Differences in cardiac geometry in relation to body size among neonates with abnormal prenatal growth and body size at birth.

OBJECTIVES: Both excessive and restricted fetal growth are associated with changes in cardiac geometry and function at birth. There are significant issues when indexing cardiac parameters for body size in the neonatal period. The aims of this study were to determine to what extent cardiac geometry is dependent on body size in term and preterm neonates with restricted or excessive fetal growth and how this is affected by adiposity. METHODS: This was a cross-sectional study of neonates born between 31 and 42 weeks of gestation, divided into three groups: (1) small-for-gestational age (SGA, birth weight > 2 SD below the mean); (2) large-for-gestational age (LGA, birth weight > 2 SD above the mean); and (3) appropriate-for-gestational-age controls (AGA, birth weight ≤ 2 SD from the mean). Cardiac geometry and function were compared between the study groups, adjusting for body size. The potential impact of infant adiposity and maternal disease was assessed. RESULTS: In total, 174 neonates were included, of which 39 were SGA, 45 were LGA and 90 were AGA. Body size was reflected in cardiac dimensions, with differences in cardiac dimensions disappearing between the SGA and AGA groups when indexed for body surface area (BSA) or thoracic circumference. The same was true for the differences in atrial and ventricular areas between the LGA and AGA groups. However, left ventricular inflow and outflow tract dimensions did not follow this trend as, when indexed for BSA, they were associated negatively with adiposity, resulting in diminished dimensions in LGA compared with AGA and SGA neonates. Adiposity was associated positively with left ventricular mass, right ventricular length and area and right atrial area. The SGA group showed increased right ventricular fractional area change, possibly reflecting differences in the systolic function of the right ventricle. We found evidence of altered diastolic function between the groups, with the mitral valve inflow E- to lateral E'-wave peak velocity ratio being increased in the LGA group and decreased in the SGA group. CONCLUSIONS: Cardiac geometry is explained by body size in both term and preterm AGA and SGA infants. However, the nature of the relationship between body size and cardiac dimensions may be influenced by adiposity in LGA infants, leading to underestimation of left ventricular inflow and outflow tract dimensions when adjusted for BSA. Adjustments for thoracic circumference provide similar results to those for BSA. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Comparative seroepidemiology of diphtheria in six European countries and Israel.

Serological surveys for diphtheria were conducted in six European countries including Czech Republic, Hungary, Ireland, Latvia, Luxembourg, Slovakia and one country outside Europe, Israel. For each country, a nationally representative population sample was collected across the entire age range and was tested for antibodies to diphtheria toxin. Although each national laboratory used its preferred assay, the results were all standardized to those of the in vitro neutralization test and expressed in international units (IU) which allowed comparative analyses to be performed. The results showed that increasing age is related to a gradual increase in seronegative subjects (<0·01 IU/ml of diphtheria antitoxin antibodies). This may reflect waning immunity following childhood vaccination without repeated booster vaccinations in adults. Differences in seronegativity were also found according to gender. In subjects aged 1-19 years, geometric mean titres of antitoxin are clearly related to the different vaccination schedules used in the participating countries. Although clinical disease remains rare, the susceptibility to diphtheria observed in these serosurveys highlights the importance of strengthened surveillance.

A randomized study on donor immunization with tetanus-diphtheria, Haemophilus influenzae type b and inactivated poliovirus vaccines to improve the recipient responses to the same vaccines after allogeneic bone marrow transplantation.

The HLA-identical sibling donors of 111 bone marrow transplantation (BMT) recipients were randomised to receive or not to receive tetanus-diphtheria (T-d), Haemophilus influenzae type b (Hib), and inactivated poliovirus (IPV) vaccines 2-10 weeks before BM harvest. Fifty-three (DV+ group) recipients received the graft from a vaccinated donor and 58 (DV- group) from an unvaccinated donor. All recipients were vaccinated with the T-d, Hib and IPV vaccines at 3, 6 and 12 months after BMT. Diphtheria and Hib antibody concentrations were consistently higher in the DV+ than in the DV- group from 6 months post transplantation onwards. The differences were significant at 6 and 13 months for diphtheria and at 12 months for Hib antibody concentrations. Tetanus, PV1, PV2 and PV3 antibody levels were similar in both groups. Patients transplanted from donors with high tetanus, diphtheria and Hib antibody concentrations had higher respective antibody concentrations after BMT than those transplanted from donors with low antibody concentrations. Especially patients whose donors have low-specific antibody concentrations may benefit from donor vaccination with protein and conjugate vaccines.

