Publications by authors named "Timo Hautala"

45 Publications

Effect of first-line antifungal treatment on ocular complication risk in or yeast blood stream infection.

BMJ Open Ophthalmol 2021 16;6(1):e000837. Epub 2021 Sep 16.

Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.

Objectives: Ocular candidiasis (OC) can complicate bloodstream infection (BSI). Antifungal treatment improves the prognosis of patients with BSI, but the effects of choice and timing of first-line medication on OC risk are incompletely understood. We explored the early treatments, risk factors and ocular presentations in BSI.

Methods And Analysis: All patients (n=304) with BSI during 2008-2017 at Oulu University Hospital were included. Those patients in whom clinical condition was appropriate for ocular examination (OE), including biomicroscopy (n=103), were carefully analysed by ophthalmologists. Criteria for patient selection were considered. and yeast species, antifungal medications, echocardiography, underlying diseases and clinical properties of the patients with BSI were analysed.

Results: Clinical condition in 103 patients had been considered appropriate for OE. OC was diagnosed in 33 of the 103 patients. was the most common finding (88%) in OC. Patients in intensive care, alcohol-related conditions or poor prognosis were less frequently examined. Persistent candidemia increased the risk of OC. Chorioretinitis and endophthalmitis were diagnosed in 94% and 48% of the patients with OC, respectively. Any early antifungal treatment decreased the endophthalmitis risk. Echinocandin lowered the OC risk in those with central venous catheters (CVCs) or abdominal malignancy.

Conclusion: Critical condition of patients with BSI affects the selection and results of OE. OC was associated with BSI especially among those with persistent candidemia, CVC or abdominal malignancy. Any early antifungal treatment reduced endophthalmitis risk. Early echinocandin treatment may reduce the risk of OC in selected patients.
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http://dx.doi.org/10.1136/bmjophth-2021-000837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449967PMC
September 2021

Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection.

Viruses 2021 May 31;13(6). Epub 2021 May 31.

Research Unit of Internal Medicine, Department of Internal Medicine, Division of Infectious Diseases, Oulu University and Oulu University Hospital, Oulu 90014, Finland.

Puumala hantavirus (PUUV), carried and spread by the bank vole (), causes a mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Acute high fever, acute kidney injury (AKI), thrombocytopenia, and hematuria are typical features of this syndrome. In addition, headache, blurred vision, insomnia, vertigo, and nausea are commonly associated with the disease. This review explores the mechanisms and presentations of ocular and central nervous system involvement in acute NE.
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http://dx.doi.org/10.3390/v13061040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229408PMC
May 2021

Clinical characteristics and evaluation of the incidence of cryptococcosis in Finland 2004-2018.

Infect Dis (Lond) 2021 09 11;53(9):684-690. Epub 2021 May 11.

HUS Diagnostic Center, HUSLAB, Clinical Microbiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: Cryptococcosis is one of the major causes of mortality among HIV patients worldwide. Though most often associated with late stage HIV infection/AIDS, a significant number of cases occur in other immunocompromised patients such as solid organ transplant recipients and patients with hematological malignancies. Immunocompromised patients are a heterogeneous group and their number increases constantly. Since little is known about the incidence and the clinical features of cryptococcosis in Northern Europe, our aim was to investigate the clinical characteristics of cryptococcosis patients in Finland.

Methods: We retrospectively reviewed the laboratory confirmed cryptococcosis cases in Finland during 2004-2018. Only those who were treated for cryptococcosis were included in the study. Initial laboratory findings and medical records were also collected.

Results: A total of 22 patients with cryptococcosis were included in our study. The annual incidence of cryptococcosis was 0.03 cases per 100,000 population. Ten patients were HIV-positive and 12 out of 22 were HIV-negative. Hematological malignancy was the most common underlying condition among HIV-negative patients.

Conclusions: To our knowledge, this is the first study of the clinical presentation and incidence of cryptococcosis in Finland. We demonstrate that invasive cryptococcal infection occurs not only in HIV/AIDS patients or otherwise immunocompromised patients but also in immunocompetent individuals. Even though cryptococcosis is extremely rare in Finland, its recognition is important since the prognosis depends on rapid diagnostics and early antifungal therapy.
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http://dx.doi.org/10.1080/23744235.2021.1922753DOI Listing
September 2021

Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction.

J Allergy Clin Immunol 2021 08 1;148(2):599-611. Epub 2021 Mar 1.

