Impaired immune responses to herpesviruses and microbial ligands in patients with MonoMAC.

MonoMAC is a complex primary immunodeficiency caused by mutations in the myeloid transcription factor GATA2, characterized by multilineage cytopenia with malignant complications and severe infections, including mycobacteria and herpesviruses. We describe the clinical presentation, genetics and antiviral inflammatory responses in a small case series. Two patients presented in childhood with mycobacterial infection and were diagnosed with MonoMAC germline GATA2 variants; their healthy fathers with the same mutations were also studied. Three patients were elderly individuals with acquired GATA2 mutations and malignant haematological conditions. Overall, this study demonstrates the heterogeneous clinical presentation and variation in immunodeficiency caused by GATA2 mutations.

Antibody response to influenza A(H1N1)pdm09 in vaccinated, serologically infected and unaffected pregnant women and their newborns.

OBJECTIVE: To evaluate the serological response in pregnant Danish women immunized during the 2009 pandemic by serologic infection or by vaccination with influenza A(H1N1) Pandemrix(®) and describe levels of passively acquired maternal antibody in their offspring. DESIGN: Observational cohort study. SETTING: Department of Obstetrics, Aarhus University Hospital, Skejby, Denmark, October to December 2009. POPULATION: Pregnant women and their offspring METHODS: Serological analysis of antibodies to influenza A(H1N1)pdm09 by hemagglutination inhibition assay in 197 women and their offspring. Blood samples were collected consecutively at delivery from the mother and the umbilical cord. In a subgroup of 124 of the 197 women, an additional blood sample from gestational weeks 9-12 was available for analysis. MAIN OUTCOME MEASURES: Seroconversion, geometric mean titer, geometric mean-fold rise and protective antibodies. RESULTS: 33 of the 124 subgroup women (27%) seroconverted during pregnancy, 79% after vaccination and 17% after serologic infection (p < 0.001). The geometric mean titer after delivery in non-vaccinated, non-serologically infected women was 17.1 (95%CI 15.7-18.6). The geometric mean titer increased significantly after serologic infection with H1N1 [76.5 (95%CI 51.3-113.9), p < 0.001] and after vaccination [589.6 (95%CI 339.3-1024.7), p < 0.001]. The geometric mean-fold rise (mother at delivery/mother early pregnancy) was significantly higher after vaccination [2.23 (1.93-2.54)] than after serologic infection [1.73 (1.59-1.87), p = 0.013]. In newborns of vaccinated mothers, 89.5% had protective antibody levels compared with 15.8% in newborns of serologically infected mothers (p < 0.001). CONCLUSIONS: Influenza vaccination during pregnancy confers passive immunity to the newborn.

Periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis.

INTRODUCTION: The periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a non-hereditary idiopathic febrile syndrome belonging to the group of autoinflammatory diseases. PFAPA does not cause long-lasting sequelae. An early diagnosis provides treatment possibilities for the patient and comfort to the family. MATERIAL AND METHODS: This study is a retrospective review of the medical records of patients diagnosed with PFAPA and admitted to our clinic from January 1999 to January 2010 (n = 31). RESULTS: The study population (n = 31) consisted of 21 males and ten females: 30 Caucasians and 1 Asian. Normal growth was seen in 30 patients. The median age at onset was 33 months. The mean duration of fever episodes was 4.45 days (95% confidence interval (CI): 3.92-4.98 days), and the mean duration of intervals between fever episodes was 29.66 days (95% CI: 25.31-34.01 days). Concomitantly with the fever, all patients had characteristic symptoms. All patients were asymptomatic in between their fever episodes. Prodromal symptoms were seen in 12 patients. Oral prednisolone was used in 24 patients and caused immediate fever reduction in 87.5%. A reduction in the duration of the asymptomatic interval after treatment was seen in 75.0%. Tonsillectomy was performed in 20 of the 31 patients causing cessation of fever episodes in 70%. Fever episodes continued in 15%, and the postoperative status remained unknown in the last 15%. Spontaneous resolution was seen in four patients. The diagnostic delay had a median duration of 28 months (range 2-160 months). CONCLUSION: The long diagnostic delay of PFAPA gives cause for concern and it indicates a need for greater awareness of the disease so that the diagnosis may be made earlier. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Demographic and clinical characteristics in relation to patient and health system delays in a tuberculosis low-incidence country.

