Geir Hetland

• Kildal, Anders Benjamin; Ueland, Thor; Mirlashari, Mohammad Reza; Nissen-Meyer, Lise Sofie; Granerud, Beathe Kiland & Riise, Anne Margarita Dyrhol [Vis alle 44 forfattere av denne artikkelen] (2026). Serial blood serum measurements of calprotectin and deoxyribonuclease in COVID-19 patients during hospitalization and recovery until one year: a prospective, multicenter, observational study. BMC Infectious Diseases. 26. doi: 10.1186/s12879-026-12939-x. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: To examine circulating calprotectin and deoxyribonuclease (DNase) serum levels during hospitalization in COVID-19 patients, their continuity post-discharge and dynamics in relation to disease severity. Methods: Serum levels were measured in samples collected from 252 COVID-19 patients during hospitalization (admission, days 3–5 and 7–10), at 3 months and after 1 year, and related to admission to intensive care unit (ICU) or high dependency unit (HDU), and 60-day total mortality. Results: During hospitalization, calprotectin and DNase levels were significantly elevated compared to healthy controls (HC). Calprotectin was increased in ICU/HDU patients compared to those at wards during hospitalization and in non-survivors compared to survivors during prolonged hospitalization. High calprotectin levels at admission were associated with male sex, PaO2/FiO2 ratio and national COVID-19 wave 2 and 3 compared to wave 1. High admission levels of both calprotectin and ferritin were associated with an approximately twofold higher odds ratio for ICU/HDU admission than either marker alone. DNase was lower at admission in non-survivors compared to survivors. Post-discharge, DNase but not calprotectin levels remained elevated extending to 1-year follow-up compared to HC. Conclusions: COVID‑19 non‑survivors showed persistently higher calprotectin levels during prolonged hospitalization, and elevated admission calprotectin was associated with later pandemic waves and poorer oxygenation. Incorporating calprotectin with ferritin improved prediction of ICU/HDU admission. DNase levels were lower at admission in non‑survivors, while overall DNase remained elevated from hospitalization through 1‑year follow‑up compared with HC, suggesting a possible role in long‑term COVID‑19–related immune alterations.

• Hauge, Truls; Lie, Maria Isabel Lopes Romao Franc; Hetland, Geir; Waage, Anne; Drewes, Asbjørn M. & Fagerhol, Magne Kristoffer (2025). LeLISA: A New Lectin-Based Immunoassay for Evaluation of Mucinous and Serous Content in Pancreatic Cystic Neoplasms. Digestive Diseases and Sciences. ISSN 0163-2116. 70(10), s. 3412–3418. doi: 10.1007/s10620-025-09188-4. Fulltekst i vitenarkiv
• Agostini, Vanessa; Henschler, Reinhard; Lunde, Turid Helen Felli; Kristoffersen, Einar Klæboe; Hetland, Geir & Danilova, Elena [Vis alle 13 forfattere av denne artikkelen] (2025). A validation study of the in vitro performance of hypoxic red blood cells for transfusion across centers in Europe. Transfusion. ISSN 0041-1132. 65(12), s. 2306–2315. doi: 10.1111/trf.18408. Fulltekst i vitenarkiv Vis sammendrag

  Background Refrigerated storage of red cell concentrate (RCC) leads to metabolic, oxidative, and structural changes that impair functionality and viability. These changes can be attenuated by hypoxic storage. Objective This study assessed the quality of leucocytes-reduced (LR), O2/CO2 reduced red blood cells (RBC) stored for 42 days after pre-storage O2/CO2 reduction with the Hemanext ONE System, to verify compliance with regional and blood center acceptance criteria across six sites. Study design and methods Validation studies of the in vitro performance of the LR, O2/CO2 reduced storage (Hemanext ONE) System were planned and executed at blood production centers in Italy, Germany, Norway and Switzerland. The endpoint-associated study acceptance criteria included total hematocrit >50%, total hemoglobin ≥40 g and hemolysis <0.8%. Results In total, 133 whole blood units donated at six blood centers were evaluated after processing with the Hemanext ONE System and after 21 and 42 days of storage. At Day 1 post-processing, total hemoglobin (mean ± SD) was 52.4 g/unit ± 3.1 and total hematocrit percentage (mean ± SD) was 60.6% ± 7.0 (range, 51.9%–81.0%). Hemolysis at Day 42 of storage: overall mean ± SD, 0.26% ± 0.14. Discussion Hypoxic RBCs met regulatory quality criteria regardless of collection and processing modalities. These results indicate that processing of RBCs stored under hypoxic conditions satisfies acceptance criteria for transfusion into patients in six European regional blood centers.

