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The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(S5): 68–71© 2012 Informa UK, Ltd.ISSN 1476-7058 print/ISSN 1476-4954 onlineDOI: 10.3109/14767058.2012.714643

Multiple organ failure (MOF) syndrome, also known as multiple organ dysfunction syndrome (MODS) represents a common but complex problem in critically ill patients in neonatal intensive care unit (NICU) centers, and a major cause of morbidity and mortality in newborns. MOF is considered the result of an inap-propriate generalized inflammatory response of the newborn to a variety of acute insults. This study was aimed at analyzing, at histology, multiple organ pathological changes in two newborns admitted to the NICU center of our University Hospital, who showed a progressive clinical picture of MOF, in order to verify the pathological changes of vascular structures and of endothe-lial cells in the different organs affected by MOF. All the samples obtained at autopsy for histological examination showed specific organ pathological changes, especially related to modi-fications in vascular structures and, in particular, in endothelial cells. The most interesting findings were found in the intestinal barrier, in the lower respiratory tract and in the endothelial barrier. The loss of the gut barrier could allow the passage into the blood of microbial factors that could trigger the production of tumor necrosis factor α (TNFα) leading to endothelial damage. Our preliminary study underlines the principal role probably played by intestinal and vascular changes in the origin of MOF in newborns.

Keywords: Histology, immunoistochemistry, multiple organ failure syndrome, newborn

IntroductionMultiple organ failure (MOF) syndrome, also known as multiple organ dysfunction syndrome (MODS) represents a common but complex problem in critically ill patients in neonatal intensive care unit (NICU) centers, and a major cause of morbidity and mortality in newborns [1,2]. The MOF syndrome has been classi-cally defined by the involvement of seven systems: the respiratory, the renal, the suprarenal, the cardiovascular, the hematologic, the hepatic, and the central nervous system [3]. Even though these seven systems should be considered as the most frequently involved in the pathogenesis of MOF, on the other hand all organ systems may be involved in MOF, including pancreas with pancreatic necrosis [4] and the gut, with necrotizing enteroco-litis followed by endotoxemia and release of proinflammatory cytokines [5]. In an experimental model of MOF, the ZIGI rat

model, neonatal MOF differed significantly from adult MOF. In newborn rats, MOF was characterized by relative sparing of lungs from injury, and by a unique progression of organ involve-ment, liver-kidney-lung. Moreover, newborn rats suffering from MOF, different from adult animals, showed an early generalized capillary leak, resulting in increasing body weight [6]. In human neonates, descriptors for multiple organ dysfunction have been identified in at least five organ systems: cardiovascular (lactic acid), hepatic (bilirubin), respiratory (Pa O2/Fi O2 ratio), hemato-logic (fibrinogen), and renal (blood urea nitrogen) [7]. In a recent study carried out on 1806 patients admitted to pediatric inten-sive care units, differences in the outcome of MOF were shown between newborns and older children. Among neonates, the mortality rate was higher, whereas neurological, cardiovascular and hepatic dysfunctions were the only significant contributors to neonatal mortality [8].

MOF is considered the result of an inappropriate generalized inflammatory response of the newborn to a variety of acute insults, including respiratory distress syndrome [9] acute kidney injury (AKI) [10], perinatal asphyxia [11,12], hypoxic-ischemic encephalopathy [13], and pandemic influenza A (H1N1) virus infection [14]. In cases in which no infectious or non infectious aetiologies are found, the definition of systemic inflammatory response syndrome (SIRS) has been suggested [15]. The following sequence of events determining multiple organ dysfunction has been hypothesized: (i) failure of the gut barrier, endotoxemia, and release of proinflammatory cytokines, including IL1β, TNFα, IL-6, and ETX (Figure 1); (ii) upregulation of adhesion molecules in the vascular bed of multiple organs by circulating cytokines; (iii) universal TNFα-induced endothelial injury and apoptosis, causing a generalized capillary leak (Figure 2); (iv) generalized oedema and activation of intrinsic inflammatory cells in different organs; and (v) organ failure [2,5]. The role of circulating proinflammatory citokines on the pathogenesis of MOF has been clarified by the therapeutic role of therapeutic plasma exchange (TPE): improvement in organ function and platelet count occurred in most pediatric patients suffering from sepsis-induced MOF [16]. Moreover, recent studies have shown that hepatocyte growth factor (HGF) should be considered a new candidate for the therapy of MOF, due to its ability to inhibit the upregulation of inflammatory cytokines and target endothelial cells, protecting them from cytokine-induced apoptosis [17]. Specific pathogenetic mechanisms may be added to this general scheme in patients

