Published online July 24, 2006
PEDIATRICS Vol. 118 No. 2 August 2006, pp. e509-e513 (doi:10.1542/peds.2005-2901)

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EXPERIENCE AND REASON

Invasive Pulmonary and Central Nervous System Aspergillosis After Near-Drowning of a Child: Case Report and Review of the Literature

Piet Leroy, MD^a, Annick Smismans, MD, PhD^b and Tatjana Seute, MD^c

^a Divisions of Pediatric Intensive Care
^b Medical Microbiology
^c Pediatric Neurology, University Hospital Maastricht, Maastricht, Netherlands

	ABSTRACT

TOP ABSTRACT CASE REPORT DISCUSSION CONCLUSIONS REFERENCES

 
Invasive aspergillosis is extremely rare in immunocompetent children. Here we describe the clinical, radiologic, and laboratory course of fatal invasive pulmonary and central nervous system aspergillosis in a previously healthy child after a near-drowning incident with submersion in a pond. Findings were compared with data from the literature, which is reviewed. Serum Aspergillus galactomannan levels were determined retrospectively and were compared with the results of routine microbiological and radiologic examinations, showing a significant diagnostic and therapeutic delay of the routine diagnostic approach in comparison with the use of the Aspergillus galactomannan assay. This delay may have contributed to the fatal course. Serial determination of serum Aspergillus galactomannan may be helpful in diagnosing invasive aspergillosis early in case of pulmonary disease after near-drowning and may contribute to an early appropriate treatment. Currently voriconazole, eventually in combination with caspofungin, should be considered as the drug of choice in the management of invasive aspergillosis after near-drowning.

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Key Words: near-drowning • invasive aspergillosis • central nervous system • galactomannan • children

Abbreviations: CNS, central nervous system • IA, invasive aspergillosis • IV, intravenous • OD, optical density • HRCT, high-resolution computed tomography

Invasive pulmonary aspergillosis and central nervous system (CNS) aspergillosis are extremely rare in immunocompetent children.¹ Invasive infections by fungi have been described in immunocompetent hosts after submersion and near-drowning, probably predisposed by the large inoculum of aspirated organisms and/or the acute lung injury sustained from the immersion event.² Fungi known to be causes of invasive disease after near-drowning are Pseudallescheria boydii (or its asexual form Scedosporium apiospermum) and, to a much lesser degree, Aspergillus species. CNS aspergillosis after near-drowning has been reported in only 2 adult cases to date.^3,4

Here we describe the clinical, microbiological, and radiologic course of fatal invasive pulmonary and CNS aspergillosis in a previously healthy 10-month-old girl after a near-drowning incident with submersion in a pond. Recently, a serum marker for invasive aspergillosis (IA) based on the release of the fungus' cell-wall component galactomannan became available. The galactomannan levels were determined retrospectively and compared with the results of routine microbiological and radiologic examinations.

	CASE REPORT

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On a summer day, after a 10-day period of warm and humid weather (mean temperature: 20–25°C; relative humidity: >75%), a previously healthy 10-month-old girl escaped her parents' notice and was found 5 minutes later lying face down in a pond. Basic life support was started by the parents. On arrival of the emergency medical team, there was respiratory arrest, but cardiac output was present. She was resuscitated and intubated successfully within 30 minutes and transferred to the PICU. On arrival, her rectal temperature was 34°C, Glasgow coma score was 4 (E1, M2, Vtube), transcutaneous O₂ saturation was 85% (despite high ventilator settings and fraction of inspired oxygen at 100%), heart rate was high, and blood pressure was normal. Blood analysis showed moderate metabolic acidosis (pH 7.24; partial pressure of carbon dioxide: 42 mmHg; base excess: –9.6 mmol/L), a normal lactate level (1.2 mmol/L), and moderate neutropenia (0.5 x 10⁹/L), which normalized within 24 hours. The chest radiograph showed bilateral infiltrates compatible with fresh-water aspiration. Cultures from blood and endotracheal aspirate were taken, and, because of high fever, intravenous (IV) antibiotic treatment (amoxicillin/clavulanate, 100/10 mg/kg per day) was started.