• Mahmood, Faiza; Hetland, Geir; Mirlashari, Mohammad Reza & Nissen-Meyer, Lise Sofie (2025). IgE sensitization profiles to food, inhalant and insect venom in Norwegian blood donors and their impact on blood transfusions. Scandinavian Journal of Immunology. ISSN 0300-9475. 101(1). doi: 10.1111/sji.13425. Fulltekst i vitenarkiv Vis sammendrag

  Allergen-specific immunoglobulin-E (As-IgE) in blood donors (BD) can be transferred to transfusion recipients via plasma-containing blood components (PCBC) and sensitize recipient's mast cells. These cells can activate upon allergen exposure and cause allergy. This study aimed to assess sensitization profiles against an array of allergens in BD to identify donors with As-IgE and explore if this IgE can lead to allergic symptoms in recipients. Furthermore IgE sensitization was characterized in donors of PCBC that were associated with allergic transfusion reactions (ATR) in recipients. Serum samples from 300 randomly selected BD (RSBD) and 40 BD selected following 26 ATRs in patients transfused with PCBC from these donors were collected. IgE sensitization was tested by a line-blot enzyme-immunoassay and an ELISA-based IgE multiplex assay. Thirty-eight per cent of the RSBD had IgE to one or several allergens. High IgE levels with a potential to transfer to recipients of PCBC were also detected in some BD. Investigation of 2/3 of the PCBC from sensitized RSBD revealed no reports of ATR in recipients. IgE testing of donors associated with an ATR showed sensitization in 65% of the cases. We conclude that IgE testing of BD can reveal sensitization to different allergens, even though persons with severe allergies are not accepted as BD. The sensitization frequency appears higher in BD of PCBC that led to an ATR compared to the RSBD. No reports on ATR were found for PCBC from sensitized RSBD. More studies are needed to address the role of IgE-sensitization of BD in ATR.

• Danilova, Elena; Ezligini, Farshid; Stöckel, Connie; Asakawa, Masafumi & Hetland, Geir (2024). An evaluation of diethylhexyl phthalate free top & bottom in-line blood collection set with a new soft housing filter. Transfusion Medicine. ISSN 0958-7578. 35(1), s. 82–90. doi: 10.1111/tme.13091. Fulltekst i vitenarkiv Vis sammendrag

  Background and Objectives Di (2-ethylhexyl) phthalate (DEHP) plasticizer must be removed from polyvinylchloride (PVC) medical devices due to toxicity. DEHP/PVC blood bags were shown to provide stable quality under blood component production and to create good storage conditions for red blood cells concentrate (RBC). It is important that substitution of the DEHP maintains the RBC quality during storage, which should be achieved with Di (isononyl) cyclohexane-1,2-dicarboxylate (DINCH), although substitution of the plasticizer has been challenging. Materials and Methods A DEHP-free Top & Bottom in-line RBC set was validated in a tertiary hospital blood bank facility. Volunteer blood donors were randomly allocated for blood collection into DINCH/PVC or DEHP/PVC set. The groups were additionally divided according to additive solution/filter combination: PAGGS-M + DINCH/PVC filter (only with DINCH/PVC set), and SAG-M + DINCH/PVC filter and SAG-M + DEHP/PVC filter (only with DEHP/PVC set). Processing and storage effects were assessed in all components. Results RBC concentrates, platelet concentrates and plasma that was processed and stored in DEHP-free set fulfilled European requirements for quality. The cells stored in PAGGS-M after filtration through DEHP-free PVC filter showed the same low haemolysis compared with conventional set at 49 days of storage. Platelets stored in DINCH/PVC bag provided a sufficient quality of platelets after 7 days of storage. Plasma maintained the coagulation factors during 12 months of storage. Conclusion A new DINCH/PVC set allows production of blood components of satisfactory quality in DEHP-free environment.

