Background Pheochromocytomas are rare neuroendocrine tumors arising from chromaffincells in the adrenal medulla, and the excessive catecholamine secreted causes serious cardiovascular effects to the patient. Adrenalectomy is the definitive treatment with a morbidity rate of 40% and a mortality rate of 2%. Intraoperative bleeding is a major concern with any surgical procedure, thus preparation of blood products for possible transfusion during the perioperative period is prudent. A religious group known as the Jehovah's witnesses recommend blood transfusion refusal to its members. We encountered a case of a Jehovah's witness with pheochromocytoma requiring adrenalectomy. CASE: A case of 54 year old, Filipino male, a Jehovah's witnesses, hypertensive for 14 years, complained of 1 week vague right upper quadrant abdominal pain and bouts of headache. A CT scan of the abdomen with contrast revealed an 11.7x 12.2×10.3cm mass on the right adrenal. Biochemical tests were consistent with pheochromocytoma that is co-secreting with ACTH, but with no physical features of hypercortisolism. An elevated levels of 24 hours urine Metanephrine (8.95 mg/ 24hrs),24 hours urine cortisol (173.98 mcg /24 hours), serum ACTH (57 pg/ml), 8am serumcortisol (22.44 mcg/dl), and 1 mg Dexamethasone suppression 8am cortisol (18.85mcg/dl). Patient consented to surgery but signed a waiver of refusal to any blood transfusion. Erythropoietin 5000 IU SC three times per week was then initiated 1month prior to the surgery. Terazosin 25 mg three times a day followed by Metoprolol25 mg twice daily, for adequate alpha and beta blockade, and hydration prior to surgery was done. The Estimated blood loss during surgery was 600 ml, patient's hemoglobin level dropped to 98 g/L on the 7th post-operative day from pre-operative level of 125 g/L, hence, the Erythropoietin was continued until was discharged. The Histopathology report showed round cell neoplasm, with positive immunohistochemical stain for synaptophysin and chromogranin, and a weak positive of NSE (Neuro-specific enolase) consistent with pheochromocytoma. References: 1. Narita et al, Surgery without Blood Transfusion for Giant Paraganglioma in a Jehovah's Witness Patient, Case Rep Oncol 2014;7: 233–238, DOI: 10.1159/0003608132. Bachman et al, Pheochromocytoma, Fulminant Heart Failure, and a Phenylephrine Challenge. The Perioperative Management of Adrenalectomy in a Jehovah's Witness Patient: A Case Report, The Journal of Critical Care Medicine 2022; 8(1): 55-60, DOI: https://doi.org/10.2478/jccm-2021-0038 Presentation: No date and time listed

Editorial on the Research TopicManagement of Immune-Related Adverse Events for Patients Undergoing Treatment With Checkpoint Inhibitors Immunotherapy with immune checkpoint inhibitors has emerged as the most significant advance in the treatment of cancer in recent years and has revolutionized cancer management (1). Until recently, it had been assumed that the immune system was not effective in protecting humans against the development of neoplastic diseases. Checkpoints inhibitors are co-receptors expressed by T cells. These co-receptors regulate T cell activation negatively and play a central role in the maintenance of peripheral self-tolerance. Co-inhibitory receptor ligands are significantly expressed in a variety of malignancies resulting in evasion of anti-cancer immunity. These molecules include programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and were discovered by Tasuku Honjo and James P. Allison in 1992 and 1996, respectively (2, 3). These scientists were jointly awarded the 2018 Nobel Prize for Physiology or Medicine in recognition of this ground-breaking research. Monoclonal antibodies targeting the CTLA-4 and PD-1 and their ligands have produced significant clinical responses against a variety of malignancies (4). FDA registered checkpoint inhibitors include pembrolizumab (5), nivolumab (6), cemiplimab (7), atezolizumab (8), darvolumab (9) and avelumab (10) for numerous indications including melanoma, lung cancer (small and non-small cell types), bladder cancer, Hodgkin's disease and others (5–10). Other co-inhibitory molecules under research include T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) (11), Lymphocyte activation gene-3 (LAG-3) (12), V-domain Ig-containing Suppressor of T cell Activation (VISTA) (13), and B- and T-lymphocyte attenuator (BTLA) (14). Treatment with antibodies inhi biting immune checkpoints are well-tolerated by the vast majority of patients and are less toxic compared to standard anticancer chemotherapy agents. These immune side-effects are referred to as immune-related adverse events (IrAE) (15). These toxicities include fatigue, dermatological, gastrointestinal, hepatic, pulmonary, endocrine, ocular, neurological, and rare toxicities such as diabetes, cardiac and hematological. Dermatological toxicities can appear following the first dose of an immune checkpoint inhibitor and can be ongoing. These rashes are frequently maculopapular and mild in nature (16). Rash, and generalized pruritus occur more commonly with CTLA-4 inhibitors compared to anti-PD-1 inhibitors (17). Rare cases of serious skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported (18). The development of vitiligo occurs in a small percentage of patients receiving immunotherapy with checkpoint inhibitors and is associated with long term survival and clinical benefit (19). Gastrointestinal side effects can occur in the form of mucositis, aphthous ulcers, gastritis, colitis, and abdominal pain. Diarrhea, with blood or mucus in the stool, can be observed. In severe cases, these complications can evolve to toxic megacolon and perforation and must be ruled out in patients with peritonitis symptoms (20). Other infectious causes of diarrhea such as Clostridium difficile infection can be associated in severe cases (20). Immune-related pneumonitis is a serious IrAE reported in patients undergoing immune checkpoint inhibition. Pneumonitis is more common with PD-1 and PDL-1 blockers, however the incidence is < 1% and presents later during the treatment phase (21). Patients undergoing immunotherapy, experiencing new symptoms of dyspnea or cough, should alert the clinician. This complication could be fatal (21). Endocrine IrAE symptoms are generally non-specific and include fatigue, mental state changes, headaches and dizziness related to hypotension (22). Hypophysitis and hypothyroidism are the most common abnormalities documented (22). Clinicians should screen for thyroid abnormalities and baseline thyroid function tests. Other hormone assays may be indicated in some patients. Ophthalmological IrAE in the form of mild, moderate or severe episcleritis, uveitis or conjunctivitis has been described (23). Neurological IrAE includes posterior reversible encephalopathy syndrome, aseptic meningitis, enteric neuropathy, transverse myelitis, and Guillain-Barre syndrome (24). Less frequent IrAE's include red cell aplasia (25), neutropenia (25), acquired hemophilia A (25), thrombocytopenia (25), hemolytic-uremic syndrome (25), pancreatitis (26), asymptomatic raise in amylase and lipase (26), renal insufficiency with nephritis (27), arthritis (28), and myocarditis (Tajiri and Ieda). Contributors to this research topic in Frontiers in Pharmacology and Frontiers in Oncology describe the importance of understanding this new class of drugs and their unique toxicities. Other areas covered include a description the current understanding of the basic mechanism of immune dysregulation in cancer patients undergoing immune checkpoint inhibitor treatment as well as potential predictive strategies for future clinical practice (Anderson and Rapoport). A second manuscript describes an unusual patient with persistent pruritus and lichenoid reaction secondary to anti-PD1 checkpoint inhibitor managed with narrowband ultraviolet B phototherapy (Donaldson et al.). A third manuscript explains the management of gastrointestinal toxicity with special reference to the immune homeostasis in the gastrointestinal tract (Dougan) and lastly a meta-analysis describing the relative risk and incidence of immune checkpoint inhibitor related pneumonitis in patients with advanced cancer (Ma et al.). It must be emphasized that IrAEs are usually low-grade and controllable; however, the reporting of these irAEs is generally suboptimal (29). Oncologists should be aware that there is a wide range of additional distinctive toxicities and side effects that can be unpredictable and severe in nature. As these agents will, in the future, be administered with targeted therapies, vaccines, chemotherapy or radiation therapy it is possible that the incidence and severity of these toxocities may change. The different mechanisms of action of anti-CTLA-4 and anti-PD-1/anti-PD-L1 antibodies resulted in the development of clinical studies investigating combination therapies in a variety of malignancies including metastatic renal cell cancer and metastatic malignant melanoma. The incidence of serious grade 3 and grade 4 adverse events due to the combination of ipilimumab and nivolumab were present in approximately half of patients. The incidence of these toxicities was significantly higher than either antibody administered separately resulting in treatment interruption in one-third of patients (30). Clinical recommendations for managing irAEs arise from general clinical consensus and experience, as there are no prospective trials to assess whether one treatment strategy is superior to another. 