Pulmonary Arterial Hypertension and Cor Pulmonale Associated with Chronic Domestic Woodsmoke Inhalation

Pulmonary Arterial Hypertension and Cor Pulmonale Associated with Chronic Domestic Woodsmoke Inhalation* Julio Sandoval, M.D.; Juan Salas, M.D.; Maria Luisa Martinez-Guerra, M.D.; Arturo G6mez, M.D.; Carlos Martinez, M.D.; Arnulfo Portales, M.D.; Andres lblomar, M.D.; Manuel Villegas, M.D.; and Roberto Barrios, M.D. We describe the clinical, radiologic, £unctional, and pulmonary hemodynamic characteristics a group 30 nonsmoking patients with a lung disease that may be related to intense, long-standing indoor wood-smoke exposure. The endoscopic and some of the pathologic Ondings are also presented. Intense and prolonged wood-smoke inhalatima may produce a chronic pulmonary disease that is similar in many aspects to other forms inorganic dust-esposure interstitial lung disease. It affects mostly country women in their 60s, and severe dyspnea and cough are the outstanding complaints. The chest roentgenograms shaw a difl'use, bilateral, reticulonodular pattern, combined with normalsi7.ed or hyperinOated lungs, as well as indirect signs pulmonary arterial hypertension (PAH). On the pulmonary function test the patients show a mixed restrictive-obstructive pattern with severe hyposemia and variable degrees of hypercapnia. Endoscopic 8ndings are those of acute and chronic bronchitis and intense anthracotic staining of the airways appears to be quite characteristic. Fibrous and

or

or

or

or

smoke is a complex mixture of gases and W ood particles with a wide range of potential deleterious respiratory efl'ects. 1•1 Several studies from developing countries, including our own country, have indicated an association between intense smoke exposure in dwellings and chronic pulmonary diseases. a-7 Most of these studies, however, are epidemiologic and the description of the clinical picture of the possible pulmonary involvement in this form of indoor pollution is less known. At our institution, the National Heart Institute, we have observed for many years patients, particularly women, with a chronic lung disease, severe pulmonary arterial hypertension (PAH) and cor pulmonale (CP) for which the etiology has not been entirely clear. They all have had the antecedent of prolonged exposure to wood smoke and therefore a possible etiologic link has been suspected. In the present study we describe the clinical, radiologic, functional, and endoscopic findings in a group of women who shared the only antecedent of intense,

•From the Cardiomilmonary and Pathol~ Departments, lnstituto Nacional de Cardiologla "Ignacio Chavez, Mexico City, Mexico. May 5. Manuscript received September 10; revision ~ted Reprint requem: Dr. Sandooal, Head, Cartlloplllmonary Seroke, lnstituto Nacional de Cardiologia, Juan BadliJno No. 1, Tlalpan 14
12

inOammatory focal thickening of the alveolar septa as well as difFuse parenchymal anthracotic deposits are the most prominent pathologic &ndings, although inftammatory changes the bronchial epithelium are also present. The patients had severe PAH in which, as in other chronic lung diseases, chronic alveolar hypoxia may play the main patbogenetic role. However, PAH in wood-smoke inhalation-associated lung disease (WSIALD) appears to be more severe than in other forms of interstitial lung disease and tobacco-related COPD. The patients we studied are a selected group and they may represent one encl of the spectrum the WSIALD. (Chat 1993; 103:1!-!0)

or

or

Cl•eardiac index; CP=cor pulmonale~=eoal pneumocoaiosis; Il.D intentitial lung •

worker's ; MMEF• muimum midexpiratory ftow; OLB =open lung biopsy; PAR• pulmonary arterial hypertension; PAP= puhDonary artery pressure; RV= residual volume; RVW =right ventricular worli:; TLC= total lung capacity; VC =vital capacity; WSIALD =wood-smoke iDbalation-associated lung disease

=

long-standing wood-smoke exposure. Particular emphasis is given to the hemodynamic behavior of the pulmonary circulation in these patients. METHODS

