INTRODUCTION — Candida has emerged as an important cause of neonatal infections and is associated with significant morbidity and mortality, especially in extremely low and very low birth weight infants (defined as birth weights <1000 g and <1500 g, respectively) [1-5]. The clinical manifestations of Candida infection in the neonate vary, ranging from localized infections of the skin and mucous membranes to life-threatening systemic infection with multisystem organ failure. Host risk factors, such as prematurity and the use of invasive procedures, are important determinants that influence the severity and type of neonatal Candida infection [3,5].
The clinical manifestations of Candida infection in the neonate will be reviewed here. The etiology, treatment, and prevention of neonatal candidal infections are discussed separately, as are the clinical manifestations of Candida in older infants and children. (See "Epidemiology and risk factors for Candida infection in neonates" and "Treatment of Candida infection in neonates" and "Candida infections in children".)
OVERVIEW — There are two broad categories of Candida infections in neonates: :
●Mucocutaneous candidiasis, which includes oropharyngeal involvement (thrush) and diaper dermatitis (see 'Mucocutaneous candidiasis' below)
●Invasive infections, which can involve the bloodstream, urinary tract, central nervous system (CNS), and other focal sites (see 'Invasive infection' below)
Although Candida albicans is the major species isolated from neonates with Candida infection, other species such as Candida parapsilosis, Candida tropicalis, and fluconazole-resistant Candida glabrata can also cause neonatal infection [1,7,8]. (See "Epidemiology and risk factors for Candida infection in neonates", section on 'Epidemiology'.)
The immaturity of host defenses and the compromise of the epithelial barrier are the primary pathogenetic factors for neonatal candidal infection. (See "Epidemiology and risk factors for Candida infection in neonates", section on 'Pathogenesis'.)
MUCOCUTANEOUS CANDIDIASIS — Mucocutaneous candidiasis is an infection of the skin and/or mucous membranes. It includes oropharyngeal candidiasis (thrush), diaper dermatitis, congenital candidiasis, and invasive fungal dermatitis. Mucocutaneous candidiasis has the potential to disseminate via the blood stream to other organs [9,10]. Prematurity and breaks in the epithelial barriers (eg, indwelling catheters) are risk factors for systemic dissemination of mucocutaneous disease. (See "Epidemiology and risk factors for Candida infection in neonates", section on 'Risk factors for invasive candidiasis'.)
Oropharyngeal candidiasis (thrush) — Oropharyngeal candidiasis is a common manifestation of Candida infection throughout infancy, both in preterm and healthy full-term infants. Among hospitalized infants in the neonatal intensive care unit, an overall incidence of oropharyngeal candidiasis of 3 percent has been reported at a median age of onset of 9 to 10 days after birth [11,12].
Maternal vaginal colonization with Candida and birth asphyxia are reported risk factors associated with oropharyngeal candidiasis . Although oropharyngeal candidiasis can be transmitted during breastfeeding, the incidence of this condition appears to be greater in infants who are formula fed .
Thrush presents as irregular white plaques with or without an erythematous base on the buccal or lingual mucosal surface of the mouth (picture 1). Most infants remain asymptomatic; however, some infants may refuse to eat because of discomfort from contact with their lesion(s) during feeding .
Diaper dermatitis — Diaper rash is a common manifestation of mucocutaneous candidiasis in the premature infant. In one review, 8 percent of very low birth weight infants (birth weight <1500 g) developed mucocutaneous candidiasis during their initial neonatal intensive care unit admission . This study also demonstrated that in premature infants, candidal diaper dermatitis was a risk factor for developing systemic infection, which was usually heralded by a change in clinical status. Infants with candidal diaper dermatitis were also more likely to have Candida colonization of the gastrointestinal tract.
Candida diaper dermatitis is characterized by an area of confluent erythema in the inguinal region, discrete erythematous papules and plaques with superficial scales, and satellite lesions (picture 2A-B).
Invasive fungal dermatitis — Invasive fungal dermatitis is a condition that is unique to extremely low birth weight (ELBW; birth weight <1000 g) premature infants during the first two weeks after birth [10,16]. In a case series of 16 infants with this condition, postnatal steroids and hyperglycemia were risk factors; 69 percent had evidence of disseminated fungal disease .
