Discussion

Fungal infections, mostly candidiasis, have become an increasing cause of morbidity and mortality in paediatric ICUs all over the world. ^{Reference Eggimann, Garbino and Pittet1,Reference Wisplinghoff, Seifert and Tallent3} Recently, yeast species have been reported to be the fourth most common cause of systemic infections in children, representing 8–15% of all nosocomial sepsis in the United States of America. ^{Reference Wisplinghoff, Bischoff and Tallent8} Xie et al evaluated the surgical patients with severe sepsis and found that 28.3% of them exhibited Invasive Candida infections; C. albicans was most frequently isolated (58%), followed by C. tropicalis (17%), C. glabrata (15%), and C. parapsilosis (10%). ^{Reference Tortorano, Kibbler and Penman9} As a result of 5-year analysis, we found the Candida bloodstream infections rate of our paediatric cardiovascular surgery ICU as 12.9%, which could be regarded as moderately high, in line with the literature. ^{Reference Ayık, Atay and Engin5} In contrast to the literature, however, non-albicans Candida species were the most frequently isolated fungal pathogens, in the present study. The distribution of identified Candida species were C. albicans (36.5%), C. parapsilosis (14.6%), C. tropicalis (5.8%), and C. glabrata (3.7%). Since it is not possible to definitively identify all Candida species, ^{Reference Lynn, Duane, Clinton and etal10} our microbiology laboratory has reported the remaining 39.4% of Candida growth as other non-albicans Candida species.

Surgical procedures, especially cardiovascular surgery, performed to correct complex congenital heart anomalies have been accepted as an important risk factor for Invasive Candida infections, most commonly Candida bloodstream infections. ^{Reference Jenkins11,Reference Jaworski, Irga and Haponiuk12} Relevantly, the patients with Candida bloodstream infections in our study had undergone surgery for the correction of cardiac pathologies as atrioventricular septal defect (18.9%), transposition of great arteries (17.6%), tetralogy of Fallot (12.4%), total anomalous pulmonary venous return (4.3%), hypoplastic left heart syndrome (3.7%), double outlet right ventricle (2.2%), pulmonary atresia (1.5%), tricuspid atresia (1.5%) and the remaining for combined cardiac pathologies (transposition of great arteries + double outlet right ventricle, total anomalous pulmonary venous return + atrioventricular septal defect, transposition of great arteries + aortic hypoplasia, ventricular septal defect + pulmonary atresia) (37.9%). The RACHS-1, risk adjustment for congenital heart surgery, scores of these surgeries were between 2 and 5 out of 6. ^{Reference Jenkins11}

The patients undergoing cardiovascular surgery have increased risk of Candida bloodstream infections because C. albicans and C. parapsilosis can form biofilms on almost any medical devices such as vascular and urinary catheters, cardiac valves, artificial vascular bypass devices, pacemakers, and ventricular assist devices. ^{Reference Tortorano, Kibbler and Penman9,Reference Lim, Rosli and Seow13} It is thought-provoking that the Candida bloodstream infections rate in our study is high despite the issue we have shown to change the indwelling devices (peripheral and central venous lines, urinary catheters, feeding tubes, etc) at recommended times. ^{Reference Mody, Krein and Saint7,Reference Wisplinghoff, Bischoff and Tallent8}