BACKGROUND: Delays in the diagnosis and treatment of tuberculosis (TB) are commonly encountered. METHODS: A study was undertaken among pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) patients in a Danish university hospital to describe demographic and clinical characteristics in relation to delay. RESULTS: Of the 313 patients enrolled, 213 (68%) were diagnosed with PTB and 100 (32%) with EPTB only. Logistic regression analysis of EPTB showed an association with female sex and non-Danish ethnicity. Mean total delay from onset of symptoms until initiation of TB treatment was 123 (95% confidence interval (CI) 106-138) days. Mean patient delay was significantly longer than mean health system delay: 90 (95% CI 74-105) vs 33 (95% CI 23-44) days (p < 0.0001). Delay was independent of ethnicity and significantly shorter for PTB patients compared to EPTB patients. Fever was found to be strongly predictive of a short patient delay (<1 month), whereas weight loss was associated with a long patient delay (> 3 months). In contrast, weight loss was associated with a short health system delay (<1 week). Elevated inflammatory markers were also associated with a short delay in the diagnosis of TB. CONCLUSIONS: This study confirmed a typical delay of months in duration in the diagnosis and treatment of TB in the low endemic country of Denmark. Increased TB awareness is needed, in particular in communities with immigrants originating from high-endemic areas.

Immunodeficiencies in children with chronic post tympanic otorrhoea.

INTRODUCTION: A minority of children treated with ventilation tubes develop chronic otorrhoea. To test the hypothesis that this condition might be caused by an underlying primary immunodeficiency, the immunological status was examined in a group of children with longstanding otorrhoea. MATERIAL AND METHODS: Eighteen children who had suffered from otorrhoea for a minimum of six months and who did not respond to relevant therapy were included. Thorough cleansing and suction was performed including removal of ventilation tubes. Swabs were obtained for microbiology and blood was collected for immunological analyses. RESULTS: One child out of 18 had a normal immune status. Five demonstrated isolated humoral deficiencies, four had isolated cellular deficiencies, whereas combined defects were identified among eight children. The humoral deficiencies consisted of selective or partial immunoglobulin A deficiencies, immunoglobulin G subclass and mannanbinding lectin deficiencies. The cellular deficiencies most often involved the cytotoxic T cells and the natural killer cells. CONCLUSION: Primary immunodeficiencies were very prevalent in a highly selected group of children suffering from longstanding post tympanic otorrhoea. The condition should therefore be considered in case of chronic, refractory otorrhoea. The serostatus should be followed carefully to obtain information of the prognosis. FUNDING: Not relevant. TRIAL REGISTRATION: Not relevant.

[Hereditary periodical fever syndromes]. / Arvelige periodiske febersyndromer.

Autoinflammatory diseases are characterized by attacks of apparently unprovoked inflammation without significant levels of autoantibodies or antigen-specific T-cells. Within the past decade, a number of different genetic causes of fever syndromes have been identified: familial Mediterranean fever (FMF), hyper IgD syndrome, cryopyrin-associated periodic syndromes and tumour necrosis factor receptor-associated periodic syndrome. The recent awareness and recognition of pathogenic mechanism of these diseases have led to new possibilities for medical treatment with targeted biological agents.

Novel STAT1 alleles in a patient with impaired resistance to mycobacteria.

Partial defects in interferon (IFN)-γ signaling lead to susceptibility to infections with nontuberculous mycobacteria. The receptors for IFN-α and IFN-γ activate components of the Janus kinase-signal transducer and activator of transcription (STAT) signaling pathway. Some defects in STAT1 mainly affect IFN-γ signaling, thus resulting in mendelian susceptibility to mycobacterial disease (MSMD). MSMD is a severe disease but patients show a favorable response to anti-mycobacterial chemotherapy. Other defects in STAT1 affect both IFN-α and IFN-γ signaling resulting in mycobacterial and lethal viral disease. We report here a patient with two novel STAT1 alleles, which in combination results in a recessive trait with partial STAT1 deficiency and mycobacterial disease. Cells from the patient did respond to mycobacterial antigen, but both the expression of STAT1 and phosphorylation of STAT1 in response to IFN-γ treatment were reduced. This is the first report of a mutation in the N-terminal part of STAT1 involved in causing mycobacterial disease.