Study Population In the last 2 years we have consecutively studied a group of 30 patients (63.3± 1.76 years old). The patients were identified as possible candidates at our outpatient clinic on the basis of the following: (1) clinical, radiologic, and electrocardiographic evidence of PAH and CP;• and (2) the antecedent of long-standing (at least 10 years) domestic wood-smoke exposure. They had to be nonsmokers, de6ned as those who have never smoked or have smoked less than one cigarette or equivalent a day for as long as 1 year.• Also, patients with obesity and/or with any history of significant organic (ie, pigeons) and/or inorganic dust exposure were excluded. Obesity is defined as having a body weight more than 20 percent of the ideal.• The patients with a clear-cut history for a known chronic lung disease (eg, tuberculosis, childhood respiratory diseases, and cystic 6brosis) were also excluded. Finally, although our study was conducted in Mexico City, all of our patients were living in the countryside so that the possible role of atmospheric air pollution of the large cities could be reasonably excluded. One of the patients included in this study was admitted to the hospital with clinical and radiologic evidence of central airway obstruction and collapse of the right upper lobe. At bronchosoopy this patient had an almost complete obstruction of the right and left main-stem bronchi by tumor. The patient eventually died and the postmortem study showed a squamous cell carcinoma. Parallel 6ndings at autopsy were the presence of diffuse and severe anthracosis of the lung

"'*'-'Y Hypertei llliol 1, Cor Pulmonale and Woodlmoke lnhal8llon (SandtNrll et al)

parenchyma with thickening of the alveolar septa. This patient was a nonsmoker and she had been exposed to wood smoke for most of her life.

Erposure to Domestic Smoke lbllution Domestic smoke is produced by burning biomass such as 6.rewood and other organic material (straw, stubble) that our patients used for cooking and heating. In regard to heating it should be pointed out that most of our patients come from small villages located in cool areas of our country at a mean altitude of 2,268 ± 381 m above sea level. The houses are heated by means of a 6.re or burning ashes of this material and the ventilation is poor as there are no chimneys. For most of the day the house is smoky and our patients spent in this environment at least 8 h every day. The mean exposure time of the group is 51.9±2.85 years. Ten of the patients had already separated from this exposure years before but 20 of them were still under exposure just before the study. Once identi6.ed, the patients were admitted to the hospital for further study. Our protocol was approved by the local committee for clinical investigation. All the medical and surgical procedures were explained to the patients beforehand and their written consent was obtained. The patients were studied in stable condition. No patients were included if they were known to have been In cardiac failure or to have had a respiratory Infection within 8 weeks prior to the study, although 16 of the 30 patients had been in right-sided cardiac failure or had had a respiratory infection and recovered between 3 and 12 months before the study. Most patients (J7 percent) had CP diagnosed on the basis of either roentgenographic or electrocardiographic evidence of right ventricular enlargement.• Treatment with their prior medication (ie, bronchodilators, diuretics) was suspended In the ward 72 h prior to the hemodynamic studies.

Hemodynamic and ftdmonary Function Studies Spirometric studies and helium-dilution measurement of functional residual capacity (FRC) were performed (with an Expirograpb/FRC computer spirometer model 16003/15422 Gould-Godart, Bilthoven, The Netherlands). Pulmonary function results were compared with the normal values reported by Comroe and coworkers,•• Baldwin and colleagues, 11 and Morris and associatesu and are expressed as a percentage of the predicted normal value. Pulmonary function studies also included the collection of expired air and arterial blood samples for analysis. From these data, the physiologic Po. difFerdead space (using Bohrs equation), the alveo~erial ence (using the alveolar air equation), oxygen consumption, C01 production, and hemoglobin content were calculated. 10 The methodology for cardiac catheterization studies performed in our laboratory has been reported elsewhere........ In brief, patients were studied resting in the supine position without anesthesia. Blood samples were obtained from the pulmonary and brachial arteries over a I-min period and immediately analyzed using a gas analyzer (127 bath, 213 electrometer; Instrumentation laboratories, Lexington, Mass). (Normal values for Mexico City are as follows: Pa01 , 67.5±2.5 mm Hg; PaC01 , 32.2±2.5 mm Hg; arterial pH, 7.33 to 7.43.aa.••) Cardiac output was measured in triplicate by thermodilution technique" with a computer (KMA-2000), and pressure measurements were obtained through a Swan-Ganz catheter (ICMA9601-7F; KMA, Inc, Oklahoma City). Standard formulas were used for calculations of cardiac index (CI), right ventricular work (RVW), and pulmonary vascular resistance .... For pulmonary shunt calcuJation (Qs/Qt), the standard formula of Berggren'" was used.

