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Candida Species
Candida infections occur frequently in neonates, infants, and children, ranging from superficial skin infections to invasive disease. The number of children at risk for invasive candidiasis (IC) continues to increase due to new cancer therapies, increasing numbers of immunosuppressed solid organ and bone marrow transplant recipients, immune modulating agents for a wide range of autoimmune and autoinflammatory diseases, and utilization of novel medical devices.
Epidemiology
The known epidemiology of infections due to Candida species is limited to invasive disease (predominately candidemia), as rates of superficial disease are not routinely recorded.
IC may be most concerning in premature neonates. In a registry study of very low birth weight (VLBW; <1500 g birth weight) infants cared for at tertiary medical centers in the US, Candida albicans and Candida parapsilosis were the overall third and fifth-most common pathogens, respectively, identified in cases of late-onset sepsis. An early prospective, multicenter cohort study of 2847 neonates admitted to neonatal intensive care units (NICUs) in the US revealed cumulative IC incidences of 5.5% and 3% in extremely low birth weight (ELBW; <1000 g birth weight) and VLBW neonates, respectively. Neonates weighing >2500 g were much less likely to develop IC (0.3%). Routine antifungal prophylaxis was not practiced at any center during the course of this study. However, it should be noted that incidence of IC varies widely across centers; in one prospective observational cohort of ELBW neonates at 19 centers in the US, the incidence over the 3-year study period varied from 2% to 28% across centers.
The incidence of IC is lower in children beyond the neonatal and infant age period. A population-based epidemiologic study of candidemia in children in England and Wales reported overall annual incidence rates of 11/100,000 person-years for infants <1 year old, 1.77/100,000 for those 1–4 years, 0.53/10,000 for those 5–9 years, and 0.47/100,000 for those 10–14 years of age. Despite the lower rates in older age groups, Candida spp. still account for a significant proportion of all infections. In a prospective surveillance study of nosocomial bloodstream infections (BSIs) in pediatric patients at 49 hospitals throughout the US, Candida spp. were the third-most common overall source of BSIs. Similarly, in a multicenter point-prevalence survey of pediatric intensive care units in the US and Canada, Candida spp. were the second most common cause of infections overall and the third most common cause of BSIs.
There is some evidence that rates of IC have decreased over the last 2 decades. A decade-long surveillance study in NICUs in the US noted a significant decrease in candidemia among ELBW infants, although not in infants with greater birth weights. Another study of >700,000 neonates discharged from NICUs over a 14-year period reported that the annual incidence of IC decreased from 3.6 episodes per 1000 patients to 1.4 episodes per 1000 patients over the course of the study. The largest decrease was seen in infants weighing 750–1000 g at birth. Similar results have been seen in studies of cases of IC beyond NICUs. A study of hospital discharges in the US over a 9-year period found rates of non-neonatal IC decreased from 2.5/10,000 inpatient days to 0.92/10,000 inpatient days. This decline may be leveling off in recent years, as was suggested by a population-based candidemia surveillance study in 4 US metropolitan areas. Decline in IC likely is multifactorial and related to reduction in central venous catheter (CVC) use, improved infection prevention and control practices, and changes in antifungal prophylaxis prescribing practices.
Species Distribution
More than 200 species of Candida have been identified, but only a small subset of these have been identified in children with invasive disease. C. albicans remains the most common species in neonates and children with IC. In several multicenter studies of pediatric IC in Europe, North America, and South America, C. albicans was the causative organism in 40%–53% of cases. However, the epidemiology of IC has slowly changed, and recent studies have reported that non- albicans species occur more frequently overall than C. albicans. , ,
C. parapsilosis remains the second-most frequently identified species in neonates and children IC. , , , This species is the cause of IC in up to 30% of neonatal IC. C. parapsilosis occurs slightly less frequently with increasing age, causing 22%–28% of cases of pediatric IC. Notably, species distribution can differ by geographic location. In a prospective surveillance study of candidemia in Australia, C. parapsilosis was identified in 42% of cases of neonatal candidemia and 38% of pediatric candidemia.
