that the patient had preexisting pulmonary abnormalities that might have made hint susceptible to bacterial overgrowth, such as cavitary disease, which may lead to the for mation o f an aspergilloma. Nor is there ciliary dys kinesia syndromes or cystic fibrosis in this case. The radiologic finding o f bilateral small, nodular opacities suggests the presence o f an underlying sub acute or chronic lung process. The differential diag nosis o f small nodules in this context includes exog enous as well as idiopathic and malignant disorders. Subacute infections such as coccidioidomycosis, blas tomycosis, histoplasmosis, and miliary tuberculosis may account for the small nodules. There was no ap parent evidence o f exposure to M. tuberculosis or a predisposition to miliary tuberculosis, however, and there is no information about skin testing. Nodules and airflow abnormalities are typical o f pneumoco nioses, such as talcosis and silicosis, as well as hyper sensitivity pneumonitis due to exposure to an organ ic antigen or beryllium, but the history in this case does not suggest either type o f exposure. Moreover, the patient's pulmonary dysfunction is not charac teristic o f asbestosis, mixed-dust disease, or exposure to heavy metals. Idiopathic disorders, including sarcoidosis, eosin ophilic granuloma, and bronchocentric granuloma tosis, may be accompanied by fever early in the course of the disease and may be associated with obstruc tive or mixed obstructive and restrictive pulmonary dysfunction. Lymphocytic interstitial pneumonitis is an unlikely diagnosis in the absence o f progressive dyspnea, cough, and underlying disease. Similarly, Churg-Strauss vasculitis is unlikely in the absence o f preexisting atopy or reactive airway disease. This pa tient may have had a bronchiole-based disorder, such as bronchiolitis obliterans or bronchiolitis obliterans with organizing pneumonia, particularly in view of the profound air trapping, with the preservation o f large airway conductance and resistance. Patients with malignant tumors present infrequently with bilateral small nodules. Non-Hodgkin's lympho ma is an unlikely diagnosis in the absence o f periph eral or hilar lym phadenopath y. P atients w ith bronchi- oloalveolar-cell carcinoma may present with nodular or alveolus-filling lesions. Lymphangitic spread o f car cinoma or leukemia may also be characterized by the presence o f such lesions. I shall return to the possi bility o f a malignant tumor. Coccidioidomycosis deserves serious consideration in this case because the patient lived in Arizona Coccidioides immitis is present in soil and is endemic in the southwestern United States Clusters o f cases in other areas have been attributed to dust storms that carried the pathogen to distant sites 1The tun gus is dimorphic, existing as a saprobe or a parasite Mycelial forms grow in soil and disarticulate, releas ing arthroconidia into the air, which are inhaled bv the host. Person-to-person transmission and indirect transmission through secretion-to-wound contact are very rare 13 Respiratory isolation is therefore not re quired. Inhalation o f arthroconidia from soil is vntually the only route o f entry into the human host, placing those who have frequent contact with con taminated soil, such as archaeologists and excavators, at highest risk. The immune response is partly T-celldependent, and the infection has increased among HIV-infected persons who live in the Southwest The parasitic portion of the life cycle entails the rc lease o f a substance with elastase activity that pro motes the degradation o f molecules in the connec tive-tissue matrix o f the host, resulting i.i the spread o f infection and the formation of the microcysts or macrocysts seen on microscopical examination 13 Clinical evidence o f disease is barely apparent in approximately 60 percent o f patients with acute pri mary infections In these patients, symptoms are ab sent or, if present, consist o f a mild cough and lowgrade fever, making them difficult to distinguish from the symptoms o f an upper respiratory tract in fection The remaining 40 percent o f p ttients ha\ c an illness one to three weeks after exposure that of ten mimics a lower respiratory tract infection, with fever, diaphoresis, dyspnea, chest pain, sputum pro duction, anorexia, arthralgias, and weakness Radio logic examination may show an infiltrate, an effusion, hilar lymphadenopathy, or a combination of these findings. Skin manifestations include enthroderma, erythema nodosum, and erythema multiforme With out specific therapy, the primary infection resolves