Etiology

Numerous reports have implied that the fecal microflora may contribute to the pathogenesis of NEC. A broad range of organisms generally found in the distal gastrointestinal tract have been recovered from the peritoneal cavity and blood of infants with NEC. Infectious agents recovered from newborns with endemic NEC are similar to those associated with epidemic NEC. Organisms cultured from the blood usually matched with those found in the stool (1,2,12). Most reports describe the predominance of members of the neonatal gut normal flora [including Enterobacteriaceae such as E. coli (12,13) and K. pneumoniae (1,2), and clostridia (14-23)], enteric pathogens (salmonellae, Coxsackie B2 virus, and coronavirus rotavirus), and potential pathogens (Bacteroides fragilis) (24-26).

The epidemic nature of NEC and the concomitant isolates of similar pathogens suggest the spread of organisms within a nursery. During the epidemic, these organisms may cause other disease manifestations, such as sepsis or diarrhea (1,2). Thus, host factors may determine the disease status. Alternatively, NEC may be a host response to multiple adverse intestinal conditions. The immature bowel may have a limited response pattern to injury, one of which is NEC.

Clostridia have been implicated as pathogens in some infants with NEC. Pedersen and colleagues (23) cultured Clostridium perfringens from the peritoneal fluids of babies who died of NEC and observed gram-positive bacilli resembling clostridia in nectrotic portions of the gut in six out of seven infants. Howard et al. (21) reported an outbreak of nonfatal NEC from Clostridium butyricum. Strum and co-workers (22) recovered C. butyricum from the peritoneal fluid and cerebrospinal fluid of a neonate with NEC. Brook et al. (27) recovered Clostridium difficile mixed with K. pneumoniae from the peritoneal fluid and blood of a patient with NEC. Warren et al. (16) recovered C. perfringens from the inflamed peritoneal cavity of two newborns with NEC with severe hemolytic anemia. Novak (18) described red blood cell alteration in four patients with NEC. Clostridium spp. were recovered in the blood or peritoneal cavity of three out of four patients. These strains elaborated red blood cells altering enzymes also in vitro. Alfa et al. (15) described an outbreak of NEC occurred in six neonates within a two-month period. Blood cultures from three of these neonates grew the same strain of what appears to be a novel Clostridium spp.

The virulence of clostridia strains in NEC could result from multiple mechanisms. Kosloske and Ulrich (28) obtained cultures of blood and peritoneal fluid with NEC. Of the 17 operated infants, 16 had bacteria in their blood and/or peritoneal fluid. The majority of resected bowel specimens from these infants contained a confirmatory morphologic type of bacterium within the wall. The clinical course of eight infants with clostridia was compared with that of eight infants with gram-negative aerobic and anaerobic bacteria (Klebsiella, E. coli, or B. fragilis). The infants with clostridia were sicker; they had more extensive pneumatosis intestinalis, a higher incidence of portal venous gas, more rapid progression to gangrene, and more extensive gangrene. These authors concluded that among infants who develop intestinal gangrene, clostridia appear to be more virulent than gram-negative bacteria. Kosloske et al. (20) recovered Clostridium spp. in 16 out of 50 infants with NEC. Of the 16,9 had C. perfringens and 7 had other species. These nine had a fulminate form of NEC analogous to gas gangrene of the intestine, and mortality was 78%. The seven infants with other Clostridium spp. had mortality comparable with that of infants with nonclostridial NEC (32%). However, Kliegman et al. (29) who isolated clostridia from seven infants with NEC, reported a similar mortality among clostridial and nonclostridial infections.

The toxin of C. difficile has not been implicated in the pathogenesis of NEC, although it has been identified in the stools of healthy infants. Kliegman and colleagues found that 17 out of 121 stools (14%) from infants up to five months of age caused cytotoxicity in tissue culture that was consistent with the effect of C. difficile toxin (29). No toxin was identified in stools from 24 patients with NEC examined by Bartlett and associates (30) or from 18 patients with NEC studied by Chang and Areson (31).

Cashore and co-workers (32) found C. difficile toxin in 5 samples from 15 patients with confirmed or suspected NEC. In addition, they recovered clostridia in 8 out of 11 confirmed NEC cases, in 7 out of 9 suspected cases, and in 4 out of 13 asymptomatic cases.