C. glabrata and C. krusei are uncommon in children, which is a distinct difference in the epidemiology compared with adults. In a retrospective study of neonatal candidemia from China, C. glabrata was identified in 19% of cases. C. glabrata was identified in 3.5% of IC cases in a pediatric retrospective study performed in Europe, and approximately 10% of cases in studies from the International Pediatric Fungal Network that included hospitals in North America and Europe. , C. krusei also occurs infrequently, and has been reported to occur in approximately 2%–3% of IC among neonates and children. , The frequency of these species have been shown to increase with increasing age based on European surveillance data. , While these pathogens are less frequent in children, they remain an important consideration in pediatric IC due to their antifungal resistance patterns.
Frequency of invasive disease due to C. tropicalis varies in neonates and children. Studies from North America and Europe suggest that C. tropicalis is infrequent, but a surveillance study from South America found nearly 15% of IC was caused by C. tropicalis. Other Candida species identified infrequently include C. lusitaniae , C. dublinensis , C. kefyr , and C. guilliermondii . C. lusitaniae is particularly concerning as isolates are resistant to amphotericin B.
Notably, Candida species that are resistant to multiple classes of antifungal agents have begun to appear in recent years. C. blankii , which has decreased susceptibility to triazole antifungal agents, has been implicated in episodes of candidemia in neonates, as well as in a lung transplant recipient. C. auris , an emerging pathogen with reduced susceptibility to triazoles and amphotericin B, has been identified in nosocomial infections in infants and children. ,
Mortality Burden of Invasive Candidiasis
The need to continue to reduce the incidence of IC is paramount as IC is associated with substantial mortality. In a prospective observational study of ELBW infants, infants with IC had an increased likelihood of neurodevelopmental impairment and mortality compared with uninfected neonates. , Neonatal IC carries substantial risk for death, with case fatality rates ranging from 19% to 40% in multicenter studies. , , , , Rates of all-cause mortality also are high in IC beyond the neonatal period, ranging from 11% to 19% in several multicenter studies across multiple geographic locales. , , A prospective surveillance study of candidemia from multiple centers in South America reported a 30-day mortality of 28%. Attribution of death is not always reported and likely the attributable case fatality rates for IC are lower. In a prospective study of non-neonatal IC from the International Pediatric Fungal Network, death was attributable to IC in 7% of cases. A retrospective cohort study using a pediatric inpatient database identified the 15% rate of all-cause case mortality in children with IC and estimated 10% IC attributable case mortality. Despite these considerations, the rate of attributable death due to IC is higher than for many pathogens.
Host Factors Increasing Risk of Infection
IC is truly an opportunistic infection, and in almost every instance, it affects patients whose immune function is compromised in some fashion. Specific risk factors for invasive disease can be loosely grouped into three categories: those that increase colonization by Candida organisms, disruption of the barrier function (e.g., epithelium or endothelium) of the host immune system, and dysfunction within the effector arms of the immune system.
Risk Factors for Colonization
Increased colonization with Candida spp. is associated with increased risk of IC in premature neonates. , Colonization in neonates begins at time of birth, and VLBW infants are colonized at slightly higher rates than newborns of normal weight. Hyperglycemia, which can develop in children receiving parenteral nutrition or corticosteroids or in those with diabetes mellitus, also is associated with increased C andida colonization. , Additionally, acid-suppressing agents, such as H 2 -blocking drugs and proton pump inhibitors, appear to be independent risk factors for the development of overgrowth of Candida in the gastrointestinal tract.
A major risk factor for Candida colonization is the administration of broad-spectrum antibiotics, which results in destruction of normal competing bacterial flora and permits Candida to flourish. Administration of all broad-spectrum antibiotics have been reported to increase risk, and third-generation cephalosporins in particular have been implicated in the development of IC.
Disruption of Host Barriers
The skin and mucosal barrier of the gastrointestinal tract play an important role in preventing invasion of microorganisms. Premature infants have both thin, fragile skin and an immature mucosal barrier that likely contribute to predisposition to IC. Children with malignancy often sustain mucosal barrier injury related to both chemotherapy and neutropenia, and children with abdominal trauma or those requiring abdominal surgery can have disruption of mucosal barriers resulting in an increased the risk of IC. Finally, the presence of a CVC in any child violates the integrity of the skin and provides direct access to the bloodstream.
