Low incidence of severe bacterial infections in hospitalised patients with COVID-19: A population-based registry study.

BACKGROUND: Bacterial infections complicating COVID-19 are rare but present a challenging clinical entity. The aim of this study was to evaluate the incidence, aetiology and outcome of severe laboratory-verified bacterial infections in hospitalised patients with COVID-19. METHODS: All laboratory-confirmed patients with COVID-19 admitted to specialised healthcare hospitals in the Capital Province of Finland during the first wave of COVID-19 between 27 February and 21 June 2020 were retrospectively studied. We gathered the blood and respiratory tract culture reports of these patients and analysed their association with 90-day case-fatality using multivariable regression analysis. RESULTS: A severe bacterial infection was diagnosed in 40/585 (6.8%) patients with COVID-19. The range of bacteria was diverse, and the most common bacterial findings in respiratory samples were gram-negative, and in blood cultures gram-positive bacteria. Patients with severe bacterial infection had longer hospital stay (mean 31; SD 20 days) compared to patients without (mean 9; SD 9 days; p < 0.001). Case-fatality was higher with bacterial infection (15% vs 11%), but the difference was not statistically significant (OR 1.38 CI95% 0.56-3.41). CONCLUSIONS: Severe bacterial infection complicating COVID-19 was a rare occurrence in our cohort. Our results are in line with the current understanding that antibiotic treatment for hospitalised COVID-19 patients should only be reserved for situations where a bacterial infection is strongly suspected. The ever-evolving landscape of the pandemic and recent advances in immunomodulatory treatment of COVID-19 patients underline the need for continuous vigilance concerning the possibility and frequency of nosocomial bacterial infections.

Childhood cancer survival in Finland (1953-2010): a nation-wide population-based study.

Population based survival studies are critical in monitoring changes in anticancer therapy, evaluating effectiveness of new treatments as well as identifying possibilities for further improvement. The previous report on cancer survival in Finland covered patients diagnosed in 1953-1995. Data on survival in the European and Nordic pediatric populations have been published with follow-up ending in 2002. We describe population-based survival of childhood cancer patients (n = 8270, age 0-14 years) in Finland overall and by disease category with follow-up extending from 1953 to 2010 and focusing on the modern treatment era. Data were collected from the Finnish Cancer Registry. Age-standardised observed survival proportions (rates) were calculated using the actuarial (or life-table) method. Trends in observed survival rates were studied over six diagnostic periods: 1953-1960, 1961-1970, 1971-1980, 1981-1990, 1991-2000 and 2001-2010. The overall 5-year survival reached 82.1% (95% CI 80.0-84.2) in the most recent period. In most diagnostic categories, the biggest leap in survival was seen between 1961-1970 and 1981-1990, after which slight improvements occurred between 1981-1990 and 1991-2000, with no significant increase thereafter. In analyses by diagnostic group, positive trends in survival over the last three decades were seen for leukemia (p = 0.000), non-Hodgkin's lymphoma (p = 0.002) and CNS tumours (p = 0.02). Although survival of childhood cancer patients overall has significantly improved from 1953 to 2000, improvement thereafter has been marginal. Future treatment efforts should be directed at bone tumours, soft-tissue sarcoma, neuroblastoma and malignant brain tumours as well as high-risk leukemia.

Higher angiopoietin-2 and VEGF levels predict shorter EFS and increased non-relapse mortality after pediatric hematopoietic SCT.

