Qspcjpujdt!jo!Jogbout; Dpogmjdujoh!Qbsbejhnt

Transcription

1 Qspcjpujdt!jo!Jogbout; Dpogmjdujoh!Qbsbejhnt Cathy Hammerman Dept. Neonatology Shaare Zedek Medical Center Hebrew University Faculty of Medicine Ofpobuft Bsf!Opu/// Njojbuvsf!Bevmut"

2 Qspcjpujdt!jo!Jogbout;!Dpogmjdujoh!Qbsbejhnt Population Dose Duration Primary Endpoint NEC Prophylaxis Premature Neonates al cfu x 1-2/day Full feeds / Term Gestation Incidence and severity NEC Nutramigen Supplemented Formula Term Infants 10 8 cfu/gm formula; all intake No limitation Diarrhea? Atopic eczema? J/Obuvsbmjtn JJ/Opo.efqsjwbujpo JJJ/Bctpmvuf!Sfmbujwjtn JW/Fmvtjwf!Joubohjcjmjuz

3 Qsfufsn!Hvu!bu!Sjtl!; Ofdspuj{joh!Foufspdpmjujt!)OFD* NEC is one of the most common GI problems of premature infants, affecting 5%-20% of infants LBW infants. Mortality 20-50% 1,000 deaths/yr in the US. Increased mortality in those lower gestational age. with 25-40% survivors at risk for subsequent neurodevelopmental impairment. Qsfufsn!Hvu!bu!Sjtl!; Ofdspuj{joh!Foufspdpmjujt!)OFD* Immature intestine is characterized by impaired mucosal barrier function which potentially increased gut permeability. Normally, at this stage of development the intestine is protected by a sterile fetal environment. Neonates enter the world with a sterile gut. However, the world which they enter is a contaminated one and bacterial colonization begins immediately. Within the first 24 hours of life, organisms are acquired from maternal vaginal, skin and rectal microflora. Healthy term, breast fed infants: Enterobacteria, E. coli, enterococci and lactobacilli are the first colonizers.

4 Jouftujobm!Njdspgmpsb!jo!8!Ebz!Pme!Ufsn!Jogbout The greatest difference in the microbiota of breastfed and formula-fed infants lies in the relative numbers of bifidobacteria. Obuvsbm!Efwfmpqnfou!pg!Jouftujobm!Njdspgmpsb;! Ufsn!Ofpobuf However, gut colonization in preterm infants is characterized by an prevalence of pathogenic bacteria Separation from mother Antibiotics Delayed feeding When the leaky intestinal barriers of the premature intestine are exposed to the pathologic bacteria colonizing the premature intestine, NEC may ensue.

5 Obuvsbm!Efwfmpqnfou!pg!Jouftujobm! Njdspgmpsb;!Cjgjepcbdufsjb!jo!Jouftujobm!Gmpsb Day of Life Bifidobacteria range from 60% - 90% of the total fecal microbiota in term breastfed infants. Outcome: Probiotics for NEC Prophylaxis Study Probiotics Ctrl RR [n] [n] [95% CI] Dani BinNun Lin Lin (2) Hoyos Total Favors Probiotics Favors

6 On March 10, 2006, The Norwegian Food Safety Authority (Mattilsynet) decided that Nutramigen 1 with Lactobacillus rhamnosus GG (LGG) could not be marketed in Norway as medical food for infants (0-4 months). One of our major concerns regarding supplementation of infant food with LGG, is the possible long-term effects from any factors that affect the establishment of intestinal microbiota in early infancy. Qspcjpujd!Obuvsbmjtn May help to naturalize abnormally pathogenic microflora of the premature gut Might have longterm un-natural [interfering?] effect on the development of the microbiota in infants with otherwise normally developing microflora