Because of impaired oxygenation, conventional ventilation was replaced by high-frequency oscillatory ventilation. Despite extreme high-frequency oscillatory ventilation settings, the patient developed profound respiratory acidosis (partial pressure of carbon dioxide: >100 mmHg) on day 2. A chest radiograph showed hyperinflation and bilateral infiltrates (Fig 1 A). Although we assumed that this condition was caused by aspirated debris obstructing small airways, we could not rule out an asthma-like condition triggered by aspiration. Therefore, IV salbutamol and prednisone (2 mg/kg per day for 3 days followed by 1 mg/kg per day for 3 days) were started. On day 3, IV antibiotic treatment was changed to piperacillin/tazobactam (200/25 mg/kg per day) and gentamicin (7 mg/kg per day) on the basis of the susceptibility results of the Streptococcus pneumoniae and Aeromonas sobria recovered from endotracheal aspirate on day 1. From day 4, her respiratory condition improved, body temperature returned to normal, and, after an initial increase up to 230 mg/L, C-reactive protein levels declined to 40 mg/L on day 6.

View larger version (158K): [in this window] [in a new window]   FIGURE 1 A, Chest radiograph on days 2, 6, 9, and 12. B, HRCT of the chest on day 14. C, Computed tomography of the brain on day 14. D, MRI of the brain on day 14 (T1-weighed + gadolinium).

 
Because of the extreme ventilatory settings, the patient was initially sedated and paralyzed, which limited neurologic examination. The unstable condition did not allow transport for neuroimaging. Electroencephalography on days 2 and 4 revealed general slowing without epileptiform abnormalities. On day 6, the patient opened her eyes, localized pain bilaterally, and had intact brainstem reflexes.

From day 7 her pulmonary condition worsened, fever returned, and C-reactive protein level increased (>150 mg/L). Between days 3 and 6, insufficient respiratory material was available for culture. Cultures recovered from endotracheal aspirate on day 6 became positive on day 8, yielding Stenotrophomonas maltophilia (piperacillin sensitive) and sporadic Aspergillus fumigatus. Both were considered at to be colonization. However, because of further pulmonary deterioration, the appearance of bilateral nodular infiltrates on chest radiograph (Fig 1 A), and data from literature that P boydii and Aspergillus species had to be considered as causes of pneumonia after near-drowning, IV itraconazole (10 mg/kg per day for 2 days followed by 5 mg/kg per day) was started on day 9.

From day 12 the girl developed epilepsy and a rapidly progressive spastic tetraparesis. On day 14, a computed tomography of her brain and lungs showed extensive destructive lesions in the lungs and multiple hypodense lesions in the brain (Fig 1 B and C). There was no sinus involvement. MRI of the brain showed multiple hypodense lesions that were enhanced after IV gadolinium (Fig 1 D). Abdominal ultrasonography did not show abnormalities, but on echocardiography an echogenic mass was seen in the interatrial septum. An open brain biopsy was performed, and microscopy showed dichotomously branching septate hyphae. Culture recovered from cerebral pus yielded A fumigatus. The patient died on day 16 as a result of therapy-resistant respiratory failure. Autopsy was refused by the parents.

Serum samples from days 2, 5, 7, and 9 were available for postmortem retrospective determination of Aspergillus galactomannan using a direct double-sandwich enzyme-linked immunosorbent assay (Platelia Aspergillus; Bio-Rad, Marnes La Coquette, France) according to manufacturer instructions. Galactomannan levels were quantified and expressed as index values by dividing the optical density (OD) of the patient sample by the OD of a standardized serum of 1 ng/mL supplied with the kit. On day 2 the galactomannan exceeded the cutoff value of the assay established by the manufacturer (OD index: 1.5) and that determined in neutropenic patients (OD index: 0.7) by 5- and 11-fold, respectively. During the next 3, 5, and 7 days, the high galactomannan levels were maintained, with index values of 10.2, 7.5, and 10.2, respectively.