spontaneously within several weeks in most cases Radiographic residua in the form o f nodules or thinwalled cavities are present in 5 percent of such cases Spontaneous clinical resolution and radiographic re sidua were features o f this patient's illness at the time of admission. Extrapulmonary disease, which develops in less than 1 percent o f patients with C. immitis infections, in cludes meningitis, osteomyelitis, septic arthritis, geni tourinary infection, and skin involvement The men ingitis may be subtle in terms o f both clinical findings a n d c e r e b r o s p in a l fluid characteristics, wai ranting d i agnostic vigilance. In regions where the infection is endemic, rapid and widespread dissemination in nn- 184 July 15, 1999 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12, 2006 Copyright 1999 Massachusetts Medical Society All rights reserved CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL munocompromised patients has closely paralleled the epidemic o f the acquired immunodeficiency syndrome. Patients receiving corticosteroids or other T-ccll sup pressants, infants, and nonwhites (particularly Filipi nos, for unclear reasons) are also susceptible to coc cidioidomycosis.13 The diagnosis can be confirmed by examination of smears of aspirated fluid from pulmonary or other sites. False positive results may be caused by the pres ence o f contaminating pollens from mulberry, cot tonwood, and elm trees.4 False negative results may be due to sampling error or a failure to alert the cytopathologist to the possibility o f C. immitis infec tion. As in this case, reactive atypia o f pneumocytes is often seen in cytologic aspirates, and if spherules are undetected, the reactive atypia may be mistaken for carcinoma.1' 7 Tissue-biopsy specimens are supe rior to cytologic aspirates for direct visualization of the organism; the large endosporulating spherules are readily visible with routine staining. Culture of the organism is possible but poses a major biohaz ard. Growth is generally visible within three to four days, although the yield is reduced in patients with HIV infection. Skin testing shows a delayed type o f hypersensitivity to intradermally injected antigen in 93 percent o f patients 14 days after the onset o f symp toms, and in 99 percent at 21 days.8 An area o f in duration, at least 5 mm in diameter, that develops 24 to 72 hours after injection is considered a posi tive result, and determining the result within this pe riod reduces the false positive rate.9 Waning o f the reaction is slow, and a positive skin test therefore does not indicate the date o f onset o f the infection. C on versely, anergy, which may result from overwhelm ing infection, impairs the sensitivity o f the test. Serologic testing is very useful for diagnosing C. immitis infection. Primary infection elicits IgM antibodies in 90 percent o f symptomatic patients within one to three weeks after the onset o f symp toms, as detected by tube-precipitin, immunodiffu sion, or latex-agglutination tests. Tests for comple ment-fixing IgG antibody become positive weeks after the onset o f symptoms -- after the IgM response -- and the titer may parallel the disease activity and dis semination. False positive results can be caused by cross-reactivity o f the organism with Histoplasma capsulatum and Blastomyces dermatitidis. Serologic results may be negative if infection is confined to the meninges. Methods that circumvent these problems are being developed, such as direct detection o f cir culating antigen and detection o f circulating genom ic material by the polymerase-chain-reaction assay.13 Inhalation o f talc may explain the bilateral micronodular disease in this patient. Industrial-grade talc is commonly used to dust rubber products; it is lu bricating, flaky, fibrous, and chemically inert. Talc is a hydrous magnesium silicate that also contains iron and trace amounts o f aluminum. Industrial talc of ten contains mixtures o f silicate, tremohte, amphi bole and serpentine asbestos, anthophyllite, and oth er talcose rocks. The content depends on the mining source, and contamination by silica and asbestos has caused considerable confusion about the Abrogane lty and carcinogenicity o f talc 1011 Obtaining a pre cise history o f exposure to talc, induci ng the respi ratory protection used and data on confounding exposure, such as exposure to other dusts or to to bacco smoke, is often a problem. Inhalation is the most frequent form o f exposure to talc. Although most talc-related illnesses are caused by exposure during the milling and processing o f talc, industrial