Johnson et al 199775 evaluated that the rate of meningitis in infants Essay

Johnson et al, (1997)75 evaluated that the rate of meningitis in infants without symptoms of meningitis may be less than 1% in the worst-case scenario. Weiss et al (1991)76, and Eldadah et al (1987)77 reported that asymptomatic infants receiving a sepsis workup because of respiratory distress have meningitis in fewer than 1% of cases.

Adjunctive, nonspecific diagnostic and screening tests: The difficulties in identifying the septic neonate have prompted evaluation of many adjunctive tests that may indicate the possibility of infection, but do not identify the inciting organism.

Because neonatal sepsis is a low-incidence, high-severity disease, it is most important for these adjunctive tests to miss no cases (high sensitivity) and to convincingly rule out sepsis when the disease is not present (high negative predictive accuracy). Tests with a high negative predictive value will typically have a low positive predictive value. Therefore, the goals of adjunctive tests are to serve as a part of the total evaluation of the patient in deciding whether to initiate antibiotic therapy and more importantly, to discontinue antibiotic treatment quickly in those in whom infection is unlikely to be present.

Adjunctive Tests for Diagnosing neonatal sepsis (Gerdes, 2004)78

White blood cell (WBC) an differential counts

Immature to total neutrophil Ratio

C-reactive protein (CRP)

Micro-ESR (Erythrocyte sedimentation rate)

Haptoglobin

Acridine orange stain

Fibronectin

Nitro blue tetrazolium ( NBT) Test

Orosomucoid

Soluble interleukin ( SIL)-2 receptor

Elastase alpha-1 proteinase inhibitor complex

Interleukin 6

Neutrophil CD11b

Granulocyte-colony stimulating factor (G-CSF)

Procalcitonin

Bacterial polymerase chain factor ( PCR)

Inter-alpha-inhibitor proteins

Interleukin 8

Tumour necrosis factor ?

White Blood Cell Count: The most frequently determined adjunctive test is the WBC and differential count, and related indices such as the absolute neutrophil count (ANC), IT ratio, total WBC, and immature leukocyte count. Manroe et al (1977)79, demonstrated that in their population, the lower limit for ANC, for example, was 1800/mm3 at birth, rose to 7200/mm3 at 12 hours of age, and then declined to 1800/mm3 by 72 hours of age.

IT Ratio: Another commonly used WBC index is the immature to total neutrophil ratio, defined as band forms plus any earlier cells such as metamyelocytes divided by the total neutrophil count (early forms plus polymorphonuclear cells). Manroe et al. (1979)80 defined the upper limit of normal IT at 0.16 in the first 3 days of life, and found a high sensitivity but weak specificity for diagnosis of sepsis using this cutoff; however, subsequent work has shown a higher limit for normal values for IT in healthy neonates, up to 0.27 (Schelonka et al,1994)81.

Further population-based studies showed only moderate sensitivity and specificity for sepsis, using an upper limit of 0.25 to 0.30 (Escobar et al, 2000)82.

Although many cytokines and inflammatory markers have been proposed as diagnostic tests for early-onset sepsis (EOS), none has been of sufficient predictive value to gain wide acceptance. Some cytokines are only secreted over a limited time frame during the start of infection, and inflammatory markers may be more sustained in their presence. C-reactive proteins are useful to exclude infection and stop antibiotics. Investigations suggest that procalcitonin and IL-6 used together may enhance laboratory diagnosis of EOS (Bender et al, 2008)83.

Akin to maternal diagnostic studies for infection, alpha1-proteinase inhibitor complex, cytokines (eg, IL-1 and IL-6 in particular, IL-1 receptor antagonist), and detection of bacterial products in neonatal blood have not gained widespread use as markers of neonatal sepsis. However, these effectors of inflammation may prove to have better predictive accuracy than WBC tests or the CRP. Procalcitonin may have better sensitivity, specificity, and positive and negative predictive value than CRP in the diagnosis of early onset neonatal sepsis (Joram et al, 2006)84. None of these tests for EOS is routinely used, especially in suburban or rural hospitals with maternity services.

