ICU Management & Practice, Volume 16 - Issue 3, 2016

Candida Spp. in the Respiratory Tract

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A Real Causality With Worse Outcomes or Just a Marker of Severity? 

  • Candida spp. is the most common cause of intensive care unit (ICU) invasive fungal infections worldwide.
  • The isolation of Candida spp. from respiratory tract secretions of non-immunocompromised, mechanically ventilated patients varies between 20% and 55%, but it might represent colonisation rather than infection.
  • Candida spp. colonisation promotes bacterial pneumonia in animal models.
  • Candida spp. colonisation could clinically increase the risk for Pseudomonas aeruginosa ventilator-associated pneumonia, prolong mechanical ventilation and stay and worsen outcomes, but to date contrasting data are available.
  • Available evidence is not sufficient to support routine antifungal therapy in non-immunocompromised patients.


Candida spp. is part of the normal skin, oropharyngeal, mucosal membranes and upper respiratory tract flora. Candida spp. ‏can reach the lungs through either haematogenous ‏dissemination or aspiration of colonised ‏oropharyngeal or gastric contents (Muray et ‏al. 1977). The isolation of Candida spp. from ‏respiratory tract secretions is frequent in nonimmunocompromised, ‏mechanically ventilated ‏patients. Several studies have reported the presence ‏of Candida spp. in the sputum of 20-55% ‏of patients receiving antibiotics (Azoulay et al. ‏2006; Delisle et al. 2008). Candida spp. is the ‏most common cause of invasive fungal infections, ‏with an incidence estimated at 72.8 cases ‏per million inhabitants per year (Guinea 2014). ‏The five main species of Candida spp (C. albicans, ‏C. parapsilosis, C. glabrata, C. tropicalis and C. krusei) are ‏responsible for more than 90% of invasive fungal ‏infections, in both intensive care unit (ICU) and ‏non-ICU patients (Maubon et al. 2014). Candida ‏pneumonia is a rare lung infection with a high ‏morbidity and mortality, commonly observed ‏as part of a disseminated Candida infection and ‏associated with predisposing clinical circumstances ‏(i.e. long-term antibiotic use, haematologic ‏malignancy or severe immunosuppressive ‏states). The majority of Candida pneumonia cases ‏are secondary to haematological dissemination ‏of Candida spp. (Masur and Rosen 1977). There ‏is no specific clinical or radiological presentation ‏of Candida pneumonia. This aspect of the ‏disease makes the diagnosis difficult to perform. ‏A definitive diagnosis of candida pneumonia is ‏now based on histopathological identification ‏of yeast parenchymal invasion with associated ‏inflammation.


Significance of Candida Spp. Isolation in Non-Immunosuppressed Patients


Invasive lung infection by Candida spp. is a rare ‏event in non-immunocompromised subjects. ‏Several studies showed that the recovery of ‏Candida spp. from sputum and other respiratory ‏tract secretions cultures or lung tissue in nonimmunocompromised ‏patients might represent ‏colonisation of the tracheobronchial tree rather ‏than infection.


El-Elbiary et al. (1997) performed an autopsy ‏study on 25 immunocompetent, mechanically ‏ventilated patients, who died in a medical ICU, in ‏order to assess the real significance of Candida spp. ‏presence in the tracheobronchial tree or lungs. ‏Immediate postmortem respiratory samples and ‏lung tissue specimens were microbiologically ‏and histologically examined. The incidence of ‏Candida spp. isolation from pulmonary biopsies ‏was 40%, while the incidence of Candida pneumonia ‏was only 8%. The presence of Candida spp. ‏in pulmonary biopsies was always associated with ‏the isolation of the same microorganism from ‏one of another respiratory sample. Furthermore ‏there was a uniform presence of Candida spp. ‏throughout the different lung regions, but the ‏fungal isolation, independently of quantitative ‏cultures, was not recognised as a good marker ‏of Candida pneumonia (el-Ebiary et al. 1997).