use o f the end product, and even the use o f talc in high doses for personal care have caused respiratory illness.10'12 Among the respiiatory diseas es associated with the inhalation o f talc hat does not contain silica or asbestos is talcosis, a dilaterai, dif fuse, micronodular, granulomatous disease affecting the pulmonary interstitium, with acute or chronicbronchitis. Emphysema with the formation o f bullae may be present. The microscopical fincings include diffuse interstitial fibrosis, occasionally with bron chial or bronchiolar distortion, ill-defined nodules with birfringent talc particles but with little of the whorled collagen that is characteristic of silicosis, and foreign-body granulomas with or without inter stitial and pleural fibrosis.1314 Pleural plaques may be present, especially after exposure to asbestos-con taining talc. Reactions to pure talc usually result in less fibrosis than those to talc that contains silica, as bestos, or both. Although there is a general dose-response rela tion in talcosis, progressive disease can occur in the absence o f continued exposure, leading to progres sive dyspnea, weight loss from labored bicathmg and hypoxia, and cor pulmonale with eventual right-sided heart failure. This patient had mild dyspnea and was slim, but no signs o f profound hypoxia or cor pul monale were apparent on physical examination or on the electrocardiogram. In patients with talcosis, chest radiographs typically show interstitial infiltration or granulomas in the midzones and bases o f the lungs, with sparing o f the apexes, in contrast to the distri bution of lesions in patients with silicosis Since talc is frequently mixed with silica and asbestos, the clin ical and radiographic findings associated with these three dusts may merge Both restrictive and obstruc tive disease can occur and even coexist n talcosis, as in other granulomatous diseases such as silicosis and sarcoidosis. Both airflow obstruction and small-air way disease have been observed m talc workers in the rubber industry.12'13 Symptoms are often mild, despite abnormalities on radiographs and pulmo nary-function testing, again as with silicosis and sar coidosis. Rubber workers who have never been exposed to talc may have " industrial bronchitis" that persists m- Volum e 341 N um bci 3 185 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12, 2006 Copyright 1999 Massachusetts Medical Society. All rights reserved The New England Journal of Medicine definitely after their exposure to rubber has ceased and they have retired. Multivariate analyses stratified for the confounding influences o f cigarette smoking and preexisting lung disease suggest that, in addition to talc, fumes from curing and other particulates in volved in rubber manufacturing are important air way irritants. 12'16'ls The biopsy report o f adenocarcinoma o f the lung in this case bears close scrutiny. Cellular atypia, par ticularly in the presence o f an acute inflammatory condition, can be difficult to distinguish from carci noma cytologically. A positive test for p53 protein may prove helpful in confirming the diagnosis of car cinoma in the future.19 The possibility o f a false pos itive cytologic report must be considered in this man, who had symptoms o f an acute illness compatible with tracheobronchitis. Atypia as a result o f coccid ioidomycosis has been reported.37 In this case, the radiographic stability o f the lesion over the course o f the illness, although nonspecific, is more compatible with the diagnosis o f a subacute or chronic inflam mation than with the diagnosis o f carcinoma. If the patient had adenocarcinoma o f the lung, it may have been metastatic. The cancer may have orig inated in the gastrointestinal tract, kidney, or pros tate gland. Gastric carcinoma has been linked to sub stances used in the chemical and rubber industries, including benzidine, a- and /3-naphthylamine, crys talline silica, and asbestos, and also to drinking water containing nitrates.20 22 However, there is no evi dence that this man, who appeared well, had an extrapulmonary primary tumor. The carcinogenicity o f inhaled talc is controver sial 10>2323 Stille and Tabershaw23 did not find an in creased number o f cases o f lung cancer in employees o f a talc-processing plant in New York State over a period o f 31 years. Similar findings have been re ported by other investigators.24 Exposure to a com bination o f silica and talc, however, results in a high er rate o f death from lung cancer than exposure to silica alone.22 The carcinogenicity o f silica has been proposed but has not