Multiple organ failure syndrome in the newborn: morphological and immunohistochemical data

Gavino Faa1, Daniela Fanni1, Clara Gerosa1, Sonia Nemolato1, Armando Faa1, Eleonora Obinu1, Elisabetta Puxeddu2, Matteo Fraschini3, Nicoletta Iacovidou4, Marco Zaffanello5 & Vassilios Fanos2

1Department of Pathology, University of Cagliari, Cagliari, Italy, 2Department of Surgery, Neonatal Intensive Care Unit, Puericulture Institute and Neonatal Section, University of Cagliari, Cagliari, Italy, 3Department of Electrical and Electronic Engineering, University of Cagliari, Cagliari, Italy, 4Department of Obstetrics and Gynaecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece, and 5Department of Life and Reproduction Sciences, University of Verona, Verona, Italy

Correspondence: Prof Gavino Faa, Department of Surgery, Institute of Pathology, University of Cagliari, Cagliari, Italy. E-mail: gavinofaa@gmail.com

The Journal of Maternal-Fetal and Neonatal Medicine

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10.3109/14767058.2012.714643

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Multiple organ failure syndrome in the newborn

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undergoing MOF in peculiar clinical settings: for example, children suffering from thrombocytopenia-associated MOF may also show diffuse thrombocytic microangiopathy [18].

On the basis of these data, this study was aimed at analyzing, at histology, multiple organ pathological changes in two newborns admitted to the NICU center of our University Hospital, who showed a progressive clinical picture of MOF, in order to verify the pathological changes of vascular structures and of endothelial cells in the different organs affected by multiple organ dysfunction.

Population study and methodsTwo newborns admitted to the NICU center of our University Hospital, respectively a male of two weeks and a female of one week, showing a progressive clinical picture of MOF leading to the exitus, were the object of the present study. All procedures performed were in accordance with the ethical national standards of the responsible committee on human experimentation. Each subject was carefully examined at autopsy. At macroscopic exami-nation, no congenital malformations were observed. Multiple samples from every organ were obtained. All the tissue samples were fixed in 10% buffered formalin, routinely processed and paraffin-embedded. Five-micron-thick paraffin sections were stained with Hematoxylin and Eosin (H&E) and Periodic Acid Schiff (PAS) staining method and examined under an optical microscope.

ResultsAll the multiple samples in the two newborns affected by multiple organ dysfunction obtained during the autopsy for histological

examination showed specific organ pathological changes, espe-cially related with vascular structures and endothelial cells. All organs did not escape to be damaged, including thymus and pancreas. The most interesting results were found in the intestinal tract, in the lower respiratory tract and in the endothelial barrier of all the organs studied.

Intestinal barrierThe histology of the colon and the ileum samples showed, in both cases, areas of epithelial loss (Figure 3). In these gut samples, the disappearance of enterocytes was constantly associated with the increase of inflammatory cells in the mucosa and in the submu-cosa. Moreover, significantly changes were observed in the blood vessels of the submucosa: they showed features of endothelial damage, occasionally associated with microthrombosis (Figure 4).

Respiratory barrierThe histological study of tracheal and bronchial specimens evidenced the presence of apoptosis of the epithelial cells covering the bronchial mucosa, resulting in the loss of the respiratory barrier (Figure 5). Apoptosis of the superficial respiratory epithe-lium was paralleled by pathological changes in the small vessels, represented by endothelial loss and congestion.

