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Zygomycosis refers to a group of uncommon, but frequently fatal mycoses caused by fungi of the class Zygomycetes. These fungi include human pathogens from the classes Mucorales and Entomophthorales.1 2,3 4,5
In children, zygomycosis may occur in similar settings to those seen in adults. However, zygomycosis also occurs in certain distinct settings in pediatric patients. These include high-risk newborns, juvenile-onset (type 1) diabetes mellitus, particularly with uncontrolled diabetic ketoacidosis, and congenital metabolic aciduria.
To date, there has been no definitive, comprehensive review of zygomycosis in children to guide our understanding of the epidemiology and outcome of this infection. Accordingly, we reviewed the English-language literature for all cases of pediatric zygomycosis. In this review, we sought to understand the epidemiology, risk factors , and outcomes of zygomycosis in children.
METHODS
Literature Search.
We initiated our search by reviewing all references from major book chapters written on the subject of zygomycosis and carefully scrutinized the references for single case reports or case series. We then expanded this initial review by conducting a MEDLINE bibliographic database (US National Library of Medicine, Bethesda, MD) search using the following key words: zygomycosis, mucormycosis, phycomycosis, Rhizopus , Mucor , Rhizomucor , Cunninghamella , Absidia , Apophysomyces , Syncephalastrum , Saksenaea , Cokeromyces , Entomophthora , Conidiobolus , and Basidiobolus. After this initial series of reports was reviewed, the individual references listed in each publication were again reviewed for ascertainment of additional case reports.
Criteria for Inclusion of Cases.
Only those cases which contained the following 7 variables were included in our review:
Age : Cases of patients between 0 and 18 years included.Documentation of infection : The zygomycete infection had to be confirmed either histologically or by culture. Information whether the infection was documented premortem or postmortem also was required.Anatomic location of infection : Documentation of the primary site of infection at time of diagnosis and whether the infection remained localized or disseminated was required. Disseminated infection was defined as 2 or more noncontiguous sites. Those patients with disseminated infection at the time of diagnosis where primary site of infection was impossible to identify were classified as having “generalized disseminated” infection. Patients with cutaneous infection were subcategorized into 3 groups: those patients in which the infection was confined to the cutaneous or subcutaneous tissue were defined as having localized disease; patients with invasion into muscle, tendon, or bone were classified as deep extension; patients with cutaneous disease involving another noncontiguous site were considered disseminated. Patients with pulmonary infection were subcategorized in a similar manner: those with disease confined to the lungs were classified as localized; those with disease that extended to the chest wall, pulmonary artery, aorta, or heart were considered deep extension; those cases, which demonstrated involvement of a noncontiguous site, were classified as disseminated.
In classifying rhinocerebral, we distinguished true cerebral involvement from localized sinus disease. We also separately categorized sino-orbital and sino-pulmonary infections. Thus, patients with sinus involvement were subcategorized as follows:
a. Sinusitis : disease confined to paranasal sinuses.
b. Sino-orbital : disease in the paranasal sinuses and infiltrating the orbit.
c. Rhinocerebral : disease in the paranasal sinuses and the brain. Cerebral involvement was defined as tissue proven invasion demonstrated by histology or culture during life or at autopsy, radiologic evidence of disease by either CT or MRI scan, or severe neurologic impairment.
Database Development.
Filemaker Pro 5.5 software (Santa Clara, CA) was used to develop a database of categoric and continuous variables. The categoric variables included gender, underlying diagnosis, diabetes (type and presence of ketoacidosis), neutropenic status, organism, diagnostic method used for recovery of organism, premortem or postmortem diagnosis, infection site (focal or disseminated disease), surgery, hyperbaric oxygen therapy, immunomodulation, and outcome. The continuous variables included year of diagnosis, year of publication, age of patient, and dose/duration of antifungal therapy. This pediatric database was generated as a prespecified subset of 929 adult and pediatric cases of zygomycosis. An analysis of the total population of 929 patients was previously reported.5
Statistical Analysis.
