Abstract
OBJECTIVES:
Chronic paracoccidioidomycosis can diffusely affect the lungs. Even after antifungal therapy, patients may present with residual respiratory abnormalities due to fungus-induced lung fibrosis.
METHODS:
A cross-sectional analysis of 50 consecutive inactive, chronic paracoccidioidomycosis patients was performed using high resolution computed tomography, pulmonary function tests, ergospirometry, the six-minute walk test and health-related quality of life questionnaires.
RESULTS:
Radiological abnormalities were present in 98% of cases, the most frequent of which were architectural distortion (90%), reticulate and septal thickening (88%), centrilobular and paraseptal emphysema (84%) and parenchymal bands (74%). Patients typically presented with a mild obstructive disorder and a mild reduction in diffusion capacity with preserved exercise capacity, including VO2max and six-minute walking distance. Patient evaluation with the Saint-George Respiratory Questionnaire showed low impairment in the health-related quality of life, and the Medical Research Council questionnaire indicated a low dyspnea index. There were, however, patients with significant oxygen desaturation upon exercise that was associated with respiratory distress compared with the non-desaturated patients. The initial counterimmunoelectrophoresis of these patients was higher and lung emphysema was more prominent; however, there were no differences in the interstitial fibrotic tomographic abnormalities, tobacco exposure, functional responses, exercise capacity or quality of life.
CONCLUSIONS:
Inactive, chronic paracoccidioidomycosis patients show persistent and disseminated radiological abnormalities by high resolution computed tomography, short impairments in pulmonary function and low impacts on aerobic capacity and quality of life. However, there was a subset of individuals whose functional impairment was more severe. These patients present with higher initial serology and more severe emphysema, stressing the importance of adequate treatment associated with tobacco exposure cessation.
Paracoccidioidomycosis; Lung; Pulmonary Function; Quality Of Life; Computed Tomography
INTRODUCTION
In 1908, Adolph Lutz first described the human Paracoccidioides brasiliensis
infection (11. Lutz A. Uma mycose pseudococcidica localisada na boca e observada no Brazil.
Contribuicao ao conhecimento das hyphoblastomycoses americanas. Bras Med.
1908;(22):121-4.). This thermally dimorphic fungus is acquired by
inhalation of the infective forms of the organism and causes notable, systemic mycosis (22. Funari M, Kavakama J, Shikanai-Yasuda MA, Castro LG, Bernard G, Rocha MS, et al.
Chronic pulmonary paracoccidioidomycosis (South American blastomycosis): high-resolution CT findings
in 41 patients. AJR Am J Roentgenol. 1999;173(1):59-64.
3. Bethlem EP, Capone D, Maranhao B, Carvalho CR, Wanke B. Paracoccidioidomycosis.
Curr Opin Pulm Med. 1999;5(5):319-25,
http://dx.doi.org/10.1097/00063198-199909000-00010.
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Crit Care Med. 2011;32(6):764-74, http://dx.doi.org/10.1055/s-0031-1295724.
http://dx.doi.org/10.1055/s-0031-1295724...
). The disease, termed
paracoccidioidomycosis (PCM), is the most common systemic mycosis affecting non-immunocompromised
hosts in South America and Brazil, which account for more than 80% of all reported cases (55. Blotta MH, Mamoni RL, Oliveira SJ, Nouer SA, Papaiordanou PM, Goveia A, et al.
Endemic regions of paracoccidioidomycosis in Brazil: a clinical and epidemiologic study of 584 cases
in the southeast region. Am J Trop Med Hyg. 1999;61(3):390-4.
6. Coutinho ZF, Silva D, Lazéra M, Petri V, Oliveira RM, Sabroza PC, et al.
Paracoccidioidomycosis mortality in Brazil (1980-1995). Cad Saúde Pública. 2002;18(5):1441-54,
http://dx.doi.org/10.1590/S0102-311X2002000500037.
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7. Rodrigues Gda S, Severo CB, Oliveira Fde M, Moreira Jda S, Prolla JC, Severo LC.
Association between paracoccidioidomycosis and cancer. J Bras Pneumol.
2010;36(3):356-62.-88. Bellissimo-Rodrigues F, Machado AA, Martinez R. Paracoccidioidomycosis
epidemiological features of a 1,000-cases series from a hyperendemic area on the southeast of
Brazil. Am J Trop Med Hyg. 2011;85(3):546-50,
http://dx.doi.org/10.4269/ajtmh.2011.11-0084.
http://dx.doi.org/10.4269/ajtmh.2011.11-...
). Additionally, cases
outside these areas continue to be reported and are generally associated with long periods of
latency, representing endogenous reactivation of the infectious focus that was previously acquired
in endemic regions (44. Queiroz-Telles F, Escuissato DL. Pulmonary paracoccidioidomycosis. Semin Respir
Crit Care Med. 2011;32(6):764-74, http://dx.doi.org/10.1055/s-0031-1295724.
http://dx.doi.org/10.1055/s-0031-1295724...
). PCM is subdivided into the following
two groups that are differentiated by their time course and the age of the host: juvenile and
chronic forms. The juvenile form has an acute or subacute clinical course with a predominantly
lymphatic distribution. The chronic or reactivation form has a more insidious course in which the
lung is the most frequently involved organ, with lesser involvement of the reticuloendothelial and
lymphatic systems (33. Bethlem EP, Capone D, Maranhao B, Carvalho CR, Wanke B. Paracoccidioidomycosis.
Curr Opin Pulm Med. 1999;5(5):319-25,
http://dx.doi.org/10.1097/00063198-199909000-00010.
http://dx.doi.org/10.1097/00063198-19990...
,44. Queiroz-Telles F, Escuissato DL. Pulmonary paracoccidioidomycosis. Semin Respir
Crit Care Med. 2011;32(6):764-74, http://dx.doi.org/10.1055/s-0031-1295724.
http://dx.doi.org/10.1055/s-0031-1295724...