Endothelial barrierThe pathological changes in the endothelial cells were detected in all tissue samples examined. Vascular pathological changes were mainly detected in capillaries and, in general, in small vessels, but endothelial lesions were also found in medium-sized arteries (Figure 6) and veins (Figure 7). Vascular change was often not restricted to the endothelium: fibrinoid necrosis interesting the whole arterial wall (Figure 8) was occasionally observed. Endothelial damage was often associated to adhesion of inflam-matory cells and microthrombosis (Figure 4).

DiscussionIn this study, we show that the accurate histological study of two newborns affected by MOF may give interesting data dealing with the pathogenesis of this severe syndrome, characterized by a high mortality rate. The first interesting finding regards data obtained

Figure 1. The sequence of events determining multiple organ dysfunction begins with the damage and the failure of intestinal barrier, endotoxemia, and release of proinflammatory cytokines.

Figure 2. The lipopolysaccarides (LPS) introduced in the blood after loss of the intestinal barrier interact with monocytes and dendritic cells, stimulating production of TNFα, causing apoptosis of endothelial cells. Figure 3. Intestinal mucosa showing the loss of the epithelial layer.

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by the study of the intestinal and of the respiratory mucosa. In both newborns, we found relevant changes of the surface epithelium, mainly represented by apoptosis, associated with

inflammation of the mucosa, congestion and microthrombosis. These findings confirm previous studies in experimental animal models on the role played by the loss of intestinal barrier in the development of MOF [6]. The loss of the gut barrier could allow the passage into the blood of microbial factors, including lipopolysaccarides (LPS) that could trigger the production of tumor necrosis factor α (TNFα) leading to endothelial damage (Figure 2).

Figure 4. Blood vessel in the intestinal wall showing loss of endothelial cells (endothelial damage), adhesion of inflammatory cells and thrombosis.

Figure 5. Apoptosis of the epithelial cells covering the bronchial mucosa.

Figure 7. Vascular pathological changes with endothelial detacement in veins.

Figure 8. The fibrinoid necrosis interesting the whole arterial wall observed in thymus.

Figure 9. Endothelial loss in a pancreatic artery.

Figure 6. A medium-sized artery with multiple vascular pathological changes.

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This hypothesis was confirmed in our study by the frequent observation of relevant pathological changes in the blood vessels of the intestinal mucosa and of all the other organs examined. The main pathological vascular changes were represented by apoptosis of the endothelial cells followed by inflammation, microthrombosis and leakage of plasma and red blood cells. We ought to underline that, in spite of the relevant changes observed in the gut of both newborns, they had not a clinical picture typical of necrotizing enterocholitis (NEC). This means that an accurate histological examination of the intestinal tract should be suggested in every cases of MOF, irrespectively of the presence or not of a clinical picture of NEC.

The histological study of respiratory mucosa revealed the alike damage observed in the intestinal tract, including the apoptosis of the epithelial cells covering the bronchial mucosa and resulting in the loss of the respiratory barrier. This new finding, at the best of our knowledge previously unreported in newborns affected by MOF, induces to focus on the respiratory barrier loss as a possible relevant site for the passage into the organism of bacterial toxins included LPS.

Another relevant finding of our study is the presence of endothe-lial damage in all the organ analyzed, including thymus (Figure 8) and pancreas (Figure 9), two organs, rarely included in MOF.

The loss of the endothelial barrier probably represents the unifying lesion, the most important pathological change able to explain why, after starting with a single organ pathology, the disease, often suddenly, transforms into MOF, contemporarily affecting multiple organs and systems. Our study confirms previous data, mainly obtained in experimental animals [6] and clearly indicates vascular damage as the main pathological sign of MOF in human newborns.

In conclusion, our preliminary study underlines the principal role played by intestinal and vascular changes in the origin of MOF in newborns. Further studies are needed on a large series of newborns affected by MOF in order to confirm our preliminary data even by immunohistochemical studies of the endothelial damage.

Declaration of Interest: The authors report no conflicts of interest.

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