In 2009 Meersseman et al. performed a similar ‏study. Data from autopsies of patients, who died in a medical ICU and with evidence of ‏pneumonia, were analysed in order to define the ‏value of Candida spp. isolation in airway samples ‏of those patients. Histopathological evidence ‏of pneumonia was found in 58% of patients. ‏Of these, 57% had positive tracheobronchial ‏samples for Candida spp. performed during the ‏preceding two weeks. No cases of candida pneumonia ‏were identified amongst those cases or in ‏patients without Candida isolation. These results ‏confirmed that the presence of Candida spp. in ‏respiratory samples does not indicate pneumonia ‏and that this is an extremely rare event in ICU ‏patients (Meersseman et al. 2009).


Candida Spp. Colonisation as Risk Factor for P. Aeruginosa Ventilator-Associated Pneumonia OR Multi-Drug Resistant Bacteria


Although the diagnosis of isolated Candida pneumonia ‏is rare, the presence of Candida spp. on ‏pathological samples should not be clinically ‏ignored. P. aeruginosa and Candida spp. are among ‏the most prevalent organisms in ICU-acquired ‏infections (Vincent et al. 1995), and they could ‏coexist in the endotracheal tube or medical ‏devices biofilm of patients (Adair et al. 1999). ‏These two pathogens have physical, chemical, ‏environmental and phylogenetic similarities ‏(Ader et al. 2008; Hogan and Kolter 2002). The ‏question of how they interplay in the respiratory ‏tract has been investigated, with contrasting ‏results, in animal studies.


Ader et al. (2011) showed that P. aeruginosa ‏lung injury was reduced in the presence of C. ‏albicans in a mouse model, as well as the amount ‏of alive P. aeruginosa recovered in lungs. Antifungal ‏treatment with caspofungin removed this effect in ‏those cases. However, mortality rate and bacterial ‏dissemination did not vary between colonised ‏and not colonised animals (Ader et al. 2011). ‏


Conversely, in 2009 Roux et al. performed ‏a randomised controlled animal study with the ‏aim of determining the effect of C. albicans presence ‏on P. aeruginosa pneumonia. P. aeruginosa was ‏instilled in the tracheobronchial tree of animals ‏with or without previous C. albicans tracheobronchial ‏colonisation. Animals with C. albicans ‏tracheobronchial colonisation developed more ‏frequently P. aeruginosa pneumonia compared with ‏those without. In addition, higher levels of proinflammatory ‏cytokines (TNFα, IFγ, IL-6) were ‏measured in the lungs of animals instilled with ‏P. aeruginosa with previous C. albicans colonisation, ‏compared with those without C. albicans ‏colonisation (Roux et al. 2009).


In addition a preliminary report showed that ‏C. albicans colonisation favours the occurrence of ‏pneumonia related to S. aureus and E. coli (Roux et ‏al 2009). Similarly, a recent study suggests that ‏fungal colonisation also facilitated the development ‏of Acinetobacter baumanii pneumonia in a ‏rat model, with a protective role of antifungal ‏therapy on this event (Tan et al. 2016). Thus ‏the mechanism by which Candida spp. colonisation ‏promotes bacterial pneumonia could be ‏independent of bacterial species.


ICU-acquired pneumonia (ICUAP) is the ‏leading infection in critically ill patients, ‏accounting for prolonged mechanical ventilation ‏and length of stay, poor outcome and ‏excess costs. There is evidence of interactions ‏between Candida spp. and P. aeruginosa, with fungal ‏colonisation possibly increasing the risk for P. ‏aeruginosa infection. Some clinical reports have ‏shown a possible association between the presence ‏of Candida spp. in respiratory secretions ‏and an increased risk for P. aeruginosa ventilatorassociated ‏pneumonia (VAP), longer mechanical ‏ventilation, prolonged stay and worse outcomes.


In a cohort of immunocompetent mechanically ‏ventilated patients, Azoulay et al. (2006) ‏found the isolation of Candida spp. in the tracheobronchial ‏tree as an independent risk factor ‏for pneumonia, due to P. aeruginosa. Candida spp. ‏colonisation was not associated with higher ‏mortality, but colonised patients showed a ‏significantly longer time on ventilation, and ‏longer ICU and hospital stays compared to ‏patients without Candida spp. isolation from ‏the respiratory tract.