Other Studies In 22 of the patients, the consent for bronchoscopy was obtained. Following intramuscular premedication with atropine (0.6 mg), 10 percent lidocaine spray was used to anesthetize the upper respfra-

tory tract. Bronchoscopy was carried out transnasally with a Bexible 6.beroptic instrument (Fujinon FB-SBF9031001, Fuji Photo Optical). Besides the complete inspection of the airways performed in all patients, a bronchial biopsy specimen was obtained In 14 of the patients and sent for routine histologlc study. After careful evaluation, lung biopsy specimens were considered necessary, in the last few cases, by the local medical-surgical committee to rule out other Interstitial and obstructive diseases to learn about the pulmonary involvement in this form of ind~r pollution, to determine the nature and degree of the vascular lesions, and to aid in the assessment of the future treatment of PAH. After the procedure was explained to the patients and their consent was obtained, open lung biopsies (OLBs) were performed in 6ve patients. Biopsy specimens were taken from the right middle lobe or lingula. A fragment was 6.xed in 1 percent buft'ered rormaldehyde (at a pH of7.40) for 12 hat room temperature ror routine histologic sections. Another fragment was submitted for bacteriologic study. Special stains for bacteria and fungi were negative In all cases. Sections stained by the hematoxylin-eosin and Masson trichrome techniques were examined. The Heath and Edwards19 classi6cation of pulmonary arterial disease was used to assess the degree of vascular lesions. As a point of reference, the pulmonary function test results and the hemodynamic 6.ndings at rest in our patients with wood-smoke

Table I-Clinical firatrma, Badiologic, ElsctrocartUogr, and Lung Scan Findings in 30 ltdimta W"dh WSIAW No.of Patients (CJ>) Symptoms Dyspnea Cough Dry Productive Hemoptysic Signs Cyanosis Clubbing Crackles Fine Coarse Wheeze Increased pulmonic second sound Hepatomegaly Edema Radiologic Lung volume preserved or increased Reticular and/or reticulaJ'.nodular pattern Generalized

30 28 3 25 2

(100) (93) (11) (89) (7)

19 1 21 16 5 7 16 18 22

(63) 3) (70) (76) (24) (23) (53)

(60) (73)

28 (93) 9:1 (90) 17 (63)

Basal

10 (37) 26 (87)


6 (20) 17 (57) 7 (23)

Suggestive signs of PAH"" Cardiothoracic ratio ~

>61CJ> Electrocardiogram Sinus rhythm Right ventricular (RV) hypertrophy RV systolic and or diastolic overload Lung scan• Normal Diffuse V/Q defects Segmental V/Q defects

29 (97) 23 (77) 23 (77)

2 (18) 8 (73) 1 (9)

•n • 11; V/Q =ventilation/perfusion. CHEST 1103 I 1 I JANUARY, 19113

13

F1cuRE 1. The radiologic appearance ofWSIALD. The reticular and/or reticular-nodular pattern is diffuse and bilateral (A) or predominant in lung bases (B). Characteristically the lung volume is preserved and sometimes it appean increased (C). Although not frequent, there may be evidence of bullae (D). Cardiomegaly and evidence of pulmonary arterial hypertension are remarkable llndings in our patients.

inhalation-associated lung disease (WSIALD) were compared with those in our patients with stable chronic obstructive pulmonary disease (COPD)"" and interstitial lung disease (ILD)11 previously reported. Statistical analysis and significance of results were calculated using paired and unpaired t tests and standard analysis for linear regression. All results are expressed as the mean± 1 SEM. RESULTS

The mean age of the patients was 63.3 ± 1. 76 years and the mean time of exposure was 51.9±2.8 years. The clinical feablres as well as the radiologic, electrocardiographic, and perfusion lung scan findings are shown in Table 1. Dyspnea and cough were the main complaints. In most of the patients, dyspnea was 14

related to mild and minimal physical activity (97 percent). Cough was mostly productive of hyaline · h · d.b sputum except unng exacer abons w en it was purulent. On physical examination, bilateral and predominantly basal crackles as well as central cyanosis were the most prominent findings. At the time of hospital admission, most of the patients had clinical signs of CP. Characteristically, clubbing was absent. Chest roentgenogram was abnormal in all patients. The most frequent radiologic finding was that of a generalized or at least basal reticular and/or reticuJ.ar. nodular pattern, with a normal and sometimes increased lung volume (Fig I). Radiologic signs of lung Pulmonary Hyper1at lllion, Cor Pulmonale and Woodsmoke Inhalation (Sand'1ial et al)