Dysfunction of Cellular Components of the Immune System
Impaired killing of Candida spp. permits progression from colonization to invasive disease. A variety of primary innate and acquired immunodeficiencies have been described to increase risk of IC. Primary immune deficient states predisposing to IC include chronic granulomatous disease, a disease of impaired neutrophil killing as well as deficiencies in IL-17 or signal transducer and transcription activator 3 (STAT3), or activating mutations of STAT1 that predispose to chronic mucocutaneous candidiasis. Autoimmune polyendocrinopathy syndrome type 1 (known as APS-1 or APECED), caused by deficiency of the autoimmune regulator (AIRE) protein, results in impaired T-lymphocyte tolerance and increased risk for chronic mucocutaneous candidiasis. Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor protein downstream from receptors that recognize fungal pathogen-associated molecular patterns; patients with CARD9 deficiency have impaired defense against fungi, including Candida spp., and can develop severe IC.
Premature infants also have immature lymphocyte function, resulting in increased risk of IC. The T-lymphocyte response is delayed compared with adults, and antibody production also is delayed.
Impairment of defense against Candida also can be iatrogenic. Chemotherapeutic regimens in children with cancer that lead to severe and prolonged neutropenia are associated with heightened risk of invasive fungal disease, including IC. Receipt of conditioning chemotherapy in hematopoietic cell transplantation (HCT) often results in both a period of neutropenia and a more prolonged period of T-lymphocyte dysfunction. Immunosuppressive drugs given to solid organ transplant recipients affect T-lymphocyte function and increase risk of IC. ,
Administration of corticosteroids also has been associated with increased risk of IC. Corticosteroids cause substantial down-regulation of the immune system, including a decrease in cytokine production and chemotaxis, and acceleration of lymphocyte apoptosis.
Clinical Manifestations
Candida can cause a variety of infections, ranging from superficial candidiasis involving the skin or mucosal surfaces to IC involving the blood and/or multiple organs. Superficial candidiasis can occur commonly in otherwise healthy children, but IC is rare in immunocompetent children.
Superficial and Mucosal Candidiasis
Diaper Dermatitis and Other Cutaneous Disease
Diaper dermatitis is one of the most common skin conditions in neonates and infants, and superficial candidiasis is a frequent cause. Classically, Candida dermatitis usually manifests as a confluent erythematous rash with satellite lesions. In term infants, diaper dermatitis is most common from 9 to 12 months of age, but manifests earlier in preterm infants. Diaper dermatitis in term infants is rarely associated with systemic disease, but cutaneous disease can progress to invasive disease in preterm infants.
Oropharyngeal Candidiasis (Thrush)
Thrush is a common condition in infants or immunocompromised children and is generally characterized by pseudomembranous, white, curd-like, plaques on the buccal mucosa, throat, tongue, or gingivae. An erythematous base is often seen after removal of the plaque, although the mucosa can be normal in color. Thrush may not cause symptoms or can cause a painful, burning sensation, which can lead to decreased intake of food and liquids. Thrush occasionally progresses to esophagitis, laryngitis ( Fig. 243.1 ), or invasive disease in severely immunocompromised patients.
Esophagitis
Candida esophagitis is a disease of immunocompromised patients, most commonly HIV-infected individuals. Patients frequently complain of severe dysphagia or odynophagia and may not have signs or symptoms of oral candidiasis. Diagnosis can be made based on clinical presentation and setting or on the presence of characteristic mucosal irregularities on barium esophagram. However, Candida esophagitis can occur simultaneously with other pathogens such as cytomegalovirus or herpes simplex virus, and definitive diagnosis requires endoscopic biopsy.
Chronic Mucocutaneous Candidiasis
Recurrent or persistent superficial candidiasis of the skin, mucous membranes, and nails is rare and raise concerns for deficiencies in cell-mediated immunity, specifically those causing poor responses to Candida spp. Such primary immune deficiencies include mutations in IL-17 or STAT1 or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. ,
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