Candida spp. has been identified as a risk factor ‏for multidrug-resistant bacteria. Hamet et al. ‏(2012) conducted a prospective observational ‏study in order to investigate the significance ‏of Candida spp. airway colonisation in patients ‏with suspected VAP and the potential link with ‏isolation of multidrug-resistant (MDR) bacteria. ‏Fifty-six percent of patients with suspected VAP ‏had Candida spp. airway colonisation. Candida ‏spp. airway colonisation was an independent ‏risk factor for MDR bacteria isolation without ‏significant differences in aetiological pathogens. ‏Colonised patients were similar to non-colonised ‏patients regarding VAP severity; however, in this ‏study mortality rate was greater in patients with ‏fungal airway colonisation than in those without ‏(Hamet et al. 2012). ‏


In a retrospective analysis of the Canadian ‏VAP study, Delisle et al. (2008) found Candida ‏spp. isolation in respiratory samples in 17.8% ‏of all patients. Colonised patients showed longer ‏hospital stay than non-colonised patients and ‏a significant increase in hospital mortality. In ‏that population Candida spp. presence was independently ‏associated with hospital mortality. ‏Antibiotic administration, co-morbidities and a ‏more severe illness are probable factors associated ‏to Candida spp. isolation (Delisle et al. 2008; ‏Terraneo et al. 2016).


In 2015 we performed a prospective noninterventional ‏study in a medical and surgical ‏ICU of a teaching hospital. The purpose of this ‏study was to compare the characteristics, microbiology, ‏inflammatory response and outcomes ‏of patients diagnosed with ICUAP (mechanically ‏ventilated or not), with and without Candida spp. ‏presence in lower respiratory tract samples, and ‏to assess the characteristics and outcomes associated ‏with the antifungal therapy. We conducted ‏the study in view of the discrepancy between ‏the uncertain clinical relevance of the isolation ‏of Candida spp. in respiratory tract secretions and ‏its association with adverse clinical outcomes ‏in patients with VAP. ‏


Candida spp.-colonised patients showed higher ‏severity scores than patients without airways ‏fungal colonisation, but similar inflammatory ‏pattern. Clinical outcomes were similar between ‏colonised and non-colonised patients, including ‏28-day and 90-day mortality, with the exception ‏of an increased risk of intubation in patients with ‏Candida sp. colonisation (Terraneo et al. 2016).


See Also: Infections in the Immunosuppressed and Immunocompromised Patient 

Antifungal Treatment


Although Candida spp. is frequently isolated from ‏respiratory tract samples, antifungal treatment is ‏not routinely recommended, because pneumonia ‏caused by this fungal species is exceptional in ‏non-neutropenic patients (Garnacho-Montero et ‏al. 2013). Inappropriate use of antifungal treatment ‏could be associated with higher rates of ‏fungal resistance and mortality in ICU patients; ‏therefore, Candida spp. isolation from respiratory ‏secretions alone should not be promptly ‏treated (Cuenca-Estrella 2012; Rello et al. 1998). ‏Nevertheless antifungal therapy is frequently prescribed for immunocompetent mechanically ‏ventilated patients with isolation of Candida spp. ‏from respiratory tract samples (Azoulay et al. ‏2004; van der Geest et al. 2014). The effect ‏of antifungal therapy in patients with Candida ‏spp. airways colonisation has been extensively ‏studied with discordant results.


A retrospective case-control study conducted ‏by Nseir et al. (2007) showed that the prescription ‏and length of the antifungal treatment were ‏associated with a reduced risk for P. aeruginosa ‏VAP development or tracheobronchial isolation ‏in mechanically ventilated patients colonised ‏by Candida spp.


Wood et al. (2006) performed a retrospective ‏study in trauma ICU patients. Candida spp. was ‏isolated from 8% of diagnostic bronchoalveolar ‏lavages (BALs). Most of the isolations were considered ‏colonisation and no specific therapy was ‏prescribed. No patients developed candidaemia ‏or serious fungal infections after isolation of ‏Candida spp., despite the lack of antifungal therapy. ‏Furthermore, Candida spp. was not isolated in ‏subsequent follow-up BALs. No significantly ‏greater mortality rate was observed in patients ‏with a high level of Candida spp. in BAL, despite ‏the lack of therapy (Wood et al. 2006).