Univariate analyses were conducted to determine the association between potential risk factors and death. Categoric variables were compared by χ2 analysis or Fisher's exact test; whereas, continuous variables were compared by Wilcoxon rank sum test. Univariate analysis of potential risk factors for mortality was performed. All variables with P < 0.20 on univariate analysis were considered for inclusion in a multivariate model, as were those variables noted to be confounders on stratified analysis. Multivariate analysis was performed using logistic regression methods. Survey estimation was applied to the logistic regression models, to adjust for the modest degree of case clustering among the reporting sites. Clustering was evident from estimates of significant but modest interclass correlation (by site). The analyses used standard algorithms t variance estimates for this correlation.6 P values are somewhat larger than would be estimated by conventional logistic regression methods. A 2-tailed P < 0.05 was considered to be statistically significant. All statistical calculations were performed using standard programs in Stata, version 7.0 (Stata).
RESULTS
We identified 157 cases of zygomycosis in pediatric patients. The earliest case of pediatric zygomycosis analyzed in this study occurred in 1939.7 –120
Demographic and Clinical.
The demographic and clinical characteristics of patients with zygomycosis are presented in Table 1 . The median age was 5 years (interquartile range, 0.16–13) and neonates accounted for 28 (18%) of the cases. Of these, 27 were premature. Neutropenia (absolute neutrophil count ≤500/mm3 ) was as common as prematurity (defined as presence of absence of prematurity listed in the case report) as an underlying condition (18%). Children with Type I diabetes mellitus represented 13% of the cases, and 10% of the cases presented with ketoacidosis. Of note, 22 patients had no identifiable underlying condition and were characterized as normal hosts.
TABLE 1:
Microbiology.
All patients had infection documented by histopathology or culture (Table 2 ). Among 77 patients with an isolate identified to the species level, Rhizopus spp. was most commonly identified, followed by Mucor spp.
TABLE 2:
Site of Infection.
Localized disease was present in 95 (61%) cases and disseminated disease in 50 (32%) cases. The distribution of infection sites is shown in Figure 1 . The most common patterns of zygomycosis were cutaneous (27%), gastrointestinal (21%), rhinocerebral (18%), and pulmonary (16%). Gastrointestinal infection was significantly associated with prematurity (P < 0.03). The percentage of GI cases decreases from 20% to 13% after excluding the neonatal cases. The percentage of patients with cutaneous disease after excluding the neonatal cases was 23%.
FIGURE 1.:
Clinical manifestations of zygomycosis and associated mortality.
Management of Zygomycosis.
The treatments used for children with zygomycosis are shown in Figure 2 . Approximately half of the patients received some form of antifungal therapy. Among the 81 patients who received antifungal therapy, 59 received an amphotericin B preparation only, with 54 patients receiving deoxycholate amphotericin B, 3 receiving lipid amphotericin B formulation, and 2 receiving both deoxycholate amphotericin B and a lipid formulation. Sixteen patients received amphotericin B in combination with one or more of the following: flucytosine, fluconazole, itraconazole, caspofungin, clotrimazole, ketoconazole. Six patients received one of the following agents as monotherapy: potassium iodide, sodium iodide, or ketoconazole. The mortality in patients who were not treated with antifungal therapy was higher than in treated patients (88% versus 36%). There was no association between the year the case occurred and the receipt of antifungal therapy. Ninety-two (59%) patients underwent surgery as part of the treatment of zygomycosis. The mortality in patients who underwent surgery was lower than those who did not. Seventeen patients received other adjunctive therapies, 11 received hyperbaric oxygen, 1 received granulocyte transfusions, and 5 were treated with granulocyte colony stimulating factor.
FIGURE 2.:
Antifungal therapeutic strategies.
Mortality Associated With Zygomycosis.
Cerebral, gastrointestinal, and disseminatedzygomycosis were associated with the highest mortality rates, 100, 100, and 88%, respectively (Fig. 1 ). No patients with localized cutaneous disease died. As shown in Table 3 , multivariate regression analysis revealed that patients with disseminated infection were 7 times more likely to die than patients without disseminated disease (OR: 7.18; 95% CI: 3.02–36.59). A second independent risk factor for death was being an infant less than 1 year of age (OR: 3.85; 95% CI: 1.05–7.43). The receipt of any antifungal therapy reduced the risk of death by 92% (OR: 0.07; 95% CI: 0.04–0.25). Surgery was also independently protective of death (OR: 0.16; 95% CI: 0.09–0.61).
