Epidemiology and presentation of invasive fungal infections in pediatric patients

The neonate

Candida spp. colonize the vaginal tract of approximately 30% of pregnant women; very rarely, they can become the cause of chorioamnionitis and intrauterine infection [29, 30]. Candida rapidly colonizes the mucocutaneous surfaces [31, 32]; in healthy infants, this colonization may result in thrush and diaper dermatitis [31]. In hospitalized, ill neonates, however, Candida has evolved as important cause of life-threatening invasive infections, particularly in very low birth weight infants. Candida spp. now account for 9-13%

Epidemiology Fungi
Figure 1. Clinical classification of fungal pathogens observed in humans.

of all bloodstream isolates in neonatal intensive care units (NICUs) [33, 34]. In the U.S., Candida spp. currently are the third most common cause of late onset sepsis, and second only to polyresistant Enterobacter spp. in mortality [35, 36]. Case series indicate that invasive candidiasis occurs in up to 5% of infants with a birth weight of < 1500 g and in 8-28% of infants with a birth weight of < 1000 g; the crude mortality associated with these infections ranges from 15% to 30% with an attributable mortality of 6-22% despite appropriate therapy [37-50]. Moreover, a recent large analysis showed that 73% of extremely low birth weight infants (< 1000 g) with invasive candidia-sis did not survive or had significant neurodevelopmental impairment [51]. Invasive candidiasis in preterm infants is most commonly due to C. albicans and C. parapsilosis [43, 47] and associated with prior mucocutaneous colonization, vascular catheters, the use of broad-spectrum antibiotics and corticosteroids, and parenteral hyperalimentation [47, 52-55]. Most neonates with systemic candidiasis are symptomatic at the onset of their disease and present with signs and symptoms that are virtually identical to those of non-fungal etiological agents. Among deeply invasive infections, cutaneous, renal, pulmonary, and cerebral involvement are disproportionally common [28], and Candida is increasingly recognized as causative agent of infections associated ventricular shunts and drains [56]. Fungemia persisting for 14 days and longer despite appropriate management has been reported to occur in as much as 10% of extremely low birth weight infants with candi-demia and poses a particular challenge to the infectious disease specialist [51, 57]. Numerous outbreaks have been reported, which underscores the

Invasive fungal infections in children: advances and perspectives Table 1. Pediatric populations at risk for invasive fungal infections

- Neonates

- Infants

- Children with congenital immunodeficiencies

- defects of phagocytic host defenses

- defects of specific cellular host defenses

- Children with acquired immunodeficiencies

- iatrogenic immunosuppression

- treatment for cancer

- HIV infection

- Children with acute illnesses

- Children with chronic airway diseases importance of appropriate infection control measures for prevention of these infections [44, 53].

Malassezia spp. are lipophilic commensal yeasts that colonize the human skin and may cause pityriasis, a skin infection that is only cosmetically relevant. However, these organisms also may gain access to the bloodstream via percutaneous vascular catheters to cause a potentially fatal systemic infection in premature infants receiving parenteral nutritional lipid supplements [58, 59]. Similar to Candida, the most probable mode of acquisition is via the hands of health care workers [60], but direct contamination through contaminated intravenous (IV) solutions and catheters has also been reported [61]. Special media containing olive oil are required for isolation [58].

Infections by Aspergillus species and zygomyces are very rare in the neonatal setting. They tend to have a predilection for the skin, and, in the case of the zygomycetes, for the gastrointestinal tract, resulting in necrotizing skin lesions and devastating necrotizing gastroenterocolitis, respectively. Potential sources of the organism are contaminated water, contaminated ventilation systems and contaminated dressing materials or infusion boards [1-4, 62]. A large literature review in the late 1990 found 44 cases of invasive aspergillosis that were reported in children of s 3 months of age. Most of these infants had either invasive pulmonary (23%), primary cutaneous (25%), or disseminated aspergillosis (32%). Prematurity, chronic granulomatous disease, and a complex of diarrhea, dehydration, malnutrition, and invasive bacterial infections accounted for the majority of underlying conditions (82%). Only few patients were neutropenic, but at least 41% had received corticosteroids. While all other forms of the disease mainly occurred in term infants, cutaneous as well as alimentary tract aspergillosis occurred almost exclusively in preterm neo-nates. Disseminated disease was uniformly fatal, but patients who received appropriate therapy had over 70% survival [4]. Invasive mould infections in the setting of neonatal medicine should be considered in infants with expanding, necrotizing skin lesions or gastrointestinal perforation. Surgical debridement is essential in most cases [3, 4].

