Acta Pñdiatr 88: 1290±7. 1999
CLINICAL OBSERVATIONS
Neonatal gastrointestinal mucormycosis mimicking necrotizing enterocolitis MD Nissen1, AK Jana2, MJ Cole2, JM Grierson3 and GL Gilbert1 Departments of Clinical Microbiology1, Perinatal Medicine2, and Anatomical Pathology3, Westmead Hospital, Westmead, New South Wales, Australia
Mucormycosis is a rare opportunistic infection caused by fungi of the order Mucorales within the class Zygomycetes. The order includes the genera Absidia, Mucor, Rhizomucor and Rhizopus (Mucoraceae). These fungi are ubiquitous saprophytes of soil and decaying vegetable matter producing large numbers of airborne spores. Disease is frequently associated with a state of immunocompromise and can be disseminated or localized to the rhinocerebral area, lungs, gastrointestinal tract or skin. Neutrophil leucocytes are thought to be the prominent components of the host response to Mucoraceae (1). Predisposing risk factors include diabetes mellitus, malignancy, extreme prematurity, malnutrition, acidosis, neutropenia, and corticosteroid therapy (1). Gastrointestinal (GIT) involvement with mucormycosis in neonates is rare, usually fatal, and uncommonly diagnosed during life (2–13). Such presentations are usually diagnosed as necrotizing enterocolitis (NEC), resulting in a delay of specific treatment. We describe a case of neonatal GIT mucormycosis, diagnosed during life, highlighting the delayed diagnosis and subsequent poor prognosis of the condition. The medical literature for the disease, based on a complete Medline search, is then reviewed. The possibility that mucormycosis may co-exist or be a serious complication of NEC in premature neonates is discussed.
Case report A female infant was born at 24 wk gestation by vaginal breech delivery at Westmead Hospital, Australia. Her 25-y-old mother had suffered recurrent urinary tract infections for which she was still receiving oral amoxycillin. The infant weighed 730 g. Apgar scores were 1 and 6; she required intubation and mechanical ventilation. The postnatal period was complicated by the following: hyaline membrane disease needing surfactant therapy, pulmonary haemorrhage, pulmonary interstitial emphysema, pneumothorax, bilateral subependymal haemorrhages and jaundice. Hyperkalaemia was treated with calcium resonium enemas. A patent Scandinavian University Press 1999. ISSN 0803-5253
ductus arteriosus was ligated on day 3 of life. Rectal bleeding was detected on day 9 and a left iliac fossa mass could be palpated on day 11. Intravenous ampicillin and amikacin were commenced. Abdominal radiographs showed a paucity of bowel gas, but no pneumatosis or free gas (Fig. 1). As the abdomen was soft and the baby stable, a diagnosis of calcium resonium faecolith was entertained. A laparotomy on day 12 revealed a gangrenous colon and perforated ileum, which was closed. A diagnosis of NEC was made. A sub-total colectomy was performed and colostomy fashioned. The next day histopathological specimens from surgery showed mucormycosis of the colon (Fig. 2). Therapy with intravenous amphotericin B was started. Endotracheal aspirates collected on day 10 grew Rhizopus microsporus on day 11, and Ureaoplasma urealyticum. Cultures of blood, peritoneal fluid, umbilical artery catheter and gastric aspirate were negative for fungi and bacteria. The infant developed gangrene of the anterior abdominal wall on day 14 and died at 16 d of age. The infant had never been neutropenic or fed orally. A request for autopsy was declined.
