Clinical characteristics and treatment outcome of Candida tracheobronchitis

Abstract

Although Candida species can cause invasive fungal diseases, such as disseminated infection and pneumonia, they rarely cause tracheobronchitis, which is often fatal.

To identify the clinical characteristics of Candida tracheobronchitis, we retrospectively evaluated 8 patients who had pathologically proven Candida tracheobronchitis.

Their median age was 64 (range: 51–70) years and 5 were females. Three patients had solid cancers and 5 had hematological malignancies. We classified tracheobronchitis into localized and diffuse types. Of the 8 patients, 5 had localized and 3 had diffuse tracheobronchitis. While all patients with diffuse tracheobronchitis had predisposing risk factors for invasive fungal disease, such as prolonged corticosteroid use, recent use of nucleoside analogues, or recent neutropenia (<500/m3), only 2 of the 5 with localized tracheobronchitis had predisposing risk factors. Four of the 5 patients with localized tracheobronchitis had loco-regional bronchial mucosal damage (e.g., radiation or photodynamic therapy). Although all 8 patients ultimately died, some improved with or without antifungal treatment. Two of the 5 patients (1 with localized and the other with diffuse tracheobronchitis) who received antifungal agents improved after treatment, and 1 patient with localized tracheobronchitis who did not receive antifungal treatment improved spontaneously. Two of the 3 patients with diffuse tracheobronchitis did not respond to antifungal treatment.

Candida tracheobronchitis can present as both localized and diffuse types. While the former was influenced more by loco-regional mucosal damage, the latter was influenced more by the patient's immune status. The treatment outcomes were especially poor in patients with diffuse tracheobronchitis.

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Clinical characteristics and treatment outcome of
Candida tracheobronchitis
Hyun-Il Gil, MD
a
, Bumhee Yang, MD
b
, Taebum Lee, MD, PhD
c
, Min Yeong Kim, MD, PhD
d
,
Hayoung Choi, MD, PhD
e
, Hongseok Yoo, MD, PhD
f
, Hojoong Kim, MD, PhD
f
, O. Jung Kwon, MD, PhD
f
,
Sung Jun Chung, MD
g
, Hyun Lee, MD, PhD
g,∗
Abstract
Although Candida species can cause invasive fungal diseases, such as disseminated infection and pneumonia, they rarely cause
tracheobronchitis, which is often fatal.
To identify the clinical characteristics of Candida tracheobronchitis, we retrospectively evaluated 8 patients who had pathologically
proven Candida tracheobronchitis.
Their median age was 64 (range: 51–70) years and 5 were females. Three patients had solid cancers and 5 had hematological
malignancies. We classified tracheobronchitis into localized and diffuse types. Of the 8 patients, 5 had localized and 3 had diffuse
tracheobronchitis. While all patients with diffuse tracheobronchitis had predisposing risk factors for invasive fungal disease, such as
prolonged corticosteroid use, recent use of nucleoside analogues, or recent neutropenia (<500/m
3
), only 2 of the 5 with localized
tracheobronchitis had predisposing risk factors. Four of the 5 patients with localized tracheobronchitis had loco-regional bronchial
mucosal damage (e.g., radiation or photodynamic therapy). Although all 8 patients ultimately died, some improved with or without
antifungal treatment. Two of the 5 patients (1 with localized and the other with diffuse tracheobronchitis) who received antifungal
agents improved after treatment, and 1 patient with localized tracheobronchitis who did not receive antifungal treatment improved
spontaneously. Two of the 3 patients with diffuse tracheobronchitis did not respond to antifungal treatment.
Candida tracheobronchitis can present as both localized and diffuse types. While the former was influenced more by loco-regional
mucosal damage, the latter was influenced more by the patient’s immune status. The treatment outcomes were especially poor in
patients with diffuse tracheobronchitis.
Abbreviations: CT =computed tomography, IFD =invasive fungal diseases, TEVAR =thoracic endovascular aortic repair.
Keywords: bronchial disease, Candida, invasive fungal disease
1. Introduction
The mortality rate is higher in critically ill patients with
nosocomial fungal infection than in those without it.
[1]
Although
the incidence of fungal tracheobronchitis is lower than that of
other invasive fungal diseases (IFD),
[2,3]
it can progress rapidly
and cause airway obstruction, leading to respiratory failure and
death.
[4]
Common etiologies of invasive fungal tracheobronchitis
are Aspergillus,Coccidioides,Cryptococcus, and Zygomycota
Editor: Oana Sa˘ndulescu.
HG and BY contributed equally to this manuscript as first authors.
None of the authors received any financial support for this study.
The Institutional Review Board of Samsung Medical Center approved this study (SMC 2018-11-032).
The authors have no conflicts of interests to disclose.
All data generated or analyzed during this study are included in the published article. The datasets used and analyzed during this study are available from the
corresponding author on reasonable request.
This study was supported by the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. 2020R1F1A1070468 and
2021M3E5D1A0101517621) and the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of
Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (No. 202014X08-03).
a
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul,
b
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Chungbuk National University, Cheongju,
c
Department of Pathology, Chonnam National
University Medical School, Hwasun Hospital, Hwasun-gun,
d
Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine,
e
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital,
f
Division of
Pulmonology and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine,
g
Division of Pulmonary
Medicine and Allergy, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea.
∗
Correspondence: Hyun Lee, Division of Pulmonary Medicine and Allergy, Department of Internal Medicine, Hanyang University College of Medicine, 222-1 Wangsimni-
ro, Seongdong-gu, Seoul 04763, Republic of Korea (e-mail: namuhanayeyo@naver.com).
Copyright ©2021 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to
download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.
How to cite this article: Gil HI, Yang B, Lee T, Kim MY, Choi H, Yoo H, Kim H, Kwon OJ, Chung SJ, Lee H. Clinical characteristics and treatment outcome of Candida
tracheobronchitis. Medicine 2021;100:6(e24606).
Received: 28 August 2020 / Received in final form: 10 December 2020 / Accepted: 7 January 2021
http://dx.doi.org/10.1097/MD.0000000000024606
Observational Study Medicine®
OPEN
1

