Intestinal Zygomycosis due to Absidia Corymbifera Mimicking Necrotizing Enterocolitis in a Preterm Neonate

Abstract

Zygomycosis is a rare fungal disease that occurs in compromised human hosts, including the preterm infant. The three clinical forms of zygomycosis are cellulitis, disseminated, and gastrointestinal, and the last often mimics necrotizing enterocolitis (NEC), complicating the diagnosis. This report details a case of primary gastrointestinal zygomycosis due to Absidia corymbifera, mimicking NEC, in a preterm infant, and emphasizes features that may lead to earlier diagnosis and treatment of future cases.

Perinatal/Neonatal Case PresentationIntestinal Zygomycosis due to Absidia Corymbifera Mimicking

Necrotizing Enterocolitis in a Preterm NeonateSteven C. Diven, MD

Carlos A. Angel, MD

Hal K. Hawkins, MD, PhD

Judith L. Rowen, MD

Karen E. Shattuck, MDZygomycosis is a rare fungal disease that occurs in compromised humanhosts, including the preterm infant. The three clinical forms of zygomycosisare cellulitis, disseminated, and gastrointestinal, and the last often mimicsnecrotizing enterocolitis (NEC), complicating the diagnosis. This reportdetails a case of primary gastrointestinal zygomycosis due to Absidiacorymbifera, mimicking NEC, in a preterm infant, and emphasizes featuresthat may lead to earlier diagnosis and treatment of future cases.Journal of Perinatology (2004) 24, 794796. doi:10.1038/sj.jp.7211186INTRODUCTIONZygomycosis is a rare fungal disease that occurs in compromised

human hosts, including the preterm infant. The majority of

human pathogens are from the class Zygomycetes and are

included in the genera Absidia, Mucor, Rhizomucor, or Rhizopus,

which is the most common isolate in clinical disease.1 The three

clinical forms of zygomycosis are cellulitis, disseminated, or

gastrointestinal, which often mimics necrotizing enterocolitis

(NEC), complicating the diagnosis.2 Instrumentation of the

gastrointestinal tract is presumably the port of entry.3 This report

details, to our knowledge, the first case of primary gastrointestinal

zygomycosis due to Absidia corymbifera, mimicking NEC, in a

preterm infant, and emphasizes features that may lead to earlier

diagnosis and treatment of future cases.4CASE REPORTA baby girl, 704 g and 25 weeks gestation at birth was delivered by

c-section to a mother with pregnancy-induced hypertension (PIH),

who received one dose of dexamethasone and ampicillin prenatally.

Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. The

infant received surfactant twice and weaned to nasal CPAP by day4. Therapy with ampicillin and gentamicin was begun at birth for

suspected sepsis, and indomethacin was given for intraventricular

hemorrhage prophylaxis (0.1 mg/kg Q 24 hours on days 13 of

life). The initial white blood count was 2600/mm3 with an absolute

neutrophil count of 560, consistent with the history of maternal

PIH.On day 5, an orogastric tube was placed and feedings were

initiated with an electrolyte solution; however, feedings were

discontinued after 12 hours due to abdominal distention. The

abdominal film was normal. On day 7, due to the onset of

hypotension, oliguria, metabolic acidosis, hyperglycemia, bilious

gastric aspirate, and worsening abdominal distention, sepsis with

possible NEC was suspected. The infant improved with medical

management that included continuation of gentamicin,

substitution of vancomycin for ampicillin, intravenous crystalloid

boluses, dopamine therapy, and mechanical ventilation. Serial

films demonstrated mild distention of the small bowel without

pneumoperitoneum or pneumatosis intestinalis. The white blood

cell count remained low at 3400/mm3 with 2% segmented

neutrophils and 33% band neutrophils. On day 10, copious bilious

gastric drainage was noted, with recurrence of metabolic acidosis

and hypotension. The abdominal film demonstrated

pneumoperitoneum. At emergency laparotomy, meconium-stained

fluid was found in the abdominal cavity and sent for culture. The

entire colon from the cecum to the sigmoid was compromised with

areas of necrotic tissue. The small bowel appeared normal, and no

specific site of perforation was identified. A subtotal colectomy with

creation of an ileostomy and sigmoid mucous fistula was

performed. At that time, the white blood cell count was 10,700/

mm3 with 9% segmented and 49% band neutrophils. Clindamycin

was added to the antibiotic regimen. The babys condition

improved over the next several days.The hematoxylineosin (H&E) stain of the surgical specimens

revealed extensive necrosis of the colonic mucosa and muscularis

with an intense inflammatory reaction in the necrotic areas and an

area of transmural necrosis in the ascending colon. Fine

vacuolization was evident in areas with inflammatory infiltrates.