In 2014 van der Geest et al. (2014) performed ‏a retrospective analysis of non-neutropenic ‏mechanically ventilated patients with positive ‏Candida spp. cultures of the respiratory tract ‏treated or not with amphotericin-B deoxychlorate ‏inhalation therapy in the context of ‏selective decontamination of the digestive tract. ‏Treated patients did not decolonise more rapidly ‏as compared to untreated patients. The duration ‏of mechanical ventilation was increased by treatment ‏independently of Candida spp. presence, ‏suggesting a direct toxicity of the drug in the ‏lung. No differences in VAP development or ‏overall mortality were observed in this study ‏(van der Geest et al. 2014).


In 2014 Albert et al. performed a double-blind, ‏placebo-controlled, multicentric, pilot randomised ‏clinical trial in order to evaluate inflammatory ‏profiles and clinical outcomes of patients with ‏suspected VAP and Candida spp. presence, treated ‏or not with antifungal therapy. The isolation of ‏Candida spp. was associated with persistent inflammation ‏and immunosuppression, but markers ‏of inflammation and all clinical outcomes had ‏similar results between patients treated and not ‏treated with antifungal therapy, both at baseline ‏and over time (Albert et al. 2014).


In our study we observed a more frequent ‏prescription of antifungal therapy in patients ‏with evidence of Candida spp. in respiratory tract ‏samples or patients with multiple co-morbidities ‏or a more severe illness. However, in our group ‏of patients, antifungal therapy was not associated ‏with different outcomes in patients with Candida ‏spp. in respiratory samples (Terraneo et al. 2016).



Despite the frequent isolation of Candida spp. ‏from respiratory specimen of ICU patients, the ‏development of real candida pneumonia is very ‏unlikely when immunocompetent subjects are ‏considered. However, the presence of Candida spp. ‏in pathological samples should not be clinically ‏ignored because it could probably be associated ‏with a more severe illness. What remains ‏unsolved is the question about a real causality ‏between Candida spp. and worse outcomes, since ‏Candida spp. could be simply a marker of severity. ‏As of today, available evidence is not sufficient ‏to support routine antifungal therapy in these ‏patients. In addition, further studies are required ‏to understand the real impact of Candida spp. on ‏respiratory infection development and patients’ ‏outcomes and consequently the possible protective ‏role of antifungal agents’ administration.



Support statement: 2009-SGR-911, IDIBAPS,ICREA academia 2013.


Conflict of Interest


Silvia Terraneo, Miquel Ferrer and Antoni Torres declare no conflict of interest.



BAL bronchoalveolar lavage

ICU intensive care unit

ICUAP intensive care unit-acquired pneumonia

MDR multidrug-resistant

VAP ventilator-associated pneumonia

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Adair CG, Gorman SP, Feron BM et al. (1999) Implications of endotracheal tube biofilm for ventilator-associated pneumonia. Intensive Care Med, 25(10): 1072–6.



Ader F, Faure K, Guery B et al. (2008) [Pseudomonas aeruginosa and Candida albicans interaction in the respiratory tract: from pathophysiology to a therapeutic perspective]. Pathol Biol (Paris), 56(3): 164–9.



Ader F, Jawhara S, Nseir S et al. (2011) Short term Candida albicans colonization reduces Pseudomonas aeruginosa-related lung injury and bacterial burden in a murine model. Crit Care, 15(3): R150.



Albert M, Williamson D, Muscedere J et al. (2014) Candida in the respiratory tract secretions of critically ill patients and the impact of antifungal treatment: a randomized placebo controlled pilot trial (CANTREAT study). Intensive Care Med, 40(9): 1313–22.



Azoulay E, Timsit JF, Tafflet M et al. (2006) Candida colonization of the respiratory tract and subsequent pseudomonas ventilator-associated pneumonia. Chest, 129(1): 110–7.