(Mucorales) spp.
[5]
Candida spp. are often the cause of
disseminated IFD, but they rarely invade the lower respiratory
tract. Traditionally, Candida spp. found in respiratory specimens
have been considered nonpathogenic colonizers.
[6]
However,
recent studies have shown that Candida spp. can cause lower
respiratory IFD.
[7]
However, there are limited data on the clinical
characteristics and prognosis of Candida tracheobronchitis. The
purpose of this study was to elucidate the clinical characteristics
and natural course of Candida tracheobronchitis.
2. Materials and methods
We retrospectively reviewed the medical records of 196 patients
diagnosed with any type of pulmonary IFD between January
1995 and May 2015 at Samsung Medical Center, a referral
hospital in Seoul, South Korea. All cases were confirmed
histologically by bronchial or lung biopsies. After excluding
185 patients who were diagnosed with a fungal infection other
than Candida (Aspergillus [n =125], Cryptococcus [n =22],
mucormycosis [n =8], or unspecified [n =30]), 11 cases were
found to have invasive Candida infection (pneumonia [n =3] or
tracheobronchitis [n =8]). The 8 patients with Candida trache-
obronchitis were reviewed. This study was approved by the
Institutional Review Board of Samsung Medical Center (IRB
number SMC 2018-11-032).
To identify invasive candidiasis, we followed the guidelines of
the European Organization for Research and Treatment of
Cancer/Invasive Fungal Infections Cooperative Group and the
National Institute of Allergy and Infectious Diseases Mycoses
Study Group for invasive fungal infection diagnosis. Tracheo-
bronchitis was defined as an ulceration, nodule, pseudomem-
brane, plaque, or eschar in the trachea, or a bronchus revealed by
bronchoscopy.
[8]
Plain chest radiography and computed tomography (CT) were
performed at the time of Candida tracheobronchitis diagnosis
in all patients except patient no. 7. All 8 patients underwent
bronchoscopic biopsy for diagnosis. The radiological and
bronchoscopic findings were reviewed by 4 physicians (H Gil,
B Yang, MY Kim, and H Lee). Based on the CT and
bronchoscopic findings, we classified Candida tracheobronchitis
as localized or diffuse.
[9,10]
Localized tracheobronchitis was
defined as an endobronchial nodule, mass, pseudomembrane, or
necrotic change not affecting more than 2 spurs of the bronchi.
Diffuse tracheobronchitis was defined as a diffuse pseudomem-
brane spreading over an entire tracheobronchial segment or more
than 2 spurs of the bronchi. A pathologist (T Lee) reevaluated all
bronchial tissue samples obtained from the 8 patients to confirm
invasive fungal infection.
3. Results
The median patient age was 64 (range: 51–70) years and 5 were
female. Three patients had solid-tumor cancer (lung cancer [n =2]
or tracheal adenoid cystic carcinoma [n =1]). Five patients had
hematological malignancies (lymphoma [n =2], multiple myelo-
ma [n =1], or acute leukemia [n =2]). Five patients had localized
tracheobronchitis and 3 had diffuse tracheobronchitis. Five
patients (2 with localized and 3 with diffuse tracheobronchitis)
had predisposing host factors for IFD, such as prolonged
corticosteroid use (>0.3 mg/kg/day of prednisone equivalent for
>3 weeks), use of nucleoside analogues within the past 90 days,
or recent history of neutropenia (<500/mm
3
) for >10 days at the
Table 1
Clinical characteristics and prognoses of patients with Candida tracheobronchitis.
Patient
No.
Sex/Age
(years)
Underlying
disease
Host factors
predisposing to IFD
Previous
locoregional
treatment
Morphological
classification of
tracheobronchitis
Antifungal
treatment
Improvement
of Candida
tracheobronchitis
Survival time (days)
after diagnosis of
tracheobronchitis
Cause of death
1 F/63 Tracheal ACC No Endobronchial brachytherapy Localized No No 9 ACC
2 M/70 NSCLC No Chemoradiation Localized No Yes 1130 NSCLC
3 F/60 DLBCL No Radiation therapy of thoracic vertebra Localized Yes No 52 DLBCL
4 M/70 NSCLC Corticosteroid Endobronchial photodynamic therapy Localized No No 35 Pneumonia
5 F/51 MM Corticosteroid No Localized Yes Yes 111 MM
6 F/59 AML Neutropenia & nucleoside analogue No Diffuse Yes No 3 Pneumonia
7 F/67 Burkitt’s lymphoma Neutropenia No Diffuse Yes No 4 Airway obstruction by Candida
tracheobronchitis
8 M/65 AML Neutropenia & nucleoside analogue No Diffuse Yes Yes 203 AML
ACC =adenoid cystic carcinoma, AML =acute myeloid leukemia, DLBCL =diffuse large B cell lymphoma, IFD =invasive fungal disease, MM =multiple myeloma, NSCLC =non-small cell lung cancer.
Gil et al. Medicine (2021) 100:6 Medicine
2