The roles of angiogenesis and angiogenic factors after allogenic hematopoietic SCT (HSCT) and during acute GVHD (aGVHD) are not known. Studies on pediatric patients are extremely scarce. Levels of angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF) were analyzed from blood samples of 67 consecutive patients. The levels were correlated with aGVHD grades, routine laboratory parameters and outcome. Pre-transplant Ang2 values correlated with the occurrence of intestinal aGVHD (P=0.009), whereas post-transplant measurements correlated with the severity of skin and liver aGVHD (P=0.03, P=0.04, respectively). Pre-transplant levels of VEGF were associated with the occurrence of skin aGVHD (P=0.04), whereas post-transplant levels correlated to the severity of intestinal aGVHD (P=0.04). High Ang2 levels were associated with shorter EFS (P=0.039) and increased non-relapse mortality (NRM) (P=0.009). In conclusion, higher Ang2 levels predict higher NRM and, with coexisting high VEGF, also shorter EFS after pediatric HSCT. Our results suggest that both pre- and post-transplant levels of Ang2 and VEGF seem to correlate to the clinical state of the patient. However, the pathophysiology of this connection needs further studies.

Lactobacillus GG treatment during pregnancy for the prevention of eczema: a randomized controlled trial.

BACKGROUND: Probiotic supplementation in early life may be effective for preventing eczema. Previous studies have suggested that prenatal administration may be particularly important for beneficial effects. OBJECTIVE: We examined whether prenatal treatment with the probiotic Lactobacillus rhamnosus GG (LGG) can influence the risk of eczema during infancy. METHODS: We recruited 250 pregnant women carrying infants at high risk of allergic disease to a randomized controlled trial of probiotic supplementation (LGG 1.8 × 10(10) cfu/day) from 36 weeks gestation until delivery. Infants were assessed during their first year for eczema or allergic sensitization. Immunological investigations were performed in a subgroup. Umbilical cord blood was examined for dendritic cell and regulatory T cell numbers and production of TGFß, IL-10, IL-12, IL-13, IFN-γ and TNFα. Maternal breast milk was examined for total IgA, soluble CD14 and TGFß. RESULTS: Prenatal probiotic treatment was not associated with reduced risk of eczema (34% probiotic, 39% placebo; RR 0.88; 95% CI 0.63, 1.22) or IgE-associated eczema (18% probiotic, 19% placebo; RR 0.94; 95% CI 0.53, 1.68). Prenatal probiotic treatment was not associated with any change in cord blood immune markers, but was associated with decreased breast milk soluble CD14 and IgA levels. CONCLUSIONS: Prenatal treatment with Lactobacillus rhamnosus GG was not sufficient for preventing eczema. If probiotics are effective for preventing eczema, then a postnatal component to treatment or possibly an alternative probiotic strain is necessary.

Reduced membrane bound CD14 expression in the cord blood of infants with a family history of allergic disease.

BACKGROUND: Infants at increased risk of allergic disease have altered immune function at birth, but the specific immune changes described differ between studies and their precise nature is not well defined. Changes affecting innate immune responses may be particularly important in allergic disease pathogenesis. OBJECTIVE: We investigated whether inherited risk of allergic disease is associated with altered markers of innate immunity, T cell regulation or dendritic cell (DC) percentage in human newborns. METHODS: Cord blood was collected from infants at low risk (no parent affected by allergic disease, n=14), intermediate risk (one affected parent, n=54) or high risk (two affected parents, n=25) of developing allergic disease. Cord blood mononuclear cells were cultured with ovalbumin (OVA), lipopolysaccharide, lipoteichoic acid (LTA), heat-killed lactobacillus, alpha-CD3 or medium alone. Cells were analysed by flow cytometry for expression of CD14, FoxP3 and DC percentage, and by real-time RT-PCR for TLR2 and TLR4 expression in infants at intermediate or high risk of allergic disease. RESULTS: Infants at high risk of allergic disease had reduced percentage of CD14(+) monocytes (P=0.01) and reduced CD14 mean fluorescence intensity (P=0.01) in uncultured mononuclear cells. They also had decreased DC percentage in mononuclear cells cultured with OVA (P=0.04), lipopolysaccharide (P=0.01), LTA (P=0.02) and alpha-CD3 (P=0.03) as compared with infants at intermediate or low risk of allergic disease. No relationship was seen between risk of allergic disease and TLR2 or TLR4 expression, or FoxP3 expression in cultured cells. CONCLUSIONS: Infants with a biparental history of allergic disease have altered markers of innate immunity at birth, with reduced expression of membrane bound CD14 and consequently reduced in vitro development of DCs. Further work is needed to understand the role that these alterations play in the pathogenesis of allergic disease, and whether interventions to up-regulate fetal CD14 expression can prevent allergic disease.