,99. Shikanai-Yasuda MA, Telles Filho Fde Q, Mendes RP, Colombo AL, Moretti ML.
[Guidelines in paracoccidioidomycosis]. Rev Soc Bras Med Trop. 2006;39(3):297-310.). The cure rate is high when adequate treatment
is readily administered, and mycological eradication can be achieved with sulfonamides, azole
compounds or amphotericin (99. Shikanai-Yasuda MA, Telles Filho Fde Q, Mendes RP, Colombo AL, Moretti ML.
[Guidelines in paracoccidioidomycosis]. Rev Soc Bras Med Trop. 2006;39(3):297-310.
10. Shikanai-Yasuda MA, Benard G, Higaki Y, Del Negro GM, Hoo S, Vaccari EH, et al.
Randomized trial with itraconazole, ketoconazole and sulfadiazine in paracoccidioidomycosis. Med
Mycol. 2002;40(4):411-7.-1111. Tercarioli GR, Bagagli E, Reis GM, Theodoro RC, Bosco Sde M, Macoris SA, et al.
Ecological study of Paracoccidioides brasiliensis in soil: growth ability, conidia production and
molecular detection. BMC Microbiol. 2007;7:92,
http://dx.doi.org/10.1186/1471-2180-7-92.
http://dx.doi.org/10.1186/1471-2180-7-92...
). However, in pulmonary parenchyma, even after treatment, P.
brasiliensis induces chronic damage that leads to the development of lung fibrosis, which
is most likely due to persistent antigenic stimulus that elicits a continuous inflammatory response
(1212. Restrepo S, Tobon A, Trujillo J, Restrepo A. Development of pulmonary fibrosis
in mice during infection with Paracoccidioides brasiliensis conidia. J Med Vet Mycol.
1992;30(3):173-84, http://dx.doi.org/10.1080/02681219280000241.
http://dx.doi.org/10.1080/02681219280000...
). This process can result in a severe restriction of
respiratory function and a decline in work capacity, thereby affecting patient quality of life
(44. Queiroz-Telles F, Escuissato DL. Pulmonary paracoccidioidomycosis. Semin Respir
Crit Care Med. 2011;32(6):764-74, http://dx.doi.org/10.1055/s-0031-1295724.
http://dx.doi.org/10.1055/s-0031-1295724...
,1313. Tuder RM, el Ibrahim R, Godoy CE, De Brito T. Pathology of the human pulmonary
paracoccidioidomycosis. Mycopathologia. 1985;92(3):179-88,
http://dx.doi.org/10.1007/BF00437631.
http://dx.doi.org/10.1007/BF00437631...
,1414. Lemle A, Wanke B, Miranda JL, Kropf GL, Mandel MB, Mandel S. Pulmonary function
in paracoccidioidomycosis (South American blastomycosis). An analysis of the obstructive defect.
Chest. 1983;83(5):827-8, http://dx.doi.org/10.1378/chest.83.5.827.
http://dx.doi.org/10.1378/chest.83.5.827...
). In fact, in more than 50% of cases in which the patient
receives an adequate course of therapy, pulmonary fibrosis is radiographically documented at the end
of the treatment period (1515. Tobon AM, Agudelo CA, Osorio ML, Alvarez DL, Arango M, Cano LE, et al. Residual
pulmonary abnormalities in adult patients with chronic paracoccidioidomycosis: prolonged follow-up
after itraconazole therapy. Clin Infect Dis. 2003;37(7):898-904,
http://dx.doi.org/10.1086/377538.
http://dx.doi.org/10.1086/377538...
). However, the true incidence and
severity of radiographical and functional disability of the patient following treatment for this
endemic mycosis remain unknown.
The objective of this study was to characterize both the residual pulmonary involvement in PCM by high resolution computed tomography (HRCT) and the sequelae related to lung function, exercise capacity and quality of life in the inactive chronic form of PCM.
PATIENTS AND METHODS
From July 2008 to July 2010, all PCM patients seen in the outpatient clinic of the Pulmonary and
Infectious Diseases Divisions of the Hospital das Clinicas at the University of Sao Paulo were
invited to participate in the study. The patients were included if the PCM diagnosis was confirmed
by the identification of P. brasiliensis yeast cells in biopsies and/or other
clinical specimens and/or serological diagnosis. The patients were enrolled if they met the criteria
for inactive disease as determined by a treatment length of at least 6 months, negative mycological
examinations, resolution of skin and mucosal lesions, low anti-P. brasiliensis
antibody titers by counterimmunoelectrophoresis (CIE) (titers <1:4 or a fall in at least four
dilutions) and a lack of radiological activity on chest radiographs (99. Shikanai-Yasuda MA, Telles Filho Fde Q, Mendes RP, Colombo AL, Moretti ML.
[Guidelines in paracoccidioidomycosis]. Rev Soc Bras Med Trop. 2006;39(3):297-310.,1616. Del Negro GM, Pereira CN, Andrade HF, Palacios SA, Vidal MM, Charbel CE, et al.
Evaluation of tests for antibody response in the follow-up of patients with acute and chronic forms
of paracoccidioidomycosis. J Med Microbiol. 2000;49(1):37-46.,1717. de Camargo ZP. Serology of paracoccidioidomycosis. Mycopathologia.
2008;165(4-5):289-302, http://dx.doi.org/10.1007/s11046-007-9060-5.
http://dx.doi.org/10.1007/s11046-007-906...
). The
exclusion criteria were pulmonary co-infections, such as tuberculosis, histoplasmosis or other
chronic infections, or lung neoplasia. From a cohort of 81 PCM patients, 72 met the inclusion
criteria, and 22 were excluded. Of the 22 excluded patients, 10 had the juvenile form, seven had
tuberculosis co-infections, three were tracheotomized, one had microstomia and one refused. Of the
50 patients included in the study, 47 were men ranging in age from 35 to 78 years, with a mean age
of 56.9 years. All were previously diagnosed based on mycological examination, including direct
visualization and/or culture of smears of lesions and/or biopsies.