PEDEGO Research Unit, University of Oulu, Oulu, Finland.

Background: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency.

Objective: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1.

Methods: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used.

Results: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain.

Conclusions: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.
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http://dx.doi.org/10.1016/j.jaci.2020.12.656DOI Listing
August 2021

Herpes simplex virus 2 encephalitis in a patient heterozygous for a TLR3 mutation.

Neurol Genet 2020 Dec 25;6(6):e532. Epub 2020 Nov 25.

Department of Internal Medicine (T.H., T.P.), Oulu University Hospital, Finland; Research Unit of Biomedicine (T.H., V.G., P.Å.), University of Oulu, Finland; St. Giles Laboratory of Human Genetics of Infectious Diseases (J.C., J.-L.C., S.-Y.Z.), Rockefeller Branch, The Rockefeller University, New York, NY; Department of Neurology (L.T., S.W.), Oulu University Hospital; Institute for Molecular Medicine Finland (J.L., J.S.), HiLIFE, and The Folkhälsan Research Center and Medicum (J.L.), University of Helsinki, Finland; Centre for Molecular Medicine Norway (J.S.), University of Oslo, Norway; Department of Clinical Genetics (M.K., O.K.), Oulu University Hospital, Finland; Department of Medical Microbiology (T.V.), Turku University Hospital and Institute of Biomedicine, University of Turku, Finland; Department of Clinical Neurophysiology (U.H.), Oulu University Hospital, Finland; Paris Descartes University (L.L., J.-L.C., S.-Y.Z.), Imagine Institute, Paris; Laboratory of Human Genetics of Infectious Diseases (J.-L.C., S.-Y.Z.), Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, Paris; Pediatric Hematology-Immunology Unit (J.-L.C.), Necker Hospital for Sick Children, Paris, France; Howard Hughes Medical Institute (J.-L.C.), New York, NY; Adult Immunodeficiency Unit (M.R.J.S.), Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Finland; and Rare Disease Center and Pediatric Research Center (M.R.J.S.), Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Finland.

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http://dx.doi.org/10.1212/NXG.0000000000000532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720273PMC
December 2020

Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis.

J Clin Immunol 2020 11 16;40(8):1156-1162. Epub 2020 Sep 16.

Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.

Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.
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http://dx.doi.org/10.1007/s10875-020-00834-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567724PMC
November 2020

Prevalence, incidence and epidemiology of childhood uveitis.

Acta Ophthalmol 2021 Mar 26;99(2):e160-e163. Epub 2020 Jun 26.

Department of Ophthalmology, Oulu University Hospital, Oulu, Finland.

Purpose: To analyse the prevalence, incidence and aetiology of paediatric uveitis.

Methods: A retrospective, population-based cohort study of Finnish children with uveitis in Northern Ostrobothnia Hospital District in 2008-2017. The data included parameters for age, gender, age at diagnosis, laterality, chronicity, anatomical distribution of the disease, aetiology and systemic association.

Results: One hundred fifty patients aged <16 years (mean age 6.9 ± 3.9 years) with uveitis were included, out of whom 53% were girls. The first uveitis episode occurred at 1-6 years in 59%, and 62% of them were girls. In the age group of 7-15 years, boys were diagnosed with uveitis more frequently than girls (61% versus 39%, respectively). Seventy percent of the girls were diagnosed with their first uveitis episode at the age of 1-6 years, whereas only 48% of the boys were diagnosed at that age. The prevalence of uveitis increased from 64/100 000 children <16 years in 2008 (95% CI, 47.7-84.2) to 106/100 000 in 2017 (95% CI, 84.6-130.2). The incidence of childhood uveitis in 2008-2017 was 14/100 000 person-years in children <16 years (95% CI, 11.3-16.5). Eighty-seven percent of the cases were non-infectious, 9% were infectious, and 3% had masquerade syndromes. Sixty-one percent of patients had juvenile idiopathic arthritis (JIA).

Conclusion: The prevalence of paediatric uveitis has increased during the last decade in both genders. Uveitis is more frequent in girls, and they were diagnosed at a younger age than boys. Idiopathic cases and JIA accounted for a majority of aetiological features.
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http://dx.doi.org/10.1111/aos.14535DOI Listing
March 2021

Tonsillar granuloma associated with hypogammaglobulinemia.

Allergy Asthma Clin Immunol 2020 29;16:43. Epub 2020 May 29.

