Candida Spp. in the Respiratory Tract

• 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).

 
Conclusion

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.

 
Acknowledgements

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

Conflict of Interest

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

Abbreviations

BAL bronchoalveolar lavage

ICU intensive care unit

ICUAP intensive care unit-acquired pneumonia

MDR multidrug-resistant

VAP ventilator-associated pneumonia