Distribution of Haptoglobin Phenotype in Septic and Non Septic Pre-term Neonates (PTSH)
Condition: Neonatal Sepsis
MeSH terms: Neonatal Sepsis
Study type: Observational

Summary: 
      The Haptoglobin (Hp) gene locus at chromosome 16q22 is polymorphic with two alleles denoted 1
      and 2 .The gene product exists in three phenotypes: 1-1, 2-1, and 2-2.

      The Haptoglobin 2 allele is found only in man and is believed to have arisen from the
      Haptoglobin 1 allele by a partial intragenic duplication. Haptoglobin 2 allele frequency is
      higher than the Haptoglobin 1 allele. It has been hypothesized that the Haptoglobin 2 allele
      was spread in man due to its selective advantage against life-threatening infections.

      In vitro, only the Haptoglobin 2 allele protein, binds to the streptococcus T antigen,
      resulting in its aggregation and slowing its growth .

      Individuals homozygous for the Haptoglobin 1 allele (1-1 genotype) are more prone to the
      streptococcal infection than individuals with the Haptoglobin 2 allele(2-1 or 2-2 genotype).

      The investigators wish to explore the linkage between Hp phenotype and sepsis in pre-term
      neonates, considering that in this early stage in life, genetic properties which provide a
      defense against infectious agents will be of heightened importance.
    

Detailed description: 
      The Haptoglobin (Hp) gene locus at chromosome 16q22 is polymorphic with two alleles denoted 1
      and 2 .The gene product exists in three phenotypes: 1-1, 2-1, and 2-2. Hp 2 allele DM
      individuals have larger myocardial infarctions than homozygous Hp 1 DM individuals. This may
      be due to differences in the antioxidant and anti-inflammatory properties of these
      proteins.The same phenomenon was demonstrated in a murine coronary ischemia-reperfusion
      model.

      The Haptoglobin is an acute phase protein with anti-oxidant, bacteriostatic and
      anti-inflammatory functions.

      The Haptoglobin 2 allele is found only in man and is believed to have arisen from the
      Haptoglobin 1 allele by a partial intragenic duplication. Haptoglobin 2 allele frequency is
      higher than the Haptoglobin 1 allele. It has been hypothesized that the Haptoglobin 2 allele
      was spread in man due to its selective advantage against life-threatening infections.

      In vitro, only the Haptoglobin 2 allele protein, binds to the streptococcus T antigen,
      resulting in its aggregation and slowing its growth .

      We proposed that in individuals homozygous for the Haptoglobin 1 allele (1-1 genotype), the
      streptococcal infection would be more severe than in individuals with the Haptoglobin 2
      allele (2-1 or 2-2 genotype).

      During a severe outbreak of impetigo in two infantry units in the Israeli Defense Forces,
      over 60% (57/91) of the soldiers developed impetigo caused by a single pathogen-group A
      streptococcus. 33% of them developed serious life-threatening complications requiring
      hospitalization. The risk of Haptoglobin 1-1 genotype individuals developing severe infection
      was significantly higher than individuals with Haptoglobin 2 genotype (45.5% (5/11) vs. 17.5%
      (14/80), risk ratio 2.6 (95% confidence interval 1.2-5.8), p=0.05). This supports the notion
      that the Haptoglobin genotype determines the susceptibility to streptococcus infection, an
      important pathogen early in human evolution, and explains the spread of Haptoglobin 2 allele
      in human.

      Another study demonstrated that Diabetic dialysis patients at the age of 60 and above
      carrying the Hp1-1 phenotype had a lower mortality rate compared to the patients who are
      Hp2-2. However, younger population has shown the opposite. This can be explained by the
      survivorship pattern of Hp1-1 diabetic patients who have lower risk for diabetic
      complications. They will also survive dialysis in older age by suffering less from vascular
      complications compared to Hp2-2. However, in Hp2-2 younger patients, the infectious parameter
      is more significant and mortality will be lower.

      We wish to explore the linkage between Hp phenotype and sepsis in pre-term neonates,
      considering that in this early stage in life, genetic properties which provide a defense
      against infectious agents will be of heightened importance.

      During the study period of one year, all preterm neonates (a total of 150 preterm babies, 35
      weeks or younger) admitted to the preterm unit at Carmel hospital will be typed for Hp
      phenotype by a blood test. Hp phenotyping needs only about 500 microliters of blood which
      will be taken during routine blood drawn. All blood samples will be identified with the
      patient's I.D. number and name in addition to the study consecutive serial number. The blood
      samples will be sent to the laboratory of vascular medicine in the faculty of medicine at the
      Technion. If the number of participating infants during one year will be insufficient (less
      than 150), we will ask for additional permission of the ethical committee to continue the
      study for the second year.

      Septic neonates will be recognized by clinical deterioration (abnormal body temperature
      and/or disturbed skin perfusion and/or apathy and/or increase in apnea/bradycardia episodes
      and/or abnormal CBC, leukocytosis or leucopenia or left shift or thrombocytopenia) and
      concomitant positive blood cultures, without another explanation of non infectious etiology.
      Details of the bacteria including antibiotic resistance profile will be documented.
      Demographic data will be collected for all patients.

      In addition data regarding known pre-maturity complications such as Retinopathy of
      Pre-maturity (ROP), Necrotizing Entero-Colitis (NEC), Broncho-Pulmonary Dysplasia (BPD) will
      be assessed and documented according to the admission summary.

      Blood transport, Hp typing and data collection will be done by a MD student as part of her MD
      thesis.

      As part of the informed consent, we will ask the permission for a possible follow up one year
      after discharge from the hospital which will be done by a phone questionnaire and acquiring
      the patients medical file data with the help of his family
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        All preterm neonates ( a total of 150 preterm babies, 35 weeks or younger) admitted to the
        NICU in Carmel hospital.
      
Biospecimen description: 
      Hp phenotype in blood test.
    
Keywords: Haptoglobin; sepsis; premature babies