PubMed  ↗


Azoulay E, Cohen Y, Zahar JR et al. (2004) Practices in non-neutropenic ICU patients with Candida-positive airway specimens. Intensive Care Med, 30(7): 1384–9.



Cuenca‐Estrella M, Verweij PE, Arendrup MC et al. (2012) ESCMID* guideline for the diagnosis and management of Candida diseases 2012: diagnostic procedures. Clin Microbiol Infect, 18 Suppl 7: 9-18.



Delisle MS, Williamson DR, Perreault MM et al. (2008). The clinical significance of Candida colonization of respiratory tract secretions in critically ill patients. J Crit Care, 23(1): 11–7.



el-Ebiary M, Torres A, Fàbregas N et al. (1997) Significance of the isolation of Candida species from respiratory samples in critically ill, non-neutropenic patients. An immediate postmortem histologic study. Am J Respir Crit Care Med, 156 (2 Pt 1): 583–90.

PubMed ↗


Garnacho-Montero J, Olaechea P, Alvarez-Lerma F et al. (2013) Epidemiology, diagnosis and treatment of fungal respiratory infections in the critically ill patient. Rev española Quimioter publicación Of la Soc Española Quimioter, 26(2): 173–88



Guinea J (2014) Global trends in the distribution of Candida species causing candidemia. Clin Microbiol Infect, 20 Suppl 6: 5-10.



Hamet M, Pavon A, Dalle F et al. (2012) Candida spp. airway colonization could promote antibiotic-resistant bacteria selection in patients with suspected ventilator-associated pneumonia. Intensive Care Med, 38(8): 1272–9.



Hogan DA, Kolter R (2002) Pseudomonas-Candida interactions: an ecological role for virulence factors. Science, 296(5576): 2229–32.



Maubon D, Garnaud C, Calandra T et al. (2014) Resistance of Candida spp. to antifungal drugs in the ICU: where are we now? Intensive Care Med, 40(9): 1241–55.



Masur H, Rosen PP, Armstrong D (1977) Pulmonary disease caused by Candida species. Am J Med, 63(6): 914–25.



Meersseman W, Lagrou K, Spriet I et al. (2009) Significance of the isolation of Candida species from airway samples in critically ill patients: a prospective, autopsy study. Intensive Care Med, 35 (9): 1526–31.


Murray PR, Van Scoy RE, Roberts GD (1977) Should yeasts in respiratory secretions be identified? Mayo Clin Proc, 52(1): 42–5.



Rello J, Esandi M-E, Diaz E et al. (1998) The Role of Candida sp Isolated From Bronchoscopic Samples in Nonneutropenic Patients. Chest, 114(1): 146–9.



Roux D, Gaudry S, Dreyfuss D et al. (2009) Candida albicans impairs macrophage function and facilitates Pseudomonas aeruginosa pneumonia in rat. Crit Care Med, 37: 1062-7.



Roux D, Gaudry S, Khoy-Ear L et al. (2009) Candida Albicans airway colonization  favors bacterial pneumonia. Am J Respir Crit Care Med, 179: A3269.


Tan X, Chen R, Zhu S et al. (2016) Candida albicans Airway Colonization Facilitates Subsequent Acinetobacter baumannii Pneumonia in a Rat Model. Antimicrob Agents Chemother, 60(6): 3348–54.



Terraneo S, Ferrer M, Martín-Loeches I et al. (2016) Impact of Candida spp. isolation in the respiratory tract in patients with intensive care unit-acquired pneumonia. Clin Microbiol Infect, 22(1): 94.e1–8.



Van der Geest PJ, Dieters EI, Rijnders B et al. (2014) Safety and efficacy of amphotericin-B deoxycholate inhalation in critically ill patients with respiratory Candida spp. colonization: a retrospective analysis. BMC Infect Dis, 14: 575.



Vincent JL, Bihari DJ, Suter PM et al. (1995) The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA,  274(8): 639–44. PubMed


Wood GC, Mueller EW, Croce MA et al. (2006) Candida sp. isolated from bronchoalveolar lavage: clinical significance in critically ill trauma patients. Intensive Care Med, 32(4): 599–603.




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