The infant

Disseminated histoplasmosis is a classical example for the potentially dismal course of a primary infection by an endemic fungus in apparently healthy infants that were exposed to the organisms. The disease is fatal if not detected and treated. Its clinical manifestations include prolonged fevers, failure to thrive, hepatosplenomegaly, pancytopenia, and ultimately, disseminated intravascular coagulation and multiorgan failure [19, 20, 63]. Not much is known about blastomycosis and cocidioidomycosis in this age group, but ultimately fatal cases have been reported [21, 64, 65]. Conceptually, primary infection by endemic fungi during infancy is reminiscent of the infantile form of pulmonary pneumocystosis, which is associated with young age, malnutrition, and endemic exposure [66].

Candida albicans is a ubiquitous agent of diaper dermatitis, which may be precipitated by moisture, occlusion, fecal contact and urinary pH. Its classical presentation is that of an erythema bordered by a collarette of scale with satellite papules and pustules. Concomitant dermatophytosis may occasionally be present. Treatment consists of the correction of physiological factors and topical antifungal treatment [28].

Children with congenital immunodeficiencies

Among the phagocyte-defect syndromes, myeloperoxidase (MPO) deficiency is the most common entity. While MPO-deficient cells have only minor microbicidal abnormalities against bacteria in vitro, killing of Candida spp is highly deficient and may serve as explanation for invasive Candida infections reported in some patients with this disorder [67, 68]. Chronic granu-lomatous disease of childhood (CGD) is a genetically diverse congenital disorder of the NADPH oxidase complex that is associated with an inability of phagocytic cells to provide antimicrobial oxidants and to kill ingested microorganisms [69]. It is the prime example for an inherited immune disorder with a high risk of invasive mycoses; at the same time, it serves as a paradigm for the importance of phagocytosis in the defense of infections by opportunistic moulds. Invasive mycoses, particularly invasive aspergil-losis, may repeatedly complicate the course of this disorder, accounting for an estimated lifetime incidence of between 16% and 40% [24, 25, 70, 71]. Interferon-y (IFN-y) or prophylactic antifungal triazoles may reduce the frequency of these infections [72, 73]. Treatment is protracted and consists of antifungal chemotherapy, IFN-y, and appropriate surgical interventions; the precise role of gene therapies and HSCT has yet to be defined [28, 74-76].

The role of immunoglobulins in host defenses against fungi is important against cryptococcosis and possibly mucosal and invasive candidiasis [77], but it is not well understood for other mycoses. Children with inherited deficits of B lymphocytes appear to be not at increased risk for fungal infection, unless there is a concomitant disorder of T lymphocytes or phagocytosis. This includes individuals with the x-linked hyper-IgM syndrome [78], and patients with the hyper-IgE syndrome, which is associated with chronic mucocutaneous candidiasis, and possibly with cryptococcosis and aspergil-losis [79].

Inherited immunodeficiencies involving the number or function of T lymphocytes predispose to mucocutaneous and, occasionally, invasive candidiasis, and conceptually, to cryptococcosis and histoplasmosis [22, 77]. Severe combined immunodeficiency (SCID) and severe types of thymic hypoplasia (DiGeorge syndrome) are medical emergencies of the neonatal period that can be managed successfully only with HSCT or thymus transplantation, respectively [80-82]. Refractory mucocutaneous candidiasis is a hallmark of these disorders and can therefore be an important clue to the appropriate immunological work-up. Chronic mucocutaneous candidiasis is a less severe congenital immunodeficiency with an impaired T cell response to Candida antigens [83]. It is characterized by chronic recurrent candidiasis of nails, skin, perineum, and oropharynx and may be idiopathic or associated with either the polyendocrinopathy syndrome type I or the hyper-IgE syndrome [79, 84].