7 Obuvsbmjtn Uif! obuvsbm! ifbmjoh! gpsdf! xjuijo! fbdi! pof! pg! vt! jt! uif! hsfbuftu! gpsdf! jo! hfuujoh! xfmm/! Pvs! gppe! tipvme! cf! pvs! nfejdjof///! pvs! nfejdjof! tipvme! cf!pvs!gppe/ Hippocrates (460 BC BC) Opo.Efqsjwbujpo;! B!Efwfmpqnfoubm!Jnqfsbujwf In prematures, natural gut colonization with protective Bifidobacteria is both delayed and impaired, 2 o exposure to maternal microflora Delayed enteral feeding Frequent exposure to long-term, broadspectrum antibiotics Should the normal condition of the premature neonate therefore be ll id d b f

8 Njdspcjbm!Efqsjwbujpo!Tzoespnf;! Jouftujobm!Wbtdvmbuvsf Normal colonization of the gut is necessary for development of a healthy intestinal vasculature: Animals raised in a germ-free environment have poorly developed intestinal vasculature. (a) Capillary network in the small intestinal villi of a germ-free mouse Bacteria restore intestinal angiogenesis: (b) Capillary network in the small intestinal villi of an age matched, previously gnotobiotic mouse taken 10 days after microbiota was restored with normal flora harvested from a conventionally raised donor mouse. Stappenbeck TS, et al. Proc Natl Acad Sci U S A a b Njdspcjbm!Efqsjwbujpo!Tzoespnf A normal microbiota is needed not just for intestinal angiogenesis, but also for normal immune function and normal intestinal epithelial development. Too little microbial stimulation early in life can lead to: Hypoplastic intestinal epithelia Abnormal gut motility with peristalsis Conversely, introduction of normal flora to gnotobiotic animals restores intestinal function, mucosal proliferation and immune development, and improves barrier function. The significance of all of these regulatory functions culminates at an early age, once the mucosal barrier and immune system mature

9 Qspcjpujd!Opo.Efqsjwbujpo Is it safe to give an infant probiotic supplements? Is it safe not to give a pathogenically colonized premature neonate or a relatively deprived term infant probiotic supplements? Bctpmvuf!Sfmbujwjtn;!B!Cbmbodjoh!Bdu! Xifo!zpv!bsf!dpvsujoh!b! ojdf! hjsm! bo! ipvs! tffnt! mjlf! b! tfdpoe/! Xifo! zpv! tju! po! b! sfe.ipu! djoefs! b! tfdpoe! tffnt! mjlf! bo! ipvs/!uibu(t!sfmbujwjuz/ - Albert Einstein

10 B!Cbmbodjoh!Bdu;!Tipsu!Ufsn! In medicine, perfect safety is unattainable. Safety is not an absolute risk free condition, but rather is a relative state in which benefits outweigh risks and adverse effects are considered minimal. Even if some potentially mild toxicity exists, it must be weighed against health benefits of a treatment which has been shown to have a protective effect against a serious disease with a high mortality or against the potential of as yet unidentified long-term effects Uif!Tipsu!Ufsn!Cbmbodjoh!Bdu;!Jogfdujpo Non-pathogenicity - Lactobacilli are considered to be of low and basically nonpathogenic. Nevertheless, there are four reported cases of lactobacillus sepsis in infants [3-11 mos old]. Three of these had short gut syndrome and one post complicated repair double outlet right ventricle. Lactobacilli and bifidobacteria are ubiquitous in the human diet and the human digestive tract. As such, lactobacillemia may occur naturally without exogenous administration. Do infections necessarily result from probiotic ingestion or might hey be due to natural flora breaching leaky mucosal barriers? There have been no reported cases of bifidobacteria sepsis related to probiotic consumption in infants.

11 Cbmbodjoh!Bdu;!B!Ovnfsjdbm!Qfstqfdujwf 1990 Lactobacillus rhamnosus GG was introduced universally into dairy products in Finland. National surveillance of bloodstream infections by Finland s National Public Health Institute showed that increasing consumption of probiotic lactobacilli did not reveal an increase in bacteremia or in opportunistic infections in consumers (Salminen et al. 2002). A retrospective review of patients with lactobacillemia also showed a predominance of severe underlying conditions. Probiotic ingestion was not mentioned in any of the patients. The risk of infection is in the negligible range, considering universal exposure. B!Cbmbodjoh!Bdu!. cz!uif!ovncfst! Lactobacilli were found in 0.02% of all blood cultures and in 0.2% of blood cultures with any positive bacterial growth. Based on Finnish estimates (assuming universal dairy product ingestion and a background incidence of zero): If 0.02% of blood cultures are positive for lactobacilli, more than 830,000 patients would need to be treated with probiotics and studied prospectively in order to detect a 10% increase in Lactobacillus bacteremia. But even this is probably an underestimation, as blood was cultured in the Finnish study for clinical indications; the expected yield would be even lower if we routinely cultured blood from healthy patients who ingested probiotics prophylactically.

