1 - Immunocompromised
Host Section, Pediatric Oncology Branch, National Cancer
Institute, Bethesda, MD, USA and
2 - Division of
Neonatology, Department of Pediatrics, Johann Wolfgang Goethe
University Hospital, Frankfurt am Main, Germany
Address for correspondence:
Andreas H. Groll, M.D.
Senior Staff Fellow
Immunocompromised Host Section
Pediatric Oncology Branch
National Cancer Institute
Building 10, Room 13N240
10 Center Drive
Bethesda, MD 20892
Phone: (301) 435-3355
Fax: (301) 402-0575
E-mail:
grolla@mail.nih.gov
As of the end of 1998, 49 cases of proven (cultural and histological evidence) or probable (histological or cultural evidence) invasive aspergillosis have been reported in neonates and infants </= three months of age [Groll et al., 1998; Meessen et al., 1998; Singer et al., 1998]. Most patients had primary cutaneous aspergillosis (n=16), invasive pulmonary aspergillosis (n=10), or disseminated aspergillosis (n=14). Prematurity, chronic granulomatous disease, and a complex of diarrhoea, dehydration, malnutrition and invasive bacterial infections accounted for the majority of underlying conditions. Routes of infection, clinical symptoms, fungal isolates and patterns of disease were similar to those observed in pediatric [Walmsley et al., 1993] and adult [Bodey & Vartivarian, 1989; Denning, 1996] populations. Only one of the reported infants had been neutropenic prior to diagnosis, but at least half had been given corticosteroids in pharmacological doses prior to diagnosis. Almost all cases of primary cutaneous aspergillosis occurred in extremely premature neonates; pulmonary and disseminated infection mainly occurred in term neonates. The disease was uniformly fatal in untreated patients. In contrast, outcome was relatively favorable in patients receiving appropriate systemic antifungal and/or surgical therapy [Groll et al., 1998; Singer et al., 1998].
Prolonged and profound neutropenia and administration of high doses of corticosteroids are the predominant clinical risk factors for development of invasive aspergillosis [Bodey & Vartivarian, 1989; Denning, 1996]. While neutropenia was reported in only one single patient, functional impairment of phagocytosis through either prematurity, a diagnosis of chronic granulomatous disease, or therapy with corticosteroids was present in more than 80 % of the reported cases [Groll et al., 1998; Meessen et al., 1998; Singer et al., 1998].
It is well known that mono- and polymorphonuclear phagocytes of term- and in particular preterm neonates have diminished chemotactic, phagocytic and microbicidal activity, especially under conditions of severe illness and stress [Lewis & Wilson, 1995]. In comparison to this somewhat increased general susceptibility to invasive bacterial and fungal infections, chronic granulomatous disease (CGD) of childhood, a congenital disorder causing inability of phagocytic cells to provide antimicrobial oxidants and intracellular killing [Quie, 1993], is associated with a cumulative lifetime incidence of invasive aspergillosis of 16 to 40 % [Cohen et al., 1981; Mouy et al., 1989]. That corticosteroids are an important risk factor for invasive fungal infections in the neonatal setting has been demonstrated for preterm infants with invasive forms of candidiasis [Botas et al., 1995; Rowen et al., 1995]. Indeed, neonatal mononuclear phagocytes may have an increased sensitivity to the effects of corticosteroids [Lortie et al., 1990; Kavelaars et al. 1995]. In addition, pharmacokinetic aspects such as a comparatively lower systemic clearance of dexamethasone [Jusko & Ludwig, 1992; Charles et al., 1993], low serum albumin and liver function abnormalities (both commonly encountered in neonatal intensive care) can all lead to an increased systemic exposure to the drug [Jusko & Ludwig, 1992].
Preceding local trauma appears to be a prerequisite for primary cutaneous aspergillosis [Walsh, 1998]. Immature barrier functions of the skin, reduced thickness of the epidermis and maceration by tape, armboards, cutaneous sensors, and other devices may be responsible for most cases of primary cutaneous aspergillosis in very immature neonates of < or = three weeks of postgestational age [Rowen et al., 1995; Meesen et al., 1998; Singer et al., 1998].
