The investigation of many hemostatic defects in the newborn is limited by the lack of normal reference values. This study was designed to determine the postnatal development of the human coagulation system in the healthy full-term infant. Consecutive mothers of healthy full-term infants born at St JosePh′s Hospital in the city of Hamilton were approached for consent. One hundred eighteen full-term infants (37 to 42 week's gestational age) were entered into the study. Demographic information and a 2-mL blood sample were obtained in the postnatal period on days 1, 5, 30, 90, and 180. Between 40 and 79 full-term infants were studied on each day for each of the coagulation tests. Plasma was fractionated and stored at -70 degrees C for batch assaying of the following tests: prothrombin time, activated partial thromboplastin time, thrombin clotting time, and factor assays (biologic): fibrinogen, II, V, VII, VIII, IX, X, XI, XII, and high- molecular weight kininogen. Factor XIII subunits A and S, von Willebrand factor, and the inhibitors antithrombin III, alpha 2- antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, C1 esterase inhibitor, protein C, and protein S were measured immunologically. Plasminogen, prekallikrein, and heparin cofactor II were measured by using chromogenic substrates. The large number of infants studied at each time point allowed us to determine the following: the range of normal for each test at five time points in the postnatal period; that coagulation tests vary with the postnatal age of the infant; that different coagulation factors show different postnatal patterns of maturation; and that near-adult values are achieved for most components by 6 months of life. In summary, this large cohort of infants studied consecutively in the postnatal period allowed us to determine the normal development of the human coagulation system in the full-term infant.

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This study was designed to determine the postnatal development of the human coagulation system in the healthy premature infant. Consecutive mothers of healthy premature infants born at either St Joseph's Hospital or McMaster University Medical Centre in Hamilton were asked for consent. One hundred thirty-seven premature infants (30 to 36 weeks of gestational age) entered the study. The premature infants did not have any major health problems and did not require ventilation or supplemental oxygen. Demographic information and a 20-mL blood sample were obtained in the postnatal period on days 1, 5, 30, 90, and 180. Between 40 and 96 premature infants were studied on each day for each of the following tests: prothrombin time, activated partial thromboplastin time, thrombin clotting time, plasminogen; 13 factor assays [fibrinogen, II, V, VII, VIII, IX, X, XI, XII, XIII, high-mol-wt kininogen (HMWK), prekallikrein (PK), von Willebrand factor (vWF)] and eight inhibitors [antithrombin III (AT-III), heparin cofactor II, alpha 2-antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, C1 esterase inhibitor, protein C (PC), and protein S (PS)]. A combination of biologic and immunologic assays were used. Between 30 to 36 weeks there was a minimal effect of gestational age for levels of AT-III, PC, and factors II and X only; therefore, the entire data set was used to generate reference ranges for these components of the coagulation system for premature infants. Next, the results for the premature infants were compared with those of a previously published study in 118 fullterm infants and with those for adults. An effect of gestational age was shown for plasminogen, fibrinogen, factors II, V, VIII, IX, XI, XII, HMWK, and all eight inhibitors. In general, the postnatal maturation towards adult levels was accelerated in premature infants as compared with the fullterm infants. By 6 months of age, most components of the coagulation system in premature infants had achieved near adult values.

A cohort study was performed to determine the postnatal development of the coagulation system in the “healthy” premature infant. Mothers were approached for consent and a total of 132 premature infants were entered into the study. The group consisted of 64 infants with gestational ages of 34-36 weeks (prem 1) and 68 infants whose gestational age was 33 weeks or less (prem 2). Demographic information and a 2 ml blood sample were obtained on days 1, 5, 30, 90, and 180. Plasma was fractionated and stored at −70°C for batch assaying of the following tests: screening tests, PT, APTT; factor assays (biologic (B)); fibrinogen, II, V, VII, VIII:C, IX, X, XI, XII, prekallikrein, high molecular weight kininogen, XIII (immunologic (I)); inhibitors (I), antithrombin III, aα2-antiplasmin, α2-macroglobulin, α-anti-trypsin, Cl esterase inhibitor, protein C, protein S, and the fibrinolytic system (B); plasminogen. We have previously reported an identical study for 118 full term infants. The large number of premature and full term infants studied at varying time points allowed us to determine the following: 1) coagulation tests vary with the gestational age and postnatal age of the infant; 2) each factor has a unique postnatal pattern of maturation; 3) near adult values are achieved by 6 months of age; 4) premature infants have a more rapid postnatal development of the coagulation system compared to the full term infant; and 5) the range of reference values for two age groups of premature infants has been established for each of the assays. These reference values will provide a basis for future investigation of specific hemorrhagic and thrombotic problems in the newborn infant.

