Wiskott-Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival.

ABSTRACT: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3.

The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked-like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4(-)CD8(-)) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.

The evolution of cellular deficiency in GATA2 mutation.

Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.

An autochthonous case of cystic echinococcosis in Finland, 2015.

We report a case of pulmonary cystic echinococcosis in a child from eastern Finland with no history of travelling abroad. The cyst was surgically removed and the organism molecularly identified as Echinococcus canadensis genotype G10. This parasite is maintained in eastern Finland in a sylvatic life cycle involving wolves and moose; in the present case, the infection was presumably transmitted by hunting dogs.

[Lymphadenitis caused by nontuberculous mycobacteriae]. / Lasten atyyppiset mykobakteeri-infektiot lisääntyvät.

Lymphadenitis caused by nontuberculous mycobacteriae has been increasingly seen in Finland since the cessation of universal BCG vaccination in 2006. An otherwise healthy child develops a slowly growing unilateral mass in the cervicofacial region. Without treatment, the lymphadenitis suppurates and forms a draining sinus, which dries after some weeks or months, leaving a scar. Surgical excision is curative treatment but cannot always be performed because of risk to the facial nerve or need of extensive surgery. In these cases, observation without antimicrobial treatment is usually recommended. The parents need professional information and support.

Effect of Social Distancing Due to the COVID-19 Pandemic on the Incidence of Viral Respiratory Tract Infections in Children in Finland During Early 2020.

BACKGROUND: Social distancing measures are used to reduce the spreading of infection. Our aim was to assess the immediate effects of national lockdown orders due to coronavirus disease 2019 (COVID-19) on pediatric emergency room (ER) visits and respiratory tract infections in hospitals and nationwide in Finland. METHODS: This register-based study used hospital patient information systems and the Finnish national infectious disease register. The participants were all patients visiting pediatric ER in 2 Finnish hospitals (Kuopio University Hospital, Mikkeli Central Hospital) covering 1/5th of the Finnish children population, 4 weeks before and 4 weeks after the start of the nationwide lockdown on March 16, 2020. Nationwide weekly numbers of influenza (A + B) and respiratory syncytial virus (RSV) in children were assessed from the infectious disease register from 2015 to 2020. RESULTS: A major decrease in the rate of daily median pediatric ER visits was detected in both hospitals in the study during the nationwide lockdown compared with the study period before the lockdown (Mikkeli, 19 vs. 7, P < 0.001; Kuopio, 9 vs. 2,5, P < 0.001). The influenza season was shorter (8 weeks from peak to no cases), and the weekly rate of new cases decreased faster compared with the previous 4 influenza seasons (previously 15-20 weeks from peak to no cases). A similar decrease was also seen in RSV cases. No pediatric cases of COVID-19 were found in participating hospitals during the study period. CONCLUSION: These results strongly suggest that social distancing and other lockdown strategies are effective to slow down the spreading of common respiratory viral diseases and decreasing the need for hospitalization among children.

Clinical case review: a method to improve identification of true clinical and radiographic pneumonia in children meeting the World Health Organization definition for pneumonia.

BACKGROUND: The World Health Organization's (WHO) case definition for childhood pneumonia, composed of simple clinical signs of cough, difficult breathing and fast breathing, is widely used in resource poor settings to guide management of acute respiratory infections. The definition is also commonly used as an entry criteria or endpoint in different intervention and disease burden studies. METHODS: A group of paediatricians conducted a retrospective review of clinical and laboratory data including C-reactive protein concentration and chest radiograph findings among Filipino children hospitalised in the Bohol Regional Hospital who were enrolled in a pneumococcal vaccine efficacy study and had an episode of respiratory disease fulfilling the WHO case definition for clinical pneumonia. Our aim was to evaluate which disease entities the WHO definition actually captures and what is the probable aetiology of respiratory infections among these episodes diagnosed in this population. RESULTS: Among the 12,194 children enrolled to the vaccine study we recorded 1,195 disease episodes leading to hospitalisation which fulfilled the WHO criteria for pneumonia. In total, 34% of these episodes showed radiographic evidence of pneumonia and 11% were classified as definitive or probable bacterial pneumonia. Over 95% of episodes of WHO-defined severe pneumonia (with chest indrawing) had an acute lower respiratory infection as final diagnosis whereas 34% of those with non-severe clinical pneumonia had gastroenteritis or other non-respiratory infection as main cause of hospitalisation. CONCLUSION: The WHO definition for severe pneumonia shows high specificity for acute lower respiratory infection and provides a tool to compare the total burden of lower respiratory infections in different settings. TRIAL REGISTRATION: ISRCTN62323832.