[Urine samples from children collected in their homes]. / Børneurinprøver indsamlet i hjemmet.

INTRODUCTION: Children at high risk of urinary tract infection (UTI) enter a programme for domestic urine sampling at the Paediatric Department in Aarhus. Parents collect urine, describe symptoms and post the samples. We wanted to determine the value of domestic urine sampling and to evaluate the programme. MATERIAL AND METHODS: All samples received in 2004 were studied. RESULTS: A total of 706 urine samples from children in the programme were cultivated. In all 76 children fulfilled the criteria for UTI when culture and symptoms were compared. Dip-slide analysis had a sensitivity of 72% and a negative predictive value of 96%. A total of 329 urine samples with negative dip-slide analyses were collected from children with no urinary tract symptoms. Only 27 of these samples were culture-positive and none of these children developed signs of UTI. CONCLUSION: The results from this study suggest that home urine sampling from children at high risk of UTI with no symptoms does not contribute towards avoiding the development of pyelonephritis. A home urine sample analysis programme for children with symptoms is, however, a valuable instrument for early and efficient treatment of UTI in children with high risk of UTI. Urine samples should only be cultivated if the child has symptoms or the dip-slide test is positive.

Hypothermia of newborns is associated with excess mortality in the first 2 months of life in Guinea-Bissau, West Africa.

OBJECTIVE: To examine the long-term effects of neonatal hypothermia (HT) on survival. METHODS: Using the longitudinal community and hospital surveillance system of the Bandim Health Project, we followed children born between 1997 and 2002 at the only maternity ward in the city. All children's axillary temperature was measured within 12 h of birth. They were followed from birth to 6 months of life through regular home visits. RESULTS: We identified 2926 live births in the study area and 177 deaths before 6 months of age. Based on mortality risk, we defined a temperature below 34.5 degrees C as the cut-off point for HT. Two hundred and thirty-eight (8%) children had HT. Controlled for birth weight, HT was associated with a nearly fivefold increase in mortality during the first 7 days of life [mortality ratio (MR) = 4.81 (2.90-8.00)] and with increased mortality from 8 to 56 days of life [MR = 2.55 (1.29-5.04)]. CONCLUSION: HT is associated with excess mortality beyond the perinatal period up to at least 2 months of age, especially among low-birth-weight children. Hence, failure to comply with the WHO guidelines for care of newborns in low-income countries may have long-term consequences for child survival which have not previously been assessed. The WHO definition of HT should be based on mortality data.

Increased mortality in the year following discharge from a paediatric ward in Bissau, Guinea-Bissau.

BACKGROUND: Few studies in developing countries have examined posthospital mortality and little is known about the magnitude of posthospital mortality and risk factors for long-term survival. A better understanding of the determinants of posthospital mortality could help improve discharge policies and interventions with implications for overall childhood mortality. STUDY POPULATION: In the period from 1991 to 1996 all paediatric admissions coming from the Bandim Health Project's area were registered at the National Hospital in Bissau, Guinea-Bissau. Posthospitalization information from a population-based surveillance system was available for 4153 admissions contributed by 3373 individuals having between 1 and 8 admissions during the period. Three thousand six hundred forty seven (3647) admissions by 2950 children resulted in live discharges. Postdischarge mortality included all deaths during 1 year following live discharge. RESULTS: Among the 221 children who died during the first year after discharge, 170 died in the community and 51 children died during a subsequent hospitalization; thirty-eight died on the day of discharge and almost one third had died within the first 2 weeks. The overall in-hospital and 12-month posthospital mortality was 20%. Compared to the mortality level in the community and controlled for other determinants of childhood mortality, children discharged from hospital had 12 times higher risk of dying during the first 2 weeks after discharge. The mortality rate ratio (MR) was 6.2 (95% confidence interval 3.8-10.2) times higher when we excluded those who died at the day of discharge. For the period 30-91 days after discharge the MR ratio was 3.7 (2.5-5.5), and in the period 3-6 months after discharge, the risk estimate was still 2.5 (1.6-3.9) times higher than community mortality. In a multivariate analysis, the all-dominating risk factor was discharge status as 'fled' in the sense of nonmedical discharge, the MRs being 18.6 (9.5-36.6) in the first 2 weeks after discharge and 4.0 (2.0-8.3) in the remaining part of the first year. Other significant risk factors for postdischarge mortality included ethnic group, housing quality and maternal education, and were similar to risk factors for community mortality. The same diagnoses that had high acute mortality, including anaemia, diarrhoea and 'other', were also associated with high postdischarge mortality. CONCLUSION: There was a marked increase in mortality after hospitalization, the effect being particularly strong for children who fled the hospital. Improved discharge and follow-up policies might have an important impact on survival after paediatric hospitalization. Studies on the effect of focused intervention at discharge are needed.