The lesions vary in appearance. They include macular, papular, vesicular, or pustular lesions that are typically in dependent or intertriginous areas of the skin. The erosions can be extensive and sometimes involve the whole area of the abdomen or back.
Skin biopsy is diagnostic and shows Candida hyphae invading the dermis. Blood cultures should be obtained since dissemination of infection to the bloodstream is common. If candidemia is detected, the infant should undergo additional evaluation to determine the extent of infection. (See 'Invasive infection' below and 'Evaluation for extent of dissemination' below.)
Congenital candidiasis — Congenital cutaneous candidiasis is a rare disorder that results from a Candida infection acquired in utero or during delivery. The risk of ascending infection is increased by ruptured membranes, presence of a uterine or cervical foreign body, and a history of vaginal candidiasis [17,18]. It occurs more commonly in preterm than term infants, though term infants can be affected [17,19]. The risk of systemic dissemination is greatest among ELBW infants .
The affected infant typically presents on the first day after birth with a generalized eruption of 2 to 4 mm erythematous macules and/or papules that rest upon a 5 to 10 mm erythematous base. These lesions evolve into pustules, vesicles, or even bullae (picture 3A-B) [17,20]. Unlike erythema toxicum neonatorum or miliaria, this condition is characterized by the frequent involvement of the palms and soles. Oral thrush may be present at birth, and yellow-white papules may be observed on the umbilical cord.
In preterm infants, the rash may have a variable presentation including widespread pustular and vesicular lesions or diffuse erythematous macular patches resembling a burn . Crusting of the skin may be the presenting feature of such cases. In term infants, the skin lesions generally resolve with desquamation by the first week after birth.
Demonstration of budding yeast and pseudohyphae, usually in large numbers, on a potassium hydroxide preparation of scrapings from the skin lesions is helpful in making the diagnosis. Skin biopsy may be needed in some cases. Cultures should also be obtained of blood, urine, and cerebrospinal fluid (CSF). (See 'Diagnosis' below.)
INVASIVE INFECTION — Preterm infants, particularly extremely low birth weight (ELBW; birth weight <1000 g) infants, are at increased risk for developing invasive Candida infections because of the immaturity of their immune and host epithelial protection, compromise of their epithelial protection with invasive procedures (eg, intubation, central venous catheters, and/or surgery), and factors that promote increased density of candidal colonization (eg, administration of broad-spectrum antibiotics). (See "Epidemiology and risk factors for Candida infection in neonates", section on 'Risk factors for invasive candidiasis'.)
Evaluation for extent of dissemination — In the newborn, invasive focal infections are generally due to seeding of individual organ system from hematogenous dissemination. Infants who are diagnosed with Candida infection involving the bloodstream, urinary tract, central nervous system (CNS), eyes, heart valves, bone, or joints should undergo evaluation to determine the extent of systemic infection, which informs management decisions. The following tests should be performed [22-24]:
●Cultures of the blood, urine, and cerebrospinal fluid (CSF)
●Dilated eye examination
●Echocardiography to assess for cardiac thrombi or vegetations
●Ultrasound imaging of the liver, spleen, and kidney
Although any organ can be involved, the most common sites include the urinary tract, eye, heart valves, and CNS [22,25,26].
Candidemia — The presentation of neonatal candidemia can vary depending upon the extent of systemic disease. The most common presentation is similar to that of bacterial sepsis. Symptoms include lethargy, feeding intolerance, hyperbilirubinemia, apnea, cardiovascular instability, and/or respiratory distress [15,25]. In the most severe cases, cardiorespiratory function is severely compromised, with multiorgan failure. The combination of persistent hyperglycemia and thrombocytopenia in ELBW infants is strongly associated with candidemia, and, if these are present, the infant should undergo evaluation for candidemia .
The hallmark of candidemia is involvement of multiple organ systems, especially in low birth weight infants. Infants with multiorgan failure have a poor prognosis. The finding of involvement of one organ system should prompt a thorough examination and evaluation to detect candidemia and other organ involvement. (See 'Evaluation for extent of dissemination' above.)