[Granstein et al., 1980; Roth et al., 1991; Rowen et al., 1992; Lackner et al., 1992; Perzigian et al., 1993; van den Anker et al., 1993; Walsmley et al., 1993; Rowen et al., 1995; Papouli et al., 1995; Gupta et al., 1996; Meessen et al., 1998; Singer et al., 1998]. Primary cutaneous aspergillosis (PCA) is a disease of very immature preterm infants and tends to occur early during the postpartum period: Fifteen of the 16 reported patients were premature neonates with a mean birth weight of 793 g (range, 440 to 1500g), and the age at the time of diagnosis ranged from three to 30 days (mean, 11.3 days). Prior exposure to corticosteroids was documented in eight cases. None of the patients were neutropenic (absolute neutrophil count < or = 500/µL) or had a documented immunodeficiency disorder [Groll et al., 1998; Meessen et al., 1998; Singer et al., 1998].
In all but two cases, PCA was diagnosed during lifetime. The most frequently encountered species was A.fumigatus (n=10), followed by A.flavus (n=4), A.niger and Aspergillus spp. (n=1 case each). The clinical presentations included single or multiple plaques, papules, pustular lesions, small abscesses, focal and spreading skin necroses, and crusting ulcerations. In four cases, skin lesions were located on the infant's back, and thus probably related to prolonged positioning as part of the minimal handling approach to the care of these highly vulnerable infants [Groll et al., 1998]. In a series of four extremely immature male neonates, skin lesions started from the penis and the perigenital area, and were ultimately due to the utilisation of contaminated fingerstalls for collection of urine specimens [Singer et al., 1998]. Other documented sites of entry included skin defects due to adhesive tape (n=2), an oxymeter sensor, or a contaminated tongue depressor used for fixation of intravenous catheters [Groll et al., 1998; Meessen et al., 1998; Singer et al., 1998].
In two cases, no information was available regarding treatment and ultimate outcome. One patient underwent complete excision of the lesion and died later from unrelated complications with no evidence for aspergillosis at autopsy. Eight patients received systemic antifungal treatment with intravenous amphotericin B with or without 5-flucytosine and one patient was treated with systemic antifungals and surgical incision of the lesion. Seven of these patients were cured and eventually survived. Among the remaining two patients, one had Aspergillus-endophthalmitis diagnosed three weeks after apparently successful completion of a four-weeks-course of amphotericin B (AmB), and the other died with PCA from unrelated causes without evidence for dissemination at postmortem. One patient, who was treated with 5-flucytosine alone, died early after initiation of antifungal therapy from multiorgan failure and had disseminated aspergillosis at autopsy. In two patients, the diagnosis of PCA was established only at autopsy and both had disseminated disease at postmortem examination [Groll et al., 1998; Meessen et al., 1998; Singer et al., 1998].
[Brass, 1975; Burger et al., 1978; Krasinski et al., 1985; Mouy et al., 1985; Schoumacher et al., 1987; Gonzalez et al., 1994; Mouy et al., 1995; Groll et al., 1998]. In contrast to PCA, eight of the ten reported neonates and infants with invasive pulmonary aspergillosis (IPA) were delivered at term. Five had documented, and one probable CGD, and two patients had diarrhoea, dehydration and invasive bacterial infections as their underlying condition. The mean age at diagnosis was 31 days (range, 01 to 57 days). At least half of the patients had community-acquired disease. The mean duration of prior hospitalisation in the cases considered as hospital acquired was 19 days (range, 01 to 45 days). Prior exposure to corticosteroids was reported in three cases. None of the patients had been neutropenic; instead, four presented with marked leukocytosis [Groll et al., 1998].
Similar to other settings, A.fumigatus accounted for the majority of cultured isolates. The clinical presentation of IPA consisted of lower respiratory tract symptoms and/or new pulmonary infiltrates on chest x-ray. Of note, fever was an inconsistent feature. At least one patient had cardiovascular instability, and one patient presented with massive diffuse pulmonary hemorrhage. In retrospect, the presumable portal of entry was the respiratory tract in all cases. Construction work at or nearby the hospital was reported in two circumstances [Groll et al., 1998].