Research Unit of Biomedicine, University of Oulu, Oulu, Finland.

Background: Rare tonsillar granulomas may be caused for example by infections, malignancies or sarcoidosis. Granulomas also occur in inborn errors of immunity (IEI) such as common variable immunodeficiency (CVID) with B cell maturation defects and hypogammaglobulinemia. CVID shares various features with sarcoidosis and drug-induced secondary hypogammaglobulinemia; careful consideration of differential diagnosis between these conditions is warranted.

Case Presentation: A 29-year-old female with epilepsy developed dysphagia, dyspnea and impaired exercise tolerance. Obstruction caused by swollen lingual tonsil and edema in the epiglottis and arytenoid mucosa were found. Lingual tonsil and epiglottis biopsies displayed non-necrotizing granulomas. There was no evidence of viral, bacterial, mycobacterial or fungal infections. Chest X-ray, computerized tomography of chest and ultrasound of neck and abdomen remained unremarkable. Positron emission tomography/computed tomography (PET/CT) showed laryngeal enhancement. Empiric antimicrobials combined with prednisolone were insufficient to control her disease. In immunological evaluation, the patient had normal counts of B and T cells. Proportions of CD27 memory B cells (30.3%) and IgDIgMCD27 switched memory B cells (7.2%; normal range 6.5-29.2%) were normal. Percentage of activated CD21 B cells was high (6.6%; normal range 0.6-3.5%). IgG (3.5 g/L; normal range 6.77-15.0 g/l) and all IgG subclass concentrations were low. Anti-polysaccharide responses were impaired, with 3/10 serotypes reaching a level of 0.35 µg/ml after immunization with Pneumovax. The findings were consistent with hypogammaglobulinemia resembling CVID, possibly secondary to antiepileptic medication. Her dyspnea and dysphagia responded favorably to subcutaneous IgG and rituximab.

Conclusions: Tonsillar granulomas can be the presenting and only clinical feature of B cell deficiency, highlighting the diversity of symptoms and findings in primary or secondary immunodeficiencies.
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http://dx.doi.org/10.1186/s13223-020-00441-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257222PMC
May 2020

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.

J Allergy Clin Immunol 2020 10 9;146(4):901-911. Epub 2020 Apr 9.

Primary Immunodeficiencies Unit, Hospital Dona Estefania, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.

Background: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes.

Objective: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations.

Methods: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling.

Results: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents.

Conclusions: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.
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http://dx.doi.org/10.1016/j.jaci.2019.11.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246418PMC
October 2020

A Family With A20 Haploinsufficiency Presenting With Novel Clinical Manifestations and Challenges for Treatment.

J Clin Rheumatol 2020 Jan 21. Epub 2020 Jan 21.

Clinicum, Faculty of Medicine, University of Helsinki, Helsinki.

Background: Tumor necrosis factor α-induced protein 3 gene (TNFAIP3, also called A20) haploinsufficiency (HA20) leads to autoinflammation and autoimmunity. We have recently shown that a p.(Lys91*) mutation in A20 disrupts nuclear factor κB signaling, impairs protein-protein interactions of A20, and leads to inflammasome activation.

Methods: We now describe the clinical presentations and drug responses in a family with HA20 p.(Lys91*) mutation, consistent with our previously reported diverse immunological and functional findings.

Results: We report for the first time that inflammasome-mediated autoinflammatory lung reaction caused by HA20 can be treated with interleukin 1 antagonist anakinra. We also describe severe anemia related to HA20 successfully treated with mycophenolate. In addition, HA20 p.(Lys91*) was found to associate with autoimmune thyroid disease, juvenile idiopathic arthritis, psoriasis, liver disease, and immunodeficiency presenting with specific antibody deficiency and genital papillomatosis.

Conclusions: We conclude that HA20 may lead to combination of inflammation, immunodeficiency, and autoimmunity. The condition may present with variable and unpredictable symptoms with atypical treatment responses.
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http://dx.doi.org/10.1097/RHU.0000000000001268DOI Listing
January 2020

Aetiology of posterior uveitis in a tertiary centre in Finland.

Acta Ophthalmol 2020 Feb 5;98(1):e135-e136. Epub 2019 Jul 5.

Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.

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http://dx.doi.org/10.1111/aos.14182DOI Listing
February 2020

Primary Immunodeficiency, a Possible Cause of Neutrophilic Necrotizing Dermatosis.