Skin abscesses, which appear as clusters of painless pustules on an erythematous base or nodules, have been described in neonates with candidemia and are thought to be caused by septic emboli . They can be distinguished from congenital candidiasis based on the timing (the lesions in congenital candidiasis are present around the time of birth) and the distribution (the lesions in congenital candidiasis tend to be diffuse, whereas septic emboli from systemic candidiasis typically occur in isolated focal areas in the skin).
Catheter-related infections — Infants who have indwelling catheters in place for >7 days are at risk for developing a catheter-related Candida infection . Infected catheters increase the risk of disseminated disease.
An infant with a nondisseminated catheter-related infection may exhibit nonspecific symptoms of sepsis (eg, temperature instability, feeding intolerance, apnea, hyperglycemia) without evidence of multiorgan involvement . Thrombocytopenia is a common finding. An infected thrombus or fungal ball can form on the catheter tip, which consumes platelets and can be a source of septic emboli.
Urinary tract infection — Candida is a common cause of urinary tract infection (UTI) in infants in the neonatal intensive care unit setting [30,31]. In one case series of 57 infants with 60 documented UTIs, Candida was responsible for 25 of the 60 infections .
The spectrum of Candida UTI in neonates ranges from Candida cystitis in infants with indwelling urinary catheters to parenchymal renal disease from candidemia. Clinical manifestations are nonspecific and include apnea, bradycardia, glucose intolerance, and decreased urine output. Findings specific to the kidney and/or urinary tract may be noted in some cases (eg, urinary obstruction, hypertension, or acute kidney injury) [32-35].
In case series, reported rates of renal involvement in infants with candidemia ranged from 5 to 33 percent [7,22,36]. In one case series of 25 infants with candidal UTI cared for in the neonatal intensive care unit, candidemia was present in 50 percent. In a cohort study that prospectively followed 30 infants diagnosed with Candida UTI without extrarenal involvement, 13 percent subsequently developed extrarenal candidiasis .
Risk factors for Candida UTI include congenital anomalies of the kidney and urinary tract, obstruction, urinary stasis, and the presence of an indwelling bladder catheter [31,36,38]. (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)
The diagnosis of Candida UTI is based upon a positive urine culture. A Candida UTI is present if there are >1000 colony forming units per mL (CFU/mL) in a specimen collected by suprapubic aspiration  or >10,000 CFU/mL in a specimen collected by catheterization .
Ultrasonography of the bladder and kidneys is an important component of the evaluation as it can detect renal parenchymal infiltration, calyceal mycetoma, or fungal masses (ie, fungal balls) in the urinary tract [31,36,38]. In addition, renal ultrasonography screens for congenital anomalies of the kidney and urinary tract.
In one retrospective review of neonates with candidemia, abdominal ultrasonography detected abnormalities due to Candida in the kidneys in 3 of 65 (5 percent) . Lesions may not be present at the initial study but may become evident on subsequent examinations . In infants with oliguria, obstruction due to discrete fungal masses can be detected by ultrasonography [32,33]. Serial studies are also used to follow the response to therapy and the resolution of fungal masses [31,36].
Central nervous system infection — CNS infections are the result of hematogenous spread of Candida and usually manifest as meningitis. Less commonly, brain abscesses, ventriculitis, vasculitis, and fungal masses within the subarachnoid space may occur .
The presentation of Candida CNS infection varies from a subacute, indolent illness, which is only identified because of a high index of suspicion , to severe illness with cardiorespiratory instability and multiorgan failure . Clinical signs may be the same as in acute bacterial meningitis. These include temperature instability, irritability, poor feeding or vomiting, respiratory distress, and apnea. In some cases, the diagnosis may be suggested by the appearance of CNS parenchymal abscesses on cranial imaging obtained for other reasons . (See "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Clinical features'.)
CSF findings are variable and relate to the type of CNS involvement (meningeal versus parenchymal disease). Normal CSF chemistries, cell count, and Gram stain do not exclude CNS involvement, because the inflammatory response may be limited or delayed and the inoculum of the organism may be low [40,42,43]. Definitive diagnosis is based on isolating Candida from the CSF culture.