In four of the reported cases, IPA was diagnosed only at autopsy, and no antifungal treatment was given. In three of those cases, IPA was an incidental finding and had no relationship to the cause of death. The fourth patient died from suffocation by pulmonary mass bleeding in the presence of overwhelming necrotising Aspergillus infection of the lung. Six of the ten patients received medical treatment alone; one of these patients died after eight days of AmB therapy with bilateral Aspergillus pneumonia and cerebral venous thrombosis without evidence for fungal involvement. The remaining five patients, representing the cases with proven CGD, responded to prolonged medical treatment, and at least four of them were cured and survived [Groll et al., 1998].
[Wittig et al. 1973; Rhine et al. 1986; Green et al. 1991; Rowen et al. 1992]. Four cases of isolated Aspergillus infection of the central nervous system (CNS) in the first three months of life are reported. In all cases, the most likely portal of entry was the lung. Underlying conditions were prematurity, immunosuppression after liver transplantation, cyanotic heart disease with cardiac surgery and infectious complications, and staphylococcal pneumonia and septicemia. The infection was hospital acquired in three cases, and the mean age at diagnosis was 51 days (range, 27 to 84 days). While none of the patients had been neutropenic, all had received corticosteroids and in one case, additional cyclosporin A and anti-OKT3 antibodies [Groll et al., 1998].
Instability, fever, seizures, culture-negative but unspecifically abnormal cerebro spinal fluid (CSF) findings and ring enhancing lesions on imaging studies were the presenting symptoms. In three of the four patients, diagnosis was established by needle aspiration; A.fumigatus was cultured in two and A.flavus in one case. With prolonged systemic, intralesional and/or intraventricular antifungal treatment and surgical drainage or excision, all three patients were ultimately cured and survived, despite considerable neurologic sequelae. In the remaining patient [Wittig et al., 1973], who had widespread invasive staphylococcal infection and possibly CGD as an underlying disorder, diffuse Aspergillus- meningoencephalitis was an incidental autopsy finding [Groll et al., 1998].
[Steiner et al., 1979; Bruyere et al., 1983; Rowen et al., 1992]. Two of the three reported cases of gastrointestinal aspergillosis occurred in preterm neonates. In the third paediatric case, although not formally diagnosed, a congenital T-cellular immunodeficiency disorder was the most likely retrospective diagnosis.
The exclusive clinical presentation was intestinal perforation, and the presumed portal of entry was the gastrointestinal tract. In one patient, the small bowel was affected, and in another, the stomach. One additional patient [Bruyere et al., 1983] with necrotising enterocolitis had Aspergillus niger cultured from a stool sample and the peritoneal cavity, but no histologic evidence was provided. All cases were hospital acquired and diagnosed during lifetime at a mean age of 14 days (range, 4 to 32 days). One patient had been exposed to corticosteroids.
While the patient with gastric perforation did not survive diagnostic surgery, the second patient was cured and survived after resection of necrotic intestinal tissue and prolonged treatment with AmB. The third patient died from unrelated causes after resection of necrotic bowel and topical antifungal treatment only; autopsy revealed no evidence for invasive aspergillosis [Groll et al., 1998].
Sihota et al. (Sihota et al., 1987) reported a case of biopsy proven bilateral Aspergillus - endophthalmitis in an otherwise healthy boy of 30 days. He was reportedly cured and survived after intravenous AmB treatment and enucleation of the left eye. Rhaghavan et al., (Rhaghavan et al., 1987), in an autopsy survey, list a case of isolated Aspergillus - myocarditis detected in a child of 42 days who had been hospitalised for diarrhoea and bacterial bloodstream infection.