Multinucleated giant cells were present near the site of perforation

(Figure 1). The terminal ileum, cecum, and appendix appeared

normal. The findings were reported as consistent with the clinical

diagnosis of NEC.Department of Pediatrics (S.C.D., J.L.R., K.E.S.), University of Texas Medical Branch, Galveston,TX, USA; Department of Surgery (C.A.A.), University of Texas Medical Branch, Galveston, TX, USA;and Department of Pathology (H.K.H.), University of Texas Medical Branch, Galveston, TX, USA.Address correspondence and all reprint requests to Steven C. Diven, MD, 301 University,Galveston, TX 77555-0526, USA.Journal of Perinatology 2004; 24:794796r 2004 Nature Publishing Group All rights reserved. 0743-8346/04 $30www.nature.com/jp794Intestinal Zygomycosis Mimicking NEC in a Preterm Neonate Diven et al.Figure 1. Histologic section of H&E stained colon ( [notdef] 100). There is a

mixed inflammatory infiltrate (i) consisting mostly of neutrophils.

Scattered multinucleate giant cells (m) are present in the muscularis

propria. No fungal elements were seen, but focal fine vacuolation

(arrows), corresponding to unstained fungal elements, could be found

in retrospect.Figure 2. Colon section stained with the Gomori methenamine silver

stain ( [notdef] 200). Multiple fungal hyphae (arrows) were present in the

inflammatory exudates on the serosal surface of the colon, and in the

muscularis propria. These hyphae were broad and variable in size, and

septa were not seen in them.On day 12, the peritoneal fluid culture obtained intraoperatively

was reported to be growing mold, which was suspected to be a

contaminant but was not discarded. The umbilical artery catheter

was removed on day 14 and the tip, which was cultured as part of a

research surveillance study, was noted to be growing fungus 24

hours later. Of note, the culture of the UVC tip, removed on day 6

and cultured as part of the same study, was also found to be

growing two colonies of mold. All other perioperative cultures of

blood and fluids were negative, and the white blood cell count

was now normal. Antibiotics were stopped and liposomal

antifungal treatment was begun with amphotericin B at adaily dose of 5 mg/kg. The colon specimen, at the distal

resection margin, was reevaluated with the Gomori

methenamine silver stain and demonstrated numerous

nonseptate hyphae (Figure 2).On day 17, the infants condition again deteriorated with

evidence of clinical sepsis. Pooled IgG and G-CSF was given, and

vancomycin and gentamicin therapy were restarted. Coagulasenegative staphylococci was grown from blood and tracheal aspirate.

The echocardiogram was negative for endocarditis and a

paracentesis was nonproductive of fluid. The baby improved, and

orogastric feeding was initiated on day 22. However, she again

developed abdominal distention on day 24. Specimens of blood,

tracheal aspirate, anal swab, and cerebralspinal fluid were

negative for bacteria and fungus. On day 29, abdominal ultrasound

revealed thin wispy echogenicities undulating along the length of

the inferior vena cava. This was confirmed on ultrasound on day31. The baby developed progressive renal failure and she expired on

day 35. Request for autopsy was denied. A. corymbifera was

identified as the fungal species from the abdominal fluid and

arterial catheter tip.DISCUSSIONPreterm infants represent a special group at risk of developing