CNS involvement is common in infants with disseminated infection. Reported rates of CNS involvement in infants with candidemia range from 10 to 64 percent [40-42,44]. This variability is primarily due to differences in the degree and thoroughness of evaluation for CNS disease. In the largest case series that included 106 cases of neonatal systemic candidiasis, 23 infants had Candida meningitis (22 percent) . The median gestational age of these patients was 26.2 weeks with a median birth weight of 820 g, and the median age at onset of illness was eight days after birth.
Complications of CNS infection include obstructive hydrocephalus, cerebral atrophy, and poor neurodevelopmental outcome .
Candida endocarditis is a common complication of candidemia. In one retrospective review of 86 infants with candidemia, echocardiogram demonstrated thrombi or vegetations in 11 of 72 infants (15 percent) . Infants with fungemia that lasted five or more days were more likely to have cardiac lesions as well as renal or ophthalmologic abnormalities. Although the presence of a central venous catheter was not associated with an increased risk of cardiac involvement in this study, other studies in premature infants have demonstrated an increased risk of fungal endocarditis associated with central venous catheters [46,47]. (See "Candida infections in children", section on 'Endocarditis'.)
Ocular involvement — The term "Candida endophthalmitis" is often used to describe both Candida chorioretinitis (minimal or no vitreous inflammation) and endophthalmitis (marked vitritis); although, the correct term to include both is "ocular candidiasis." However, "Candida endophthalmitis" is the more commonly used term in the ophthalmology literature.
In the neonate, ocular involvement results from the hematogenous spread of Candida to the eye. The reported incidence varies from 6 to 50 percent of premature infants with disseminated candidiasis [22,44,48]. In a case series that included 86 infants with candidemia, 4 of the 67 infants (6 percent) in whom indirect ophthalmoscopy examination was performed had retinal abnormalities indicative of candidal infections.
Indirect ophthalmoscopic examination should be performed to evaluate for candidal chorioretinitis in all infants with suspected or proven candidemia because affected neonates may not present with any clinical signs or symptoms and, if not treated, endophthalmitis may lead to loss of vision. The classic ophthalmologic findings are focal, glistening, white, infiltrative, often mound-like lesions on the retina with indistinct borders (picture 4). Vitreous extension occurs occasionally and can be seen as a vitreal haze or as fluffy white balls ("snowballs") within the vitreous (picture 5). (See "Treatment of endogenous endophthalmitis due to Candida species".)
Candidemia without ocular involvement may be associated with an increased risk of developing severe retinopathy of prematurity (ROP) [22,49-53]. Although one study did not find any association with ROP after controlling for gestational age , several others have shown an association between candidemia and ROP requiring laser surgery [50,52,53]. Thus, based upon the available data, preterm infants of any gestational age who develop candidemia should be followed closely by an ophthalmologist for the late development of severe ROP that may require surgical intervention.
Other focal infections — Other sites of focal infection may include peritonitis and osteoarticular infections.
●Peritonitis – There are several case reports and small case series that have reported Candida peritonitis in very low birth weight premature infants (birth weight <1500 g) with necrotizing enterocolitis or focal gastrointestinal perforations [29,55-58].
In particular, spontaneous intestinal perforation is associated with disseminated infection. This was illustrated in one small case series of premature infants with spontaneous intestinal perforation, in which 33 percent of the affected infants had Candida isolated from a culture of blood, peritoneal fluid, CSF, or urine . In these cases, pathologic examination of the perforated intestinal area demonstrated fungal invasion of the mucosa. It is unclear whether the perforation was due to a primary invasion of the mucosa or whether Candida is a colonizing organism that invades bowel wall that was already damaged from a primary insult . (See "Neonatal necrotizing enterocolitis: Clinical features and diagnosis".)
●Osteoarticular infections – In the neonate, Candida osteomyelitis or arthritis rarely occurs as an isolated event and typically occurs because of disseminated infection [59-61]. The signs and symptoms of these infections caused by Candida are similar to those that occur in septic arthritis or osteomyelitis caused by bacteria (ie, swelling and decreased range of motion). (See "Hematogenous osteomyelitis in children: Clinical features and complications" and "Bacterial arthritis: Clinical features and diagnosis in infants and children".)