Discussion Gastrointestinal mucormycosis has been described in at least 18 neonates (12 premature and 6 term), with a premortem diagnosis made in only 5 (28%) cases (2– 13). As in this case, all patients showed no clinical features of mucormycosis. The GIT sites most commonly invaded were the gastric and colonic mucosa (50%), small intestine (39%), and oesophagus (11%). Multiple GIT sites with spread of infection to adjacent organs occurred in 39% of infants, with disseminated disease beyond the abdominal cavity in 17%. The most likely portal of entry of the fungus in this baby was the oropharnyx, with subsequent spread to the GIT and respiratory tracts. All reported cases, except two (one Rhizomucor (11) and one Absidia (13)) were infected with Rhizopus spp. Postmortem or laparotomy tissue specimens provided the diagnosis in all babies. This patient is different in that the organism was isolated
ACTA PÆDIATR 88 (1999)
Fig. 1. Plain abdominal radiograph showing a paucity of intestinal gas with no pneumatosis intestinalis or free intra-abdominal air.
initially from the respiratory tract 2 d before a histological diagnosis was obtained. There has been speculation that GIT mucormycosis may be an aetiological variant of NEC (7). NEC is a multifactorial illness where perinatal and postnatal factors reducing GIT blood flow have been implicated (14). The presentation in premature babies in the medical literature was consistent with NEC in 11 (92%) cases, with abdominal distension present in all 12 patients, and haematochezia (42%) or pneumoperitoneum (50%). Only 2 (17%) presented with an abdominal mass or pneumatosis coli. Four (33%) had been given steroids, a known risk factor. In term neonates, only 1 (16%) case was consistent with NEC (guaiac-positive stools and pneumo-peritoneum). The commonest days for the onset of symptoms were 4 to 9 d of age (75%). Only 2 babies have survived the infection (5, 11), at a rate much lower that seen with NEC (11% versus 60–80%) (7). It is therefore possible that fungal invasion in premature neonates could be secondary to some combination of GIT vascular compromise, mucosal injury or even NEC itself, since
Clinical observations
1291
devitalized or dead tissue is more prone to fungal invasion. Most of the reported cases (75%) had preexisting medical conditions (i.e. hyaline membrane disease and/or sepsis) prior to the appearance of their abdominal symptoms. They also underwent interventions that may have increased their risk for mucosal injury, such as endotracheal (58%) and/or nasogastric (44%) intubation, and antibiotic (55%) or indomethacin (17%) therapies. Kesckes et al. hypothesized that the nursing of premature infants in the high ambient humidity (85%) of enclosed incubators may favour the growth of and an increased environmental exposure to Mucoraceae (11). The failure to respond to antibiotic therapy for NEC, especially in a premature neonate, or an atypical presentation of the illness as demonstrated in this baby, should warrant a search for causes other than NEC. The absence of enteral feeding and pneumatosis also intimated a clinical diagnosis other than NEC. However, no features surgically distinguished this case from NEC; the diagnosis was made only by histology. The GIT mucosa shows black, necrotic ulcers with hyperaemic margins. The presence of broad aseptate fungal hyphae and the invasion, with thrombosis, of blood vessels is microscopically distinctive. The delayed diagnosis in past cases has relied on visualizing invasive hyphae in tissue specimens. The culture of surgical material is typically of low yield (33%). Swabs from abnormal tissue or discharge are inappropriate and may give misleading information (1, 7). Isolation of Mucoraceae maybe improved by potassium hydroxide (KOH) preparations of touch slides of biopsied tissue, obtaining fresh and non-refrigerated pieces of tissue from active lesions that are minced, rather than ground, prior to cultivation, and incubating specimens on media that do not contain cycloheximide (15). As noted in this case, the isolation of Mucoraceae in oropharyngeal, respiratory or gastric aspirate cultures in neonates with suspected NEC may indicate GIT or disseminated mucormycosis. The addition of amphotericin B therapy, and early laparotomy, should therefore be considered in such patients. This could improve the dismal prognosis for the condition. Gentle preparation of tissue for culture and rapid histological processing of surgical specimens with additional GrocottGiomori methenamine-silver nitrate (GMS) or periodic acid-Schiff (PAS) tissue stains in suspected cases will also hasten the diagnosis. Rifampin use maybe synergistic with amphotericin B (16). A minimum course of amphotericin B for 6 wk is only an adjunct to surgical debridement that should be more complete than usually performed for NEC (10). Subsequent surgery may also be required to ensure a near total excision of the involved bowel, as noted by Kesckes et al. (11). Acknowledgements.—We thank Ok Cha Lee for especiating the Rhizopus isolate, Martina Reinhold for translation, and Penelope Shackelford, MD for reviewing the manuscript.