Effects of Lactobacillus GG treatment during pregnancy on the development of fetal antigen-specific immune responses.

BACKGROUND: Several clinical trials suggest that probiotics may have a role in the prevention of eczema. The optimal timing and mechanisms underlying this intervention are not clear. In particular it is not known whether such treatment works during pregnancy or whether postnatal exposure is important. OBJECTIVE: We investigated whether the probiotic Lactobacillus rhamnosus strain GG (LGG) influences fetal immune responses when administered to pregnant women, as a possible mechanism for its protective effects against the development of eczema. METHODS: Peripheral blood mononuclear cell from 11 adults treated with LGG, and cord blood mononuclear cells (CBMCs) from 73 women participating in a randomized controlled trial of LGG treatment were cultured with heat-killed LGG, ovalbumin (OVA) or without stimulus. Cells were analysed by flow cytometry and real-time PCR for markers of dendritic cell (DC) phenotype, T cell proliferation and regulation. Cytokine secretion was analysed in culture supernatants by multiplex cytokine assay. RESULTS: LGG treatment of adults led to systemic immune responses suggestive of antigen-specific tolerance including reduced CD4(+) T cell proliferation to heat-killed LGG (30% reduction; P=0.03). LGG treatment of pregnant women did not influence CD4(+) T cell proliferation, forkhead box P3 expression, DC phenotype or cytokine secretion in CBMCs cultured with heat-killed LGG or OVA. CONCLUSION: LGG treatment of pregnant women fails to influence fetal antigen-specific immune responses. This suggests that modulation of fetal immune responses may not be a major mechanism by which probiotics such as LGG prevent eczema.

Elevated serum transferrin receptor concentration in children with juvenile chronic arthritis as evidence of iron deficiency.

OBJECTIVES: Active juvenile chronic arthritis (JCA) is accompanied by anaemia of chronic disease, which may be indistinguishable from anaemia due to iron deficiency. We speculate that elevation of the serum transferrin receptor (sTfR) concentration, which should not be influenced by inflammation, would be useful for detecting the role of iron status in anaemic children with JCA. METHODS: sTfR concentrations were measured in 30 children with JCA. RESULTS: The median sTfR was elevated, 6.1 (range 3.4-13.0) mg/l. In 13 patients (43%) the concentrations exceeded the upper limit for healthy subjects. Haemoglobin (r = - 0.48, P = 0.008), mean corpuscular volume (r = - 0.47, P = 0.009) and mean corpuscular haemoglobin (r = - 0.65, P = 0.0001) correlated inversely with sTfR concentration. CONCLUSIONS: In 13 of the 30 patients with JCA, the sTfR concentration, which is an indicator of iron status and erythropoiesis, was elevated. The results raise the possibility that sTfR is able to distinguish iron-deficiency anaemia from anaemia of chronic disease. It should be further explored as a candidate.

The serum transferrin receptor concentration in seven fetuses with hemolytic disease.

Six pregnant women who received intrauterine transfusions and their seven fetuses were followed during gestation. Hemoglobin concentration, hematocrit value, serum ferritin, and serum transferrin receptor (TfR) concentrations were measured. In the fetal samples, there was a tendency for the TfR concentration to decrease during gestation and after the intrauterine transfusions. Serum TfR values varied between 0.7 and 5.2 mg/L, which is near the postnatal level measured in premature infants. On the contrary, one would have expected to find highly elevated values due to the active fetal erythropoiesis. The fetal regulation of TfR production may differ from that described postnatally.