JAMA Dermatol 2019 07;155(7):863-864

Rare Disease Center, New Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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http://dx.doi.org/10.1001/jamadermatol.2019.1201DOI Listing
July 2019

Outcomes for Nitazoxanide Treatment in a Case Series of Patients with Primary Immunodeficiencies and Rubella Virus-Associated Granuloma.

J Clin Immunol 2019 01 24;39(1):112-117. Epub 2019 Jan 24.

Division of Allergy Immunology, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.

Purpose: Nitazoxanide was recently reported as having in vitro effectiveness against the rubella virus. Immunodeficiency-related vaccine-derived rubella occurs in some patients who have an inherited immunodeficiency and who received the MMR vaccine. This study investigated the in vivo effectiveness of nitazoxanide therapy.

Methods: This is a retrospective analysis of seven patients treated with nitazoxanide as salvage therapy for immunodeficiency-related vaccine-derived rubella infection. The patients were recruited from an ongoing rubella detection surveillance project.

Results: Seven patients with persistent rubella were treated with nitazoxanide and one demonstrated significant clinical improvement. Two additional patients exhibited diminished viral capsid production with one patient having transient slowing of progression. The cohort overall generally had low T cell counts and had a high burden of comorbidities. There were three deaths. Two deaths were from PML and one was related to hematopoietic stem cell transplantation.

Conclusions: Nitazoxanide has limited in vivo anti-viral effects for immunodeficiency-related vaccine-derived rubella. Most patients did not exhibit clinical improvement.
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http://dx.doi.org/10.1007/s10875-019-0589-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383808PMC
January 2019

Haploinsufficiency of A20 impairs protein-protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation.

RMD Open 2018 17;4(2):e000740. Epub 2018 Oct 17.

Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.

Objectives: encodes A20 that negatively regulates nuclear factor kappa light chain enhancer of activated B cells (NF-κB), the major transcription factor coordinating inflammatory gene expression. polymorphisms have been linked with a spectrum of inflammatory and autoimmune diseases and, recently, loss-of-function mutations in A20 were found to cause a novel inflammatory disease 'haploinsufficiency of A20' (HA20). Here we describe a family with HA20 caused by a novel loss-of-function mutation and elucidate the upstream molecular mechanisms linking HA20 to dysregulation of NF-κB and the related inflammasome pathway.

Methods: NF-κB activation was studied in a mutation-expressing cell line using luciferase reporter assay. Physical and close-proximity protein-protein interactions of wild-type and p.(Lys91*) mutant A20 were analysed using mass spectrometry. NF-κB -dependent transcription, cytokine secretion and inflammasome activation were compared in immune cells of the HA20 patients and control subjects.

Results: The protein-protein interactome of p.(Lys91*) mutant A20 was severely impaired, including interactions with proteins regulating NF-κB activation, DNA repair responses and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The p.(Lys91*) mutant A20 failed to suppress NF-κB signalling, which led to increased NF-κB -dependent proinflammatory cytokine transcription. Functional experiments in the HA20 patients' immune cells uncovered a novel caspase-8-dependent mechanism of NLRP3 inflammasome hyperresponsiveness that mediated the excessive secretion of interleukin-1β and interleukin-18.

Conclusions: The current findings significantly deepen our understanding of the molecular mechanisms underlying HA20 and other diseases associated with reduced A20 expression or function, paving the way for future therapeutic targeting of the pathway.
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http://dx.doi.org/10.1136/rmdopen-2018-000740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203104PMC
October 2018

ADA2 deficiency: Clonal lymphoproliferation in a subset of patients.

J Allergy Clin Immunol 2018 04 31;141(4):1534-1537.e8. Epub 2018 Jan 31.

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.01.012DOI Listing
April 2018

Fatal Puumala Hantavirus Disease: Involvement of Complement Activation and Vascular Leakage in the Pathobiology.

Open Forum Infect Dis 2017 21;4(4):ofx229. Epub 2017 Oct 21.

Medicum, University of Helsinki, Helsinki, Finland.

The case-fatality rate of hantavirus disease depends strongly on the causative hantavirus, ranging from 0.1% to 40%. However, the pathogenesis is not fully understood, and at present no licensed therapies exist. We describe fatal cases caused by Puumala hantavirus indicating involvement of complement activation and vascular leakage.
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http://dx.doi.org/10.1093/ofid/ofx229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726462PMC
October 2017

Nitazoxanide May Modify the Course of Progressive Multifocal Leukoencephalopathy.

