The Host Response to Sepsis and Developmental Impact

Abstract

Invasion of the human by a pathogen necessitates an immune response to control and eradicate it. When this response is inadequately regulated, systemic manifestations can result commonly manifested in physiologic changes described as "sepsis". Recognition, diagnosis, and management of sepsis remain among the greatest challenges shared by the fields of neonatology and pediatric critical care medicine. Sepsis remains among the leading causes of death in both developed and under-developed countries with an incidence that is predicted to increase each year. Despite these sobering statistics, promising therapies derived from pre-clinical models have universally failed to obviate the substantial mortality and morbidity associated with sepsis. Thus, there remains a need for well-designed epidemiologic and mechanistic studies of neonatal and pediatric sepsis to improve our understanding of the causes-both early and late-of deaths attributed to the syndrome. In reviewing the definitions and epidemiology, developmental influences and regulation of the host response to sepsis, it is anticipated that an improved understanding of this host response will assist clinician-investigators in identifying improved therapeutic strategies. Keywords sepsis; septic shock; developmental influence; hemodynamics; coagulation cascade; immune function Definitions characterizing the host responses in sepsis"Sepsis" referring to the "decomposition of animal or vegetable organic matter in the presence of bacteria" 1 first appeared over 2700 years ago in the poems of Homer. Hippocrates also used the term "sepsis" and believed the decomposition could release "dangerous principles" that could cause "auto-intoxication" 2 . Lewis Thomas furthered this concept when he proposed that the clinical responses seen in sepsis were the result of the host's response to the infectious agent 3 . In 1991, an American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was convened to create a framework in which to define the systemic response to sepsis which resulted in defining criteria for the systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis and septic shock 4, 5 . These criteria were refined a decade later (2001) Through clinical observations, pediatricians and neonatologists had recognized that the systemic inflammatory response of tachycardia, tachypnea, hyperthermia and leukocytosis (Table 1) most commonly triggered by infection, could also be present following trauma, burn injury, pancreatitis and various other insults. As a result, this physiologic response was defined as the systemic inflammatory response syndrome (SIRS) with no reference to the presence of infection. Sepsis was defined as a SIRS response associated with infection based on either microbiologic cultures or strong clinical evidence of the presence of an infection. Severe sepsis was defined as sepsis plus evidence of organ dysfunction define around pediatric parameters (Table 2) while septic shock was defined as sepsis criteria ...

Faktor Risiko yang Berperan pada Mortalitas Sepsis

“…[6][7][8][9] Status imun pejamu merupakan faktor pen ting yang menentukan luaran pada sepsis. 10 Respons pejamu terhadap sepsis bergantung pula terhadap kematangan sistem imunitas. Tahap perkembangan sistem imun menunjukkan bahwa semakin muda usia, semakin sedikit tingkat kematangan sistem imun yang telah dicapai, sehingga semakin rendah pula kemampuan membunuh patogen.…”

“…Tahap perkembangan sistem imun menunjukkan bahwa semakin muda usia, semakin sedikit tingkat kematangan sistem imun yang telah dicapai, sehingga semakin rendah pula kemampuan membunuh patogen. 10 Selain usia muda, imunodefisiensi dapat ditemukan pada kondisi malnutrisi, penyakit kronis, luka bakar, atau penyakit keganasan. 4,[7][8][9] Hasil penelitian yang ada saat ini masih menunjukkan hasil yang tidak konsisten mengenai peran usia sebagai faktor risiko mortalitas sepsis pada anak.…”

“…13 Malnutrisi terutama gizi buruk juga merupakan salah satu penyulit yang cukup banyak ditemukan pada pasien anak dengan sepsis. 10,14 Survei terkini melaporkan angka kejadian malnutrisi yang meliputi gizi kurang dan buruk pada pasien rawat inap di PICU berkisar 10%-24%, dengan insiden infeksi dan mortalitas yang tinggi. 15,16 Komplikasi malnutrisi pada anak dengan sepsis dapat mengenai seluruh sistem, seperti menurunkan respon imun, atrofi, dan mempermudah terjadinya translokasi bakteri saluran cer na akibat peningkatan permeabilitas barier intesti nal.…”

Activin-A exerts a crucial anti-inflammatory role in neonatal infections

“…In brief, the clinical signs considered indicative of sepsis were: poor peripheral circulation, respiratory distress, cyanosis, irritability, lethargy, apneic spells, tachycardia, bradycardia, unstable temperature, poor feeding, instability of blood sugar levels, and jaundice. Laboratory findings considered indicative of sepsis were: neutrophilia (polymorphonuclear leukocytes >9,000/mm 3 ) or neutropenia (polymorphonuclear leukocytes <1,000/mm 3 ), increased immature to total neutrophil ratio (I/T >0.2), increased C-reactive protein (CRP >15 mg/dl), thrombocytopenia (platelet count <80,000 mm 3 ), disseminated intravascular coagulopathy and x-ray findings consistent with pneumonia, respiratory distress syndrome, and pneumothorax (24,37). The diagnosis of suspected sepsis was established when at least three clinical signs and two laboratory findings of infection were present.…”

“…Peripheral blood (4 ml) was obtained from healthy neonates (BW > 2,800 g; GA >38 wk (37)(38)(39)(40)(41); n = 9-10), and PBMCs were isolated by Histopaque (Sigma-Aldrich, St Louis, MO). PBMCs were cultured in Roswell Park Memorial Institute medium with GlutaMAX (Invitrogen, Carlsbad, CA) supplemented with 2% penicillin/streptomycin (SigmaAldrich) at 37 °C , 5% CO 2 for 1 h. Nonadherent lymphocytes were collected and cultured for 4, 24, or 48 h in the presence or absence of PHA (0.1 mg/ml; Sigma-Aldrich), as previously described (40).…”