Oral iron is sufficient for erythropoietin treatment of very low birth-weight infants.

UNLABELLED: The aim of this study was to compare two different doses and means of administration of iron in recombinant human erythropoietin (rHuEPO)-treated very low birth-weight (VLBW) infants. VLBW infants (n = 41) were randomized to one of three groups. Fourteen infants were treated with rHuEPO (300 IU/kg three times a week s.c.) and oral iron (ferrofumarate, 6 mg of iron/kg per day). Another 14 infants received the same erythropoietin dose and intramuscular iron (ferroxypolymaltose, once 12 mg of iron/kg weekly). Thirteen infants were treated with the same dose of intramuscular iron but did not receive rHuEPO. After the 3-week study period, haemoglobin concentrations and reticulocyte counts were similar in the rHuEPO-treated groups and both were higher than in the group not receiving rHuEPO (P < 0.001). In both rHuEPO-treated groups the transferrin receptor concentration increased from 6.8-7.2 mg/l to 10.5-11.3 mg/l. CONCLUSION: In erythropoietin-treated very low birth weight infants the iron need for erythropoiesis can be met by oral administration of iron.

Very low rate of type I collagen synthesis and degradation in newly diagnosed children with acute lymphoblastic leukemia.

In children with acute lymphoblastic leukemia (ALL), the metabolism of type I collagen, the major collagen of bones, may be changed at diagnosis and during early chemotherapy. In the present study, bone formation and degradation rates were evaluated longitudinally in 35 children with ALL, using two serum markers of bone collagen formation: the amino-terminal (PINP) and carboxyterminal (PICP) propeptides; and a marker of degradation: the carboxyterminal telopeptide of type I collagen (ICTP). These serum markers were determined at diagnosis, during induction treatment (at 1, 4, and 6 weeks), and during consolidation treatment (at 8 and 12 weeks). The changes in the serum markers suggested that, at diagnosis, type I collagen turnover (i.e., both synthesis and degradation) was remarkably low. The median serum levels of PINP, PICP, and ICTP were -2.6 SDS (standard deviation score), -1.5 SDS, and -2.5 SDS, respectively. The PICP and PINP levels declined further during the first week of therapy (p < 0.001), whereas the ICTP levels had risen by end of the induction phase (p < 0.05). By the end of the 12 week interval, the concentrations of the formation and degradation markers had returned to normal (p < 0.01). Our findings suggest that ALL is accompanied by low turnover of bone collagen. The abnormalities are at first aggravated, but then corrected, by treatment.

Mechanism underlying early anaemia in children with familial juvenile nephronophthisis.

Familial juvenile nephronophthisis (NPH) is a hereditary form of chronic tubulointerstitial nephritis with onset in childhood. About one-third of patients develop anaemia before renal insufficiency. We investigated the pathogenetic mechanisms leading to anaemia by comparing 6 patients with NPH and 12 reference patients with other renal diseases. We studied their iron metabolism and measured transferrin receptor-ferritin ratios. There was no evidence for iron deficiency or haemolysis. The serum erythropoietin concentrations of the patients with NPH (12 +/- 2.3 U/I) were low compared with the 12 reference patients (25 +/- 18.9 U/I). In the 2 patients with NPH who were fully investigated, the pharmacokinetics of recombinant human erythropoietin appeared normal. Thus, anaemia in patients with NPH does not result from iron deficiency or correlate with impaired iron status. The mechanism underlying the anaemia of NPH appears to affect the function or regulation of the cells producing erythropoietin.

Peripheral blood cell counts in infants with Down's syndrome.