J Clin Immunol 2018 01 20;38(1):4-6. Epub 2017 Nov 20.

Immunodeficiency Unit, Inflammation Center and Center for Rare Diseases, Children's Hospital, Helsinki University and Helsinki University Hospital, Helsinki, Finland.

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http://dx.doi.org/10.1007/s10875-017-0463-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086546PMC
January 2018

Inhibition of rubella virus replication by the broad-spectrum drug nitazoxanide in cell culture and in a patient with a primary immune deficiency.

Antiviral Res 2017 Nov 30;147:58-66. Epub 2017 Sep 30.

Division of Viral Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, MS C22, Atlanta, GA 30333, USA. Electronic address:

Persistent rubella virus (RV) infection has been associated with various pathologies such as congenital rubella syndrome, Fuchs's uveitis, and cutaneous granulomas in patients with primary immune deficiencies (PID). Currently there are no drugs to treat RV infections. Nitazoxanide (NTZ) is an FDA-approved drug for parasitic infections, and has been recently shown to have broad-spectrum antiviral activities. Here we found that empiric 2-month therapy with oral NTZ was associated in the decline/elimination of RV antigen from lesions in a PID patient with RV positive granulomas, while peginterferon treatment had no effect. In addition, we characterized the effects of NTZ on cell culture models of persistent RV infection. NTZ significantly inhibited RV replication in a primary culture of human umbilical vein endothelial cells (HUVEC) and Vero and A549 epithelial cell lines in a dose dependent manner with an average 50% inhibitory concentration of 0.35 μg/ml (1.1 μM). RV strains representing currently circulating genotypes were inhibited to a similar extent. NTZ affected early and late stages of infection by inhibiting synthesis of cellular and RV RNA and interfering with intracellular trafficking of the RV surface glycoproteins, E1 and E2. These results suggest a potential application of NTZ for the treatment of persistent rubella infections, but more studies are required.
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http://dx.doi.org/10.1016/j.antiviral.2017.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127570PMC
November 2017

Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes.

J Allergy Clin Immunol 2017 Sep 21;140(3):782-796. Epub 2017 Jan 21.

Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Rare Diseases Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: The nuclear factor κ light-chain enhancer of activated B cells (NF-κB) signaling pathway is a key regulator of immune responses. Accordingly, mutations in several NF-κB pathway genes cause immunodeficiency.

Objective: We sought to identify the cause of disease in 3 unrelated Finnish kindreds with variable symptoms of immunodeficiency and autoinflammation.

Methods: We applied genetic linkage analysis and next-generation sequencing and functional analyses of NFKB1 and its mutated alleles.

Results: In all affected subjects we detected novel heterozygous variants in NFKB1, encoding for p50/p105. Symptoms in variant carriers differed depending on the mutation. Patients harboring a p.I553M variant presented with antibody deficiency, infection susceptibility, and multiorgan autoimmunity. Patients with a p.H67R substitution had antibody deficiency and experienced autoinflammatory episodes, including aphthae, gastrointestinal disease, febrile attacks, and small-vessel vasculitis characteristic of Behçet disease. Patients with a p.R157X stop-gain experienced hyperinflammatory responses to surgery and showed enhanced inflammasome activation. In functional analyses the p.R157X variant caused proteasome-dependent degradation of both the truncated and wild-type proteins, leading to a dramatic loss of p50/p105. The p.H67R variant reduced nuclear entry of p50 and showed decreased transcriptional activity in luciferase reporter assays. The p.I553M mutation in turn showed no change in p50 function but exhibited reduced p105 phosphorylation and stability. Affinity purification mass spectrometry also demonstrated that both missense variants led to altered protein-protein interactions.

Conclusion: Our findings broaden the scope of phenotypes caused by mutations in NFKB1 and suggest that a subset of autoinflammatory diseases, such as Behçet disease, can be caused by rare monogenic variants in genes of the NF-κB pathway.
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http://dx.doi.org/10.1016/j.jaci.2016.10.054DOI Listing
September 2017

Combined immunodeficiency and hypoglycemia associated with mutations in hypoxia upregulated 1.

J Allergy Clin Immunol 2017 04 29;139(4):1391-1393.e11. Epub 2016 Nov 29.

Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland; Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.