Passively acquired anti-tetanus and anti-Haemophilus antibodies and the response to Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infancy.

OBJECTIVE: To study the influence of maternally inherited tetanus antitoxin (anti-TT) antibodies on the response to the Haemophilus influenzae type b (Hib) capsular polysaccharide (PS)-tetanus toxoid conjugate (PRP-T) vaccine. DESIGN: One hundred thirty healthy infants received their first dose of PRP-T in the same syringe with diphtheria-tetanus-pertussis vaccine (DTP) at 1 to 2 months, and 66 of them received a second dose at 3 to 4 months of age. RESULTS: Maternal anti-TT antibodies did not interfere with the anti-Hib PS response to the first PRP-T vaccination; the geometric mean concentration (GMC) of anti-Hib PS was 0.14 microgram/ml in those with the lowest preimmunization anti-TT (< 0.3 IU/ml, n = 15) and 0.13 microgram/ml in those with the highest anti-TT (> or = 3 IU/ml, n = 25). After the second dose of PRP-T there was a positive correlation (r = 0.37, P = 0.004) between the anti-Hib PS response and the preimmunization anti-TT; those with the lowest preimmunization anti-TT (< 0.3 IU/ml, n = 9) achieved GMC of anti-Hib PS of 1.22 micrograms/ml and those with anti-TT > or = IU/ml (n = 22) anti-Hib PS GMC of 2.67 micrograms/ml. High preimmunization anti-Hib PS antibodies did not interfere with the final antibody concentrations; the GMC of anti-Hib PS after the second dose of PRP-T was 1.60 micrograms/ml in those with a preimmunization titer > or = 1.0 microgram/ml (n = 12) and 1.57 micrograms/ml in those with a titer of < 1.0 microgram/ml (n = 53). CONCLUSION: The data suggest that infants can be safely vaccinated with PRP-T even though they have received high concentrations of anti-TT from their mother.

Effect of transplacentally acquired tetanus antibodies on the antibody responses to Haemophilus influenzae type b-tetanus toxoid conjugate and tetanus toxoid vaccines in Filipino infants.

BACKGROUND: Pregnant women in developing countries are vaccinated with tetanus toxoid (TT) to prevent neonatal tetanus. In populations in which the maternal TT-vaccination program is efficiently implemented, responses of the infant to TT and TT-conjugated vaccines such as Haemophilus influenzae type b (Hib) capsular polysaccaride (PS) TT-conjugate (Hib-TT) vaccine may be depressed. OBJECTIVES: To study the influence of transplacentally acquired anti-TT antibodies on responses to TT vaccination and to Hib-TT vaccine. METHODS: One hundred ninety-four healthy Filipino infants received three doses of a Hib conjugate (either Hib-TT, PRP-OMP or HbOC) with diphtheria-tetanus-pertussis vaccine (DTP) given simultaneously but in a separate syringe at the age of 6, 10 and 14 weeks (primary series). In addition 54 of the study children received a booster dose of Hib-TT at 9 months simultaneously with the measles vaccine. RESULTS: Transplacentally acquired anti-TT did not interfere with the anti-Hib PS antibody (anti-Hib PS) response to any of the conjugates. The transplacentally acquired anti-TT was not significantly associated with the concentration of anti-Hib PS either before or after the booster dose of Hib-TT. High concentrations (> or =1 IU/ml) of transplacentally acquired anti-TT inhibited the infants' anti-TT responses. CONCLUSIONS: High concentration of transplacentally acquired anti-TT did not depress anti-Hib PS responses to the Hib-TT vaccine. On the other hand the high anti-TT concentrations somewhat depressed the anti-TT responses of the infants. However, the anti-TT concentrations attained were in the protective range in all study children after either the primary series (DTP + Hib-TT) or the booster dose of Hib-TT.

Cell-mediated immune responses to antigens of Bordetella pertussis and protection against pertussis in school children.