Persisting high hospital and community childhood mortality in an urban setting in Guinea-Bissau.

AIM: To describe paediatric hospitalization in a West African capital in relation to overall childhood mortality in the community and to evaluate the potential impact of improved management at the hospital. METHODS: Hospital data on child admissions in a 6-year period were linked to information in a community-based longitudinal surveillance system. Paediatric hospitalization rates, risk factors for hospitalizations, community mortality, in-hospital mortality and the proportion of deaths occurring at hospital were examined. RESULTS: Almost 15% of infants and 45% of children less than 5 years of age had been hospitalized, and 24% of all deaths in the community occurred in-hospital. Community infant and under-three mortality rates were 110 and 207 per 1,000 person-years, respectively. In-hospital mortality remained persistently high from 1991 to 1996 and the overall in-hospital mortality was 12%. It was found that wet season, lack of maternal schooling and living in a specific district were significant risk factors for both community and in-hospital death, whereas higher hospitalization rates were associated with better-off families. CONCLUSION: In populations with high hospitalization rates, even minor improvements in acute case management of sick children attending the hospital would be expected to result in substantial reduction in overall childhood mortality. Persistently high acute in-hospital mortality reflects the need of immediate and appropriate care at the hospital. Treatment should be free of charge, in order to minimize the impact of social inequality.

DTP with or after measles vaccination is associated with increased in-hospital mortality in Guinea-Bissau.

BACKGROUND: The sequence of routine immunisations may be important for childhood mortality. Three doses of diphtheria-tetanus-pertussis vaccine (DTP) should be given at 6, 10, and 14 weeks and measles vaccine (MV) at 9 months of age. The sequence is not always respected. We examined in-hospital mortality of children having received DTP with or after measles vaccine. SETTING: The only paediatric ward in Bissau, Guinea-Bissau. PARTICIPANTS: Children hospitalised during two periods in 1990-1996 and 2001-2002 who had received MV prior to hospitalisation. MAIN OUTCOME MEASURE: The all-cause case fatality at the hospital for children aged 6-17 months. RESULT: The case fatality was increased for children who had received DTP with or after measles vaccine compared with children who had received measles vaccine as the most recent vaccine, the ratio being 2.53 (1.37-4.67) and 1.77 (0.92-3.41) in the two periods, respectively. The combined estimate was 2.10 (1.34-3.28). These results were not explained by differences in nutritional status, number of doses of DTP or discharge policy. CONCLUSION: Administration of DTP with, or after MV, may reduce the beneficial effect of MV.

Childhood mortality after oral polio immunisation campaign in Guinea-Bissau.