HRCT scans were obtained using 1 or 2 mm collimation at 10 mm intervals (Multislice Philips
Brilliance CT40, Cleveland, United States). Two investigators (CF and CRRC) blinded to the clinical
history of the patients retrospectively read the CT scans, and when necessary, final decisions were
reached by consensus. The findings were analyzed with regard to distribution in the lung parenchyma,
(central, peripheral or both) and upper (above the level of the tracheal carina), middle (between
the level of the carina and inferior pulmonary veins) and lower zones (below the level of the
inferior pulmonary veins) or a combination of zones (22. Funari M, Kavakama J, Shikanai-Yasuda MA, Castro LG, Bernard G, Rocha MS, et al.
Chronic pulmonary paracoccidioidomycosis (South American blastomycosis): high-resolution CT findings
in 41 patients. AJR Am J Roentgenol. 1999;173(1):59-64.,1818. Souza AS, Jr., Gasparetto EL, Davaus T, Escuissato DL, Marchiori E.
High-resolution CT findings of 77 patients with untreated pulmonary paracoccidioidomycosis. AJR
Am J Roentgenol. 2006;187(5):1248-52,
http://dx.doi.org/10.2214/AJR.05.1065.
http://dx.doi.org/10.2214/AJR.05.1065...
).
For the pulmonary function tests (PFT), all measurements were obtained using the recommended
standards (1919. Pereira CA, Sato T, Rodrigues SC. New reference values for forced spirometry in
white adults in Brazil. J Bras Pneumol. 2007;33(4):397-406.
20. Neder JA, Andreoni S, Castelo-Filho A, Nery LE. Reference values for lung
function tests. I. Static volumes. Braz J Med Biol Res.
1999;32(6):703-17.
21. Neder JA, Andreoni S, Peres C, Nery LE. Reference values for lung function
tests. III. Carbon monoxide diffusing capacity (transfer factor). Braz J Med Biol Res.
1999;32(6):729-37, http://dx.doi.org/10.1590/S0100-879X1999000600008.
http://dx.doi.org/10.1590/S0100-879X1999...
-2222. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al.
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38,
http://dx.doi.org/10.1183/09031936.05.00034805.
http://dx.doi.org/10.1183/09031936.05.00...
).
Spirometry was performed using a calibrated pneumotachograph (Medical Graphics Corporation, MGC, St.
Paul, MN, USA, 2005), whereas lung volumes and CO diffusing capacity (DLCO) were obtained
with a body plethysmograph (Elite Dx, Elite SeriesTM, MGC). The following variables were
considered: FVC (forced vital capacity), FEV1 (expiratory forced volume in the first
second), IC (inspiratory capacity), TLC (total lung capacity), RV (residual volume), MVV (maximal
voluntary ventilation) and DLCO. The predicted values were derived based on the Brazilian
population (1919. Pereira CA, Sato T, Rodrigues SC. New reference values for forced spirometry in
white adults in Brazil. J Bras Pneumol. 2007;33(4):397-406.
20. Neder JA, Andreoni S, Castelo-Filho A, Nery LE. Reference values for lung
function tests. I. Static volumes. Braz J Med Biol Res.
1999;32(6):703-17.-2121. Neder JA, Andreoni S, Peres C, Nery LE. Reference values for lung function
tests. III. Carbon monoxide diffusing capacity (transfer factor). Braz J Med Biol Res.
1999;32(6):729-37, http://dx.doi.org/10.1590/S0100-879X1999000600008.
http://dx.doi.org/10.1590/S0100-879X1999...
).
For the cardiopulmonary exercise test (CPET), a ramp symptom-limited CPET was performed on a cycle
(Corival, Lode B.V. Medical Technology, Groningen, The Netherlands) consisting of a 2 min period of
rest and 2 min period of warm-up, followed by an incremental work-rate period, which was increased
from 10 to 20 W/min. Oxygen saturation (SpO2) by pulse oximetry (NONIN-ONYX, model 9500,
Plymouth, MN, USA) and electrocardiography (Welch Allyn CardioPerfect, Inc, NY) were monitored
continuously (2323. Neder JA, Nery LE, Castelo A, Andreoni S, Lerario MC, Sachs A, et al. Prediction
of metabolic and cardiopulmonary responses to maximum cycle ergometry: a randomised study. Eur
Respir J. 1999;14(6):1304-13, http://dx.doi.org/10.1183/09031936.99.14613049.
http://dx.doi.org/10.1183/09031936.99.14...
). The following variables were recorded
(CardiO2 System, MGC): work rate, VO2, minute-ventilation (VE),
carbon dioxide output (VCO2), tidal volume (VT), respiratory rate (RR),
respiratory exchange rate (RER) and heart rate (HR). The predicted values for CPET were calculated
based on the Brazilian population (2323. Neder JA, Nery LE, Castelo A, Andreoni S, Lerario MC, Sachs A, et al. Prediction
of metabolic and cardiopulmonary responses to maximum cycle ergometry: a randomised study. Eur
Respir J. 1999;14(6):1304-13, http://dx.doi.org/10.1183/09031936.99.14613049.
http://dx.doi.org/10.1183/09031936.99.14...
). The six-minute walk
test (6MWT) was performed according to the ATS guidelines (2424. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care
Med. 2002;166(1):111-7.), and the parameters analyzed were the distance walked (meters), SpO2 minimum
maintained for at least 10 seconds and the difference between the basal saturation (at rest) and
minimal saturation achieved during the test (SpO2 basal - SpO2 min). The
distance was analyzed based on the predictive equations for the adult Brazilian population (2525. Soares MR, Pereira CA. Six-minute walk test: reference values for healthy adults
in Brazil. J Bras Pneumol. 2011;37(5):576-83.).