Primary versus non-primary maternal cytomegalovirus infection as a cause of symptomatic congenital infection - register-based study from Finland.

BACKGROUND: Both primary and non-primary maternal cytomegalovirus (CMV) infection during pregnancy can lead to vertical transmission. We evaluated the proportion of maternal primary/non-primary infections among 26 babies with symptomatic congenital CMV infection born in Finland from 2000 to 2012. METHODS: We executed a database search on hospital records from all five university hospitals in Finland to identify infants with congenital CMV infection. The preserved maternal serum samples drawn at the end of the first trimester were analysed for CMV antibodies. Maternal infection was classified to be non-primary, if there was high avidity CMV immunoglobulin G (IgG) in the early pregnancy samples. Infection was considered primary in the case of either low avidity IgG (primary infection in the first trimester or near conception) or absent CMV IgG at the end of the first trimester (primary infection in the second or third trimester). RESULTS: The majority of the symptomatic congenital CMV infections (54%) were due to maternal non-primary infection, 27% due to maternal primary infection in the first trimester or near conception, and 19% during the second or third trimester. Long-term sequelae occurred in 59% of patients: in 6/7 after primary infection in the first trimester, in 0/5 after primary infection in the second or third trimester, and in 9/14 after non-primary infection. CONCLUSIONS: In this register-based cohort, non-primary infections caused the majority of symptomatic congenital CMV infections, and resulted in significant morbidity.

Invasive Group A Streptococcal Infections in Children: A Nationwide Survey in Finland.

BACKGROUND: The incidence of invasive group A streptococcus (iGAS) infections varies in time and geographically for unknown reasons. We performed a nationwide survey to assess the population-based incidence rates and outcomes of children with iGAS infections. METHODS: We collected data on patients from hospital discharge registries and the electronic databases of microbiological laboratories in Finland for the period 1996-2010. We then recorded the emm types or serotypes of the strains. The study physician visited all university clinics and collected the clinical data using the same data entry sheet. RESULTS: We identified 151 children with iGAS infection. Varicella preceded iGAS infection in 20% of cases and fasciitis infection in 83% of cases. The annual incidence rate of iGAS infection was 0.93 per 100,000 in 1996-2000, 1.80 in 2001-2005 and 2.50 in 2006-2010. The proportion of emm 1.0 or T1M1 strains peaked in 1996-2000 and again in 2006-2010, to 44% and 37% of all typed isolates. The main clinical diagnoses of the patients were severe soft-tissue infection (46%), sepsis (28%), empyema (10%), osteoarticular infection (9%) and primary peritonitis (5%). Severe pain was the most typical symptom for soft-tissue infections. More than half of the patients underwent surgery and received clindamycin. The readmission rate was 7%, and the case fatality rate was 2%. CONCLUSIONS: The incidence rate of pediatric iGAS infections tripled during our study. The increase was not, however, the result of a change in the strain types causing iGAS. Varicella immunization would likely have prevented a significant number of the cases.

Serologically indicated pneumococcal pneumonia in children: a population-based study in primary care settings.

The aim of the study was to assess age-specific incidences of community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae and diagnosed serologically in a child population. The study was population-based, and prospective, and performed in primary health care settings. During a surveillance period of 12 months from 1981-1982, all pneumonia cases in a defined child population (57% urban residents) were registered prospectively. In total, 201 CAP cases were diagnosed (mean age 5.6 years; 57% boys; 58% urban residents). S. pneumoniae etiology was studied by antibody and immune complex (IC) assays to C-polysacchride (C-PS), type-specific capsular polysaccharides (CPS), and to pneumolysin (Ply), in acute and convalescent sera. Serologic evidence of S. pneumoniae etiology was indicated in 57(28%) cases, 35(61%) being mixed infections with other microbes. The distribution of pneumococcal cases was 44%, 30% and 26% in the three 5-year age groups, respectively. There were 33 (58%) males and 34 (60%) urban residents. In total, 26 cases were identified by antibody assays and 35 cases by IC assays, 26/35 being positive in acute sera. Responses to C-PS, CPS and Ply, when antibody and IC results are combined, were found equally often in 23-25 cases. The total annual incidence of pediatric S. pneumoniae CAP was 6.4/1000/year. S. pneumoniae etiology was found in 28% of the children and was similar at all ages. The incidence of pneumococcal CAP was assessed for the first time, being high (19/1000/year) in 0- to 4-year-old urban boys and rather stable (5-9/1000/year) in all other groups by age, sex and residence.