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http://dx.doi.org/10.1016/j.jaci.2016.09.050DOI Listing
April 2017

Enrichment of rare variants in population isolates: single AICDA mutation responsible for hyper-IgM syndrome type 2 in Finland.

Eur J Hum Genet 2016 10 4;24(10):1473-8. Epub 2016 May 4.

Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.

Antibody class-switch recombination and somatic hypermutation critically depend on the function of activation-induced cytidine deaminase (AID). Rare variants in its gene AICDA have been reported to cause autosomal recessive AID deficiency (autosomal recessive hyper-IgM syndrome type 2 (HIGM2)). Exome sequencing of a multicase Finnish family with an HIGM2 phenotype identified a rare, homozygous, variant (c.416T>C, p.(Met139Thr)) in the AICDA gene, found to be significantly enriched in the Finnish population compared with other populations of European origin (38.56-fold, P<0.001). The population history of Finland, characterized by a restricted number of founders, isolation and several population bottlenecks, has caused enrichment of certain rare disease-causing variants and losses of others, as part of a phenomenon called the Finnish Disease Heritage. Accordingly, rare founder mutations cause the majority of observed Finnish cases in these mostly autosomal recessive disorders that consequently are more frequent in Finland than elsewhere. Screening of all currently known Finnish patients with an HIGM2 phenotype showed them to be homozygous for p.(Met139Thr). All the Finnish p.(Met139Thr) carriers with available data on their geographic descent originated from the eastern and northeastern parts of Finland. They were observed to share more of their genome identity by descent (IBD) than Finns in general (P<0.001), and they all carried a 207.5-kb ancestral haplotype containing the variant. In conclusion, the identified p.(Met139Thr) variant is significantly enriched in Finns and explains all thus far found AID deficiencies in Finland.
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http://dx.doi.org/10.1038/ejhg.2016.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027683PMC
October 2016

Long-term hormonal follow-up after human Puumala hantavirus infection.

Clin Endocrinol (Oxf) 2016 Jan 14;84(1):85-91. Epub 2015 Sep 14.

Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.

Objective: Nephropathia epidemica (NE) is a haemorrhagic fever with renal syndrome (HFRS) caused by Puumala hantavirus (PUUV). Pituitary haemorrhage and hypopituitarism may complicate recovery from acute NE.

Design: Forty-seven of our recent cohort of 58 NE patients volunteered to be re-examined in order to estimate the burden of hormonal deficiency 4 to 8 years after the acute illness. Two patients had suffered from pituitary haemorrhage, but many others exhibited pituitary oedema during their acute infection. In this study, we searched for symptoms of hormonal deficiency, performed hormonal laboratory screening, and most patients underwent pituitary MRI examination.

Results: The pituitary size had diminished in all patients in whom MRI was performed (P < 0·001). One patient with acute phase haemorrhage had made a complete recovery while the other continued to require hormonal substitution. In addition, hormonal laboratory abnormalities were observed in nine other patients; these being attributable to several reasons, for example independent peripheral hormonal diseases, side effects of medication or other secondary causes such as obesity. None of them had signs of late-onset pituitary insufficiency caused by their previous NE. Health-related quality of life (mean and median 15D score) of patients was comparable to that of age-standardized general population.

Conclusions: None of our patients had developed obvious late-onset hypopituitarism despite of the fact that pituitary gland can be affected during acute NE. We recommend requesting a history of hantavirus infection whenever the possibility of pituitary dysfunction is suspected at least in patients originating from regions with high NE infection rate.
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http://dx.doi.org/10.1111/cen.12863DOI Listing
January 2016

TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk.

Neurology 2014 Nov 22;83(21):1888-97. Epub 2014 Oct 22.

Authors' affiliations are listed at the end of the article.

Objective: To determine the proportion of children with herpes simplex encephalitis (HSE) displaying TLR3 deficiency, the extent of TLR3 allelic heterogeneity, and the specific clinical features of TLR3 deficiency.

Methods: We determined the sequence of all exons of TLR3 in 110 of the 120 patients with HSE enrolled in our study who do not carry any of the previously described HSE-predisposing mutations of TLR3 pathway genes (TLR3, UNC93B1, TRIF, TRAF3, and TBK1). All the new mutant TLR3 alleles detected were characterized experimentally in-depth to establish the causal relationship between the genotype and phenotype.