been definitively demonstrat ed in humans26 2!i; the carcinogenicity o f asbestos is well documented.29 Industrial exposure to a mixture o f talc and silica or talc and asbestos may explain the development o f lung cancer in this patient, who did not have a history o f heavy smoking, but it is an un likely explanation A considerable number o f nontalc substances used in the rubber industry are also known or suspected lung carcinogens, such as nitrosanunes. Although bronchogenic carcinoma, especially ade nocarcinoma, can occur in the absence o f known ex posure to carcinogens, such cases account for less than 5 percent o f cases o f lung cancers in the general population. The risk o f lung cancer depends partly on host factors, including the presence or absence of preexisting lung disease, diet, family history, and ge netic factors.20 Polymorphisms o f genes associated with carcinogenesis have been reported to confer a risk o f lung cancer.31 The need to identify a carcinogen or a host risk factor would be obviated by ruling out carcinoma in the lesion in question. Radiographic evidence o f mul tiple lesions usually indicates the presence of either metastatic cancer or a noncancerous process Bronchioloalveolar-cell carcinoma is a notab c* exception, with lesions that arc often multifocal A careful re view o f the cytopathological smears would therefore be an important diagnostic approach. It is not clear whether this patient could tolerate resection o f an adenocarcinoma. A curauve lobecto my might remove enough functioning lung tissue to impair his subsequent tolerance o f physical exertion. Until recently, the criterion for resectability of the lung was an estimated postoperative forced expira tory volume in one second (FEV,) o f 0 80 liter, a re quirement this man might meet if he needed a right upper lobectomy, but not if he requned a pneu monectomy. The refined criteria for operability in clude a measure o f integrated cardiopulmonary and muscular function, a test readily available in most pulmonary-function laboratories.2234 Some surgeons consider this test excessive and instead have patients walk upstairs to test their tolerance o f exertion The ability to climb three flights o f stairs may be corre lated with maximal oxygen uptake rate " This patient's ratio o f FEV, to vital capacity is low, clearly indicating an obstructive component of his pulmonary dysfunction that was unresponsive to the inhalation o f a /32-agonist. The usual sites of airflow obstruction that are evident on spirometry are the small bronchi and bronchioles, as in patients with asthma, emphysema, or chronic bronchi is This pa tient's low forced expiratory volume mav be due to air trapping behind obstructed airways or to an in dependent restrictive process, such as interstitial fi brosis. These two possibilities arc best distinguished by body-box plethysmography. The high values for residual volume and total lung capacity are compat ible with severe air trapping as the predominant dys functional process. Major or minor airway obstruc tion, bullous lung disease, or both can cause this pattern, but bullae were absent on CT scanning. The low carbon monoxide diffusing capacity (which can be falsely decreased by anemia and heavy cigarette smoking, neither o f which applies to this patient) must be attributed to parenchymal damage, probablv sim ilar to that causing the air trapping. Possible explanations for this patient's lung dvsfunction include one or more o f the following, small airway disease due to coccidioidomycosis, chronic ob structive small-airway disease caused by exposure to talc or rubber fumes, previously undetected chronic airflow o b stru ctio n of unknow n o rigin , or a c o n founding repair process such as bronchiolitis obliter ans with or without organizing pneumonia. A patho- 186 July 15, 1999 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12, 2006 Copyright 1999 Massachusetts Medical Society All rights reserved CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL logic repair process often occurs after a variety of pulmonary insults such as viral infections in infants and young children, M. pneumoniae or L. pneu mophila infection in adults, inhalation o f nitrogen oxide, connective-tissue disease, drug reactions, and bone marrow and lung transplantation.36-37 Tests of airway resistance and conductance measure airflow across the smallest total cross-sectional area o f the air ways -- paradoxically, the large airways; thus bron chiole-based lesions have relatively little effect on such measurements.311In cases o f bronchiolitis, meas