Table 2-Lung Function Data in 29 lbtienta With WSIAID*

Results

vc. %pred RY,% predt TLC, %predt FEV,. %pred FEV/FVC, % MMEF, %pred Pa01 , mm Hg PaC01 , mm Hg AaP01 , mmHg Arterial pH Vo/VT Qs/Qt, %t

68±3.S 99±3.3 82±2.8 56±3.0 61±2.S 29±3.S 45::!: 1.0 36::!: 1.0 30::!: 1.2 7.41±0.007 0.5±0.02 11±0.8

No. of Patients Outside Limits Nonruillty

ot

20 3 10 25 23 28 30 12 29 1

27 19

*VC =vital capacity; RV= residual volume; TLC= total lung capacity; FEV1 =forced expiratory volume in 1 s ; FVC =forced vital capacity; MMEF=maximal midexpiratory Bow; AaP0 1 =alveo~ arterial Po1 difference; Vo/VT= physiologic dead space/tidal volume ratio; Qs/Qt =anatomic shunt. tn=l8. tn=26.

hyperinflation in the posteroanterior roentgenognun22 were found in eight (26.6 percent) of the patients. Neither hilar adenopathy nor focal airway disease was observed, although bullae were present in two of the patients. Cardiomegaly and suggestive signs of PAH 23 were also prominent findings in this group. Most of our patients were in sinus rhythm and presented ECG evidence of right ventricular systolic overload.14 The lung scan showed diffuse, small, nonspecific ventilation/perfusion abnormalities in most of the patients. Results of pulmonary mechanics and gas exchange

FIGURE 2. Endoscopic findings in WSIALD. Anthracotic stains in the bronchial mucosae sometimes of large size and localized more ol\en in the upper segmental bronchial orifices are quite characteristic. Note also the congestive aspect of the bronchial mucosae.

determinations are shown in Table 2. A combined restrictive and obstructive pattern was observed in most of the patients. As noted, residual volume (RV) and total lung capacity (TLC) were measured in only 18 of the 30 patients. Ten (55 percent) of these 18 patients showed a reduction in the predicted values of both vital capacity (VC) and TLC (59 ± 4 and 73 ± 2. 7 percent, respectively). In eight of these ten patients, the FEV ifFVC ratio was lower than normal (57 ± 2.4 percent). The TLC in the remaining eight patients was within normal limits (91±2.4 percent of predicted). The RV was increased (> 120 percent of predicted) in only 3 of the 18 patients in whom it was measured. Severe hypoxemia at rest was a constant feature and 12 of the 30 patients had hypercapnia. Arterial pH was normal in all but one patient. At exercise (18 patients), Pa02 decreased from 45.6 ± 1.3 to 39.5±1.6 mm Hg (p<0.05). At bronchoscopy (22 patients), generalized changes compatible with acute and chronic airway inOammation such as mucosal erythema and edema, dilated ducts of mucous glands, transverse ridges, longitudinal light bands seen running down the main-stem bronchi out into the smaller divisions, and abundant mucus were observed in most of the patients. The most characteristic finding, however, was the presence of intense, dark blue, anthracotic staining of the bronchial mucosa, which we observed in 14 of 22 patients (Fig 2). These dark lesions were mainly located at the bifurcation level of the main-stem bronchi, particularly in the upper lobes. Light microscopy of the bronchial biopsy specimens of these lesions showed pathologic changes compatible with moderate to severe chronic bronchitis (Fig 3). Prominent findings were as follows: (1) an abnormal thickening of the basal membrane by both fibrosis and inOammatory infiltration with lymphocytes and plasma cells; (2) goblet cell hyperplasia; (3) acute and chronic inflammatory infiltration of the submucosa with deposition of anthracotic

FIGURE 3. Bronchial biopsy specimen. The bronchial epithelium

shows squamous metaplasia, in8ammatory cells present in the lumen as well as in the bronchial wall, and marked thickening of the basement membrane (hematoxylin-eosin stain; original magnification, x 220). CHEST I 103 I 1 I JANUARY, 1993