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(2019) 2:479–85. doi: 10.1007/s00432-018-2805-3 CrossRef Full Text | Google Scholar Keywords: immune related adverse effects, colitis, pneumonitis, anti CTLA 4, anti-PD 1 Citation: Rapoport BL (2019) Editorial: Management of Immune-Related Adverse Events for Patients Undergoing Treatment With Checkpoint Inhibitors. Front. Oncol. 9:365. doi: 10.3389/fonc.2019.00365 Received: 28 February 2019; Accepted: 18 April 2019; Published: 08 May 2019. Edited and reviewed by: Copyright © 2019 Rapoport. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Bernardo Leon Rapoport, [email protected]

Editorial on the Research TopicExercise and Sport: Their Influences on Women's Health Across the Lifespan This Research Topic of Frontiers in Physiology is dedicated to the memory of Professor Nigel Stepto, the Lead Guest Editor of this issue, who sadly passed away during its formation. Prof. Stepto was a passionate and recognized world leader in the field of Exercise Physiology with outstanding contributions, particularly in the area of women's reproductive health. Nigel's research passion was in understanding the mechanistic effects of exercise for health and therapy with a special interest in insulin resistance and polycystic ovary syndrome, the leading cause of anovulatory infertility in young women of reproductive age. He was the co-Deputy Director—Research Training at the Institute of Health and Sport (IHeS) at Victoria University, Melbourne, Australia, and held adjunct associate professorial roles at Monash University and the University of Melbourne. He was Chair of the Exercise and Sports Science Association (ESSA) Research Committee, Project Director of the Australian Institute for Musculoskeletal Science (AIMSS) and an active member of the Australian Physiological Society (AuPS). Alongside his influential research career and leadership roles, Nigel was a strong advocate for post-graduate and early career researchers. His collaborative nature and approach to research ensured those mentored by him were considered, included and valued members across his many research projects and initiatives. Nigel's impact and influence on the careers of early researchers will continue at Victoria University with both a Nigel Stepto Travel Award and Nigel Stepto Ph.D. Scholarship established in his honor. Nigel was great friend and colleague to many and is very much missed. Nigel is survived by his wife, Fiona and two children Matilda (14 years) and Harriet (11 years). Vale, Professor Nigel Stepto (12 September 1971−4 February 2020). Physiological responses and adaptations to exercise that influence both health and sports performance is a broad and well-documented area of research with acute and prolonged effects now widely understood. Resultantly, exercise is recognized as a potent therapy for the prevention and treatment of chronic disease in adults. Yet a significant research gender bias toward males remains with research elucidating differential reproductive and life-phase effects across clinical exercise, exercise and sports science in women, currently limited. This Research Topic was introduced to better explore physiological responses to exercise in women across the spectrum of health promotion to sports performance and the interplay of the reproductive lifespan on health and performance outcomes. This Research Topic consists of nine articles, including six original research articles, two narrative review articles, and one systematic review and meta-analysis. A broad range of themes are covered across female exercise physiology, including the role of hormonal regulation and inflammation on exercise performance; the beneficial role of exercise in anovulatory conditions including polycystic ovary syndrome and perspectives of exercise during pregnancy and its role in hypertensive disorders. Fluctuation in ovarian hormone levels induces physiological alterations that can produce differences in exercise performance during the menstrual cycle (Janse de Jonge, 2003). For example, progesterone has been shown to increase ventilation and body temperature at rest (Marsh and Jenkins, 2002), whereas oestradiol modulates vascular flow (Joyner et al., 2015). Mandrup et al. investigated how menopausal status and high intensity exercise training influence adipose tissue mass, glucose uptake and protein content. They demonstrate similar improvements in cardiorespiratory fitness and decreases in