Serum procalcitonin concentrations in bacterial pneumonia in children: a negative result in primary healthcare settings.

A microbe-specific diagnosis in community-acquired pneumonia (CAP) is difficult in children, and studies on nonspecific chest radiographic and host response markers have been inconsistent. Serum procalcitonin (PCT) is a newly recognized, promising marker for differentiating between bacterial and viral infections. Serum PCT was measured by a luminometric assay in 190 children with CAP diagnosed in the primary healthcare setting during a population-based study in a geographically defined population. The pneumococcal, mycoplasma, chlamydia, and viral etiology of infections was studied by an extensive serologic test panel. The median PCT concentrations were 0.47, 0.46, and 0.35 ng/mL in children aged <5 years, 5-9 years, and >/=10 years (P = 0.004). An elevated PCT >1.0 ng/mL was seen in 12.1% and >2.0 ng/mL in only 2.1% of the children. No association was seen between severity (inpatient vs. outpatient care) and etiology of CAP (evidence for pneumococcal, mycoplasma, or chlamydia, vs. viral infection). We conclude that serum PCT measurements have no role in the diagnosis of bacterial CAP in children in primary healthcare settings.

Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.

Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.

Simkania negevensis may be a true cause of community acquired pneumonia in children.

Simkania negevensis, a recently found Chlamydia-like organism, has been associated with bronchiolitis and pneumonia in children. S. negevensis findings have been common also in healthy, non-symptomatic subjects. Antibodies to S. negevensis were measured by microimmunofluorescence in 174 frozen paired sera obtained from children with community acquired pneumonia in a population-based study. There was evidence of S. negevensis infection in 18 (10%) cases. All diagnoses were based on the presence of specific IgM antibodies. The numbers of S. negevensis cases increased from 2 (4%) at <24 months to 7 (15%) at > or = 10 y of age. 12 (67%) were mixed infections with viruses or other bacteria. 16 children (9%) had measurable IgG antibodies to S. negevensis, but significant rises were not found in any cases. Thus, S. negevensis may be a real, though rare, cause of CAP in children, occurring often in mixed infections with viruses and other bacteria.

Incidence of community-acquired pneumonia in children caused by Mycoplasma pneumoniae: serological results of a prospective, population-based study in primary health care.

OBJECTIVE: The objective of the present study was to assess the incidence of community-acquired pneumonia (CAP) in children caused by Mycoplasma pneumoniae. METHODOLOGY: During 12 months in 1981-1982, all CAP cases in a defined child population were registered. M. pneumoniae aetiology, initially measured by complement fixation (CF) test, was in 1999 supplemented by measurement of IgG and IgM antibodies using enzyme immunoassays (EIA). RESULTS: M. pneumoniae was detected in 61 (30%) of 201 paediatric CAP cases, being the most common aetiological agent in those 5 years of age or over. At that age, M. pneumoniae was responsible for over 50% of cases, and over 90% of mycoplasmal cases were treated as outpatients. The EIA detected 17 new cases over and above the 44 detected by CF, while CF alone revealed 10 cases. The incidence of M. pneumoniae CAP increased with age, being over 10/1000 children at the age of 10 years or more. Co-infections with Streptococcus pneumoniae and Chlamydia pneumoniae were present in over 30% and 15%, respectively, of mycoplasmal CAP cases. CONCLUSION: M. pneumoniae is a common cause of paediatric CAP in primary health care, and co-infections with S. pneumoniae are common. Both S. pneumoniae and M. pneumoniae should be taken into account when starting antibiotics for children with CAP.