time of Candida tracheobronchitis diagnosis.
[8]
However, 3 of
the 5 patients with localized tracheobronchitis had no known
host factors for IFD (Table 1). Figures 1 and 2 show the
bronchoscopic and pathological findings.
Of the 5 patients with localized tracheobronchitis, 3 did not
receive antifungal treatment because the attending physicians did
not consider the localized Candida infection to be serious. Despite
the lack of antifungal treatment, the Candida tracheobronchitis
Figure 2. Pathological findings of Candida tracheobronchitis. Each bronchial specimen was subject to hematoxylin and eosin or Grocott’s methenamine silver
staining. Numbers are the patient numbers.
Figure 1. Bronchoscopic findings of Candida tracheobronchitis. Numbers are the patient numbers: #1 to #5 had localized tracheobronchitis and #6 to #8 had
diffuse tracheobronchitis. No bronchoscopy image was available for patient no. 1.
Gil et al. Medicine (2021) 100:6 www.md-journal.com
3

improved spontaneously in 1 patient (patient no. 2), who
survived for more than 3 years after the initial diagnosis of
Candida tracheobronchitis. Of the 2 patients who received
antifungal treatment, 1 improved (patient no. 5).
Of 3 patients with diffuse Candida tracheobronchitis who
received antifungal treatment, 1 improved, but all ultimately died
after 3, 4, and 203days due to pneumonia-associated septic
shock, airway obstruction caused by Candida tracheobronchitis,
and progression of underlying lymphoma, respectively. One
patient with diffuse tracheobronchitis and another with localized
tracheobronchitis improved after antifungal treatment, but
ultimately died from their underlying malignant diseases.
4. Discussion
Here, we present the results of a retrospective study of the clinical
manifestations and natural course of Candida tracheobronchitis.
To our knowledge, this is the first study to comprehensively
describe the 2 types of Candida tracheobronchitis. Whereas
localized Candida tracheobronchitis was associated with loco-
regional mucosal damage rather than immunosuppression,
diffuse Candida tracheobronchitis was mainly associated with
immunosuppressive conditions, particularly neutropenia.
Among immunocompromised patients, those with IFD had a
poor prognosis regardless of the site of infection.
[11]
However,
few studies have focused on fungal tracheobronchitis caused by
Candia spp. Compared with invasive tracheobronchitis caused
by Aspergillus spp., Candida tracheobronchitis is not well-
recognized because most reports describing this entity are
principally concerned with other fungal diseases.
Although a few studies have reported Candida tracheobron-
chitis,
[2,5,12–15]
they included small numbers of cases and
did not fully describe the presentation or clinical course of
Candida tracheobronchitis. In addition, previous studies did not
clearly demonstrate tissue invasion by Candida spp., which is
crucial for diagnosing tracheobronchitis.
[2,4,5]
In this study,
we assessed the clinical presentation and course of both the
localized and diffuse types of (pathologically confirmed) Candida
tracheobronchitis.
As shown by our results, the development of localized
tracheobronchitis is associated with local mucosal damage. In
1 case report, localized Candida tracheobronchitis occurred
several days after thoracic endovascular aortic repair
(TEVAR).
[13]
The patient did not have predisposing factors for
systemic IFD; loco-regional ischemic damage to the airway