The study of surface markers of inflammation on leukocytes has provided variable diagnostic use in EOS (Ng et al, 2006)85. More research is needed in this field.

Molecular methods to identify pathogenic bacteria in neonatal blood have engendered enormous interest because a rapid diagnosis is possible. Most hospital laboratories do not have the equipment because it is expensive and the training of laboratory personal takes considerable time. A wide range of molecular probes is also required to accomplish this diagnostic task. (Ohlin and Rossner, 1996)86.

Studies have re-examined the WBC counts and the leukocyte profiles present in extremely preterm infants (Christensen et al, 2006)87. Other diagnostic tests (eg, inflammatory factors, adhesion molecules, cytokines, neutrophil surface antigens, or even bacterial DNA) may be superior alternatives to this test. To date, these markers of neonatal inflammation/infection have not replaced leukocyte counts as diagnostic methods.

?

Predictive value of adjunctive Diagnostic Tests (Gerdes, 2004)73:

Sensitivity

(%) Specificity

(%) Positive Predictive value (%) Negative Predictive Value (%)

ANC ?1750/mm 38-96 61-92 20-77 96-99

ANC?10% (1.0mg/dL 70-93 78-94 7-43 97-99.5

WBC?5000/mm3 IT?0.2, and CRP>1.0mg/dL

(Screen +if 2/3 are abnormal) 100 83 27 100

Other investigators have stressed that cases of meningitis are missed with this approach. The medical literature contains good evidence that meningitis may occur in association with sterile blood cultures. Because meningitis is a devastating neonatal infection, no lumbar puncture may result in inadequate antibiotic therapy. Thus, many believe a lumbar puncture should be performed as part of the evaluation for EOS (Wiswell et al, 1995)88.

A low total leukocyte count below 5,000 has also been correlated with the diagnosis of neonatal sepsis, although many septic infants have higher counts, giving this test a low sensitivity of 29 %, but a reasonable specificity of 91% (Gerdes, 1991)78.

WBC profiles and kinetics are influenced by the genetic make-up of the patient, the gestational age, maternal noninfectious disorders such as pregnancy-induced hypertension (PIH), medications administered to the mother, fetal disease, and other factors. Reference range WBC counts in the neonate do not exclude infection, and serial studies of WBC indices at approximately 6-hour intervals may be more useful in detecting sepsis (Christensen, 1987)89. A continued assessment of WBC kinetics offers more information regarding decision making. For example, a physician should be particularly concerned with a falling total WBC count, a declining absolute mature neutrophil count, and a rising immature-to-total neutrophil ratio. These findings, taken together, indicate depletion in the bone marrow–related storage pool of neutrophils (Christensen et al, 1982)90.

Rozycki et al (1987)91, reported 13 (21%) patients with a falsely normal WBC screening test. The patients with true positive and falsely normal WBC counts did not differ by risk factors for sepsis, birth weight, age, outcome or severity of the disease. However, there was a significant delay between the screening test and the positive blood culture in patients with false normal WBC counts and not in the patients with positive abnormal WBC counts (14.9±5.9 hours vs. 2.8±1.4hr, mean±SD, p less than 0.001). A WBC count obtained soon after birth as currently utilized may not adequately screen for early-onset neonatal sepsis.

An outcome of Neonatal sepsis:

Respiratory Outcome:

Most recently, a cohort study including 301 infants with a gestational age of 32 weeks has outlined another interesting effect of prenatal exposure to inflammation respiratory physiology in infants at risk for RDS and BPD (Been et al, 2010)92. Histological chorioamnionitis deteriorated the response to exogenous surfactant associated with a longer need for mechanical ventilation in this study. This effect was more prominent in infants who also had histological signs of a fetal inflammatory response. In the group of infants treated with an exogenous surfactant, those with a fetal inflammatory response developed BPD more frequently than those without signs of systemic inflammation.