	DISCUSSION

TOP ABSTRACT CASE REPORT DISCUSSION CONCLUSIONS REFERENCES

 
We have described IA with a rapidly progressive and fatal pulmonary and CNS course in an apparently previously healthy child after a near-drowning incident. Poor outcome after near-drowning in children has been associated with asystole, immersion time >15 minutes, absence of bystander cardiopulmonary resuscitation, resuscitation time >30 minutes, the administration of epinephrine, profound metabolic acidosis, and a low core body temperature.^5,6 In the absence of these risk factors, the a priori prognosis for this child was possibly not poor.

IA is a severe disease with a high mortality risk. CNS involvement, delay of diagnosis, and persistence of low cell-mediated immunity have all been associated with mortality rates of >85%.^4,7,8 IA is very rare in immunocompetent hosts but has been reported in previously healthy individuals after near-drowning. Using the terms "aspergillosis" and "near-drowning," a PubMed (US National Library of Medicine, Bethesda, MD) search yielded 5 articles, published between 1984 and 2004. The 5 reported cases were in adults; CNS aspergillosis was reported in 2 of them.^3,4 Comparing the main features of these 2 cases with our case shows remarkable similarities in climatic conditions (warm climate or season), submersion incident (stagnant natural water), presence of aspirating pneumonia, Aspergillus species, presence of invasive pulmonary aspergillosis, radiologic findings, delay of diagnosis, and antifungal treatment and outcome (Table 1).

View this table: [in this window] [in a new window]   TABLE 1 Characteristics of Patients With CNS Aspergillosis Reported After Near-Drowning

 
At least 6 pediatric cases of brain infections caused by P boydii (or its asexual form S apiospermum) after near-drowning have been reported, of which 2 survived.

Several factors could have been responsible for the severe and fatal course in this particular case. The relatively high ambient temperature during the days preceding this accident may have contributed to a higher concentration of Aspergillus in the aspirated pond water, leading to a large inoculum. The injury sustained by the lungs in the immersion event may have made them more susceptible to microbial proliferation and invasion. Hypoxic damage to the blood-brain barrier may have enhanced brain invasion by Aspergillus. The transient moderate neutropenia (minimum: 0.5 x 10⁹/L on day 1) and the short-term therapy with corticosteroids may have made our patient more vulnerable to IA. Finally, the diagnosis was delayed, as demonstrated by the significant time period by which the high serum titer of Aspergillus galactomannan on day 2 preceded the first positive culture (recovered from sputum on day 6, with a positive result on day 8), the clinical deterioration after the initial recovery (day 7), and the first indications for IA on a chest radiograph (day 9).

Because delay of treatment has been associated with worse outcome, early diagnosis is highly relevant. At present, high-resolution computed tomography (HRCT) and serial screening for galactomannan are commonly used in high-risk patients suspected of having IA. On chest HRCT, cavitation and, especially, air crescent formation (the so called "halo sign") occur early in the course of IA in adults.⁹ Galactomannan is an exoantigen released by all pathogenic Aspergillus species during growth. A prospective study in adult allogenic stem cell transplant recipients demonstrated that positive galactomannan titers preceded fever by 3.5 days, positive chest HRCT by 6 days, positive chest radiograph by 8 days, positive cultures by 9 days, and a definitive diagnosis of IA by 14 days (all values are medians).¹⁰ However, both diagnostic tools have important limits, especially early in the course of disease and in children. The HRCT findings are strongly suggestive but not pathognomonic for aspergillosis.¹⁰ In addition, they are seen less frequently in young children with IA.¹ In comparison to adults, galactomannan assays in children show a lower specificity and a significant higher rate of false-positive results. Cross reactivity with intestinal Bifidobacterium bifidum and the presence of galactomannan and mannan in infant formula have both been suggested as explanations.^11,12 Our patient was still partially fed with infant formula at home but received lactose-free drip feed from day 2. Furthermore, antibiotics such as amoxicillin/clavulanate and piperacillin/tazobactam can cause false-positive reactivity if therapeutic serum levels of the drug are achieved.^13,14 Therefore, it is advisable to collect serum samples for galactomannan determination before the administration of these antibiotics. The serum samples available for retrospective galactomannan determination had all been taken immediately before administration of amoxicillin/clavulanate (day 2) or piperacillin/tazobactam (days 5, 7, and 9), making false-positive galactomannan results caused by these antibiotics unlikely. Besides the generation of false-positive results, false-negative Aspergillus antigenemia can be provoked by antifungal drug therapy or encapsulation of the infection.