IntroductionThe REGAL (RSV [respiratory syncytial virus] Evidence—a Geographical Archive of the Literature) series provides a comprehensive review of the published evidence in the field of RSV in Western countries over the last 20 years. This first of seven publications covers the epidemiology and burden of RSV infection.MethodsA systematic review was undertaken for articles published between Jan 1, 1995 and Dec 31, 2015 across PubMed, Embase, The Cochrane Library, and Clinicaltrials.gov. Studies reporting data for hospital visits/admissions for RSV infection among children (≤18 years of age), as well as studies reporting RSV-associated morbidity, mortality, and risk factors were included. Study quality and strength of evidence (SOE) were graded using recognized criteria.Result2315 studies were identified of which 98 were included. RSV was associated with 12–63% of all acute respiratory infections (ARIs) and 19–81% of all viral ARIs causing hospitalizations in children (high SOE). Annual RSV hospitalization (RSVH) rates increased with decreasing age and varied by a factor of 2–3 across seasons (high SOE). Studies were conflicting on whether the incidence of RSVH has increased, decreased, or remained stable over the last 20 years (moderate SOE). Length of hospital stay ranged from 2 to 11 days, with 2–12% of cases requiring intensive care unit admission (moderate SOE). Case-fatality rates were <0.5% (moderate SOE). Risk factors associated with RSVH included: male sex; age <6 months; birth during the first half of the RSV season; crowding/siblings; and day-care exposure (high SOE).ConclusionRSV infection remains a major burden on Western healthcare systems and has been associated with significant morbidity. Further studies focusing on the epidemiology of RSV infection (particularly in the outpatient setting), the impact of co-infection, better estimates of case-fatality rates and associated risk factors (all currently moderate/low SOE) are needed to determine the true burden of disease.FundingAbbvie.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-016-0123-0) contains supplementary material, which is available to authorized users.

Specific host/environmental factors can be used to identify which 33-35GA infants are at greatest risk of hospitalization for RSV infection and likely to benefit from palivizumab prophylaxis.

IntroductionThe REGAL (RSV Evidence – A Geographical Archive of the Literature) series has provided a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. This seventh and final publication covers the past, present and future approaches to the prevention and treatment of RSV infection among infants and children.MethodsA systematic review was undertaken of publications between January 1, 1995 and December 31, 2017 across PubMed, Embase and The Cochrane Library. Studies reporting data on the effectiveness and tolerability of prophylactic and therapeutic agents for RSV infection were included. Study quality and strength of evidence (SOE) were graded using recognized criteria. A further nonsystematic search of the published literature and Clinicaltrials.gov on antiviral therapies and RSV vaccines currently in development was also undertaken.ResultsThe systematic review identified 1441 studies of which 161 were included. Management of RSV remains centered around prophylaxis with the monoclonal antibody palivizumab, which has proven effective in reducing RSV hospitalization (RSVH) in preterm infants < 36 weeks’ gestational age (72% reduction), children with bronchopulmonary dysplasia (65% reduction), and infants with hemodynamically significant congenital heart disease (53% reduction) (high SOE). Palivizumab has also shown to be effective in reducing recurrent wheezing following RSVH (high SOE). Treatment of RSV with ribavirin has conflicting success (moderate SOE). Antibodies with increased potency and extended half-life are currently entering phase 3 trials. There are approximately 15 RSV vaccines in clinical development targeting the infant directly or indirectly via the mother.ConclusionPalivizumab remains the only product licensed for RSV prophylaxis, and only available for high-risk infants. For the general population, there are several promising vaccines and monoclonal antibodies in various stages of clinical development, with the aim to significantly reduce the global healthcare impact of this common viral infection.FundingAbbVie.Electronic supplementary materialThe online version of this article (10.1007/s40121-018-0188-z) contains supplementary material, which is available to authorized users.

IntroductionThe REGAL (RSV Evidence—a Geographical Archive of the Literature) series provide a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. The objective of this fifth publication was to determine the long-term respiratory morbidity associated with RSV lower respiratory tract infection (RSV LRTI) in early life.MethodsA systematic review was undertaken for articles published between January 1, 1995 and December 31, 2015. This was supplemented by inclusion of papers published whilst drafting the manuscript. Studies reporting data on the incidence and long-term wheezing and asthma following RSV LRTI in early life were included. Study quality and strength of evidence (SOE) were graded using recognized criteria.ResultsA total of 2337 studies were identified of which 74 were included. Prospective, epidemiologic studies consistently demonstrated that RSV LRTI is a significant risk factor for on-going respiratory morbidity characterized by transient early wheezing and recurrent wheezing and asthma within the first decade of life and possibly into adolescence and adulthood (high SOE). RSV LRTI was also associated with impaired lung function in these children (high SOE). Respiratory morbidity has been shown to result in reduced quality of life and increased healthcare resource use (moderate SOE). The mechanisms through which RSV contributes to wheezing/asthma development are not fully understood, but appear to relate to the viral injury, preexisting abnormal lung function and/or other factors that predispose to wheezing/asthma, including genetic susceptibility, altered immunology, eosinophilia, and associated risk factors such as exposure to environmental tobacco smoke (high SOE).ConclusionThere is growing evidence that RSV LRTI in early childhood is associated with long-term wheezing and asthma and impaired lung function. Future research should aim to fully elucidate the pathophysiological mechanisms through which RSV causes recurrent wheezing/asthma.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-017-0151-4) contains supplementary material, which is available to authorized users.