Though previous studies have suggested a non-specific beneficial effect of oral polio vaccine (OPV), there has been no evaluation of the mortality impact of national polio immunization days. On the other hand, studies examining the effect of OPV and diphtheria-tetanus-pertussis (DTP) vaccines, which are usually administered together in routine immunisation programmes in low-income countries, have found no beneficial or even a negative effect on infant survival. In 1998, we used the opportunity of two national immunisation days to examine the impact of OPV administered alone on survival for the 6103 children less than 5 years of age in the Bandim Health Project's study area in Guinea-Bissau. Survival was ascertained through regular surveillance from March 1998 until the beginning of the war on June 7, 1998, the end of 1998, or the end of 1999, respectively. The child register was linked with a register for the only paediatric ward in Bissau to determine the risk of hospitalisations. Among children under 5 years of age, 82% had received 1 or 2 doses of polio vaccines during the campaign. Though polio vaccination during the campaign was associated with slightly lower mortality, this difference was not significant for all children under 5 years of age (mortality ratio (MR)=0.46 (0.18-1.15)). However, oral polio vaccination was associated with a beneficial effect for children under 6 months of age at the time of the campaign, the mortality ratio being 0.09 (95% CI 0.01-0.85) in the 3 months before the war controlling for significant background factors, including routine immunizations, antenatal consultations, and arm circumference. The polio-vaccinated children aged 0-5 months had fewer hospitalisations than children who had not been polio vaccinated (RR=0.27 (0.10-0.76)). With longer follow-up to December 1998 or December 1999, the difference in mortality gradually disappeared, the MR for polio-vaccinated children being 0.61 (0.32-1.14) and 0.83 (0.51-1.34), respectively. Among children aged 6-59 months of age, measles vaccine was associated with a 56% reduction in mortality (MR=0.44 (0.28-0.69)) and no effect of oral polio vaccine was measurable in this age group. The effect of polio vaccine among children less than 6 months of age could be due to selection bias but might also represent a non-specific beneficial immune stimulation and there is nothing to suggest that OPV might have a negative effect on infant survival. Studies of the possible non-specific effects of oral polio vaccine are warranted before OPV is withdrawn.

Routine vaccinations associated with divergent effects on female and male mortality at the paediatric ward in Bissau, Guinea-Bissau.

Several studies have suggested that routine childhood immunisations may have non-specific effects on mortality. To examine which disease categories might be affected, we investigated whether immunisation status had an impact on the case fatality for hospitalised children. Between 1990 and 1996, the Bandim Health Project maintained a register of all children from the study area hospitalised at the paediatric ward of the central hospital in Bissau, Guinea-Bissau. The study included 2079 hospitalised children aged 1.5-17 months coming from the Bandim study area. Among children whose vaccination card had been seen at admission, the case fatality ratio for measles-vaccinated children versus measles-unvaccinated children was 0.51 (0.27-0.98), the beneficial effect being significantly stronger for girls than for boys (test of interaction, p=0.050). The protective effect of measles vaccine remained unchanged when hospitalised measles cases were excluded from the analysis (0.49 (0.26-0.94)). The effect of measles vaccine was strongest for children with pneumonia (MR=0.28 (0.07-0.91)) and presumptive malaria (MR=0.40 (0.13-1.18)). For measles-vaccinated children, the female to male case fatality ratio was 0.54 (0.28-0.97). Among children having received diphtheria-tetanus-pertussis (DTP) and oral polio (OPV) as the last vaccines, girls had higher case fatality than boys, the mortality ratio being 1.63 (1.03-2.59). The female to male ratios were significantly inversed for DTP and OPV versus measles vaccine (test of interaction, p=0.003). These results remained unchanged if 1-month post-discharge deaths were included in the analysis, and in multivariate analyses controlling for determinants of mortality. In conclusion, measles vaccine was associated with reduced mortality from diseases other than measles, the beneficial effect being stronger for girls than for boys. On the other hand, DTP and OPV vaccine were associated with higher case fatality for girls than for boys. Understanding the divergent non-specific effects of common vaccines may contribute to better child survival in developing countries.

Oral polio vaccination and low case fatality at the paediatric ward in Bissau, Guinea-Bissau.

Oral polio vaccine (OPV) and diphtheria-tetanus-pertussis (DTP) vaccines are given simultaneously in routine immunisation programmes in developing countries. It is therefore difficult to determine the separate effects of these vaccines on survival. We used the shortage of DTP vaccine in Bissau to examine the impact of OPV on the case fatality at the paediatric ward in Bissau. For 719 children less than 5 years of age whose vaccination card had been seen at admission and who had not yet received measles vaccine, having received OPV only was associated with a case fatality of 6% compared with 15% for children having received combined DTP and OPV vaccinations, the case fatality ratio (CFR) being 0.29 (95% confidence interval (CI) 0.11-0.77). Even if children fleeing the hospital were assumed to have died shortly after leaving the hospital, the case fatality would still be lower for children having received OPV only (CFR = 0.41; (95% CI 0.20-0.81)). The tendency was similar for children hospitalised with pneumonia, diarrhoea, and presumptive malaria. Control for background factors had no impact on the estimate. In areas with high mortality, OPV administered alone may have non-specific beneficial effects or DTP may have a negative effect for children who had received both DTP and OPV.