subcutaneous and visceral adipose tissue mass following 3 months' training in pre- and post-menopausal women. They also report of similar insulin-stimulated glucose uptake in abdominal, gluteal, and femoral adipose tissue depots in pre- vs. post-menopausal women, in contrast to earlier findings from the same trial showering skeletal muscle insulin resistance in post- compared to premenopausal women (Mandrup et al., 2018). High-repetition, low-load resistance training in group class settings has gained popularity for weight control, especially among women. One example of this type of training is BodyPump (Les Mills International), which is claimed to result in high energy expenditure. Rustaden et al. assessed energy expenditure during BodyPump compared with heavy load resistance exercise using indirect calorimetry in women who were overweight and found that both training modalities produced similar energy expenditure during and up to 140 min after the exercise session. Pereira et al. summarized the effects of the ovarian hormone fluctuations during the menstrual cycle on exercise-induced fatigability in a mini-review based on 46 studies comparing the follicular phase with the luteal phase of the menstrual cycle. In total, 15 studies demonstrated a statistical difference between the menstrual cycle phases studied. However, the results were inconsistent with seven studies reporting less fatigability during the luteal phase and eight studies reporting less fatigability during the follicular phase. The inconsistences could be explained by differences in exercise mode, the limb used, type of contraction and the classification of the menstrual cycle phase. The authors concluded that further studies are needed to determine the effects of a specific menstrual cycle phase on exercise-induced fatigability. Exogenous hormones introduced through oral contraceptive use have also been found to influence exercise capacity (Lebrun et al., 2003) and change the metabolic, cardiovascular, and ventilatory responses to exercise (Charkoudian and Joyner, 2004; Isacco et al., 2012; Schaumberg et al., 2017). Schaumberg et al. observed a dampened response of central physiological adaptations to sprint interval training, demonstrated by pulmonary oxygen uptake kinetics, in women taking oral contraceptives compared to women with natural menstrual cycles. The potential underlying mechanisms for these observations include the influence of exogenous hormones on the overall endocrinological profile. Again, more knowledge is needed regarding the effect of oral contraceptives on exercise training adaptations. In another study by Larsen et al., blood samples were collected from 53 elite female athletes prior to the Rio Olympic Games. The study showed that those who were taking oral contraceptives had higher levels of C-reactive protein (CRP) in the blood than those without hormonal contraception. CRP is a marker of inflammation and tissue damage, and it was suggested that this marker could have potential consequences for athlete performance and recovery. Other markers of stress and inflammation were comparable between groups. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age and characterized by anovulation, hyperandrogenism, and polycystic ovarian morphology (Charkoudian and Joyner, 2004). This condition is highly associated with reproductive, metabolic and mental complications. Insulin resistance and obesity are important etiological factors contributing to the severity of the symptoms. Lifestyle intervention, including exercise, is recommended as a first-choice therapy to improve health outcomes (Charkoudian and Joyner, 2004). However, it is unclear what kind of exercise is most effective. Patten et al. performed a systematic review and meta-analysis of exercise interventions in PCOS. Based on 19 articles and 777 women, it was demonstrated that exercise training improved cardiorespiratory fitness, body composition, and insulin resistance. It was also clear that improvements were dependent on exercise intensity rather than duration. The results suggest that a minimum of 120 min of vigorous intensity per week is needed to provide beneficial health outcomes for women with PCOS. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally and have been suggested to be of importance for the pathophysiology of insulin resistance in PCOS. Lionett et al. studied circulating and adipose tissue miRNAs in women with PCOS compared to controls and in response to randomized low-volume or high-volume high intensity interval training. They found that women with PCOS have higher circulating levels of miRNA-27b compared to non-PCOS women but comparable adipose tissue miRNAs. miRNA-27b has been implicated in several metabolic and cellular processes, such as fatty acid metabolism, adipocyte differentiation and inflammation (Chen et al., 2012). In response to 16 weeks of low-, but not high-volume, high intensity training, levels of miRNA-27b were reduced. The clinical significance of these findings needs to be studied further. European and American guidelines advocate that pregnant women should be physically active at least 150 min/week to optimize gestational weight gain and prevent adverse pregnancy outcomes, such as gestational diabetes and hypertensive disorders (2015; Gynaecologists RCoO, 2015). However, <15% of pregnant women adhere to these recommendations (Gjestland et al., 2013). This Research Topic contains a Mini Review (Witvrouwen et al.) on the effects of exercise training during pregnancy on vascular health, with a focus on gestational hypertensive disorders (gestational hypertension and pre-eclampsia). Conflicting reports were found with a need for further research to fully elucidate efficacy of exercise in reducing risk of hypertensive disorders during pregnancy. The largest systematic review [22 randomized controlled trials (RCTs), n= 5,316] and meta-analysis to date showed that exercise during pregnancy significantly reduced the risk of gestational hypertension (OR 0.61, 95% CI 0.43–0.85), as well as pre-eclampsia (OR 0.59, 95% CI 0.37–0.94) (15 RCTs, n = 3,322) (Davenport et al., 2018). However, five out of nine systematic reviews and meta-analyses showed no significant effect. The authors suggest that the discrepancies may be caused by different methodological issues. Yet given the benefits of regular physical activity on health and well-being generally, health care providers should be encouraged to discuss lifestyle behaviors with pregnant women to optimize maternal and child health outcomes. Health care provider perspectives on lifestyle advice, during pregnancy, weight gain, physical activity, and nutrition was explored by Haakstad et al. While most midwives viewed lifestyle counseling as important, nearly 40% did not give advice on gestational weight gain or gave advice discordant with the recommendations from the Institute of Medicine (Rasmussen and Yaktine, 2009), emphasizing the need for increased support and guidance for health professionals initiating healthy lifestyle conversations during pregnancy. The manuscripts included in this Research Topic contribute to much needed research into the role and influence of reproduction on physiological responses to exercise across the spectrum of female exercise physiology. Beneficial effects of exercise are reported underscoring its importance in women's health broadly. Yet importantly, as a collective, this issue emphasizes the many research gaps that remain. Exercise intervention studies are largely heterogeneous by nature, with significant variation in type, duration, frequency and intensity as well as in their overall reach, penetration and compliance. Reporting quality across studies introduces variation in the identification of particular components of exercise that contribute to positive outcomes. Taken together, this contributes to ambiguity in the field and limits translation and implementation of clinical recommendations. This issue highlights the critical need for further high quality, robustly designed research with transparent reporting in this area of exercise physiology. CH and TM drafted the manuscript, with input from ALH. All authors approved the final version. TM was supported by a European Foundation for the Study of Diabetes/Novo Nordisk Foundation Future Leaders Award (NNF19SA058975) and ALH was supported by the Swedish Research Council for Sport Science. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (2015). ACOG Committee Opinion No. 650: physical activity and exercise during pregnancy and the postpartum period. Obstetr. Gynecol. 126, e135–e142. doi: 10.1097/AOG.0000000000001214 CrossRef Full Text | Google Scholar Charkoudian, N., and Joyner, M. J. (2004). Physiologic considerations for exercise performance in women. Clin. 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Edited by: Reviewed by: Copyright © 2021 Harrison, Hirschberg and Moholdt. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Cheryce L. Harrison, [email protected]