Results: In addition to the 3 previously reported TLR3-deficient patients from the same cohort, 6 other children or young adults with HSE carry 1 of 5 unique or extremely rare (minor allele frequency <0.001) missense TLR3 alleles. Two alleles (M374T, D592N) heterozygous in 3 patients are not deleterious in vitro. The other 3 are deleterious via different mechanisms: G743D+R811I and L360P heterozygous in 2 patients are loss-of-function due to low levels of expression and lack of cleavage, respectively, and R867Q homozygous in 1 patient is hypomorphic. The 3 patients' fibroblasts display impaired TLR3 responses and enhanced herpes simplex virus 1 susceptibility. Overall, TLR3 deficiency is therefore found in 6 (5%) of the 120 patients studied. There is high allelic heterogeneity, with 3 forms of autosomal dominant partial defect by negative dominance or haploinsufficiency, and 2 forms of autosomal recessive defect with complete or partial deficiency. Finally, 4 (66%) of the 6 TLR3-deficient patients had at least 1 late relapse of HSE, whereas relapse occurred in only 12 (10%) of the total cohort of 120 patients.

Conclusions: Childhood-onset HSE is due to TLR3 deficiency in a traceable fraction of patients, in particular the ones with HSE recurrence. Mutations in TLR3 and TLR3 pathway genes should be searched and experimentally studied in children with HSE, and patients with proven TLR3 deficiency should be followed carefully.
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http://dx.doi.org/10.1212/WNL.0000000000000999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248460PMC
November 2014

Plasma B-type natriuretic peptide (BNP) in acute Puumala hantavirus infection.

Ann Med 2014 Feb 6;46(1):38-43. Epub 2014 Jan 6.

Institute of Diagnostics, Department of Medical Microbiology, University of Oulu , Oulu , Finland.

Background: Nephropathia epidemica (NE) is a haemorrhagic fever with renal syndrome (HFRS) caused by Puumala hantavirus (PUUV). Acute infection causes transient kidney injury, permeability disorder, and fluid retention, for example.

Methods: B-type natriuretic peptide (BNP) and N-terminal peptide (NT-proBNP) during NE were investigated; disease severity and development of clinical symptoms were considered.

Results: Mean concentrations were 80.2 pg/mL and 55.2 pg/mL for BNP, and 2362.5 pg/mL and 1057.0 pg/mL for NT-proBNP in males and females, respectively. Hospitalization was 6.3 versus 5.2 days (P = 0.01) and 5.9 versus 4.4 days (P = 0.01) for patients with elevated BNP (> 100 pg/mL) or NT-proBNP (> 300 pg/mL), respectively, compared to those with normal peptide concentrations. Weight change during hospitalization was -2.8 or -0.3 kg (P <0.05) in patients with elevated or normal BNP, respectively. Heart rate (r = -0.46, P = 0.001 and r = -0.37, P = 0.01), creatinine clearance (r = -0.46, P = 0.001 and r = -0.56, P = 0.000), blood haemoglobin concentration (r = -0.55, P = 0.000 and r = -0.52, P = 0.000), and C-reactive protein (r = -0.47, P = 0.001 and r = -0.36, P = 0.01) measured when the peptide samples were collected correlated with BNP and NT-proBNP, respectively. In addition, anterior chamber depth of eye and plasma BNP (r = -0.39, P < 0.05) displayed a correlation.

Conclusions: BNP and NT-proBNP levels are associated with severity of several clinical features of acute NE.
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http://dx.doi.org/10.3109/07853890.2013.862960DOI Listing
February 2014

Elevated cerebrospinal fluid neopterin concentration is associated with disease severity in acute Puumala hantavirus infection.

Clin Dev Immunol 2013 31;2013:634632. Epub 2013 Jul 31.

Department of Internal Medicine, Oulu University Hospital, P.O. Box 20, 90029 Oulu, Finland.