These observations underline that chorioamnionitis has synergistic effects with mechanical ventilation on the development of BPD. Moreover, they allow the assumption that RDS after preterm birth resulting from chorioamnionitis may be distinct from that after preterm birth due to other reasons (Jobe &Kallapur, 2010)93.

Thus, current evidence suggests that histological chorioamnionitis seems to decrease the risk of RDS in preterm infants through a maturational effect which in turn seems to contribute to susceptibility of the lung for further postnatal injury.

Fig. 3. Potential pathogenic sequences linking exposure of the fetus to prenatal inflammation with subsequent disturbed lung development and cerebral injury under the further influence of postnatal factors (Wolfgang Thomas and Christian P. Speer, 2011).

In addition to the activation of inflammation and adverse neurologic outcomes, the risk of long-term pulmonary disease may be heightened. Controversy is declining about the significance of colonization or in utero infection because many studies show Ureaplasma and Mycoplasma are strongly related to fetal inflammatory response and chronic lung disease of prematurity. Congenital pneumonia caused by Ureaplasma and Mycoplasma often requires longer mechanical ventilation and oxygen therapy of preterm infants and initiates a prolonged cytokine release in the neonatal lung (Namba et al, 2010)95.

In the late 1990s, an association between elevated amniotic fluid concentrations of proinflammatory cytokines and the development of BPD was demonstrated. These data suggested that fetal aspiration of cytokines contributes to a local pulmonary inflammation which makes the lung more susceptible to further injury from barotrauma or oxygen toxicity. In a retrospective study, amniotic fluid concentrations of matrix metalloproteinase-8 and intraamniotic white blood cell counts were higher in infants born with gestational age 32 weeks who developed BPD without RDS compared to infants with BPD after RDS (Lee et al, 2009)96.

Clinical chorioamnionitis has been identified as an independent risk factor for RDS in premature infants, whereas histological chorioamnionitis seems to confer a beneficial effect on the incidence of RDS (Dempsey et al, 2005)97.

Neurological outcome

Most recently, the large multicenter ELGAN (extremely low gestational age newborn) study supplied strong epidemiological evidence for a role of prenatal inflammation in the evolution of WMD and CP in infants at highest risk for these outcomes. Placental tissue for histological and microbiological assessment could be obtained from more than 1,200 infants born in 1 of 14 participating institutions before 28 weeks of gestation of which 899 of them had a neurological examination by the corrected age of approximately 24 months. Histological chorioamnionitis, as well as detection of microorganisms from placental tissue, predicted ventriculomegaly, detected by cranial ultrasound and diparetic CP at follow-up. Moreover, recovery of microorganisms was also associated with cerebral white matter echolucencies in ultrasound scans (Leviton et al, 2010)98.

With advances in neonatal care the incidence of cystic PVL, diagnosed by cranial ultrasound, has decreased in extremely premature infants. With the emergence of magnetic resonance imaging (MRI) noncystic diffuse or focal white matter disease (WMD) has been recognized as the most prevalent form of brain injury associated with adverse neurodevelopmental outcome in these infants (Miller et al, 2005)99.

Cerebral palsy (CP), a nonprogressive impairment of posture and motor function, is a major cause for physical disability in childhood. In very premature infants, CP is clearly associated with cystic periventricular leukomalacia (PVL). Epidemiological studies addressing the risk for cystic PVL and later development of CP after perinatal infection/inflammation have come to variable results. Elevated cytokine levels in amniotic fluid and in cord blood, indicating FIRS, were described to be related with CP in preterm and term neonates (Nelson et al, 2003)100.

Intraventricular haemorrhage in the premature infant:

The association of chorioamnionitis with IVH in premature infants has been addressed in several studies.

Most of them suggested histological chorioamnionitis as a risk factor for IVH (Dexter et al, 2000)101, whereas others did not (Sarkar et al, 2005)102.