Children with acquired immunodeficiencies Iatrogenic immunosuppression

Treatment with pharmacological dosages of glucocorticosteroids rapidly provides a functional impairment of phagocytosis by mono- and polymor-phonuclear leukocytes. Similar to adults, such therapy is one of the most important reasons for the increased susceptibility to invasive mycoses of children with immunosuppressive therapy for immunological disorders, solid organ transplantation, and for graft-vs.-host disease (GVHD) following HSCT [28, 85, 86].

Cancer

While current treatment for pediatric cancers is curative in most instances, highly dose-intensive chemotherapy regimens and aggressive supportive care measures also result in profound impairments of host defenses. Prolonged, profound granulocytopenia is the single most important risk factor for opportunistic fungal infections in children and adolescents with cancer [87, 88]. Other well-known, but notable risk factors include chemotherapy-induced mucositis, extended courses of broad-spectrum antibiotics, the presence of indwelling central venous lines, and, particularly in children with acute leukemia, the therapeutic use of glucocorticosteroids [89].

Oropharyngeal candidiasis (OPC) may occur in up to 15% of children undergoing intensive chemotherapy or bone marrow transplantation despite various forms of topical or systemic antifungal prophylaxis [90]. Esophageal candidiasis is also not uncommon, even in the absence of conspicuous OPC [28], and Candida epiglottitis and laryngeal candidiasis may emerge in neutropenic children as life-threatening causes of airway obstruction [9, 10, 91].

Similar to the adult cancer population, Candida- and Aspergillus spp are the most common causes of invasive fungal infections in children with cancer [88, 92]. Invasive candidiasis in neutropenic children may present as catheter-associated candidemia, acute disseminated candidiasis, and deep single organ candidiasis. Its overall frequency in children with high-risk leu-kemias and/or bone marrow transplantation is between 5% and 10%; the crude mortality associated with these infections is at least 20% and close to 100% in patients with persistent neutropenia [88, 93-100]. Catheter-associated fungemia is most commonly caused by C. albicans, but non-albicans Candida spp., particularly C. parapsilosis, and previously uncommon yeast pathogens are increasingly encountered [88, 100-102]. Whether the primary source of fungemia or a target for attachment of circulating organisms, the intravascular catheter serves as a source for continued seeding of the bloodstream and should be removed whenever feasible [103-106]. Acute disseminated candidiasis occurs typically in granulocytopenic children and manifests with persistent fungemia, hemodynamic instability, multiple cutaneous and visceral lesions and high mortality despite antifungal therapy [28, 97]. Candida albicans is the most frequent cause, although C. tropicalis has been increasingly implicated as an important pathogen in neutropenic children. Flynn et al. [107] reported 19 children treated for leukemia in whom C. tropicalis infections developed. Fungemia without meningitis in 11 children was treated successfully, whereas meningitis in 7 children was uniformly fatal, underscoring that meningitis is a critical factor for outcome of this infection. Chronic disseminated candidiasis typically presents with fever despite granulocyte recovery, often coupled with right upper quadrant abdominal pain, and increased alkaline phosphatase levels [108, 109]. Imaging studies demonstrate multiple lesions in liver, spleen, and other organs that correspond morphologically to large granulomas with extensive chronic inflammatory reaction [110]. Treatment is protracted [28], but may not necessarily require the interruption of anticancer therapy, provided that the disseminated infection has stabilized or is resolving [111].

Invasive aspergillosis has emerged as important cause for morbidity and mortality in children with hematological malignancies or undergoing bone marrow transplantation; more recent pediatric series indicate a frequency of 4.5-10% in this setting with an associated crude mortality of 40-94% [88, 94, 102, 112-114]. The disease is rather rare in children treated for solid tumors, underscoring the role of prolonged neutropenia and corticosteroid therapy in its pathogenesis [94, 112]. Similar to the adult setting, the lungs are the most frequently affected site, and disseminated disease is found in approximately 30% of cases [113]. While paranasal sinus aspergillosis appears to be less common than in adults [112, 115, 116], primary cutaneous aspergillosis has been preferentially reported in the pediatric setting in association with lacerations by armboards, tape, and electrodes and at the insertion site of peripheral or central venous catheters [115, 117-120]. With combined surgical and medical therapy, primary cutaneous aspergil-losis has a comparatively more favorable prognosis [115]. The outcome of invasive aspergillosis children with hematological malignancies may not be as dismal as in adults [88, 112]. In a recent small series, all patients who were treated with amphotericin B for a minimum of 10 days responded to medical or combined medical and surgical therapy, and 64% were cured [112]. Nevertheless, the overall long-term survival was merely 31% after a median follow-up of 5.6 years. Apart from recurrent or refractory cancer, in that study, the main obstacles to a successful outcome were failure to diagnose the invasive aspergillosis during lifetime and, in patients with established diagnosis, catastrophic pulmonary or cerebral hemorrhage.