1292
Clinical observations
ACTA PÆDIATR 88 (1999)
Fig. 2. Histological sections of the colon (haematoxylin and eosin stain). (a) Non-septate fungal hyphae (arrows) within the muscularis mucosae (250). (b) An engorged colonic wall venule with invading fungal hyphae (arrows) (250).
References 1. Sugar AM. Agents of mucormycosis and related species. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone, 1995: 2311–21 2. Gatling RR. Gastric mucormycosis in a newborn infant. Arch Pathol 1959; 67: 249–55 3. Levin S, Isaacson C. Spontaneous perforation of the colon in the newborn infant. Arch Dis Child 1960; 35: 581–4 4. Pena C. Deep mycotic infections in Columbia. Am J Clin Pathol 1967; 47: 505–20 5. Michalak DM, Cooney DR, Rhodes KH, Telander RL, Kleinberg F. Gastrointestinal mucormycosis in infants and children: a cause of gangrenous intestinal cellulitis and perforation. J Pediatr Surg 1980; 15: 320–4 6. Donhuijsen K, Grothey A, Volker B, Dermoumi H. Zygomykosen: Klinik und Pathologie bei 10 Patienten. Schweiz Med Wochenschr 1991; 121: 1493–8 7. Woodward A, McTigue C, Hogg G, Watkins A, Tan H. Mucormycosis of the neonatal gut: a “new” disease or a variant of necrotizing enterocolitis? J Pediatr Surg 1992; 27: 737–40 8. Mooney JE, Wanger A. Mucormycosis of the gastrointestinal tract in children: report of a case and review of the literature. Pediatr Infect Dis J 1993; 12: 872–6
9. Reimund E, Ramos A. Disseminated neonatal gastrointestinal mucormycosis: a case report and review of the literature. Pediatr Pathol 1994; 14: 385–9 10. Vadeboncoeur C, Walton JM, Raisen J, Soucy P, Lau H, Rubin S. Gastrointestinal mucormycosis causing an acute abdomen in the immunocompromised pediatric patient—three cases. J Pediatr Surg 1994; 29: 1248–9 11. Kesckes S, Reynolds G, Bennett G. Survival after gastrointestinal mucormycosis in a neonate. J Paediatr Child Health 1997; 33: 356–9 12. Sharma MC, Gill SS, Kashyap S, Katatia R, Gupta DK, Sahni P, et al. Gastrointestinal mucormycosis—an uncommon isolated mucormycosis. Indian J Gastrointest 1998; 17: 131–3 13. Singer S, Singer D, Stohr G, Ruchel R, Rothe H, Harms K. Mukormykose als Ursache einer nekrotisierenden Enterokolitis. Monatsschr Kinderheilkd 1998; 146: 26–9 14. Stoll B. Epidemiology of necrotizing enterocolitis. Clin Perinat 1994; 21: 205–18 15. Richardson MD, Shankland GS. Rhizopus, Rhizomucor, Absidia and other agents of systemic and subcutaneous zygomycoses. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, editors. Manual of clinical microbiology. 6th ed. New York: American Society for Microbiology Press, 1995: 809–24 16. Christenson JC, Shalit I, Welch DF, Guruswamy A, Marks MI. Synergistic action of amphotericin B and rifampin against
Clinical observations
ACTA PÆDIATR 88 (1999)
1293
Rhizopus species. Antimicrob Agents Chemother 1987; 31: 1775–8
Hospital, 660 S. Euclid Ave., St. Louis, MO 63110, USA (Tel. 314 362 4779, fax. 314 362 1232, e-mail.