BACKGROUND: Increasing evidence suggests that cell-mediated immunity (CMI) is involved in immune response against Bordetella pertussis. However, there are practically no studies evaluating the significance of pertussis-specific CMI in relation to protection against clinical pertussis. METHODS: An outbreak of pertussis was studied prospectively in 13-year-old pupils in a rural school. B. pertussis infection was diagnosed by culture, microagglutination and enzyme immunoassay serology with the use of pertussis toxin, filamentous hemagglutinin and pertactin as antigens. Pertussis-specific CMI responses were assessed by in vitro proliferation assay of peripheral blood mononuclear cells. RESULTS: At the initial sampling 7 of 22 children had symptoms suggestive of pertussis and 15 were asymptomatic. Of the latter 3 remained healthy, 8 were later confirmed to have had asymptomatic infection, 3 developed laboratory-confirmed pertussis and 1 developed cough without laboratory evidence of pertussis. Initial in vitro proliferations of peripheral blood mononuclear cells induced by pertussis toxin, filamentous hemagglutinin and/or pertactin were positive in all 3 healthy children, in 6 of 8 children who had asymptomatic infection, but in none of the 3 children who later developed pertussis. Although some children who remained healthy had high values of antibodies, no clear association was found between initial serum antibody values and clinical outcome. CONCLUSIONS: These preliminary data suggest that CMI may have an important role in protection against clinical pertussis but do not exclude a role for antibodies. Furthermore the results stress a multifactorial nature of the immune protection against B. pertussis.

Loss of protective immunity to polio, diphtheria and Haemophilus influenzae type b after allogeneic bone marrow transplantation.

Immunity to poliovirus, diphtheria and Haemophilus influenzae type b (Hib) was studied in 16 adult recipients of a bone marrow transplant from an HLA-identical sibling donor in order to evaluate the need for revaccinations. T-cell depletion was not done in any case. The donors and patients were studied before bone marrow transplantation (BMT) and the patients 1, 3, 6, and 12 months later. Prior to the BMT 10 of 11 patients were immune (titre > or = 4) to all vaccine poliovirus types by a standard microneutralization assay. At 12 months after BMT only two of seven patients were immune to all vaccine types, and none had immunity against an antigenically altered poliovirus type 3 strain Finland. The geometric means of antibody titres against poliovirus types 1, 2, and 3 strain Saukett and strain Finland declined gradually after 1 month postgrafting, being 4.4, 5.4, 3.3, and 1.3 respectively at 12 months after BMT. At 1 year 6 of 11 patients had immunity against diphtheria by a toxin neutralization method, but the antitoxin geometric mean level had decreased to a barely protective level, 0.01 IU/ml. The geometric mean Hib antibody concentration decreased during the first 6 months after BMT and thereafter increased slightly. A significant proportion of BMT recipients lose their protection against polio, diphtheria and Hib, and revaccinations are necessary.

A randomized comparison between early and late vaccination with tetanus toxoid vaccine after allogeneic BMT.

Forty-five adult HLA-matched sibling BMT recipients were randomized to receive tetanus toxoid (TT) vaccine at 6, 8 and 14 months (early group, n = 23) or at 18, 20 and 26 months after BMT (late group, n = 22). At 6 months after BMT, prior to the first vaccination, 90% of the early group patients had a protective tetanus antibody concentration of > or = 0.1 HU/ml (passive haemagglutination test) but only 70% of the late group patients did so at 18 months after BMT. The antibody responses 1 month after each of the three TT vaccine doses were similar in the two vaccination groups, except that after the first dose, four-fold responses occurred more frequently in the late group. All vaccinated patients achieved the protective antibody concentration of > or = 0.1 HU/ml. In the late group the recipient antibody responses after the first and second vaccine doses correlated with the donor anti-TT level. A tetanus vaccination schedule consisting of three vaccine doses is equally immunogenic when started at 6 or 18 months after BMT. Donor immunity against tetanus may influence recipient responses to TT vaccination.

The role of the O antigen in adjuvant activity of lipopolysaccharide.

Adjuvant activities of isogenic Salmonella enterica, serovar Typhimurium, O-6,7 and O-4,5,12 lipopolysaccharide (LPS), lipid A and Bordetella pertussis LPS were compared by immunizing groups of mice subcutaneously with diphtheria and tetanus toxoid vaccine alone or mixed with one of the LPS derivatives. Five weeks later the mice were bled and the tetanus and diphtheria antibodies in the sera were measured. All the LPS derivatives efficiently increased the antibody responses when compared to the vaccine alone, but the mannose-rich O-6,7 LPS and lipid A were significantly more potent than O-4,5,12 LPS and B. pertussis LPS. We conclude that the quality of the O antigen influences the adjuvant activity of LPS.