mucosa appeared to be the cause of the tracheobronchitis,
consistent with our finding that loco-regional damage may be a
risk factor for this condition. In that case, localized tracheo-
bronchitis occurred as a result of ischemic changes in the airway
mucosa caused by a reduction in bronchial artery blood flow due
to graft placement during TEVAR. Other studies reported
Candida tracheobronchitis at the anastomosis site in lung
transplant patients.
[2,5,15,16]
We also found that local mucosal
injuries caused by endobronchial brachytherapy, photodynamic
therapy, and radiation therapy can contribute to Candida
tracheobronchitis.
Other studies reported cases of Candida tracheobronchitis not
associated with local mucosal damage.
[12,17]
Our study, and
several previous ones, showed that diffuse Candida tracheo-
bronchitis can occur in immunocompromised patients. Previous
studies also showed that immunocompromised patients, includ-
ing those with neutropenia, poorly controlled diabetes mellitus,
and heavy alcohol consumption, can suffer from IFD caused by
Candida spp.
[8,12,17]
We summarize the reported cases of
Candida tracheobronchitis in Table 2.
[4,12–14,16–19]
It is generally considered that the presence of Candida spp. in
lower respiratory tract samples is not indicative of severe
infection or associated with treatment outcomes.
[20]
However,
recent studies have shown that Candida spp. can cause lower-
respiratory IFD, such as Candida pneumonia.
[6]
However,
Candida tracheobronchitis is rarely reported and not well
recognized. Although rare, our study, and previous ones, clearly
showed that Candida infection can manifest as tracheobronchitis,
similar to other fungal infections. Our results indicate that
clinicians should be aware that loco-regional mucosal damage
and a severely compromised immune system can predispose
patients to localized and diffuse Candida tracheobronchitis,
respectively, and that the prognosis of this disease is poor
(especially for diffuse Candida tracheobronchitis).
This study had several limitations. First, it used a retrospective,
single-center design. Second, the number of cases analyzed was
small because of the rarity of the disease. Further studies with
more patients are needed. However, our study was the first to
comprehensively assess pathologically proven Candida trache-
obronchitis, in terms of its presentation, histopathology,
treatment, and natural course.
5. Conclusions
Candida tracheobronchitis can present in localized and diffuse
forms. The former is mainly associated with loco-regional
mucosal damage, while the latter is more dependent on the
Table 2
Reported cases of Candida tracheobronchitis.
Study Number of cases Diagnostic method Form of tracheobronchitis Suspected predisposing factor
Spear, 1976
[18]
1 EBBx Diffuse Broad-spectrum antibiotics
Clarke, 1991
[19]
2 EBBx (1 case) Autopsy (1 case) Diffuse Metastatic cancer (1 case) Unknown (1 case)
Nunley, 2002
[16]
2 EBBx Localized Lung transplantation
Khan, 2016
[17]
1 EBBx Diffuse Fulminant hepatic failure
Schaenman, 2009
[14]
12 EBBx (4 cases) BAL (8 cases) NA Lung transplantation
Lin, 2017
[4]
2 EBBx and/or BAL NA NA
Tanaka, 2017
[12]
1 BAL Diffuse Uncontrolled DM
Takaki, 2018
[13]
1 EBBx Localized Ischemia after TEVAR
BAL =bronchoalveolar lavage, DM =diabetes mellitus, EBBx =endobronchial biopsy, NA =not available, TEVAR =thoracic endovascular aortic repair.
Gil et al. Medicine (2021) 100:6 Medicine
4