15

Table 3-.Rming Pulmonary Hemodgnamica in !1 flrtientt WUhWSIALD*

Mean

No. of Patients Outside Umits ± 1 SE Normal"·•3.t• of Normality

7.4 RAP, mm Hg 1.0 RVEDP, mm Hg 11.0 1.0 PAP, mm Hg 46 3.4 PWP, mm Hgt 11.0 1.0 PAd-PWP, mm Hgt 20.2 2.9 CI, Umin/m1 3.5 0.25 SV, ml/beat 59.5 3 C(a-v)01 , vol -.,t 5.0 0.4 TPVR, dyneslstcm-• 826 103 PAR, dyneslslcm-• 617 88 2.59 0.29 Rvw, kWmlmin Hb, gi'lOO mli 18 0.5 54 1.5 Ht, -.,*

<6 <16 <15 <5 2.8-5.4 50-80 4.1±0.6 <255 <90 .7-1 15-17.5 40-50

CL

f

•

• • •

•

20

10

• t4

•

•

ti

36±2.4 4.15±0.28 630±73*

6.5±3 28±8 20±4 49± 1.6 39±1.2 7.40± .01 27±2.2 3.4±0.21 433±41

§n-20.

artery pressure (PAP) (Fig 4). We did not find significant correlation between PAP and other variables such as the time of exposure to woodsmoke in years, FEV1 , maximum midexpiratory flow (MMEF), VC, and PaC01 • The average PAP, CI, and pulmonary vascular resistance as well as the mean value of other pulmonary function variables for patients with tobacco smoke-related C0Pl)20 and ILD21 and for those with WSIALD are shown in Table 4. As noted, there is evidence for more airways obstruction in patients with COPD than in patients with WSIALD. Also, VC is lower in patients with ILD than in patients with WSIALD. The PAP and pulmonary vascular resistance are, however, significantly higher in the group of patients with WSIALD. Light microscopy of the OLB specimen revealed thickening of the alveolar septa by deposition of collagen as well as cellular infiltration with lymphocytes and plasma cells in all cases associated with dense anthracotic pigment deposition (Fig 5). The degree of involvement was variable but in most cases (n = 4), the mixed pattern of alveolar wall 6brosing

•

40

:so

§47±4 §84±2.6 §59±3.3 §49±1.7 §29.5±1.2

COPD (n=28)

*P
material; (4) hyperplasia of mucous glands; and (5) hyperplasia and squamous metaplasia of the bronchial epithelium. The hemodynamic data at rest appear in Table 3; PAH and increased pulmonary vascular resistance were noted in all patients. The CI was normal in 17 of the 21 patients, and the right ventricular end-diastolic pressure was elevated in 18. Hemoglobin and hematocrit measurements were abnormally elevated in all patients. There was a significant positive correlation (r=0.63; p<0.05) between arterial oxygen unsaturation (100-sat percent) and resting mean pulmonary

70

68±3 61±2 31±3 45± .9 36±1.1 7.41±.007 t46±3.4* t3.5±.2 t826± 103*

ILD (n=23)

•Abbreviations as in Tables 2 and 3. tn=21.

*RAP=rigbt abial pressure; RVEDP=rigbt ventricular end diastolic pressure; PAP= mean pulmonary artery pressure; PWP = pulmonary wedge pressure; PAd-PWP =pulmonary diastolicwedge pressure difference; Cl =cardiac index; SV =stroke volume; C(a·v)01 = arteriovenous oxygen content difference; TPVR =total pulmonary vascular resistance; PAR= pulmonary arteriolar resis· tance; RVW =right ventricular work; Hb =hemoglobin; Ht= hematocrit. tn=l9. in=30.

80

WSIALD (n=30) VC,% FEV/FVC, % MMEF,% Pa01 , mm Hg PaC01 , mm Hg Arterial pH PAP, mm Hg Cl, Umin/m1 TPVR, dyneslstcm•

17 18 21 3 17 4 17 10 21 21 19 20 20

()-4

Table 4-Ptllmonary Function and llemodgnomk Findmgs in lbtienta With WSIAID, IW,u and Smoking-related COPD8*

r•0.64 pcO.O&

• 21

II

10

14

H

41

tOO-Sot % F1cuu 4. A signi&cant positive correlation between arterial oxygen unsaturation (100-sat -.,) and mean pulmonary arterial pressure (PAP) was found in 18 patients with stable WSIALD. Patients with more resting hypoxemia are also those with more pulmonary hypertension.

11

FIGURE 5. Open lung biopsy specimen. There is dense deposition of anthracotic pigment associated with irregular focal 8brosis (hematoxylin-eosin stain; original magni&cation, x 100).