[email protected])
MD Nissen, Departments of Molecular Microbiology and Pediatrics, Washington University School of Medicine, St. Louis Children’s
Received Jan. 8, 1999; revision received March 8, 1999; accepted April 9, 1999
ÐÐÐÐÐÐÐÐÐÐÐÐ
Cardiomyopathy, myopathy, cataracts and CNS disorders: fourth case of a new familial disease? GV Zuccotti, G Biasucci, A Giovannini, G Mogavero and E Riva Department of Pediatrics, University of Milan, Italy
Cardiomyopathy, myopathy, cataracts and neurological disorders are common features in a number of diseases, but, despite this, the association of these abnormalities, to our knowledge, has never been reported except in the case of three patients described by Lyon et al. in 1990 (1). We report a case with neonatal onset of the abovementioned clinical picture.
Case report G.F., male and the first child of healthy non-consanguineous parents, was born at term after uneventful pregnancy and uncomplicated delivery. Birthweight was 2970 g (25th percentile), length 46 cm (25th percentile) and head circumference 34 cm (50th percentile). Soon after birth he had severe deglutition and feeding difficulties. Enteral drip nutrition quickly became necessary. Since the first week of life he has also experienced several febrile respiratory infections. When 1.5 mo old, he showed marked axial hypotonia, absence of ocular fixation and pursuit, polypnea and increasing feeding difficulties with failure to thrive. Chest X-ray, electrocardiography and echocardiography revealed a biventricular non-obstructive hypertrophic cardiomyopathy, suggestive of glycogen storage disease (GSD) type II (2). He was therefore referred to our attention at the age of 2 mo. His weight, length and head circumference were below the 3rd percentile. Unlike his parents, he featured red hair and pale skin; no dysmorphic sign was evident, except for a triangularshaped upper lip and bilateral 2nd and 3rd toe syndactylia. Despite the clinical and echographic picture, GSD type II was soon excluded by means of lymphocyte acid maltase normal concentration. Peroxysomal disorders and compatible forms of GSD
and mucopolysaccharidosis were also ruled out (3, 4) by means of plasma very long chain fatty acid detection, enzymatic activity of lysosomal a-1,4-glucosidase, phosphorylase, 3-phosphoglycerate-kinase, phosphogluco-isomerase, phosphogluco-mutase, aldolase, enolase, pyruvate-kinase, and lactic-dehydrogenase, urinary organic acid and mucopolysaccharide detection. Karyotype was normal. No alteration of blood or urinary parameters, including gas analysis, carnitine (5), lactate and pyruvate concentrations (6), amino acids, organic acids and oligosaccharides, was present, except for increased levels of serum creatine-kinase (mean values 600 U/ L) and aspartate aminotransferase (mean values 160 U/ L) in repeated blood samples. Congenital myotonic dystrophy was excluded by means of normal parameters on parents’ electromyography (7). Histological evaluation of the muscle biopsy showed preferential type I fiber hypotrophy with vacuolar myopathy due to glucidic accumulation. Electronmicroscopy revealed extralysosomial glycogen (which is not compatible with GSD II) and autophagicdegenerative material storage. Immunocytochemical and Western blot analysis showed a normal dystrophin and merosin-laminin complex. All the enzymes of glycolysis muscular pathway were also tested, giving normal results. Metabolic disorders such as pyruvate dehydrogenase complex deficiency and respiratory chain disorders were investigated in muscle biopsy with normal results (8, 9). The brain magnetic resonance image revealed complete corpus callosum agenesia, enlargement of the 3rd ventricle and bilateral temporal cortex hypotrophy. The electroencephalogram was characterized by a diffuse, slow dysrhythmia. A slit lamp ophthalmological investigation showed bilateral anterior subcapsular catar-