To distinguish fungal from bacterial infection, the diagnosis is dependent upon isolating Candida from either cultures of the synovial fluid or bone aspirate.
Mucocutaneous candidiasis — The diagnosis of mucocutaneous candidiasis depends upon the presentation:
●Oropharyngeal candidiasis and diaper dermatitis are diagnosed clinically based on the characteristic appearance (picture 1 and picture 2A-B). It is usually not necessary to obtain cultures of the lesion. In infants who fail topical therapy, a culture may be useful to identify the Candida species and assess its sensitivity to the antifungal agent used.
●Invasive fungal dermatitis may be suspected based upon the appearance of skin lesions (macular, papular, vesicular, or pustular lesions in dependent or intertriginous areas of the skin). The definitive diagnosis is confirmed by a skin biopsy with isolation or histologic identification of the organism.
●In patients with congenital candidiasis, a presumptive diagnosis can be made by identifying the organism by Gram stain of the vesicular contents or by potassium hydroxide preparations of skin scrapings (picture 6). Confirmation of the diagnosis is made with isolation of the organism from a culture of the discrete lesions or swabs of the affected skin areas.
Invasive infections — Neonates with documented invasive Candida infection should undergo evaluation to determine the extent of infection. (See 'Evaluation for extent of dissemination' above.)
●Blood culture – The diagnosis of candidemia is made by isolating a Candida species from the blood culture (picture 7). Because the sensitivity of a single blood culture is low in detecting disseminated candidiasis, multiple or repeat blood cultures should be performed to increase the likelihood of detecting candidemia. If a central venous catheter is present, cultures should be obtained through the catheter and a peripheral vessel to distinguish between disseminated infection and catheter-related candidiasis.
A drawback of all blood culture systems as the primary means of establishing the diagnosis of candidemia is that one to four days are required for growth of the organism. While awaiting culture results, empiric systemic antifungal agents should be administered if the clinical suspicion is high. (See "Treatment of Candida infection in neonates".)
●Beta-D-glucan – The detection of beta-D-glucan (a cell wall component of many fungi) in blood may be a useful tool in the evaluation for fungal infection. While the test is not diagnostic of candidemia, it provides support for the diagnosis of invasive fungal infection. In a meta-analysis of eight studies (465 neonates), the sensitivity and specificity of beta-D-glucan with a cutoff threshold of 80 pg/mL were 89 percent and 60 percent, respectively . Several commercial assays are available for detecting beta-D-glucan, though the test is not available in all settings. Beta-D-glucan assay is not specific for Candida species and can be positive in patients with a variety of invasive fungal infections, including Aspergillus. (See "Diagnosis of invasive aspergillosis", section on 'Beta-D-glucan assay'.)
●Molecular diagnostic methods – Polymerase chain reaction (PCR) tests to detect fungal ribosomal DNA in blood samples are available in some settings. These tests may be useful when used in conjunction with cultures, but they do not have sufficient diagnostic accuracy to replace cultures. In addition, PCR tests do not provide information on susceptibility to antifungal agents. In a systematic review that included four studies specifically evaluating the use of fungal PCR tests in neonates, the sensitivity ranged from 77 to 95 percent and specificity from 70 to 95 percent .
Candida urinary tract infection — The diagnosis of Candida urinary tract infection (UTI) is based upon a positive urine culture (ie, >1000 colony forming units per mL [CFU/mL] in a specimen collected by suprapubic aspiration or >10,000 CFU/mL in a catheterized specimen) [30,38].
Candida central nervous system infection — The diagnosis of Candida central nervous system (CNS) infection is made by isolating a Candida species from the cerebrospinal fluid (CSF) culture. CSF findings (eg, cell count, chemistries) are variable; normal CSF findings do not exclude CNS involvement, because the inflammatory response may be limited or delayed.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis".)
SUMMARY AND RECOMMENDATIONS
●Candida has emerged as a common cause of infections in infants admitted to the neonatal intensive care unit, particularly in preterm infants. There are two broad categories of Candida infections in neonates: noninvasive mucocutaneous candidiasis (eg, thrush, diaper dermatitis) and invasive infections (which can involve the bloodstream, urinary tract, central nervous system [CNS], and other focal sites). (See 'Overview' above.)