The current literature indicates that several abnormalities have been observed in the three hematopoietic cell lines of infants with Down's syndrome. This prospective, longitudinal study was designed to clarify the physiological variation in peripheral blood cell values of children with Down's syndrome by following 25 such infants during their first year of life. Apart from polycythemia in the first week of life, the hemoglobin concentration was, in general, the same as in normal term infants. At 9-12 months of age values for mean corpuscular hemoglobin and mean corpuscular volume tended to be elevated. Serum erythropoietin concentrations were low to normal. White blood cell counts were slightly lower in children with Down's syndrome than in normal children. The study infants had profound thrombocytosis from the age of 6 weeks to the end of follow-up at 1 year. This study, the first longitudinal follow-up of such subjects, indicates that infants with Down's syndrome often have evidence of polycythemia soon after birth and red blood cell macrocytosis and thrombocytosis later in infancy. In conclusion, we carried out peripheral blood cell counts in 25 infants with Down's syndrome, but with no actual hematological disturbance, during their first year of life, and compared them with values for normal term infants.

Iron availability is transiently improved by intravenous iron medication in patients on chronic hemodialysis.

Iron deficiency is common in hemodialysis patients, particularly if they are on recombinant human erythropoietin (rHuEPO) therapy. Ten anemic patients (hemoglobin concentration 89 +/- 2.2 g/l, mean +/- SEM) on hemodialysis with either storage (serum-ferritin < 60 mg/l) and/or functional (S-transferrin saturation < or = 17%) iron deficiency were followed for 5 weeks. During the first 3 weeks they were given 100 mg of iron dextran on 10 consecutive dialysis sessions. Half of the patients were concomitantly treated with rHuEPO. Iron therapy resulted in a rapid elevation in serum transferrin iron saturation from 11 +/- 1.5% to 80 +/- 7.2% (p < 0.0001), but it decreased to pre-treatment levels within 2 weeks after discontinuation of iron therapy. Serum ferritin concentration increased from 157 +/- 73 mg/l to 434 +/- 105 mg/l during iron therapy (p < 0.0001). In spite of this only 4 patients (2 rHuEPO treated) responded and had a hemoglobin increment > 10 g/l. In the whole group serum transferrin receptor (TfR) levels remained stable, but increased after the cessation of iron dextran only in the rHuEPO treated patients (p < 0.01). In the responders the TfR levels were higher during iron therapy than in the nonresponders (p < 0.02). In an attempt to explain the resistance to iron therapy, serum concentrations of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1b (IL-1b) were also analyzed.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum transferrin receptor and erythropoiesis in children with newly diagnosed acute lymphoblastic leukemia.

Thirty-five children with acute lymphoblastic leukemia were monitored weekly during the first 12 weeks of chemotherapy. The transferrin receptor (TfR) concentration was 2.8 +/- 0.2 mg/l (mean +/- S.E.M.) at diagnosis, decreased up to 3 weeks, and then increased reaching a maximal level at 8 weeks. The mean values for reticulocyte counts followed a similar pattern. In contrast, serum erythropoietin and ferritin levels were generally high. Those patients whose erythropoiesis was more accelerated had higher serum TfR concentrations. We conclude that among these patients the TfR level reflected the rate of erythropoiesis and was independent of the level of erythropoietin.

Is serum transferrin receptor useful for detecting iron-deficiency in anaemic patients with chronic inflammatory diseases?

We investigated whether determination of serum transferrin receptor (TfR) is useful for detecting iron-deficiency in patients with chronic inflammatory diseases and for differentiating between iron-deficiency anaemia and anaemia of inflammation. Using an immunofluorometric assay, serum TfR was measured in 34 anaemic patients. Of these patients, 23 had a chronic rheumatic disease, 13 with both inflammation and iron-deficiency and 10 with anaemia of inflammation only; the other 11 patients had iron-deficiency anaemia and no evidence of inflammation. Serum TfR concentrations were lower in patients with anaemia of inflammation (2.6 +/- 0.2 mg/l, mean +/- S.E.M.) than in patients with iron-deficiency anaemia (6.7 +/- 1.1 mg/l, P < 0.01) or those with both inflammation and iron deficiency (5.8 +/- 1.0 mg/l, P < 0.01). Among patients with inflammatory disease, correlations between TfR and ferritin concentrations (r = -0.62, P < 0.05) and TfR and erythropoietin concentrations (r = 0.69, P < 0.001) were observed in iron-deficient subjects only. TfR, though not superior to serum ferritin, can help to distinguish between anaemia of inflammation and iron-deficiency anaemia and to identify iron-deficiency in subjects with chronic inflammation.