zygomycosis presumably on the basis of general immune

incompetence.3 Zygomycetes are ubiquitous in nature and release

spores into the air, which then gain entry through inoculation of

tissue such as skin, respiratory mucosa, or gastrointestinal tract

causing localized infection with contiguous spread and

hematogenous dissemination. The primary clinical forms of the

disease reflect the sites of spore inoculation. In preterm infants, the

skin is the most common site, followed by the gastrointestinal

tract.5 Neonatal gastrointestinal zygomycotic infections are rare,

but lead to significant mortality and morbidity due to the

aggressive nature of the fungi and the difficulty in diagnosis. Most

cases are diagnosed postmortem, and only two premature infants

have recovered from primary intestinal zygomycoses.5,6 Definitive

diagnosis of zygomycosis requires demonstration of wide ribbonlike nonseptate hyphae in tissue specimens, and is supported by

growth in culture. The highest yield is from direct tissue

inoculation of fungal media. While ruptured bowel contents may

grow the fungi, blood and body fluid do not.1,6 The fungi grow

contiguously from the tissue site of inoculation, invading blood

vessels, leading to thrombosis with local infarction and necrosis

and the potential for hematogenous dissemination.1,3 In the case of

this baby, we speculate the following series of events occurred: TheJournal of Perinatology 2004; 24:794796 795Diven et al. Intestinal Zygomycosis Mimicking NEC in a Preterm Neonateorogastric tube introduced the fungus into the gastrointestinal tract,

and the glucose-containing electrolyte solution, the metabolic acidosis

and hyperglycemia exacerbated its growth. The colon was perforated

after fungal overgrowth and mucosal invasion, with spilling of

infected fluid into the peritoneal cavity and hematogenous seeding or

contamination of the UAC tip at the time of discontinuation. The

fungus continued to grow in the remaining intestine, inhibited but

not cleared by the amphotericin B therapy. The IVC was eventually

seeded, associated with multiorgan failure and death.In this case, the pathology of the resected colon played a key

role in diagnosis of zygomycosis, with the umbilical catheter tip

cultures providing supporting evidence. Gastrointestinal

zygomycosis may have microscopic features that are typical of NEC,

but there are a number of clues that can be seen even on the H&E

stain. These features include multinucleated giant cells, and

inconspicuous vacuolization, which actually represents fungal

hyphae that do not stain with H&E.1 The Gomori methenamine

silver stain confirms the diagnosis by demonstrating characteristic

wide ribbon-like aseptate hyphae that branch at wide angles.

Another distinct histologic feature of the Zygomycetes is vascular

invasion with thrombus formation, localized infarction, and

necrosis.1,3,6 The necrotic tissue favors further growth of the fungus

and limits tissue penetration of the antifungal agents. Pneumatosis

was not seen radiographically or pathologically in this case;

however, this can also be characteristic of spontaneous bowel

perforation without fungal infection in extremely preterm babies.The mainstays of treatment of zygomycosis are early

recognition, resection of the involved tissue with clear margins andamphotericin B.6 All of the genera are susceptible to amphotericin

B, but no definitive synergistic antifungal therapy has been

described. We suggest that zygomycosis be considered in all

extremely low birth weight babies with clinical NEC, particularly if

they have prolonged neutropenia, negligible enteral feedings and

treatment with multiple antibiotics.AcknowledgementsWe thank Michael R. McGinnis from the Department of Pathology for speciationof the Absidia isolates.References1. Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. ClinMicrobiol Rev 2000;13:236301.2. Nissen MD, Jana AK, Cole MJ, Grierson JM, Gilbert GL. Neonatalgastrointestinal mucormycosis mimicking necrotizing enterocolitis. ActaPaediatr 1999;88:12907.3. Reimund E, Ramos A. Disseminated neonatal gastrointestinal mucormycosis:a case report and review of the literature. Pediatr Pathol 1994;14:3859.4. Amin SB, Ryan RM, Metlay LA, Watson WJ. Absidia corymbifera infection inneonates. Clin Infect Dis 1998;26:9902.5. Robertson AF, Joshi VV, Ellison DA, Cedars JC. Zygomycosis in neonates.Pediatr Infect Dis J 1997;16:8125.6. Michalak DM, Cooney DR, Rhodes KH, Telander RL, Kleinberg F.Gastrointestinal mucormycoses in infants and children: a cause ofgangrenous intestinal cellulitis and perforation. J Pediatr Surg1980;15:3204.796 Journal of Perinatology 2004; 24:794796