DISCUSSION

F1cuRE 6. Fibrotic thickening of the intima (grade 3 lesion) with marked reduction of the artery lumen that was seen in two patients (Van Gieson's stain; original magnmcation, x 100).

inflammatory infiltrate was extensive with the residual airspaces lined by proliferating cuboidal epithelial cells. A remarkable finding was the deposit of anthracotic material in the lung parenchyma that wa5 more prominent in the connective tissue surrounding the small airways and arteries. Changes compatible with focal emphysema25 adjacent to the anthracotic deposits were found in two patients. Vascular lesions were prominent and consisted of medial hypertrophy of muscular arteries and arterioles in all patients. In two of the patients there was also a severe fibrous involvement of the intima that severely reduced the lumen of the vessels. Scattered evidence of old recanalized thrombus was observed in one of these OLB specimens (Fig 6, 7). The postmortem study of one of the included patients showed, besides the changes of a squamous cell carcinoma of the lung, focal areas of fibrosis and inflammatory infiltrate in the lung parenchyma with large deposits of anthracotic material. There was also evidence of recanalized vascular thrombosis.

FIGURE 7. Low-power view of open lung biopsy specimen in which there is an organized and recanalize
Wood smoke is a complex mixture of compounds, including the following: (I) suspended particles of respirable size; (2) gases, such as carbon monoxide, sulfur oxides, nitrous oxides, and aldehydes; and (3) polyorganic matter, including polycyclic aromatic hydrocarbons. 1.2.26 There is in vitro evidence that many of these compounds are mutagenic, '¥1 and they also contain irritants, cilia-toxic fractions, and coagulating agents 1•26 that can compromise respiratory system defenses and increase the risk of acute and chronic lung infections. 26.211 Likewise, there is epidemiologic evidence that intense, long-standing, domestic exposure to wood smoke contributes to the development of chronic lung disease in adults. Studies from Nepal by Pandey3·4 and those of Anderson5 and Master211 from New Guinea have shown an association between prevalence rates for chronic bronchitis and domestic wood-smoke exposure. Here in Mexico City, Melchum and coworkers7 have also identified long-term woodsmoke exposure as an important risk factor for chronic bronchitis in nonsmoker women. All mentioned studies have pointed out that length of exposure in years as well as intensity of exposure might be, among others, important determinant factors. The patients in our series might also represent an example of how the lifelong exposure to this form of indoor air pollution may lead in titne to severe respiratory symptoms and functional abnormalities and as a consequence to PAH and CP. The prevalence of this problem in our population has not been completely established. In a preliminary report, Melchum and coworkers7 found that among 61 patients admitted to their hospital with the diagnosis of chronic bronchitis, 42.6 percent of them were nonsmokers and shared the antecedent of wood-smoke exposure. This figure, although preliminary, is impressive and points out that (1) wood-smoke exposure is still a relatively common form of indoor air pollution in our country, and (2) it may represent an important determinant of respiratory disease in nonsmokers. The length and intensity of wood-smoke exposure required for development of lung ,disease as well as the complete clinical spectrum of the pulmonary involvement remain also to be fully defined. In our study, the time of exposure in years did not correlate with the severity of the pulmonary involvement as assessed by the degree of PAH and the degree of lung function impairment (spirometric and gas exchange). This lack of correlation, however, might be exi}lained by the fact that time of exposure in most of our patients was extremeiy long. They represent, in our opinion, the end of the spectrum (ie, the more affected) of WSIALD. Also, being such a common form of noxious exposure, it remains to be investigated whether, besides the exposure itself, there are other determinants in develppment of the disease (ie , indiCHEST I 103 I 1 I JANUARY. 1993