Increased concentrations of proinflammatory cytokines in umbilical cord blood as markers of a fetal inflammatory response did not consistently predict further development of IVH (Heep et al, 2003)103.

Effect on Retina

Recent evidence suggests an association between chorioamnionitis and retinopathy of prematurity (ROP). Higher rates of ROP have been demonstrated in infants born to mothers with histological and clinical chorioamnionitis relative to mothers without chorioamnionitis. (Sato et al, 2011)104.

Chorioamnionitis and the accompanying fetal inflammatory response syndrome may increase the risk of ROP by directly sensitising the developing retina to oxygen-induced changes in vasoeffective growth factor availability and subsequent vascular development and/or by causing systemic hypotension resulting in retinal hypoperfusion/ischemia (Liu et al, 2005)105.

Impact of pPROM with a special focus on baby’s weight

The direct costs of prematurity are immense. One of the major impacts identified from pPROM is poor development of baby and underweight. Estimated results from Lewit and colleagues showed that the cost of health care, child care as well as education for those born at the low birth weight was around a total of 6 billion US $, (1988 $ higher) than for those of normal weight up to 15 years of age.

Noor et al., (2007)106 investigated in determining the overall prevalence of pPROM. The study concluded from the sample population that a total of 53 (62.3%) babies born to mothers with pPROM were the low birth weight which includes 10 (11.76%) babies of extremely low birth and 30 (35.29%) babies of very low birth weight. Perinatal epidemiology shifted from measuring birthweight alone to focusing on gestational age. However, many studies, even of related pregnancy outcomes, continue to omit key measures of gestational age. pPROM infants with maternal antecedents of cerebral palsy were found to have very CP in very-low-birth-weight infants.

Necrotizing enterocolitis in preterm infants

Regardless of the statement that necrotizing enterocolitis is deliberated a sickness of premature new-borns, 20% of all pretentious new-borns at Babies Hospital over the past 20 years were products of term pregnancies. Two separate subcategories of such new-borns were distinguished: (1) five new-borns with inherited cardiac disease or congestive heart failure (e.g., hypoplastic left heart syndrome), all but one of whom progressive the disease in the first week of life; (2) eight new-born who established the disease at a greatly later age after a prolonged period of diarrhoea. The histopathologic structures of the sickness in term newborns are the same as those in untimely new-borns. Additionally, the pathogenesis of the disease in term new-borns does not seem to fluctuate fundamentally from that in premature newborns. These shreds of evidence, lead away from the perception of NEC as a disease of unassuming aetiology.

A technique of clinical dramatization for new-borns with necrotizing enterocolitis (NEC) is projected. On the base of allocated phase at the time of analysis, 48 new-borns were treated with categorized interference. The stages are classified as

Stage 1. Suspected NEC: gastric residuals, occult/ gross blood present in stool, abdominal distension, x-ray normal to mild distension, temperature instability, apnea, bradycardia

Stage 2. Definite NEC: mild to moderate systemic illness, absent bowel sounds, abdominal tenderness, pneumatosis intestinalis or portal venous gas, metabolic acidosis, decreased platelets

Stage 3. Advanced NEC: severely ill, marked distension, signs of peritonitis, hypotension, metabolic & respiratory acidosis, DIC, pneumoperitoneum if bowel perforation present

For Stage I new-borns, forceful diagnostic and sympathetic procedures are applicable. Stage II new-borns are treated pathologically, comprising parenteral and gavage aminoglycoside antibiotic, and Stage III patients need an operation. All Stage I patients was persisted, and 32 of 38 Stage II and III patients (85%) persisted the acute incident of NEC. Bacteriologic assessment of the gastrointestinal microflora in these neonates has exposed a widespread series of enteric organisms comprising anaerobes. Enteric organisms were cultured from the blood of four new-borns vanishing of NEC. Consecutive cultures of enteric organisms expose a modification of flora for the period of gavage