patient’s immune status. The treatment outcomes were especially
poor in patients with diffuse tracheobronchitis.
Author contributions
HG and BY were the major contributors to the writing of the
manuscript. They also analyzed and interpreted the data on
invasive fungal tracheobronchitis and contributed equally to this
work. TL performed the histological examinations of bronchial
tissue and contributed to the writing of the manuscript. MYK
performed the radiological review of the cases. HC and HY
helped with the writing and substantively revised the manuscript.
HK, OJK, and SJC reviewed the manuscript and provided
medical advice. HL designed the study and served as the principal
investigator and corresponding author. All authors read and
approved the final manuscript.
Conceptualization: Hyun-Il Gil, Bumhee Yang, Taebum Lee, Min
Yeong Kim, Hayoung Choi, Hojoong Kim, Sung Jun Chung,
Hyun Lee.
Data curation: Hyun-Il Gil, Bumhee Yang, Taebum Lee, Min
Yeong Kim, Hyun Lee.
Formal analysis: Hyun-Il Gil, Bumhee Yang, Taebum Lee, Min
Yeong Kim, Hyun Lee.
Investigation: Hyun-Il Gil, Bumhee Yang, Hyun Lee.
Methodology: Hayoung Choi, Hojoong Kim, O Jung Kwon,
Hyun Lee.
Project administration: Hongseok Yoo, Hyun Lee.
Resources: Hongseok Yoo.
Supervision: Hayoung Choi, Hojoong Kim, O Jung Kwon, Sung
Jun Chung, Hyun Lee.
Visualization: Taebum Lee, Min Yeong Kim.
Writing –original draft: Hyun-Il Gil, Bumhee Yang, Taebum Lee,
Min Yeong Kim.
Writing –review & editing: Hyun-Il Gil, Bumhee Yang, Hayoung
Choi, Hongseok Yoo, Hojoong Kim, O Jung Kwon, Sung Jun
Chung, Hyun Lee.
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