17

vidual susceptibility). It is interesting that our study group is composed exclusively of women living in the countryside. This may be explained in part by the selection criteria but also by the fact that the use of wood and related material for cooking and heating is prevalent in the countryside and women are the ones mainly involved in this kinds of activities. To our knowledge, the only studies regarding the clinical aspects of the lung disease associated with long-term wood-smoke exposure are those of Jones6 and Restrepo et al. 30 In their thorough study, Restrepo and coworkers describe the clinical, radiologic, and functional findings in a group of 22 patients (55 to 80 years old) who shared only the antecedent of intense wood-smoke exposure for more than 10 years. In many regards, our patients are similar to theirs. The signs and symptoms are those of chronic bronchitis, productive cough and dyspnea that followed a progressive course over the years. Chronic bronchitis in this group of patients receives support not only on clinical grounds but also on the basis of the endoscopic findings and the pathologic changes shown by bronchial biopsy specimens of our patients. The anthracotic staining of the airways at bronchoscopy appears to be a frequent finding and the intensity of the staining seems quite characteristic in this group of people as we have not seen this even in heavy-smoking patients. On pulmonary function test, the patients in the study of Restrepo et al30 as well as ours showed a combined restrictive and obstructive pattern and hypoxemia was present in all. The analysis of the pulmonary function test in the 18 patients in our study in whom static lung volumes were measured provides further support to this observation. In 50 percent of these patients, both VC and TLC were diminished suggesting a predominant restrictive pattern that goes well along with the chest roentgenographic changes and the pathologic findings shown by the OLB specimens. However; even in this group of patients, the FEV /FVC ratio and the MMEF rate were lower than normal, which points out the presence of an associated airways obstruction component. Regarding airway obstruction in the total group, the MMEF was severely affected (31±3 percent of predicted) with a FEV /FVC mean value relatively preserved (61±2 percent). This finding might suggest a predominant involvement at the level of the small airways. 31 •32 To the extent that there was radiologic evidence of lung hyperinftation in some of our patients, it is somewhat surprising that RV was abnormally elevated in only 3 of the 18 patients in whom it was recorded. This apparent discrepancy may, on the one hand, be related to the technique we use to measure lung volume (helium dilution). In the presence of airway obstruction, results might be different using the plethysmographic method. On the other hand, generalized emphysema was not the 18

prominent finding in the OLB specimen but rather the inftammatory-l:ibrosing interstitial lung involvement; therefore, the RV we measured may be correct. In the absence of generalized emphysema, the goblet cell hyperplasia and the pigmentation shown by the pathologic results may explain the airftow obstruction correlates in our patients as it has been shown in patients with COPD. 33 Thus, although our overall impression is that the patients with WSIALD have a mixed restrictive-obstructive functional pattern, the precise contribution of each component as well as the degree of pulmonary function involvement in earlier stages of the syndrome remain to be defined. According to our results (ie, increase in P(A=a)02 difference, Vo/VT, and Qs/Qt) ventilation-perfusion (V/Q) mismatching as well as an increase in the intrapulmonary shunt are physiopathologic mechanisms for' the hypoxemia. Diffusing capacity was not assessed in our study; however, Pa02 decreased in some patients during exercise, which may suggest either an aggravation of the V/Q abnormality and/or a diffusion limitation defect at least at exercise. The secondary erythrocytosis in most of our patients is in agreement with the chronicity ofhypoxemia. Many of our patients had hypercapnia, and an increase in dead space and the airway obstruction seem to be the responsible factors; however, other mechanisms might be involved. Wong and coworkers34 evaluated the response of guinea pigs to wood smoke with repeated C02 challenges. After exposure, respiratory frequency decreased and ventilatory response to C02 was diminished. These effects were transient and full recovery occurred within 3 days. Accordingly, central hypoventilation as a result of long-term wood-smoke exposure in our patients cannot be discarded as control of breathing was not assessed in the present study. This aspect merits further investigation. The chest roentgenographic findings are interesting. The reticular-nodular pattern we observed correlates with the pathologic changes of diffuse parenchymal fibrosis shown by the OLB specimen. This radiologic pattern is similar to that described in other forms of long-standing inorganic dust exposure such as silicosis and coal worker's pneumoconiosis (CWP). 25•315•36 Indeed, the radiologic involvement in our patients resembles, in many ways, that in categories 2p, 2q, 3p, and 3q for rounded small opacities and categories 2s, 2t, 3s, and 3t for the irregular small opacities seen in simple CWP. 35 In our patients, there were neither large opacities nor calcified lesions. Characteristically, the radiologic lung volume is preserved, a finding also described by Restrepo et al. 30 This is also a somewhat unexpected finding on the basis of the predominantly interstitial involvement shown by the pathologic results and it may reftect the concomitant existence of areas of focal emphysema as shown in some of our Puknonary Hypartanslon, Cor Pulrnonale and Wood8moU lnhalallon (Sando'tlal et Bl)