A standard questionnaire was administered by a pulmonologist to obtain information on age, sex,
body mass index, smoking habits and possible respiratory co-infections. Two specific respiratory
questionnaires, the Saint George Respiratory Questionnaire (SGRQ) (2626. Ferrer M, Villasante C, Alonso J, Sobradillo V, Gabriel R, Vilagut G, et al.
Interpretation of quality of life scores from the St George's Respiratory Questionnaire. Eur
Respir J. 2002;19(3):405-13, http://dx.doi.org/10.1183/09031936.02.00213202.
http://dx.doi.org/10.1183/09031936.02.00...
,2727. Sousa TC, Jardim JRB, Jones PW. Validação do Questionário do Hospital Saint
George na Doença Respiratória (SGRQ) em pacientes portadores de doença pulmonar obstrutiva crônica
no Brasil. J Bras Pneumol. 2000;16:119-25,
http://dx.doi.org/10.1590/S0102-35862000000300004.
http://dx.doi.org/10.1590/S0102-35862000...
), and Medical Research Council (MRC) Dyspnea
Questionnaire (2828. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of
the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with
chronic obstructive pulmonary disease. Thorax. 1999;54(7):581-6,
http://dx.doi.org/10.1136/thx.54.7.581.
http://dx.doi.org/10.1136/thx.54.7.581...
,2929. Kovelis D, Segretti NO, Probst VS, Lareau SC, Brunetto AF, Pitta F. Validation
of the Modified Pulmonary Functional Status and Dyspnea Questionnaire and the Medical Research
Council scale for use in Brazilian patients with chronic obstructive pulmonary disease. J Bras
Pneumol. 2008;34(12):1008-18.)
were used. The SGRQ is a standardized airway disease-specific questionnaire divided into three
subscales: symptoms, activity and impacts. The scores were calculated using algorithms as
recommended (P.W. Jones, St George's Hospital Medical School, London, UK, personal communication).
For each subscale and the overall questionnaire, scores ranged from zero, indicating no impairment,
to 100, indicating maximum impairment. Values above 10 reflected an altered quality of life for that
specific area (2626. Ferrer M, Villasante C, Alonso J, Sobradillo V, Gabriel R, Vilagut G, et al.
Interpretation of quality of life scores from the St George's Respiratory Questionnaire. Eur
Respir J. 2002;19(3):405-13, http://dx.doi.org/10.1183/09031936.02.00213202.
http://dx.doi.org/10.1183/09031936.02.00...
,2727. Sousa TC, Jardim JRB, Jones PW. Validação do Questionário do Hospital Saint
George na Doença Respiratória (SGRQ) em pacientes portadores de doença pulmonar obstrutiva crônica
no Brasil. J Bras Pneumol. 2000;16:119-25,
http://dx.doi.org/10.1590/S0102-35862000000300004.
http://dx.doi.org/10.1590/S0102-35862000...
).
The MRC breathlessness scale is a measurement of disability in patients with chronic obstructive
pulmonary disease. It comprises five statements that describe nearly the entire range of respiratory
disability from none (Grade 1) to almost complete incapacity (Grade 5) (2828. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of
the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with
chronic obstructive pulmonary disease. Thorax. 1999;54(7):581-6,
http://dx.doi.org/10.1136/thx.54.7.581.
http://dx.doi.org/10.1136/thx.54.7.581...
,2929. Kovelis D, Segretti NO, Probst VS, Lareau SC, Brunetto AF, Pitta F. Validation
of the Modified Pulmonary Functional Status and Dyspnea Questionnaire and the Medical Research
Council scale for use in Brazilian patients with chronic obstructive pulmonary disease. J Bras
Pneumol. 2008;34(12):1008-18.).
Patients were then divided into two groups based on the severity of exercise gas exchange
disability by desaturation in the 6MWT. Group A demonstrated desaturation, and Group B had no
desaturation. Desaturation was defined as a fall >4% of the resting SpO2 value (3030. Poulain M, Durand F, Palomba B, Ceugniet F, Desplan J, Varray A, et al. 6-minute
walk testing is more sensitive than maximal incremental cycle testing for detecting oxygen
desaturation in patients with COPD. Chest. 2003;123(5):1401-7,
http://dx.doi.org/10.1378/chest.123.5.1401.
http://dx.doi.org/10.1378/chest.123.5.14...
). We chose the 6MWT because it is a simple, efficient and
low-cost tool used to evaluate the performance of individuals during submaximal exercise and can be
even more sensitive than maximal incremental cycle testing for the detection of oxygen desaturation
(2424. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care
Med. 2002;166(1):111-7.,3030. Poulain M, Durand F, Palomba B, Ceugniet F, Desplan J, Varray A, et al. 6-minute
walk testing is more sensitive than maximal incremental cycle testing for detecting oxygen
desaturation in patients with COPD. Chest. 2003;123(5):1401-7,
http://dx.doi.org/10.1378/chest.123.5.1401.
http://dx.doi.org/10.1378/chest.123.5.14...
).
Statistical analysis was performed with GraphPad Prism Version 5.0 for Windows (GraphPad Software, San Diego CA, USA). Parametric variables are expressed as the mean and standard deviation (SD), and nonparametric variables are expressed as the median and interquartile range (IQ). Correlations were performed using either Pearson or Spearman tests, depending on the distribution of the variables. Comparisons between groups were performed with a Student's T test or Mann-Whitney test when appropriate. A chi-squared analysis was used to examine categorical variables, and a Fisher exact test was used for small samples. Statistical significance was assumed for p-values<0.05.
Ethics Statement
Our research was approved by our two Ethics Committees, Comissão de Pesquisa do Departamento de Cardiopneumologia and Comissão de Ética para a Análise de Projetos de Pesquisa - CAPPesq da Diretoria Clínica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, on June 09, 2007, under approval number 870/06. All patients in our study signed an informed consent form, and all clinical investigations were conducted in accordance with the principles expressed in the Declaration of Helsinki.