In this case, the first Aspergillus-positive culture recovered from endotracheal aspirate was initially considered as saprophytic colonization. In adult ICU patients, colonization is the most probable explanation for 1 in 3 of the cases in which Aspergillus is recovered from the respiratory tract.¹⁵ On the other hand, it has been demonstrated that in nonneutropenic ICU patients with certain risk factors (ie, chronic lung disease and/or treatment with corticosteroids), antifungal treatment should be considered in the presence of clinical features of pneumonia and isolation of Aspergillus species from respiratory secretions.^15,16

All antifungal drugs, with the exception of voriconazole, penetrate poorly into the CNS tissue. At the time of this accident, voriconazole was not yet available in our hospital. Itraconazole, which is approved for IA, was chosen for its broad antifungal spectrum (including P boydii). Successful treatment of CNS aspergillosis with itraconazole has been reported.^17,18 Recent literature suggests the superiority of voriconazole in adults with CNS aspergillosis¹⁹: a survival rate of 31% has been reported in adult patients with CNS aspergillosis treated with voriconazole,²⁰ and a 50% complete or partial response rate of voriconazole in 6 immunocompromised children with CNS aspergillosis has been reported.²¹ In addition, the drug is also effective against P boydii (and its asexual form S apiospermum), another and more frequently reported fungus associated with invasive pulmonary and CNS disease after near-drowning.

In a murine model of CNS aspergillosis, treatment with a combination of suboptimal doses of liposomal amphotericin B and voriconazole was more efficient than either monotherapy.²² Caspofungin, a new antifungal agent, was recently approved in the United States and Europe for treatment of IA in adult patients who are refractory or intolerant for conventional treatment.²³ A retrospective study revealed an improved 3-month survival rate in patients with IA with combination therapy of caspofungin and voriconazole as compared with voriconazole alone.²⁴ Because caspofungin exerts in vitro activity against P boydii (and its asexual form S apiospermum), whereas amphotericin B has no activity against this fungus, combination treatment with voriconazole and caspofungin might be considered in patients after near-drowning with a rapidly deteriorating course.²⁵

	CONCLUSIONS

TOP ABSTRACT CASE REPORT DISCUSSION CONCLUSIONS REFERENCES

 
This is the first report of invasive pulmonary and CNS aspergillosis in a child after near-drowning. In the presence of pulmonary disease, the detection of fungi in the sputum of patients after near-drowning should prompt additional diagnostic efforts and early empirical antifungal therapy. Nevertheless, this case report suggests that waiting for positive results of routine microbiological analyses bears the risk of a fatal delay. We believe that serial determination of serum Aspergillus galactomannan may contribute to diagnosing IA early in case of pulmonary disease after near-drowning and, by this, to avoiding a delay of appropriate treatment. In case galactomannan is not available, heightened surveillance with endotracheal cultures, HRCT scan, and lung biopsy must be considered early in the management of patients with pulmonary involvement after near-drowning. Voriconazole, eventually in combination with caspofungin, should currently be considered the drug of choice in the management of invasive mycosis after near-drowning.

	ACKNOWLEDGMENTS

 
We thank the Nijmegen Mycology Research Center (Department of Medical Microbiology, University Medical Center, Nijmegen, Netherlands) for help in the determination of the serum Aspergillus galactomannan.

	FOOTNOTES

 
Accepted Feb 28, 2006.

Address correspondence to Piet Leroy, MD, Division of Pediatric Intensive Care, Department of Pediatrics, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, Netherlands. E-mail: pler{at}paed.azm.nl

The authors have indicated they have no financial relationships relevant to this article to disclose.

	REFERENCES

TOP ABSTRACT CASE REPORT DISCUSSION CONCLUSIONS REFERENCES

 

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