●Mucocutaneous candidiasis includes the following (see 'Mucocutaneous candidiasis' above):
•Oropharyngeal candidiasis (thrush) is a common manifestation of Candida infection throughout infancy, both in preterm and healthy full-term infants. It appears as irregular white plaques with or without an erythematous base on the buccal or lingual mucosal surface of the mouth (picture 1). (See 'Oropharyngeal candidiasis (thrush)' above.)
•Diaper dermatitis is a common manifestation of mucocutaneous candidiasis in the premature infant. It is characterized by an area of confluent erythema in the inguinal region, discrete erythematous papules and plaques with superficial scales, and satellite lesions (picture 2A-B). (See 'Diaper dermatitis' above.)
•Invasive fungal dermatitis is a condition that is unique to extremely low birth weight (ELBW) infants (birth weight <1000 g) during the first two weeks after birth. Dissemination of infection to the bloodstream is common. (See 'Invasive fungal dermatitis' above.)
•Congenital cutaneous candidiasis is a rare disorder that results from an infection acquired in utero or during delivery. It typically presents on the first day after birth with a generalized maculopapular eruption (picture 3A-B). (See 'Congenital candidiasis' above.)
●Invasive infections – Preterm infants, particularly ELBW infants, are at increased risk for developing invasive Candida infections, which include the following (see 'Invasive infection' above):
•Candidemia – The presentation of neonatal candidemia is variable. Symptoms may include lethargy, feeding intolerance, hyperbilirubinemia, apnea, cardiovascular instability, and/or respiratory distress. Cardiorespiratory compromise and multiorgan failure may be seen in severe cases. The combination of persistent hyperglycemia and thrombocytopenia in ELBW infants is strongly associated with candidemia and should prompt evaluation for candidemia. (See 'Candidemia' above.)
•Catheter-related infections – Catheter-related infection is a major cause of disseminated systemic infection. Infants with catheter-related infections may exhibit nonspecific symptoms of sepsis (eg, temperature instability, feeding intolerance, apnea, and hyperglycemia). Thrombocytopenia is also a common finding. (See 'Catheter-related infections' above.)
•Urinary tract infections (UTIs) – Candida is a common cause of UTI in infants in the neonatal intensive care unit setting. Clinical manifestations are generally nonspecific and include apnea, bradycardia, glucose intolerance, and decreased urine output. Findings specific to the kidney and/or urinary tract may be noted in some cases (eg, urinary obstruction, hypertension, or acute kidney injury). (See 'Urinary tract infection' above.)
•CNS infections – CNS involvement, which typically manifests as meningitis, is common in infants with disseminated infection. The presentation varies from a subacute, indolent illness to severe illness with cardiorespiratory instability and multiorgan failure. (See 'Central nervous system infection' above.)
●Evaluation for extent of disease – Infants who are diagnosed with invasive Candida infection should undergo evaluation to determine the extent of systemic infection, including cultures of the blood, urine, and cerebrospinal fluid (CSF); dilated eye examination; echocardiography; and ultrasound of the liver, spleen, and kidney. (See 'Invasive infection' above.):
●Diagnosis – The diagnosis of neonatal Candida infection depends upon the presentation (see 'Diagnosis' above):
•Invasive fungal dermatitis is diagnosed based on skin biopsy.
•Congenital candidiasis is diagnosed based on isolation of the organism from a culture of the discrete lesions or swabs of the affected skin areas.
•The diagnosis of candidemia is made by isolating a Candida species from the blood culture.
•The diagnosis of Candida UTI is based upon a positive urine culture (>1000 colony forming units per mL [CFU/mL] in a specimen collected by suprapubic aspiration or >10,000 CFU/mL in a catheterized specimen).
•The diagnosis of Candida CNS infection is made by isolating a Candida species in CSF culture. CSF findings (eg, cell count, chemistries) are variable; normal CSF findings do not exclude CNS involvement, because the inflammatory response may be limited or delayed.
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