The 20 kDa C-terminally truncated form of pertussis toxin subunit S1 secreted from Bacillus subtilis.

The subunit S1 of pertussis toxin (PT) was purified as the recombinant product BacS1 from the culture supernatant of a Bacillus subtilis strain containing a secretion vector with a DNA fragment coding for the mature subunit S1 inserted downstream of the signal sequence of the alpha-amylase gene. The method of purification was successive ion exchange and adsorption chromatography. BacS1 occurred in two forms (28 and 20 kDa) of which the truncated 20-kDa peptide was the main one in the supernatant. The truncated BacS1 was purified and shown to have the same NH2-terminus as the full-size (28 kDa) BacS1. It was also enzymatically active indicating correct conformation. The truncated BacS1 was also shown to elicit neutralizing and protective antibodies when injected into mice or rabbits.

Treatment of hyperphosphatemia, secondary hyperparathyroidism and hypocalcemia with calcium carbonate favorably modulates vaccination response in uremic rats.

AIMS: Immune dysfunction is characteristic of renal failure, leading to suboptimal antibody generation and increased susceptibility to infections. We tested whether the treatment of uremic phosphate retention by increased calcium carbonate intake will beneficially influence vaccination response in 5/6-nephrectomized rats. METHODS: The nephrectomized (uremic) and sham-operated (control) rats were either fed 0.3% calcium diet (NTX and Sham groups, respectively) or 3% high-calcium diet (Ca-NTX and Ca-Sham groups). All rats were immunized with tetanus toxoid 6 weeks after the operations, and antitoxin levels were measured 7 weeks later. RESULTS: Plasma creatinine was significantly elevated after the nephrectomy: the values (mean +/- SD) in the NTX (n = 16), Ca-NTX (n = 11), Sham (n = 14) and Ca-Sham (n = 8) groups were 97 +/- 14, 93 +/- 17, 66 +/- 7, and 69 +/- 8 micromol/l, respectively. The NTX group developed phosphate retention and secondary hyperparathyroidism, which were completely prevented by the high calcium diet. The mean tetanus antitoxin concentrations of the groups were: NTX 0.25 +/- 0.32; Ca-NTX 0.45 +/- 0.44; Sham 0.58 +/- 0.24 and Ca-Sham 0.64 +/- 0.25 IU/ml (log of geometric mean concentration). The antibody response in the NTX group was significantly lower, i.e. 43% of that in the Sham group (p = 0.003), while the response in the Ca-NTX group was not different from that in the Sham group. The tetanus response of all the uremic rats inversely correlated with the plasma levels of phosphate (r = 0.447, p = 0.02), parathormone (r = -0.409, p = 0.03) and creatinine (r = 0.578, p = 0.002). DISCUSSION: We conclude that renal failure impairs vaccination response in rats, the impairment of which can be favorably modulated by phosphate-binding and PTH-suppressing high-calcium diet.

Plasma exchange or immunoadsorption in patients with rapidly progressive crescentic glomerulonephritis. A Swedish multi-center study.

A therapeutic removal of antibodies may be achieved by immunoadsorption (IA) or by plasma exchange (PE). The aim of this prospective randomised study was to compare the efficacy of these different techniques with regard to treatment of patients with rapidly progressive glomerulonephritis (RPG) having at least 50% crescents. Forty-four patients with a RPG were included for treatment either by IA or PE (with albumin as substitution for removed plasma). All patients were additionally treated with immunosuppression. A median of 6 sessions of PEs were performed in 23 patients compared with 6 IAs in 21 patients. Goodpasture's syndrome (GP) was present in 6 patients (PE 3, IA 3). All of them started and ended in dialysis, two died. Among the remaining 38 patients (26 men, 12 women) 87% had antibodies to ANCA. Creatinine clearance for PE versus IA were at a median at start 17.1 and 19.8 ml/min, and at 6 months 49 and 49 ml/min, respectively. At 6 months 7 of 10 patients did not need dialysis (remaining: IA 0/5 and PE 2/5, n.s.). The extent of improvement did not differ between the groups. Three patients died during the observation period of 6 months (IA 2; PE 1, on HD). Although no difference was found between the IA or the PE group this study shows that the protocol used was associated with an improved renal function in most patients (except for Goodpasture's syndrome) whereas 70% of them could leave the dialysis program.