Clostridia are implicated as a possible source of NEC by almost all studies, however, their definite role in NEC awaits further confirmation. The hypoxia and circulatory disturbances in small premature infants at risk for NEC may lead to ischemia of bowel, where multiplication of clostridia and toxin production may result in bowel ulceration, infarction, pneumatosis, and the clinical picture of NEC.

Earlier investigations failed to identify clostridia in NEC probably because peritoneal fluid was seldom cultured for anaerobes. Clostridia in the gastrointestinal tract do not cause illness unless they invade tissues and/or produce exotoxins. A low oxidation-reduction potential, which occurs in the presence of devitalized tissue, is essential for toxin production. Those infants colonized by clostridia and who have an episode of intestinal ischemia prior to the onset of NEC may, therefore, be at risk of clostridial invasion of their devitalized intestinal portions.

The gas-forming ability of some clostridia may explain the more extensive pneumatosis intestinalis and the higher incidence of portal venous gas among the infants with clostridia. The production of clostridial exotoxins, which cause cell lysis and tissue necrosis, may explain the more rapid progression to gangrene and more extensive gangrene among infants with clostridia (28). The lower platelet counts in infants with Clostridium may be due to their endotoxin production. The hemolysis seen in some patients with clostridial infections in NEC patients (16) may be caused by elaboration of hemolysins. Endotoxin, which has been detected both in blood and in peritoneal fluid of infants with severe NEC (33), produces thrombocy-topenia by direct destruction of platelets.

Anaerobes, including clostridia, are considered to be members of the normal flora of infants of this age (34). The majority of infants are colonized by 10 days of age with aerobic gram-negative rods (most frequently E. coli and Klebsiella), as well as by anaerobic flora, including B. fragilis (35,36) and clostridia species are found in a third of infants. Although clostridia are normal inhabitants of the human intestinal tract, colonization rates among neonates vary from 7% to 70% (37). The source of the neonatal intestinal flora is the environment encountered by the infant after birth. The normal flora of the cervix and vagina contains many anaerobes, including clostridia (38). Differences among neonates in gestational age, route of delivery, and type of feeding are associated with different colonization patterns of aerobic and anaerobic bacteria (36).

Waligora-Dupriet et al. (39) who fed gnotobiotic quails a lactose diet with K. pneumoniae, C. perfringens, C. difficile, Clostridium paraputrificum, or C. butyricum (two strains) found that neither K. pneumoniae nor C. difficile induced any cecal lesions. In contrast, the four other clostridial strains led to cecal NEC-like lesions with a variable occurrence. Gross aspects of the lesions was linked to the short-chain fatty acid profiles and/or concentrations: thickening of the cecal wall (C. butyricum and C. perfringens) with high proportion of butyric acid, hemorrhages (C. paraputrificum) with high proportion of iso-butyric acid, and presence of other iso-acids. In addition, C. butyricum was characterized by pneumatosis, linked to a high-gas production. The authors concluded that Clostridia species seem to be implicated in NEC through excessive production of butyric acid as a result of colonic lactose fermentation.

The similarities to clostridial enterotoxemias in adults (antibiotic-associated pseudomem-branous colitis) and animals (pig-bell disease) and the similarity to the histology noted in pseudomembranous colitis strengthen the epidemiological data and highlight the role of Clostridium spp. in NEC (1,2,32).

Epidemics of necrotizing enteritis caused by a C. perfringens type C exotoxin have been noted. These are preventable through administration of specific antitoxin or specific immunization of mothers. C. perfringens type B produces diseases in newborn fowl, calves, piglets, and lambs (40). Pig-bell is caused by C. perfringens type C enterotoxin (41). The disease is comparable to NEC in histology and clinical features. Treatment is possible with an antitoxin to type C alpha and beta Clostridial toxins, and prevention can be achieved by immunization with C. perfringens beta toxoid (42). Pseudomembranous colitis that usually follows antimicrobial therapy where C. difficile toxin appear to be the primary agent has histological features similar to NEC, except for the lack of pneumatosis intestinalis (43).

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