RESULTS
The clinical and epidemiological data for the patients and their serum titers on CIE at the time of diagnosis and the time of our evaluation are shown in Table 1. All but one of the patients were smokers. The antifungal drugs used by the patients were itraconazole (26%), sulfamethoxazole-trimethoprim (16%), sulfadiazine (12%) and ketoconazole (8%). The remaining 38% used two or more of these drugs for treatment. Patients were not HIV co-infected and had no autoimmune disease or referred use of immunosuppressant drugs.
Twenty-seven patients remained on antifungal medications because it is a common practice in the infectious diseases outpatient unit to use low-dose sulfamethoxazole-trimetropin as a maintenance treatment to prevent relapses of the chronic forms of infections. These patients represented 40% in Group A (desaturation in 6 MWT) and 60% in Group B (p = 0.34).
The serum CIE titer at diagnosis was significantly higher in Group A compared with the patients without exercise desaturation in Group B. The other clinical and epidemiological parameters were not different between these two groups.
Radiological Findings
Abnormal pulmonary findings on HRCT were observed in all but one patient, and multiple abnormalities were often present simultaneously (median of eight abnormalities/patient). CT findings included architectural distortion (90%, n = 45), interlobular septal thickening and reticulate (88%, n = 44), centrilobular or paraseptal emphysema (82%, n = 41), bronchial thickening (82%, n = 41), parenchymal bands (74%, n = 37), areas of cicatricial emphysema (66%, n = 33), nodules <3 cm (62%, n = 31) and ground glass opacities (46%, n = 23). Pleural thickening was observed in 10 (20%) patients, and mediastinal lymphadenopathy in only three cases. Thirty-eight patients presented with mosaic perfusion patterns with expiratory maneuvers. The major tomographic findings were predominantly diffuse in their distribution (84%), were most prominent in the superior and medium zones and had a combination of central and peripheral locations in 80% of cases. When predominance was apparent, these findings were most common in the upper and middle lung zones. The most frequent abnormalities are shown in Figure 1 (A-F). Notably, a comparison between Group A and B revealed no difference in the number of interstitial fibrotic CT abnormalities, which were architectural distortion, interlobular septal thickening and reticulate and parenchymal bands. However, when emphysema quantification scores were compared, they were higher (more prominent emphysema) in Group A than Group B (Figure 2), p = 0.0009).
The patterns of pulmonary alterations found on HRCT. (A) Upper lobes showing septal thickening and peripheral reticulate. (B) Upper lobes showing architectural distortion. (C) Lower lobes showing parenchymal bands. (D) Lower lobes showing non-calcified nodules in the left lower lobe. (E) Upper lobes showing centrilobular and paraseptal emphysema. (F) Lower lobes showing peribronchovascular thickening.
Figure showing that emphysema quantification by CT was significantly higher in the most severely impaired PCM patients compared to the least severely impaired PCM patients.
Pulmonary function tests (PFT)
Lung function test results are shown in Table 2.
Seven patients (14%) presented with normal PFT. An obstructive defect, defined as
FEV1/FVC<0.70, was observed in 70% (3535. Naranjo TW, Lopera DE, Diaz-Granados LR, Duque JJ, Restrepo AM, Cano LE.
Combined itraconazole-pentoxifylline treatment promptly reduces lung fibrosis induced by chronic
pulmonary paracoccidioidomycosis in mice. Pulm Pharmacol Ther. 2010;24(1):81-91.) of
patients (3131. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global
Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available at: http://www.goldcopd.org/.
Accessed 26 April 2012. Journal [serial on the Internet]. Date [cited 2011: Available from:
http://www.goldcopd.org/.
http://www.goldcopd.org/...
). Of the latter, 85% (n = 30) presented with
only a mild obstruction (FEV1>60%), and only one patient presented with a severe
obstruction (FEV1<40%). The residual volume/total lung capacity was slightly
increased, suggesting air trapping without pulmonary hyperinflation. Only one patient presented with
a pure restrictive pattern, showing a TLC of 61% of the predicted value. Diffusing capacity was
impaired in 43 (86%) patients (mean DLCO: 60.6% of the predicted value). Nine patients
presented with a severe (DLCO<40%), 15 with a moderate (40%<DLCO<60%)
and 19 with a mild reduction (DLCO>60%) in diffusion capacity. There was no
bronchodilator response (data not shown). A comparison between groups showed that Group A had
significantly reduced gas exchange and ventilatory strength than Group B (Table 2).
Exercise evaluation
The maximal exercise performance was preserved in the PCM patients, with a VO2max value of 80.8%±18.5 of the predicted value. At exercise cessation, there was a large ventilatory reserve that was accomplished without oxygen desaturation, showing a preserved performance of the respiratory system under effort. Cardiac behavior was characterized by a normal oxygen pulse (VO2/HR = 11.0±2.8 mL.min-1), and the significant cardiac reserve suggested that there were no cardiac limitations. Of the 50 patients, only one had ECG abnormalities that were compatible with coronary disease, which was not confirmed by an invasive posterior coronary study. When Groups A and B were examined, no significant difference was found between the patients for either VO2max or oxygen pulse; however, Group A had a lower ventilatory reserve with higher hyperventilation (augmented VE/VCO2). In summary, Group A presented with more serious respiratory impairments during exercise compared with Group B (Table 3).
In the 6MWT, patients achieved a normal distance with a median of 492 meters, which was 131% of the predicted value, without desaturation. The distance achieved was similar between groups. However, for the submaximal test (very large cardiac reserve at exercise cessation), 18 (36%) of the patients presented with a decrease >4% in SpO2, which was indicative of an abnormal arterial-alveolar gradient that was previously shown for PCM in other studies (3232. Lemle A, Wanke B, Mandel MB. Pulmonary localization of paracoccidioidomycosis: lung function studies before and after treatment. Rev Inst Med Trop Sao Paulo. 1983;25(12):73-8.,3333. Afonso JE, Nery LE, Romaldini H, Bogossian M, Ribeiro-Ratto O. [Pulmonary function in paracoccidioidomycosis (South American blastomycosis)]. Rev Inst Med Trop Sao Paulo. 1979;21(6):269-80.) (Table 3).