12 Cbmbodjoh!Bdu. Ovnfsjdbm!Qfstqfdujwf Prematures/ NEC NNT 8-30 ~8 NNH -Lactobacillus Sepsis (NEC studies combined) -Lactobacillus Sepsis (Finnish Data) -Adverse metabolic, immunological effects ??? Infants/ Atopic Eczema

13 Bctpmvuf!Sfmbujwjtn;!B!Tipsu!Ufsn! Cbmbodjoh!Bdu! Lactobacillus sepsis is extremely rare; bifidobacteria sepsis 2 o probiotic ingestion has not been reported Other short term morbidities confer minimal to nonexistent risk to infants Long term risks are, as yet, unknown. Potential risk of disease to be prevented is varied; related morbidity and mortality also varied. NEC with up to 50% mortality Eczema Diarrhea Mpoh!Ufsn!Cbmbodf; Fmvtjwf!Joubohjcjmjuz!!! Mjgf! jt! b! mpoh! boe! bsevpvt! rvftu! bgufs! Usvui/! Xibu! jt! fmvtjwf! boe! efdfqujwf! sftpmwft! jutfmg! joup! dsztubm! dmfbsoftt/! Mahatma Gandhi

14 Gspn!Tipsu!up!Mpoh!Ufsn!Cbmbodf/// On weaning and introduction of solid foods, the microbial profile of the breast fed infant becomes similar to that of formula fed, and bifidobacteria no longer predominate in the fecal flora. By year two of life, intestinal microbiota is considered identical to that of adults. As such, is there any long term significance of altering microbiota perinatally? It is possible that there is nothing beyond the short term effects on the microbiota. Possibly existing data are misleading in that they are largely based on culture techniques. Possibly pioneer microorganisms are retained in niches which elude discovery by current methodology. Possibly pioneer microorganisms have persistent effects on the immune system after the organisms themselves are no longer present. The effects on the immune function (immune defense, allergy, autoimmunity) when LGG is given to small children are unknown.

15 Uif!Izhjfof!Izqpuiftjt Over the years, there has been a in infectious diseases [A] in industrialized countries, with a concurrent in allergic and autoimmune diseases [B]. It s been suggested [BachNEJM 2002; 347:911] that microbial exposure during early infancy is critical for subsequent development of a healthy immune response; avoiding autoimmune pathology by inducing self tolerance. Conversely with a lack of exposure to microorganisms during infancy, the mucosal immune system fails to develop properly, leading to a greater risk for the development of atopic and autoimmune disease. This can occur 2 o improved hygiene and antibiotic usage. Nevertheless, public health measures, cleanliness and antibiotics have saved many lives from infection. These should not and cannot be reversed. I m so full of probiotics that every time I sneeze, I might cure someone!

16 Sfwfstjoh!uif!Izhjfof!Izqpuiftjt! Even in term infants, there is a relative lack of early microbial exposure in developed, hygienic world. How might probiotic formula supplements shift this delicate balance in term infants? Furthermore, in premature neonates, even the normal, albeit minimal, early exposure is not attained naturally. In prematures, probiotics may be able to serve as surrogates for initial colonization; but is this enough to establish a favorable immune balance? Fmvtjwf!Joubohjcjmjuz! Very little information exists on the long term effects on immune function or microbial ecology of individuals exposed to probiotics in early infancy. It is possible that exposure to probiotics during some critical developmental phase may lead to long term perturbations in fecal microbiota. These perturbations may be harmful to health. Might they also be beneficial???