TABLE 3: Risk Factors for Mortality Associated With Zygomycosis
DISCUSSION
This is the first published review of the epidemiology and treatment of zygomycosis in pediatric patients. Unlike other filamentous fungal pathogens that target predominately immunocompromised hosts, Zygomycetes organisms infect a broader and more heterogenous population. We found that, in addition to previously recognized risk factors for zygomycosis such as neutropenia, malignancy, bone marrow transplantation, diabetes mellitus, and ketoacidosis, prematurity was a common comorbid condition in children with zygomycosis. There was also a relatively large (14%) proportion of patients with no apparent immunocompromising condition; however, the assessment of these patients for defects in innate host defense was highly variable.
GI zygomycosis is considered a rare manifestation of zygomycosis; however, in our comprehensive review of pediatric cases, we found that GI disease was seen in 20% of the reported cases of localized disease. This proportion is higher than the proportion of GI disease reported among adults in a recently published adult review (20% of all pediatric patients versus 7% of all patients including adult and pediatric patients). Most of the GI disease developed in premature babies, some occurred in association with progressive necrotizing skin lesions,97 and some of them even mimicking the presentation of necrotizing enterocolitis only without the pathognomonic sign of pneumatosis intestinalis seen on abdominal radiography. Furthermore, a more extensive involvement of the gastrointestinal tract, from esophagus to large bowel was often observed in premature babies with gastrointestinal zygomycosis, whereas only small bowel was involved in the case of necrotizing enterocolitis.79,119 The mortality of GI zygomycosis was high, particularly in premature babies who accounted for 32% of GI cases, perhaps due to the delay in diagnosis and the underlying immunodeficiency of prematurity. In contrast to zygomycosis in other body sites, performance of surgery did not increase the survival among patients with GI zygomycosis. An increased awareness of this disease among neonatologists is clearly needed to facilitate timely diagnosis and management. We suggest that gastrointestinal zygomycosis be listed as one of the differential diagnoses of necrotizing colitis.
Among patients treated with antifungal therapy, amphotericin B was the most commonly used antifungal agent. Disseminated infection and young age (<12 months) were found to be independent risk factors of increased mortality when compared with localized diseases and older age, respectively. This trend may be due to the high incidence of prematurity among pediatric patients, other host differences that make zygomycosis more fatal in these patients, or to other age-dependent differences in difficulties in diagnosis, management, and reporting of zygomycosis in pediatric and adult patients.
Amphotericin B continues to be the mainstay of medical treatment of invasive zygomycosis in childhood. Deoxycholate amphotericin B appears to be well-tolerated in infants <3 months of age, without significant nephrotoxicity.121 122–124
As with any systematic review, the results may be biased if the included cases are a biased sample of cases in general (publication bias). Because small studies tend to display publication bias, some authors have suggested excluding studies below a certain size. One problem with this strategy is that, in some fields like zygomycosis, all or almost all studies are small, so that this strategy would exclude most observations on the topic. Furthermore, we attempted to correct for clustering of cases from a given report or site using survey estimation in our logistic regression models. Reported confidence intervals are therefore somewhat more conservative, and P values are somewhat larger than would be estimated by conventional logistic regression methods.
In conclusion, zygomycosis is a severe and fatal disease in pediatric patients with a variety of underlying diseases. The mortality is high, particularly in premature babies with GI zygomycosis. We hope this report will increase the level of awareness among pediatricians and neonatologists to add zygomycosis to the lists of differential diagnosis in certain clinical settings.
ACKNOWLEDGMENTS
The authors thank Maureen Roden for her review of cases and analysis of data for this study.
Supported by the National Institutes of Health (1K23 AI0629753-1) (to T.E.Z.). Supported in part by the intramural research program of the National Cancer Institute, NIH, Bethesda, MD.
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