Candida Colonization in the Respiratory Tract: What Is the Significance?

Abstract

Candida spp. is one of the most important components of human microecology. Among hospitalized patients, the isolation rate of Candida spp. by active screening is about 15%, while in critically ill patients, the rate can be as high as 25% (1). Although microbial colonization plays an important role in secondary infections, Candida pneumonia is seldom documented even in the intensive care unit (ICU). Thus, the common consensus is that anti-Candida therapy is rarely necessary in most cases and it should be considered as colonization in which Candida spp. are isolated from the respiratory tract (RT) (2). The co-existence of bacteria and fungi has raised great concern in the last decade. It has been indicated by some studies that Candida colonization in the RT might be an independent risk factor that could promote ventilator-associated pneumonia (VAP) and even change the antibiotic resistance patterns of pathogenic bacteria by polymicrobial biofilm formation (3, 4). Therefore, the significance of Candida colonization in RT remains controversial, and many clinical problems need to be reinterpreted. The rate of Candida spp. isolation in the RT is relatively high, especially in those with mechanical ventilation (MV) (3). However, whether VAP can be caused by Candida spp. remains controversial and the main reasons for this are listed as follows: (1) No matter what the pathogenic microorganism is, the diagnosis of VAP is still difficult due to the lack of pathological evidence. The clinical diagnostic criteria for suspected VAP are not specific, and it is difficult to distinguish between colonization and infection (5). (2) The understanding of the importance of bacterial and fungal co-existence is not deep enough. Some microbiological laboratories have not conducted further analysis when fast-growing Candida spp. are isolated from RT samples. What's more, only filamentous fungi isolation were reported in some institutions (6). (3) It is widely accepted that the cutoff value for the number of pathogenic bacteria for VAP diagnosis is 103 cfu/mL (protected specimen brush sample) or 104 cfu/mL (bronchoalveolar lavage fluid sample), but such a threshold has not yet been established for Candida (5). Therefore, Candida pneumonia must be diagnosed by histopathology. Hence, it is generally thought that Candida pneumonia is quite rare in the ICU, and the guidelines for the management of Candida spp. of both the IDSA and ESCMID do not recommend antifungal treatment unless there is clear histological evidence of infection (2, 7). Alveolar macrophages act as the first line of defense against Candida in critically ill patients. Toll-like receptor (TLR) induces a Th1 cytokine pattern to increase the levels of IFN-γ and TNF-α to facilitate the clearance of Candida spores from the alveoli. What is more, other researches have also indicated that IFN-γ favors the intracellular killing of the fungus after internalization in professional phagocytes (8). Thus, it can be inferred that Candida pneumonia may not exist in the ICU. An autopsy study with 135 patients who died of pneumonia showed that among them, 77 (57%) severely affected patients had Candida airway colonization during their hospital stay. However, none of these cases was pathologically confirmed as Candida pneumonia (9). Meanwhile, one controlled before-after study in a microbiology laboratory at Illinois University showed that limiting the identification of respiratory secretions (only filamentous fungi were reported) could reduce the prescription of antifungal drug treatment (21 vs. 39%) and shorten the length of hospital stay (10.1 vs. 12.1 days) compared with full identification (all rapidly growing yeasts were reported), p < 0.05 (6). What should ICU physicians do when they receive a microbial culture report which indicates that Candida spp. are growing fast in airway secretions? The practice guidelines recommend that antifungal therapy should not be routinely used in those with Candida airway colonization (2, 7). However, should Candida colonization in the airway of critically ill patients simply be ignored? Some in vitro experiments on the co-existence of bacteria and fungi came to different conclusions. The cell wall of Candida spp. is combined with polysaccharides and proteins. Among them, Beta-glucan (BG) is a proinflammatory factor that can cause dysfunction of macrophages and neutrophils in alveoli as well as reduce the production of reactive oxygen species (10). It is also reported that there is a strong interaction among Candida, Gram-positive and Gram-negative bacteria through quorum sensing (QS) molecules, and the extensive interaction of metabolic processes and intercellular communication among them are the basis of synergistic and antagonistic interactions (11). Through an observational study of rats injected with active Candida albicans, it was found that the increased production of cellular inflammatory factors, including interleukin-6, interferon-γ and tumor necrosis factor-α, inhibited phagocytosis by alveolar macrophages. This phenomenon led to changes in airway microecology, and an increase in the airway colonization rate of Pseudomonas aeruginosa was found (12). Moreover, this effect was not unique to Pseudomonas aeruginosa. Another study showed that Candida colonization was also beneficial for the colonization of Staphylococcus aureus and Enterobacteriaceae, which led to an increase in bacterial pneumonia (13). Candida biofilms show a reticular structure composed of Candida spores and hyphae and are easily found on the surfaces of artificial materials (such as endotracheal tubes). The biofilm matrix contains polysaccharides, proteins and other unknown components, which show strong adhesion and are difficult to remove (14) (Figure 1). Biofilms not only have a protective effect on Candida but also have a strong adsorption effect on co-existing bacteria. Animal experiments and electron microscopic...