patients and as described in patients with simple CWP. 25 It also may suggest a concomitant small airway involvemenfl7 as evident in the pulmonary function test and in some of the OLB findings in our,.patients. The main pathologic changes shown by the OLB specimens of our patients are also similar to those described in other forms of inorganic dust exposure interstitial lung disease. 25•38•39 Focal and irregular areas of thickening of alveolar septa due to a mixed pattern of fibrosing and inflammatory infiltration were prominent. In some patients, these changes were well advanced with formation of cystic cavities characteristic of end-stage ILD. In the study of Restrepo et al,30 the same pathologic fibrosing changes were found both in patients and in animals with long-term exposure to wood smoke. Ramage and coworkers«> have also described such a relationship between ILD and domestic wood burning. The hemodynamic behavior of the pulmonary circulation in this group of patients is grossly similar to that described in other forms of interstitial and/or obstructive chronic lung disease. 13·•·21•41 -44 There is an increased PAP and pulmonary vascular resistance in the presence of normal pulmonary capillary wedge pressure that points out the microvasculature as the locus of the increased vascular resistance. In our patients, other known causes of secondary pulmonary hypertension were ruled out through the ECG, lung scan, and the hemodynamic studies. Although we did not perform formal polysomnographic studies, none of our patients had hypersomnia or other manifestations attributable to sleep apnea. 45 Regarding the physiopathology of PAH in this disease, it appears that chronic alveolar hypoxia is playing an important role. It has been shown that long-standing alveolar hypoxia per se promotes specific histologic changes in the pulmonary vessels that remodel the pulmonary circulation in a way that is independent from the intrinsic lung abnormality. 39•42 •46 In this regard, the vascular pathologic changes we found are similar to those described in COPD"1•42 and particularly in patients with ILD, 21 •42 •44 •46 where hypoxia is a prominent finding. As shown in Figure 4, we found a significant correlation between the degree of arterial oxygen unsaturation, used as an index of alveolar oxygenation, and the value of PAP. Again, this kind of correlation has been shown to occur in both COPD and ILD patients. 41 •42 Although there are pathophysiologic similarities between the hemodynamic behavior of the pulmonary circulation of these patients with WSIALD and that of patients with COPD and ILD, there are differences particularly in the magnitude of the hemodynamic abnormalities. Patients with ILD and COPD studied in stable condition have levels of PAP that rarely exceed 30 to 35 mm Hg, 111 •42•44 whereas it is not unusual

to find systolic PAP above 100 mm Hg in patients with WSIALD. The higher levels of PAP in patients with WSIALD may reflect either a more advanced disease and/or the participation ofother different pathogenetic factors. We indeed believe that the patients in our study represent the end of a spectrum (ie, the more deteriorated) of what WSIALD can be. By looking at Tu.hie 4, it can be seen that patients with WSIALD neither have more airways obstruction than COPD patients nor have more restriction than ILD patients. Patients with WSIALD are, however, more hypoxemic and this may be one possible explanation for the different hemodynamic behavior. The role of altituderelated hypoxia can be discarded as patients in the three groups were born and raised at similar altitudes. This comparison of functional severity among groups is relative as diffusion capacity measurements were not performed. Alternatively, other possibilities, such as associated thrombosis of the microvasculature in WSIALD, are likely. As shown in Figure 7, evidence of recanalized thrombus and severe involvement of the intima was observed in two of the five OLB specimens and these patients had severe PAH without any demonstrable extrathoracic embolic source. It is interesting that abundant deposition of anthracotic material was also found in the connective tissue surrounding the small arteries. It is conceivable that this irritant material may be, in an as-yet-unknown way, inducing thrombosis of the microvasculature and thus participating in the genesis of the PAH in these patients. As indicated earlier in the "Methods" section, one ofour patients in this group died as result ofa squamous cell carcinoma of the lung. Atypical epithelial cells were noticed in the bronchial biopsy specimen of another patient. Tu.ken together, these findings raise the possibility of a cause-and-effect relationship between long-term wood-smoke inhalation and lung cancer. Given the mutagenic and airway irritant effects described for wood smoke, u.•.17 we believe that this possible deleterious relationship needs to be addressed in future studies regarding risk factors for lung cancer in nonsmokers. ACKNOWLEDGMENTS: The authors are indebted to Dr. Donald Greenberg and Dr. Armando Fraire for their review of the manuscript and their constructive suggestions.

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Nnonary Hyperlel llllol~

Cor Pulmonale and Woodlmoke Inhalation (SandtNel et al)