Health-related quality of life (HRQOL)
The Saint George Respiratory Questionnaire scores are presented in Table 4. Patients presented with high (worse) scores in the symptoms and
activity scales but low overall impairments in health-related quality of life. For the MRC Dyspnea
Questionnaire, the patients had a mean value of 1, which corresponds with “not troubled by
breathlessness except on strenuous exercise” (2828. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of
the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with
chronic obstructive pulmonary disease. Thorax. 1999;54(7):581-6,
http://dx.doi.org/10.1136/thx.54.7.581.
http://dx.doi.org/10.1136/thx.54.7.581...
). Even in
Group A, the more severe impairments did not translate into a worse quality of life, as measured by
either the SGRQ or MRC Dyspnea Questionnaire. There was a strong correlation between the two scores,
with p<0.0001 and r = 0.65.
Correlation studies
The initial CIE titers inversely correlated with the DLCO (p = 0.001, r = -0.44) and positively correlated with impairments the in HRQOL (p = 0.021, r = 0.33). However, there was no correlation between the CIE and any of the other parameters analyzed in the population under study.
DISCUSSION
In contrast with previous investigations of treated PCM patients, we found a consistently higher
incidence of radiological involvement, with 98% of patients presenting with at least one CT
abnormality. The most common abnormalities were architectural distortion and interlobular septal
thickening and reticulate, which were most likely related to dissemination of the fungi through the
lymphatics and subsequent fibrosis formation (1313. Tuder RM, el Ibrahim R, Godoy CE, De Brito T. Pathology of the human pulmonary
paracoccidioidomycosis. Mycopathologia. 1985;92(3):179-88,
http://dx.doi.org/10.1007/BF00437631.
http://dx.doi.org/10.1007/BF00437631...
). The
finding of peribronchovascular interstitial thickening diffusely distributed throughout the
pulmonary zones in 62% of the patients is another abnormality related to the pattern of fungal
dissemination previously described in histopathology studies (22. Funari M, Kavakama J, Shikanai-Yasuda MA, Castro LG, Bernard G, Rocha MS, et al.
Chronic pulmonary paracoccidioidomycosis (South American blastomycosis): high-resolution CT findings
in 41 patients. AJR Am J Roentgenol. 1999;173(1):59-64.). In contrast, centrilobular and paraseptal emphysema were observed in 82% of individuals,
which reflects the high tobacco exposure in our population, a feature regularly described in cohorts
of chronic PCM (88. Bellissimo-Rodrigues F, Machado AA, Martinez R. Paracoccidioidomycosis
epidemiological features of a 1,000-cases series from a hyperendemic area on the southeast of
Brazil. Am J Trop Med Hyg. 2011;85(3):546-50,
http://dx.doi.org/10.4269/ajtmh.2011.11-0084.
http://dx.doi.org/10.4269/ajtmh.2011.11-...
). Finally, different from the pre-treatment
CT scan findings (22. Funari M, Kavakama J, Shikanai-Yasuda MA, Castro LG, Bernard G, Rocha MS, et al.
Chronic pulmonary paracoccidioidomycosis (South American blastomycosis): high-resolution CT findings
in 41 patients. AJR Am J Roentgenol. 1999;173(1):59-64.,1818. Souza AS, Jr., Gasparetto EL, Davaus T, Escuissato DL, Marchiori E.
High-resolution CT findings of 77 patients with untreated pulmonary paracoccidioidomycosis. AJR
Am J Roentgenol. 2006;187(5):1248-52,
http://dx.doi.org/10.2214/AJR.05.1065.
http://dx.doi.org/10.2214/AJR.05.1065...
,3434. Marchiori E, Zanetti G, Escuissato DL, Souza AS, Jr., Meirelles Gde S, Fagundes
J, et al. Reversed Halo Sign: High-Resolution CT Scan Findings in 79 Patients. Chest.
2012;141(5):1260-6, http://dx.doi.org/10.1378/chest.11-1050.
http://dx.doi.org/10.1378/chest.11-1050...
), consolidation and cavitations were very rare,
and no reversed halo sign was observed, confirming the inactivity of the mycosis.
It has been shown by thoracic roentgenogram that fungus-induced lung fibrosis in the form of
residual lesions occurs in up to 53% of treated patients (1515. Tobon AM, Agudelo CA, Osorio ML, Alvarez DL, Arango M, Cano LE, et al. Residual
pulmonary abnormalities in adult patients with chronic paracoccidioidomycosis: prolonged follow-up
after itraconazole therapy. Clin Infect Dis. 2003;37(7):898-904,
http://dx.doi.org/10.1086/377538.
http://dx.doi.org/10.1086/377538...
), which has led to experimental studies involving pentoxifylline as a complementary
treatment for pulmonary PCM due to its immunomodulatory and anti-fibrotic properties (3535. Naranjo TW, Lopera DE, Diaz-Granados LR, Duque JJ, Restrepo AM, Cano LE.
Combined itraconazole-pentoxifylline treatment promptly reduces lung fibrosis induced by chronic
pulmonary paracoccidioidomycosis in mice. Pulm Pharmacol Ther. 2010;24(1):81-91.). However, this radiologic approach may not be beneficial for an
even greater proportion of individuals with interstitial pulmonary abnormalities because thoracic
roentgenogram is not sufficiently sensitive to evaluate these lesions. In addition, chest X-rays are
not sufficiently sensitive to confirm the possible presence of lung emphysema (1515. Tobon AM, Agudelo CA, Osorio ML, Alvarez DL, Arango M, Cano LE, et al. Residual
pulmonary abnormalities in adult patients with chronic paracoccidioidomycosis: prolonged follow-up
after itraconazole therapy. Clin Infect Dis. 2003;37(7):898-904,
http://dx.doi.org/10.1086/377538.
http://dx.doi.org/10.1086/377538...