urements of lung volume may reveal hyperinflation, reflected by high values for functional residual vol ume and total lung capacity. One usually expects a greater abnormality in gas transfer than that demon strated by ambulatory oximetry in this patient, al though the technique used even for this simple ma neuver can be questioned. Finally, this patient's initial chest C T scan was not o f high resolution and there fore would not have revealed the bronchiolar-wall thickening, bronchiolar dilatation, and mosaic per fusion that have been reported on high-resolution C T scanning in patients with this disorder.39-40 Ex piratory-phase, high-resolution C T scanning, which might have been helpful in detecting air trapping, was not performed. In conclusion, I believe that this patient had acute coccidioidomycosis, possibly complicated by obliter ative bronchiolitis, with underlying talcosis and sili cosis. I doubt that he had bronchogenic carcinoma. The most important diagnostic procedure would have been a reexamination o f the cytologic smear to detect coccidioidomycosis spherules or to confirm the presence o f a malignant tumor. The decision to perform an excisional biopsy would have depended on the results o f this reexamination. CLINICAL DIAGNOSES Talcosis. Carcinoma o f the lung. DR. SIMON D. SPIVACK'S DIAGNOSES Talcosis and silicosis due to occupational inha lation o f talc. Acute primary coccidioidomycosis, possibly with obliterative bronchiolitis. PATHOLOGICAL DISCUSSION D r E ugene J. M ark: The diagnostic procedure was an exploratory thoracotomy. The surgeon felt a mass in the right upper lobe and performed a lobec tomy. He also removed two smaller nodules from the right lower lobe. The right upper lobe contained numerous firm, gray nodules, I to 7 mm in diameter. On microscop ical examination, they were circular or resembled a caput medusae (Fig. 3). They were composed o f his tiocytes, including multinucleated forms o f a for- /. --p' -* Figure 3. Cellular Nodule with a Caput Medusae Configuration (Hematoxylin and Eosin, X35). Figure 4. Clusters of Birfringent Talc Crystals within Fibrotic Tissue, Viewed under Partially Polarized Light ( x "'5) Volume 341 Numbci 3 187 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12, 2006 Copyright 1999 Massachusetts Medical Society All rights reserved The New England Journal of Medicine Figure 5. Large Nodule with Hyalinized Fibrous Tissue In the Center (Hematoxylin and Eosin, X20). Figure 6. Multiple Ferruginous Bodies and Histiocytes in an Al veolus (Hematoxylin and Eosin, X330) eign-body type. Pale-yellow birfringent crystals were packed into clumps and sheaves within the histio cytes or in fibrotic tissue (Fig. 4). The centers of the larger nodules were replaced by hyalinized fibrous tissue (Fig. 5). L o n g crystals o f talc encrusted with iron formed ferruginous bodies in some areas (Fig 6). These crystals account for one type o f pseudo asbestos body. True asbestos bodies were present as well, but the interstitial fibrosis characteristic of as bestosis was absent. The appearance o f the lesions and the presence o f the crystals are characteristic of talcosis.lc;.41 The largest mass, which was 3 cm in diameter, had a central cavity that contained a watery mixture of talc (Fig. 7). The only case with similar pathological fea tures described in the literature consisted of multiple loculated cavities filled with talc; the talc in that case, however, had probably entered the lung through a bronchopleural fistula after the instillation o f talc m the pleural cavity to treat recurrent pleural effusions42 Inhalation o f finely dispersed talc probably caused the diffuse disease in this case, and a plug o f talc probably led to the formation o f the cavity. Also, histiocytes and talc crystals had eroded nto pulmo nary arteries in the vicinity o f the cavity and caused an obliterative endarteritis (Fig 8), whiih may have had a role in causing cavitation. Talc and other sili cates tend to cause intense vascular inflammation and sclerosis, which contributes to the pulmonary scar ring. 1C;'43 43 There were no compact granulomas, the presence o f which would have suggested infection, nor were any organisms detected with special stains Pneumocytes in areas o f scarring were icactivc and atypical, probably accounting for the cytologic diag nosis o f adenocarcinoma. Unfortunately, die cytolog ic smears were not available for review at this hospital Talc usually produces small nodular sc irs or linear interstitial fibrosis, which can lead to bronchiectasis, honeycomb fibrosis, or both, as well as progressive