[Zimmermann, 1955; Akkoyunlu et al., 1957; Allen & Andersen, 1960; Matturi & Fasoli, 1962; Luke et al., 1963; Paradis & Roberts, 1963; Tan et al., 1966; Raaf et al., 1977 and Case Records of MGH, 1976; Mangurten & Fernandez, 1979; Gonzalez-Crussi et al., 1979; Schwartz et al., 1988; Pereira et al., 1989; Rowen et al., 1992]. Interestingly, the majority of cases of disseminated invasive aspergillosis (DIA) were reported before 1980. Similar to IPA, most patients (n=10/14) were born at term. The mean age at diagnosis was 32.5 days (range, 16 to 73 days) [Groll et al., 1998].
Prematurity was the underlying condition in four cases, combined with cytomegaloviral pneumonitis in one case. One patient had confirmed CGD and one newborn had congenital myeloblastic leukemia treated with antineoplastic chemotherapy. Two patients had acute hepatic failure of unclear etiology. The remainder initially presented with diarrhoea and dehydration, failure to thrive, invasive bacterial infections, or a combination thereof. In three of these latter patients, the reported findings are in retrospect highly suspicious for CGD as an underlying illness. In most patients with sufficient information, the disease was acquired in the hospital. However, there were three cases where the infection was clearly community acquired. Exposure to corticosteroids prior to diagnosis was reported in six (43 %) cases. One patient was deeply neutropenic for prolonged periods of time. The mean length of hospitalisation prior to diagnosis was 22.5 days (range, 0 to 51 days). Construction work was not documented in any of the reports [Groll et al., 1998].
In only one patient, the diagnosis of invasive aspergillosis had been entertained during lifetime. The most common clinical symptoms were respiratory and/or central nervous system compromise in eight patients. Two patients initially presented with small bowel obstruction or perforation, and two patients had signs and symptoms of severe hepatitis. Of note, in two instances, Aspergillus spp. was isolated from blood cultures (ten days prior to death; during (unsuccessful) cardiopulmonary resuscitation). Cultures from CSF were negative in all three cases with CNS-involvement [Groll et al., 1998].
All 14 patients with DIA died, and aspergillosis was related to the cause of death in all instances. None of the patients had received any form of medical or surgical treatment. In all cases, invasive aspergillosis was widely disseminated at autopsy, and in most cases, the respiratory tract was the most likely portal of entry. Pulmonary involvement was reported in 85 %, followed by the brain (8/11 patients examined, 73 %), the heart (62 % ), kidneys and bowels (54 % each), liver (46 %), thyroid gland (31 %), spleen (23 %) and various other organs. Infective endocarditis was found in 23 %, as was meningitis. Aspergillus endophthalmitis was described in only one case (8 %). In all patients, the infection was found in at least three anatomically distinct sites. In the cases where Aspergillus had been documented microbiologically, A.fumigatus was the predominant organism (n=5), followed by A.sydowi, A.flavus, and A.niger (one case each) [Groll et al., 1998].
There are no distinct clinical symptoms or specific radiographic signs of neonatal aspergillosis. Similarly, even in widely disseminated disease, blood cultures were only exceptionally positive, and cultures from cerebrospinal fluid were negative in all seven infants with CNS-involvement [Groll et al., 1998]. Nevertheless, invasive aspergillosis should be considered as a differential diagnosis in the presence of all of the following: apparently infected skin lesions, in particular for a very low birth weight infant; infarct-like lung lesions and pulmonary haemoptysis; intestinal infarction or perforation; and with persistent signs of infection despite antibiotic therapy and negative blood cultures, especially when there is a combination of pulmonary and cerebral findings [Schwartz et al., 1988; Rowen et al., 1992; Papouli et al., 1996]. Isolation of Aspergillus spp in these circumstances should be regarded as proof of infection unless otherwise excluded, but any culture positive for Aspergillus must be considered seriously in the neonate. Ultimately, invasive procedures and biopsy evidence may be required to establish the diagnosis or to avoid unnecessary, potentially toxic treatment. If a diagnosis of invasive aspergillosis has been made, dissemination to the lungs (if not primarily involved), CNS and parenchymatous organs should be investigated and a congenital phagocytic disorder, primarily CGD, should be ruled out.