Early rise in serum concentration of transferrin receptor induced by recombinant human erythropoietin in very-low-birth-weight infants.

The serum transferrin receptor (TfR) level reflects iron status and the rate of erythropoiesis. This study was undertaken to assess the role of serum TfR in the iron status and erythropoiesis in very-low-birth-weight infants under conditions in which erythropoiesis is stimulated by large doses of recombinant human erythropoietin (rHuEPO) and oral iron. The first 34 infants were followed from the 3rd to 11th wk of life or until discharged. They received iron at a rate of 3 mg/kg/d. The subsequent 21 infants were given rHuEPO (300 U/kg three times a week s.c.) and iron at a rate of 6 mg/kg/d from the 3rd or 4th wk of life for a mean of 3.4 wk. With this treatment, the need for transfusion was reduced from 1.4 +/- 0.4 to 0.1 +/- 0.1 transfusions per infant (p = 0.02). The serum TfR concentrations in the rHuEPO-treated infants increased gradually to values several-fold higher than those in the untreated infants. This increase was not related to intrauterine or postnatal growth, protein intake, or serum albumin concentration. Neither was an association observed between Hb and TfR concentration. In the treated infants, the serum ferritin concentration was lower at the 4th, 5th, and 7th wk of life than in the untreated infants. The very-low-birth-weight infants who were given large doses of rHuEPO and iron had a marked rise in serum TfR concentration and a small decline in serum ferritin concentration. These events have been related to iron deficiency.

Erythropoiesis of very low-birth-weight infants dependent on prenatal growth rate and protein status.

This study investigated erythropoiesis in very low-birth-weight infants with special reference to the role of protein status in the regulation of erythropoiesis in 22 appropriate- and 11 small-for-gestational-age infants. Blood samples were drawn at three and six weeks of age. The serum concentrations of erythropoietin, estimated by a solid-phase enzyme immunoassay, were similar in the two groups at both study ages. The total circulating erythrocyte volume and the serum concentration of prealbumin were higher in the appropriate- than in the small-for-gestational-age infants at three and six weeks of age. The former group had a better protein status, although their protein intake was similar or lower. We conclude that erythropoiesis in very low-birth-weight infants is influenced more by protein status and prenatal growth than by serum concentration of erythropoietin.

Serum transferrin receptor for assessment of iron status in healthy prepubertal and early pubertal boys.

A recently introduced test measures the concentration of transferrin receptor (TfR) in serum, which increases shortly after the onset of iron deficiency. In adults this increase reflects the degree to which tissue iron availability is impaired. We developed a fluoroimmunoassay to quantify TfR. The purpose of this study was to evaluate the role of TfR as an index of iron sufficiency in 62 healthy prepubertal or early pubertal boys. The mean concentration of serum TfR was 3.8 (-1 SEM = 3.6, +1 SEM = 3.9) mg/L. No associations were observed between the serum TfR and the concentration of Hb, the values of packed cell volume, reticulocyte production index, mean corpuscular Hb, mean corpuscular volume, or the concentrations of serum iron, transferrin, or ferritin. Because none of the subjects had signs of iron deficiency, we determined the 95% reference intervals for Hb, red blood cell indices, and the above-mentioned serum concentrations. The reticulocyte count and reticulocyte production index were higher than expected. Our results indicated that the individual concentration of TfR in serum does not depend on any of the several other parameters of iron status in a group of healthy individuals.