). Indeed, HRCT is currently the standard approach to confirm lung parenchymal
involvement (1818. Souza AS, Jr., Gasparetto EL, Davaus T, Escuissato DL, Marchiori E.
High-resolution CT findings of 77 patients with untreated pulmonary paracoccidioidomycosis. AJR
Am J Roentgenol. 2006;187(5):1248-52,
http://dx.doi.org/10.2214/AJR.05.1065.
http://dx.doi.org/10.2214/AJR.05.1065...
,3636. Marchiori E, Valiante PM, Mano CM, Zanetti G, Escuissato DL, Souza AS, Jr., et
al. Paracoccidioidomycosis: high-resolution computed tomography-pathologic correlation.
Eur J Radiol. 2009;77(1):80-4.,3737. Barreto MM, Marchiori E, Amorim VB, Zanetti G, Takayassu TC, Escuissato DL, et
al. Thoracic Paracoccidioidomycosis: Radiographic and CT Findings. Radiographics. 2012;32(1):71-84,
http://dx.doi.org/10.1148/rg.321115052.
http://dx.doi.org/10.1148/rg.321115052...
). As expected, using HRCT, we found a greater
proportion of lung residual abnormalities than previously reported, confirming that PCM can lead to
even further radiological involvement of respiratory tissue than previously thought.
Despite these findings, the pulmonary functional impairments were not that limiting. On average,
the patients presented with a mild obstructive disorder associated with a mild reduction in
diffusion capacity and slight reduction in the maximal voluntary ventilation. Indeed, most of the
patients were classified as having mild obstructive defects, and only one patient presented with
severe obstruction. This contrasts with earlier studies in which more than 50% of the patients
evaluated presented with a moderate to severe obstructive defect (3838. Lemle A, Vieira LO, Milward GA, Miranda JL. Lung function studies in pulmonary
South American blastomycosis. Correlation with clinical and roentgenologic findings.
Am J Med. 1970;48(4):434-42.), the alveolar-arterial gradient was altered in all patients (3939. Campos EP, Cataneo AMJ. Função pulmonar na evolução de 35 pacientes com
paracoccidioidomicose. Rev Inst Med Trop Sao Paulo. 1986;28(5):330-6,
http://dx.doi.org/10.1590/S0036-46651986000500008.
http://dx.doi.org/10.1590/S0036-46651986...
,4040. Campos EP, Padovani CR, Cataneo AMJ. Paracoccidioidomicose: estudo radiológico e
pulmonar de 58 casos. Rev Inst Med Trop Sao Paulo. 1991;33(4):267-76,
http://dx.doi.org/10.1590/S0036-46651991000400005.
http://dx.doi.org/10.1590/S0036-46651991...
), and cor pulmonale was present in
almost 25% of the cases (4040. Campos EP, Padovani CR, Cataneo AMJ. Paracoccidioidomicose: estudo radiológico e
pulmonar de 58 casos. Rev Inst Med Trop Sao Paulo. 1991;33(4):267-76,
http://dx.doi.org/10.1590/S0036-46651991000400005.
http://dx.doi.org/10.1590/S0036-46651991...
). This discrepancy may be related
to the more restricted access to health care facilities in Brazil at the time these studies were
conducted, which delayed proper diagnosis and treatment. In contrast, in our patients, the
DLCO was severely impaired in only 18% of patients. A plausible explanation for these
functional findings of mild obstruction with more severe DLCO impairment is the presence
of interstitial fibrotic disease associated with pulmonary emphysema, as described for Combined
Pulmonary Fibrosis and Emphysema (CPFE). In this condition, there are subnormal spirometry exams,
despite severe impairment in DLCO, that are most likely secondary to overinflation and an
increase in pulmonary compliance due to the loss of elasticity in areas with emphysema that are
balanced by the loss of volume and decreased compliance caused by fibrosis (4141. Jankowich MD, Rounds SI. Combined pulmonary fibrosis and emphysema syndrome: a
review. Chest. 2012;141(1):222-31, http://dx.doi.org/10.1378/chest.11-1062.
http://dx.doi.org/10.1378/chest.11-1062...
).
When our patients performed maximal and submaximal exercises, their performances were normal.
Furthermore, we could not find any ventilatory or cardiac limitations. This behavior was also
reflected in the quality of life measurements. On average, the patients presented with low quality
of life impairments, as measured by the Saint George Respiratory Questionnaire. The mean score of 16
can be interpreted as altered because it is higher than 10 (2929. Kovelis D, Segretti NO, Probst VS, Lareau SC, Brunetto AF, Pitta F. Validation
of the Modified Pulmonary Functional Status and Dyspnea Questionnaire and the Medical Research
Council scale for use in Brazilian patients with chronic obstructive pulmonary disease. J Bras
Pneumol. 2008;34(12):1008-18.), but compared with the general population, it remained within the 80th
percentile limit (2626. Ferrer M, Villasante C, Alonso J, Sobradillo V, Gabriel R, Vilagut G, et al.
Interpretation of quality of life scores from the St George's Respiratory Questionnaire. Eur
Respir J. 2002;19(3):405-13, http://dx.doi.org/10.1183/09031936.02.00213202.
http://dx.doi.org/10.1183/09031936.02.00...
), indicating that the HRQOL was not
impaired in a severe manner. Indeed, in the MRC questionnaire, the patients had a mean value of
1.
There was, however, a substantial percentage (36%) of patients who presented with significant gas exchange dysfunction that was confirmed by desaturation (decrease ≥4%) in the 6MWT. This proportion of impaired patients is smaller than previously thought, but this finding suggests that a proportion of PCM patients will present with some degree of respiratory distress during exercise. Notably, both groups had comparable interstitial fibrotic alterations regarding lung CTs, type and length of treatments, age and tobacco exposure. Patients with exercise desaturation (Group A) presented with more severe emphysema than Group B, even though they had similar tobacco exposure. One likely explanation for this finding is the higher pre-treatment serology titers in Group B, denoting a putative higher fungal burden and subsequently stronger inflammatory response. In fact, the initial serology was inversely correlated with the DLCO and positively correlated with impairment in the health-related quality of life questionnaire. This aspect warrants further evaluation.