Similar to histoplasmosis [121, 122], cryptococcal meningoencephalitis or pneumonitis are rare opportunistic infections in children with cancer [19]. In patients with pediatric sarcomas, however, pulmonary cryptococcosis may be a differential diagnosis of lung metastasis [123] and case reports such as that from a child with acute leukemia in remission that died suddenly from unrecognized disseminated cryptococcosis may serve as a reminder of the risk for this potentially life-threatening infection [124].

During the last decade, previously uncommon fungal pathogens have been increasingly recognized to cause systemic infection in neutropenic patients [101, 125] (Fig. 1). Particularly notable among the yeast-like organisms is Trichosporon beigelii, a normal human commensal and the agent of White Piedra. Trichosporonosis in neutropenic patients presents in a similar way as systemic candidiasis with fungemia and disseminated infection and carries a high mortality [126, 127]. Tr. beigelii is often resistant to the fungi-cidal effects of amphotericin B, but may be amenable to antifungal azoles [128-131]. Among the filamentous fungi, the zygomycetes are notorious for their propensity to invade blood vessels, a rapidly deteriorating clinical course, and clinical refractoriness to antifungal therapy; the most common clinical presentations in the neutropenic host are rhinocerebral, pulmonary, cutaneous, and disseminated infection therapy [132, 133]. Fusarium has emerged in some institutions as the second most common filamentous pathogen after Aspergillus [134, 135]. Like the latter, the airborne organism is highly angioinvasive and leads to hemorrhagic infarction. Fusarium is among the few filamentous fungi that cause detectable fungemia and metastatic skin lesions are a hallmark of disseminated fusariosis. A clinical stabilization can sometimes be achieved with high-dose amphotericin B or voriconazole, but rapid recovery from neutropenia is always a prerequisite for survival [101, 134, 136].

HIV infection

Children are recognized as one of the most rapidly expanding populations worldwide infected with human immunodeficiency virus (HIV); mucosal as well as invasive fungal infections are major causes of morbidity and mortality in advanced stages of the disease [137].

OPC is the most prevalent opportunistic infection in HIV-infected children and, prior to the advent of highly active antiretroviral treatments (HAART), occurred in virtually all patients at some time during the course of their disease. Esophageal candidiasis in the era prior to HAART occurred in approximately 10% of patients and was associated with recurrent OPC, low CD4+ counts, and use of broad-spectrum antibiotics [138]; it may still be observed in the subgroup of patients not responding to HAART and presents without concomitant OPC or typical clinical symptoms [139]. In the absence of significant immunological reconstitution, oropharyngeal and esophageal candidiasis have an exceedingly high propensity to recur. The chronic use of fluconazole under these circumstances has been associated with the emergence of fluconazole-resistant Candida strains [140]; it has been shown that such resistant strains can be exchanged among HIV-infected family members [141].

Children with HIV infection may develop candidemia or disseminated candidiasis as a nosocomial infection during prolonged hospitalization for complicated medical problems [142]. However, with increased use of outpatient treatments, candidemia may present as a community-acquired infection that is associated with ambulatory total parenteral nutrition and IV therapy via indwelling central venous lines [143]. Univariate and multiple logistic regression reveal that the prolonged presence of a central venous catheter is the most important risk factor for fungemia in this setting [144]. Non-albicans spp. account for almost 50% of all isolates. A high rate of survival (95%) from fungemia without post-therapeutic sequelae has been obtained by early detection, appropriate antifungal chemotherapy, and removal of the vascular catheter [143].