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 studies show that bacteria and fungi can produce small molecules to interact with each other and change their morphology, function and growth environment, resulting in bacteria that are firmly adsorbed between Candida spores or biofilms. Such structures are difficult to remove. Even though the spore activity of some Candida spp. is decreased, the adsorption phenomenon is still observed (4, 15). Figure 1. Interaction of Candida spp. and bacteria in patients with mechanical ventilation. Candida biofilms are easily found on the respiratory tract or the surfaces of endotracheal tubes. Biofilms not only have a protective effect on Candida but also have a strong adsorption effect on co-existing bacteria. Multidrug-resistant bacteria could be isolated by the transmission of drug-resistant plasmid transmission and polymicrobial biofilm formation (Drawn by Chunhui Xu). Candida colonization can also change the virulence and/or host immune function of colonized bacteria. A series of animal experiments have shown that after the mixed inoculation of Candida and bacteria in the airway of mice, even if the number of inoculated Candida is very small, the bacterial load still occupies a high percentage of the alveoli. It has been suggested that the presence of Candida albicans protects the bacteria from clearance by normal alveolar macrophages (16). Acinetobacter baumannii can affect the morphology of Candida albicans through the QS molecule N-acyl homoserine lactone, whereas farnesol is the main QS molecule of Candida albicans (11). This can affect the movement ability and virulence factor expression of Acinetobacter baumannii. An animal experiment has also found that the degree of alveolar invasiveness of Acinetobacter baumannii in mice with Candida colonization during pneumonia is much higher than that of Acinetobacter baumannii during pulmonary infection (17). The existence of biofilms can also increase the resistance of bacteria to antibiotics. It is showed that Staphylococcus aureus could form a single biofilm (monoculture biofilm) in serum, but its integrity was poor, and it was easy to dissociate. If there is co-growth with Candida albicans, Staphylococcus aureus can form microcolonies on the fungal biofilm, which is closely connected to the bottom hyphae “scaffold,” to form a multi-bacterial biofilm (polymicrobial biofilm) (Supplementary Figure 1). Staphylococcus aureus matrix staining showed different phenotypes of multi-bacterial biofilms and single cell membranes (18), indicating that Staphylococcus aureus may be encapsulated in the matrix secreted by Candida albicans, resulting in an increase in its resistance to vancomycin. Further studies showed that in the environment of multi-bacterial biofilm formation, 27 Staphylococcus aureus-specific proteins were identified by gel electrophoresis, some of which could upregulate the expression of L-lactate dehydrogenase I, confer the ability to resist host-derived oxidative stress to bacteria and enhance resistance to antibiotics, while other proteins could downregulate the expression of the virulence factor CodY (19). These findings suggest that the occurrence of VAP caused by MRSA in patients with Candida albicans airway colonization is not only the result of the expression of QS molecules but can also be attributed to the differential regulation of specific drug resistance genes and virulence factors. Similar results have been obtained in other studies of Gram-negative bacteria (20, 21). In vitro studies suggest that there is mutual induction of the process of the co-existence of bacteria and fungi, so it is necessary to further describe and study the complex interactions between pathogens at the molecular level. The transition from basic research to clinical research may help to design new treatment or prevention and control strategies for bacterial and fungal superinfection. Clinical studies have pointed out that the isolation rate of Candida from the RT of ICU patients with MV could be as high as 50%, which prolonged the median hospital stay (59.9 vs. 38.6 days, p = 0.006) or even increased the hospital mortality (34.2 vs. 21.0%, p = 0.003) (22). Moreover, it might be associated with persistent immunosuppression and inflammation (23). Candida airway colonization and its concomitant secretion of inflammatory factors may affect host cellular immune function, especially in immunosuppressed hosts with severe monocyte and lymphocyte dysfunction, which results in a decrease in the effective clearance of bacteria and fungi and an increase in the incidence of VAP (24). However, the effect of Candida RT colonization on bacterial colonization and antibacterial resistance patterns has always been controversial in clinical research. It is still unclear whether Candida airway colonization could increase the incidence of VAP and whether patients with Candida airway colonization can benefit from antifungal therapy (Supplementary Table 1). One