It is also conceivable that in some patients, the diagnosis was delayed; therefore, at the time
treatment began, the fibrosis was already at an advanced stage. Similarly, differences in the
host-parasite relationship due to distinct host immune responses and regulation among the patients
could also explain the different outcomes (4242. Benard G. An overview of the immunopathology of human paracoccidioidomycosis.
Mycopathologia. 2008;165(4-5):209-21, http://dx.doi.org/10.1007/s11046-007-9065-0.
http://dx.doi.org/10.1007/s11046-007-906...
,4343. Calich VL, Vaz CA, Burger E. Immunity to Paracoccidioides brasiliensis
infection. Res Immunol. 1998;149(4-5):407-17; discussion 99-500,
http://dx.doi.org/10.1016/S0923-2494(98)80764-5.
http://dx.doi.org/10.1016/S0923-2494(98)...
). Finally, genetic differences in the response to tobacco
exposure leading to more severe emphysema in face of comparable tobacco exposure could explain why a
subgroup of patients developed higher levels of emphysema (4444. Kim WJ, Hoffman E, Reilly J, Hersh C, Demeo D, Washko G, et al. Association of
COPD candidate genes with computed tomography emphysema and airway phenotypes in severe COPD. Eur
Respir J. 2011;37(1):39-43, http://dx.doi.org/10.1183/09031936.00173009.
http://dx.doi.org/10.1183/09031936.00173...
). Also, the influence of genetic background on emphysema severity could have been
accentuated by the concomitant pulmonary insult caused by the fungi. This is of particular interest
because emphysema was the major tomographic finding associated with more intense impairments in
aerobic capacity and gas exchange.
Our study has several limitations. We could not assess the patients at the onset of antifungal
therapy, and information regarding the clinical course of the disease was retrospectively assessed.
Notably, these data are particularly difficult to interpret because the CF of the mycosis has a very
insidious and often subclinical course, and at the time of diagnosis, the patients usually exhibit
marked clinical-radiological dissociation (44. Queiroz-Telles F, Escuissato DL. Pulmonary paracoccidioidomycosis. Semin Respir
Crit Care Med. 2011;32(6):764-74, http://dx.doi.org/10.1055/s-0031-1295724.
http://dx.doi.org/10.1055/s-0031-1295724...
). Tobacco
exposure may indeed be a confounding variable. However, obtaining a group of patients without
tobacco exposure is not feasible when studying the chronic form of PCM because a smoking habit is
almost universal in individuals with this form of mycosis (22. Funari M, Kavakama J, Shikanai-Yasuda MA, Castro LG, Bernard G, Rocha MS, et al.
Chronic pulmonary paracoccidioidomycosis (South American blastomycosis): high-resolution CT findings
in 41 patients. AJR Am J Roentgenol. 1999;173(1):59-64.,88. Bellissimo-Rodrigues F, Machado AA, Martinez R. Paracoccidioidomycosis
epidemiological features of a 1,000-cases series from a hyperendemic area on the southeast of
Brazil. Am J Trop Med Hyg. 2011;85(3):546-50,
http://dx.doi.org/10.4269/ajtmh.2011.11-0084.
http://dx.doi.org/10.4269/ajtmh.2011.11-...
,4545. Santos WA, Silva BM, Passos ED, Zandonade E, Falqueto A. Associação entre
tabagismo e paracoccidioidomicose: um estudo de caso-controle no Estado do Espírito Santo, Brasil.
Cad Saúde Pública. 2003;19(1):245-53,
http://dx.doi.org/10.1590/S0102-311X2003000100027.
http://dx.doi.org/10.1590/S0102-311X2003...
).
Additionally, patients used different classes of drugs for treatment, which can be a confounding
factor for the final endpoints, but currently, there are no studies demonstrating the improved
efficacy of one antifungal drug compared with others (99. Shikanai-Yasuda MA, Telles Filho Fde Q, Mendes RP, Colombo AL, Moretti ML.
[Guidelines in paracoccidioidomycosis]. Rev Soc Bras Med Trop. 2006;39(3):297-310.,1010. Shikanai-Yasuda MA, Benard G, Higaki Y, Del Negro GM, Hoo S, Vaccari EH, et al.
Randomized trial with itraconazole, ketoconazole and sulfadiazine in paracoccidioidomycosis. Med
Mycol. 2002;40(4):411-7.,(4646. Stamm AM, Dismukes WE. Current therapy of pulmonary and disseminated fungal
diseases. Chest. 1983;83(6):911-7, http://dx.doi.org/10.1378/chest.83.6.911.
http://dx.doi.org/10.1378/chest.83.6.911...
,4747. Menezes VM, Soares BG, Fontes CJ. Drugs for treating paracoccidioidomycosis.
Cochrane Database Syst Rev. 2006;(2):CD004967.).
In conclusion, we showed that patients with the chronic form of PCM and high exposure to tobacco displayed several residual lesions on the lung CT scans in association with emphysema. However, these residual lesions did not predict severe pulmonary functional impairments or a decreased HRQOL. A subset of patients, however, persisted with gas exchange impairments during exercise and higher respiratory distress and should be identified by the simple and inexpensive 6MWT. The main factors involved with the respiratory impairments were emphysema, as shown by the HRCT scan, and higher initial serology titer, as shown by the CIE and higher initial serology titer. This stresses the value of adequate and early specific treatments associated with tobacco cessation. The factors involved in this more severe evolution of PCM, however, remain unclear and require further investigation.
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No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
Apr 2013
History
-
Received
26 Sept 2012 -
Reviewed
30 Oct 2012 -
Accepted
3 Dec 2012