High-dose (1.0-1.5mg/kg/day) amphotericin B deoxycholate (D-AmB; Fungizone) remains the cornerstone of treatment for both suspected and proven invasive aspergillosis. In neonates, the pharmacokinetics of D-AmB are characterised by an extreme interindividual variability and a comparatively lower clearance rate [Starke et al., 1987; Koren et al., 1988; Baley et al., 1990]. However, no correlations between plasma concentrations and pharmacological effects have ever been established, and there is no evidence that these pharmacokinetic characteristics result in any clinical consequences. Indeed, several case series indicate that D-AmB is usually tolerated without nephrotoxicity at daily dosages of up to 1mg/kg/day, even in very low birth weight infants of < or = 1500 g [Faix et al., 1984; Johnson et al., 1984; Starke et al., 1987; Baley et al., 1990; Butler et al., 1992; Leibovitz et al., 1992; Glick et al., 1993; Schloesser et al., 1995; Kingo et al., 1997], and daily dosages of up to 1.5mg/kg have been safely administered [Butler & Baker, 1988]. In view of the dismal prognosis of invasive Aspergillus infections, we recommend a starting dosage of at least 1 mg/kg daily. Due to its potential to cause cardiac arrhythmias, D-AmB should be infused under careful monitoring, in particular in the presence of hyperkalemia and/or renal impairment. [Walsh et al., 1996; Googe & Walterspiel, 1988]. Adequate renal blood flow should be maintained and serum levels of co-administered aminoglycosides, vancomycin and flucytosine should be monitored [Koren et al., 1988; Goren et al., 1988].
Combination of D-AmB with 5-flucytosine is controversial and has not been systematically investigated. However, the combination has been used in cases with successful outcome and may be appropriate, in particular in cases with CNS involvement [Walsh et al., 1996; Denning & Stevens, 1990]. A starting dose of 100mg/kg/day and consecutive adjustment of the dosage to maintain serum levels below 100 µg/mL is recommended [Francis & Walsh, 1992; van den Anker et al., 1995].
Liposomal AmB (L-AmB; AmBisome) has been tolerated at dosages of up to 5mg/kg/d in more than 50 term and preterm infants [Groll et al., 1998; Scarcella et al., 1998; Weitkamp et al., 1998]. Because published data on other lipid-based formulations of AmB is lacking, we consider L-AmB to be the current salvage agent of choice in neonates refractory to or intolerant of D-AmB. Based on animal data [Francis et al., 1994] and data from randomised studies in adults with D-AmB as comparator [Prentice et al., 1997; Walsh et al., 1999], we recommend a starting dose of 5 mg/kg/day for the treatment of neonatal aspergillosis with dosage adjustment only for limiting toxicity.
Itraconazole, while not being a choice for initial treatment due to its variable bioavailability, may be indicated in a stable patient with residual lesions who is able to tolerate oral medication. The drug can be absorbed by preterm neonates and be effective in treating fungal infections [Bhandari & Narang, 1992; van den Anker, 1992; van den Anker et al., 1992]. The recent licensing of intravenous itraconazole offers the opportunity to treat parenterally.
Independent of cumulative dosage and agent, effective antifungal treatment must be administered until the complete resolution of all lesions and reversal of the principal underlying deficiencies in host defenses [Denning 1996; Walsh et al., 1996]. Restoration of host defenses is paramount and includes a) the discontinuation of corticosteroids, if feasible and b) treatment with G-CSF or GM-CSF in patients with diminished neutrophil counts to achieve normal levels of circulating granulocytes. Finally, adjunctive surgical treatment is considered essential in Aspergillus endophthalmitis, endocarditis and peritonitis, and should be strongly entertained in lesions of skin and subcutaneous tissues and in Aspergillus infections of the CNS [Rowen et al., 1992; Denning, 1996].
Infections by Aspergillus spp. can occur in neonates and young infants and cause diseases that are life-threatening, but potentially amenable to treatment. Thoughtful use of corticosteroids, avoidance of skin trauma, meticulous attention to ventilation systems and appropriate measures during renovation and construction work may prevent most cases of neonatal aspergillosis. Importantly, any cultures positive for moulds obtained from a neonate should be considered seriously and prompt empirical treatment should be instituted until infection can be reliably excluded.
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