massive fibrosis.41'43 Areas o f massive fibrosis can ap pear radiographically as central or peripheral masses, and in some cases, they have been resected surgically41 Impacted talc was found to have plugged and de stroyed bronchioles in a child who died after aspirat ing talcum powder.46 Tumor-like masses on chest ra diographs o f workers in two talc factories in Greece were thought to be due to concretions o f rah rh.ir had obstructed bronchioles and then caused atelecta sis and fibrosis.47 Historically, workers in talc mines and mills were at greatest risk for talcosis.1S'41-47 Rubber workers arc now probably the most commonly exposed persons.41434349 D r . D avid J. KanareK: This patient worked m eastern Massachusetts for 28 years, making bands eight hours a day, and every time he made a rubber b a n d , b e sp ra y e d it w itb ta lc . T h e n h e m o v e d to Ar izona. His exercise tolerance was very good, despite the results o f the pulmonary-function rc'ts 188 July 15, 1999 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12, 2006 Copyright 1999 Massachusetts Medical Society All rights reserved CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL Figure 7. Edge of a Cavity (C), Containing Groups of Pale Talc Crystals (between Arrows) and Talc-Laden Histiocytes (H) (He matoxylin and Eosin, x20). Calcified concretions (dark staining) are present (top). Figure 8. Thrombosed Artery Adjacent to the Cavity (Verhoeffvan Gieson Stain, X150). Histiocytes (arrows) with talc crystals have eroded the arterial wall, causing reduplication of elastic fibers (black) and fibrosis and narrowing of the lumen (L) D r . S fivack: What was the acute illness, and whv did the pulmonary-function studies show such marked abnormalities? D r. Kanarek: The patient probably had a respi ratory tract infection, which prompted his physician to obtain the radiograph o f the chesi; the talcosis was an incidental finding. The pulmonary-function studies showed much more hyperinflation than one would expect from viewing the radiologic images The hyperinflation was probably related to the oblit eration o f the airways seen on microscopical exami nation. D r. Mark: In addition to bronchiolai scarring due to the inhalation o f talc, there was also marked centriacinar emphysema, probably related to smoking. ANATOMICAL DIAGNOSIS Pulmonary talcosis, with liquified mineral in a ca\ itated tumor-like mass, granulomatcus inflamma tion, and sclerosis. REFERENCES 1. Stevens DA Coccidioidomycosis N Engl J Med 199 5,332 1077 82 2. 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Hunt AC Massive pulmonary fibiosis horn die mhal tion of talc Tho rax 1956,11 287-94 44 Uehlinger E, Zollinger R Die klinische Bedeutung der silikmtsien Gefassschadigung Bull Schweiz Akad Med Wiss 1946,2 176 83 45. Cieevei EF Pulnum.uv vaseulai lesions m siIkusis an 1 lcland p.uluv logic changes Am J Med Su 1947,214 292-304 46. Molnar JJ, Nathcnson G, Ldbcrg S Fatal aspiration c i talcum powder by a child repon ol a case N Engl J Med 1962,266 36 7 47. Alivisatos GP, Pontikakis A r, Tcrzis B T.ilcosis ol unusualh i ipid di vclopment Br J Ind Med 1955,12 43 9 48 Miller A, Tursicm AS, Bader M L, Bader RA, Schko l IJ Talc pnui mocomosis significance ol sublighi miciobiopk inmu.il partklcs Am J Med 1971,50 395-402 49. Case Retoids of the Massachusetts General Hospital Case 35 1982! N Engl J Med 1982,307 605-14 1999, Massachusetts Medical Society _________________35-MILLIMETER SLIDES FOR THE CASE RECORDS__________________ Any reader o f the Journal who uses the Case Records of the Massachusetts General Hospital as a medical teaching exercise or reference material is eligible to receive 35-mm slides, with identifying legends, o f the pertinent x-ray films, electrocardiograms, gross specimens, and photomicrographs of each case The slides are 2 in by 2 in , for use with a standaid 35-mm projectoi 'These slides, which illustrate the current cases in the Journal, are mailed from the Department of Pathology to conespond to the week of publication and may be retained by the subscriber Each year approximately 250 slides from 40 cases are sent to each subscriber The cost of the subscription is $450 per year Application forms foi the current subscription year, which began in January, may be obtained from Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114 (telephone [617] 726-4369) Slides from individual cases may be obtained at a cost of $35 per case 190 July 15, 1999 Downloaded from www nejm org at HHS LIBRARIES CONSORTIUM on April 12, 2006 Copyright 1999 Massachusetts Medical Society All rights reserved