early prospective cohort study reported that Candida RT colonization could increase the incidence of VAP caused by Pseudomonas aeruginosa (9 vs. 4.8%, p = 0.048), and Candida RT colonization was proven to be an independent risk factor (18). Similarly, another single-center retrospective case-control study indicated that antifungal therapy in those with Candida albicans airway colonization could prevent the occurrence of Pseudomonas aeruginosa VAP (25). Some studies have also pointed out that Candida airway colonization is associated with the pathogenesis of Acinetobacter baumannii VAP. In addition, another cohort study showed that aerosol inhalation of amphotericin B in patients with MV significantly reduced the Candida load in the airway but did not change the morbidity due to VAP or mortality during the ICU stay (26, 27). The EMPIRICUS study is a randomized trial to evaluate the efficacy of micafungin for the treatment of patients with Candida colonization in multiple sites and sepsis with organ failure (28). The study noted that the incidence of VAP and the 28-days mortality during the ICU stay did not decrease in the micafungin group compared with those in the placebo group (32 vs. 39.8%, p > 0.05). Therefore, the above studies led to a change in the understanding of the co-existence of bacteria and fungi and their effects on immune function in clinical studies. FUNGIBACT, as a prospective cohort study, included 146 patients with MV for more than 96 h. After adjusting for the immune index mHLA-DR, it was concluded that there was no correlation between airway Candida colonization and the incidence of VAP [HR: 0.98; 95% CI (0.59–1.65), p = 0.95] (29). Another retrospective study reviewed 269 systemic lupus erythematosus patients with hospital-acquired pneumonia. Among them, 186 (69.1%) were found to have airway Candida colonization. Compared with that in the non-colonized group, the detection rate of multidrug-resistant bacteria was higher (58.6 vs. 36.1%, p< 0.001), and the secreted IgA and IL-17 levels returned to normal range faster after anti-fungal treatment, but this had no effect on 28-days mortality (14.5 vs. 10.8, p > 0.05) (30). One meta-analysis about the influence of Candida spp. airway colonization on clinical outcomes in patients with VAP included four prospective studies, three retrospective studies, and one cross-sectional study (31). It revealed that those with airway Candida colonization had longer durations of MV. The most noteworthy feature of the meta-analysis is that patients with Candida colonization had higher 28-days mortality (RR: 1.64; 95% CI: 1.27–2.12) and ICU mortality (RR: 1.57; 95% CI: 1.26–1.94) than those without Candida colonization. Although it has included almost all the clinical research about airway Candida colonization with high quality, limitations still exist. First, attributable mortality rate could hardly find in these studies duo to the effects of confounding factors and the insufficient sample size. Second, a highly heterogeneity could be recognized in the baseline of the enrolled patients. Reasons for MV, severity of VAP, antibiotic exposures before the diagnosis of VAP and the immune state was probably diverse among studies. Although “Candida pneumonia” is rarely confirmed in critically ill patients, Candida airway colonization may affect bacterial colonization and antibacterial resistance patterns, playing an important role in the development of bacterial pneumonia. However, the conclusions of current clinical studies are not consistent. Future clinical studies are needed to re-evaluate the potential benefits of pre-emptive antifungal therapy for preventing VAP. Y-TY and JL: conception and design. D-CC: administrative support. C-HX: provision of study materials or patients. Y-TY and C-HX: data analysis and interpretation. All authors: collection and assembly of data, manuscript writing, and final approval of manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 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(2020) 48:695–701. doi: 10.1016/j.ajic.2019.11.002 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: Candida, colonization, ventilator associate pneumonia, critical ill patients, bioflim Citation: Liu J, Yu Y-T, Xu C-H and Chen D-C (2021) Candida Colonization in the Respiratory Tract: What Is the Significance? Front. Med. 7:598037. doi: 10.3389/fmed.2020.598037 Received: 23 August 2020; Accepted: 18 December 2020; Published: 04 February 2021. Edited by: Reviewed by: Copyright © 2021 Liu, Yu, Xu and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: De-Chang Chen, [email protected] ^†These authors have contributed equally to this work