Nephropathia epidemica (NE) caused by Puumala hantavirus (PUUV) is the most common hemorrhagic fever with renal syndrome (HFRS) in Europe. The infection activates immunological mechanisms that contribute to the pathogenesis and characteristics of the illness. In this study we measured cerebrospinal fluid (CSF) neopterin concentration from 23 acute-phase NE patients. We collected data on kidney function, markers of tissue permeability, haemodynamic properties, blood cell count, length of hospitalisation, inflammatory parameters, and ophthalmological properties. The neopterin levels were elevated (> 5.8 nmol/L) in 22 (96%) NE-patients (mean 45.8 nmol/L); these were especially high in patients with intrathecal PUUV-IgM production (mean 58.2 nmol/L, P = 0.01) and those with elevated CSF protein concentrations (mean 63.6 nmol/L, P < 0.05). We also observed a correlation between the neopterin and high plasma creatinine value (r = 0.66, P = 0.001), low blood thrombocyte count (r = -0.42, P < 0.05), and markedly disturbed refractory properties of an eye (r = 0.47, P < 0.05). Length of hospitalisation correlated with the neopterin (r = 0.42, P < 0.05; male patients r = 0.69, P < 0.01). Patients with signs of tissue oedema and increased permeability also had high neopterin concentrations. These results reinforce the view that PUUV-HFRS is a general infection that affects the central nervous system and the blood-brain barrier.
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http://dx.doi.org/10.1155/2013/634632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747491PMC
February 2014

Signs of general inflammation and kidney function are associated with the ocular features of acute Puumala hantavirus infection.

Scand J Infect Dis 2012 Dec 25;44(12):956-62. Epub 2012 Jul 25.

Department of Ophthalmology, Oulu University Hospital, Oulu, Finland.

Background: Puumala hantavirus (PUUV) causes nephropathia epidemica (NE), a type of viral haemorrhagic fever with renal syndrome (HFRS). This febrile infection may affect the kidneys, central nervous system (CNS), and the eye. Acute illness is associated with increased tissue permeability and tissue oedema, and many patients experience reduced vision. The aim of this study was to explore the physiological events associated with the ocular features of acute NE.

Methods: This was a prospective study of 46 NE patients who were examined during the acute infection and 1 month after hospitalization. Visual acuity, refraction, intraocular pressure (IOP), and ocular dimensions were evaluated. Cerebrospinal fluid and blood samples were collected, brain magnetic resonance imaging and electroencephalography were recorded, and HLA haplotype was analyzed. The degrees of tissue oedema and fluid imbalance were evaluated.

Results: CNS examinations did not reveal the source of the ocular changes in acute NE. The plasma C-reactive protein concentration correlated with the lens thickness and the IOP. The plasma creatinine level was associated with the change in anterior chamber depth. However, oliguric and polyuric patients displayed similar ocular findings. Patients positive for the DR3-DQ2 haplotype experienced the least diminished visual acuity.

Conclusions: The level of systemic inflammation rather than CNS involvement appears to account for the ocular changes during acute PUUV infection, and the severity of kidney dysfunction may also have a significant role. In addition, the genetic properties of the host may well explain the ocular features of acute hantavirus infection.
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http://dx.doi.org/10.3109/00365548.2012.700119DOI Listing
December 2012

Young male patients are at elevated risk of developing serious central nervous system complications during acute Puumala hantavirus infection.

BMC Infect Dis 2011 Aug 14;11:217. Epub 2011 Aug 14.

Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.

Background: Our aim was to characterize clinical properties and laboratory parameters in patients with or without cerebrospinal fluid (CSF) findings suggestive of central nervous system (CNS) involvement, and especially those who developed serious CNS complications during acute nephropathia epidemica (NE) caused by Puumala hantavirus (PUUV) infection.

Methods: A prospective cohort of 40 patients with acute NE and no signs of major CNS complications was analyzed. In addition, 8 patients with major CNS complications associated with NE were characterized. We collected data of CNS symptoms, CSF analysis, brain magnetic resonance imaging (MRI) results, electroencephalography (EEG) recordings, kidney function, and a number of laboratory parameters. Selected patients were evaluated by an ophthalmologist.

Results: Patients with a positive CSF PUUV IgM finding or major CNS complications were more often males (p < 0.05) and they had higher plasma creatinine values (p < 0.001) compared to those with negative CSF PUUV IgM. The degree of tissue edema did not explain the CSF findings. Patients with major CNS complications were younger than those with negative CSF PUUV IgM finding (52.9 vs. 38.5 years, p < 0.05). Some patients developed permanent neurological and ophthalmological impairments.

Conclusions: CNS and ocular involvement during and after acute NE can cause permanent damage and these symptoms seem to be attributable to true infection of the CNS rather than increased tissue permeability. The possibility of this condition should be borne in mind especially in young male patients.
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http://dx.doi.org/10.1186/1471-2334-11-217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166934PMC
August 2011
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