Prolonged hospitalisation and ICU stay together with the use of indwelling medical devices are important predisposing factors for Candida bloodstream infections. ^{Reference Leon, Alverez-Lerma and Ruiz-Santana14,Reference Vincent, Rello and Marshall15,Reference Kojic and Darouiche16} In consistence with the literature, the mean length of hospital stay and the mean duration of mechanical ventilation in the present study were longer in the patients with Candida bloodstream infections than those without. As our hospital is a tertiary referral centre for paediatric cardiovascular surgery, most of the accepted children undergo surgery for the correction of complex cardiac pathologies with an elevated risk of prolonged hospital stay, mechanical ventilation, and Invasive Candida infections. Moreover, 16.1% of these operated children had syndromes or accompanying respiratory, neurologic or gastrointestinal health problems. The most common syndrome we encountered was Down syndrome (68.2%), characterised by thymic hypoplasia together with cellular and humoral immunodeficiency. ^{Reference Ram and Chinen17} Therefore, we suggest that when evaluating the children with Down syndrome in the perioperative period of cardiovascular surgery, their increased tendency to candidiasis must be considered. Prolonged use of broad-spectrum antibiotics (longer than 5 days) is also accepted as an important predisposing factor for fungal growth. ^{Reference Chakrabarti, Sood, Parnell and Rubin18,Reference Garcia-San, Cobo and Martos19} Relevantly, the average duration of broad-spectrum antibiotic use in the present study was longer in the patients with Candida bloodstream infections. Although we have taken several measures to prevent nosocomial infections (hand hygiene, wound care, sterilisation, periodic staff educations, and other standard precautions), ^{Reference Mehta, Gupta and Todi20} most of the described patients (42.7%) suffered from nosocomial bacterial infections, which led to the long-term use of broad-spectrum antibiotics and raised the tendency to Candida bloodstream infections.

According to the literature, the median time from the surgical intervention to the first symptoms of fungal infection after admitting the child to an ICU is 19-24 days. ^{Reference Chakrabarti, Sood, Parnell and Rubin18} We found the mean time between the cardiovascular surgery and the first symptoms of Candida bloodstream infections after the admission of the patient to the paediatric cardiovascular surgery ICU as 12.2 ± 7.8 days. Despite their ongoing medical treatment, these patients had fever ≥38°C, clinical deterioration, gastric intolerance, and increased acute phase reactants, which suggested fungal infection. Studies have shown that the sensitivity of blood cultures for candidemia ranges between 63% and 83%, and likely even worse in children due to lower blood volumes used, so the meantime to positivity of the culture for Candida spp exceeds 24 hours, resulting in delays in the initiation of antifungal therapy and increased mortality. ^{Reference Hope, Castagnola and Groll21,Reference Steinbach, Roilides and Berman22} Therefore, we initiated fluconazole treatment, as soon as the suspicion had arisen, after obtaining the blood cultures. Despite multiple trials to define the optimal treatment for fungal infections in adult patients, paediatricians have limited evidence-based guidelines in this regard. ^{Reference Rex, Walsh and Sobel23} There have been prospective multi-centre studies in specific regions of the world, ^{Reference Pappas, Rex and Lee24} but additional investigations are needed to complete the knowledge gaps in paediatric candidiasis.

Furthermore, there are only a few case reports for therapeutic management of Candida bloodstream infections in children undergoing cardiovascular surgery. In concordance with these limited number of guidelines, ^{Reference Clancy and Nguyen25} we treated 88.4% of our patients successfully by fluconazole and/or caspofungin in the recommended paediatric dosages, ^{Reference Rex, Walsh and Sobel23,Reference Clancy and Nguyen25} depending on their clinical course, hepatic, and renal functions and culture results.

Despite the widespread use of antifungals, Candida bloodstream infections remain the most frequent life-threatening fungal disease among ICU patients. ^{Reference Tortorano, Kibbler and Penman9,Reference Lim, Rosli and Seow13} It has been estimated that the attributable mortality of Candida infections in children is 10–15%, which reaches 39% in the subgroup of children with CHD after cardiac surgery, and it may be as high as 83% in the infants below 6 months of age. ^{Reference Chakrabarti, Sood, Parnell and Rubin18,Reference Lai, Wang and Liu26} Based on our findings, the mean age of children with Candida bloodstream infections was 20.6 ± 13.9 months and the mortality rate due to candidiasis following the CVS was 11.6%.

Limitations of our study were being a retrospective analysis and a single-centre study, the results of which could not be generalised.