HIV-related impairment of phagocytosis by mono- and polymorpho-nuclear leukocytes [145, 146] makes a major contribution to the increased susceptibility of patients with advanced HIV infection to invasive aspergil-losis [147-149]. Invasive aspergillosis has also been reported in HIV-infect-ed children [150-152]. Invasive aspergillosis was diagnosed in 7 (1.5%) of 473 HIV-infected children followed at the Pediatric Branch of the National Cancer Institute from 1987 to 1997 [152]. Invasive pulmonary aspergillosis occurred in 5, and aspergillosis of the skin and adjacent soft tissues in 2 patients. All patients had low CD4+ counts (median, 2 /^L; range, 0-338). Neutropenia (< 500/^L) lasting for longer than 7 days or corticosteroid therapy were encountered in only two patients. Consistent with the experience in other immunocompromised children [115], patients with cutaneous aspergillosis were diagnosed during life and successfully treated, whereas diagnosis of pulmonary aspergillosis was made antemortem in only one patient [152].

Compared to adults, HIV-infected children have lower rates of crypto-coccal infections, and, with the exception of disseminated penicilliosis [153], data on histoplasmosis and other endemic mycoses are very limited [137]. With an estimated 10-year point prevalence of 1% [154], cryptococcosis appears to be an infrequent opportunistic infection in HIV-infected children. It is associated with low CD4+ counts, and, in the majority of cases, a previous AIDS defining illness and older age; the clinical presentation may be subtle to fulminant, and may include unexplained fever and mostly diffuse central nervous and/or respiratory symptoms [155]. A review of 30 of an approximate total of 50 published cases indicated a crude mortality of 23% within the first month after diagnosis [154].

Children with severe acute illnesses

Invasive procedures, indwelling vascular and urinary catheters, use of broad-spectrum antibiotics and corticosteroids, mechanical ventilation and parenteral feeding as well as length of stay and severity of the underlying condition, all contribute to a heightened risk of deeply invasive Candida infections in critically ill patients requiring intensive care [156]. While few data are available for general pediatric intensive care units, recent studies in adults have confirmed the high frequency of nosocomial Candida infections in this setting [156-160]. Candida spp. are among the five most common causes of bloodstream infections in intensive care units (ICUs) [158, 159, 161] and account for up to 17% of microbiologically documented infections [158]. Mirroring the general epidemiological trend, more than half of such infections are now due to non-albicans Candida spp. [159, 162]. In a recent investigation of the distribution and susceptibility of 179 clinical isolates of Candida spp. from four children's hospitals, C. parapsilosis isolates were identified in 32%; nearly 20% were resistant to amphotericin B [163].

Zygomycosis may develop in the settings of neutropenia, corticosteroid therapy, bone marrow or solid organ transplantation, burn, and deferoxamine therapy for iron and aluminum overload states. Similar to adults [164], zygomycosis in children occurs in other distinct settings as well: Juvenile onset (type I) diabetes mellitus, particularly with uncontrolled diabetic keto-acidosis, and congenital aminoaciduria [28]. For example, among 41 reported cases of rhinocerebral zygomycosis in children beyond the neonatal age,

20 (49%) had diabetes mellitus [133]. Rhinocerebral zygomycosis usually begins as an infection of the paranasal sinuses, which progresses to invade the orbit, retroorbital region, cavernous sinus and brain. Thus, signs and symptoms of sinusitis along with ocular findings in a diabetic patient should prompt a careful evaluation for rhinocerebral zygomycosis [28, 165].

Children with chronic pulmonary diseases

Mycoses may also occur in children and adolescents with chronic sinopul-monary infection and lung destruction, as it may be associated with congenital B cell defects, the hyper-IgE syndrome, and, most commonly, cystic fibrosis. Non-invasive fungal diseases associated with the colonization of the respiratory tract by Aspergillus spp. and other moulds such as allergic bronchopulmonary aspergillosis and aspergilloma formation clearly predominate in this setting [166]. However, invasive pulmonary mould infections have been reported [79, 167, 168], and also, fungemias associated with the presence of indwelling vascular catheters [169].

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