• Hetland, Geir; Fagerhol, Magne Kristoffer; Mirlashari, Mohammad Reza; Nissen-Meyer, Lise Sofie Haug; Croci, Stefania & Lonati, Paola Adele [Vis alle 13 forfattere av denne artikkelen] (2024). Elevated NET, Calprotectin, and Neopterin Levels Discriminate between Disease Activity in COVID-19, as Evidenced by Need for Hospitalization among Patients in Northern Italy. Biomedicines. 12:766(4), s. 1–11. doi: 10.3390/biomedicines12040766. Fulltekst i vitenarkiv Vis sammendrag

  Coronavirus disease 2019 (COVID-19) displays clinical heterogeneity, but little information is available for patients with mild or very early disease. We aimed to characterize biomarkers that are useful for discriminating the hospitalization risk in a COVID-19 cohort from Northern Italy during the first pandemic wave. We enrolled and followed for four weeks 76 symptomatic SARS-CoV-2 positive patients and age/sex-matched healthy controls. Patients with mild disease were discharged (n.42), and the remaining patients were hospitalized (n.34). Blood was collected before any anti-inflammatory/immunosuppressive therapy and assessed for soluble C5b-9/C5a, H3-neutrophil extracellular traps (NETs), calprotectin, and DNase plasma levels via ELISA and a panel of proinflammatory cytokines via ELLA. Calprotectin and NET levels discriminate between hospitalized and non-hospitalized patients, while DNase negatively correlates with NET levels; there are positive correlations between calprotectin and both NET and neopterin levels. Neopterin levels increase in patients at the beginning of the disease and do so more in hospitalized than non-hospitalized patients. C5a and sC5b-9, and other acute phase proteins, correlate with neopterin, calprotectin, and DNase. Both NET and neopterin levels negatively correlate with platelet count. We show that calprotectin, NETs, and neopterin are important proinflammatory parameters potentially useful for discriminating between COVID-19 patients at risk of hospitalization.

• Fagerhol, Magne Kristoffer; Schultz, Nina Haagenrud; Mirlashari, Mohammad Reza; Wiedmann, Markus; Nissen-Meyer, Lise Sofie Haug & Søraas, Arne Vasli Lund [Vis alle 7 forfattere av denne artikkelen] (2023). DNase analysed by a novel competitive assay in patients with complications after ChAdOx1 nCoV-19 vaccination and in normal unvaccinated blood donors. Scandinavian Journal of Immunology. ISSN 0300-9475. 98(1). doi: 10.1111/sji.13274. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Increased levels of neutrophil extracellular traps (NETs) have been detected in individuals with vaccine complications after the ChAdOx1 nCov vaccine with a correlation between the severity of vaccine side effects and the level of NETosis. DNases may disrupt NETs by degrading their content of DNA, and a balance has been reported between NETs and DNases. Because of this and since the inflammatory marker NETs may be used as a confirmatory test in diagnosing VITT, it is of interest to monitor levels of DNase in patients with increased NETs levels. The current novel rapid DNase ELISA was tested in blood samples of patients with known increased levels of NETs with or without VITT after ChAdOx1 nCoV‐19 vaccination. DNase levels in VITT patients were significantly increased compared with normal unvaccinated blood donors and compared with patients with post‐vaccination symptoms but not VITT. However, since EDTA was found to inhibit DNase, serum and not EDTA‐plasma samples should be applied for DNase testing. The novel DNase assay may serve as a supplementary test to the NETs test when analysing samples from patients with suspected increased NETs levels.

• Reikvam, Håkon; Hetland, Geir; Ezligini, Farshid; Dorsch, Kim; Omert, Laurel & Dunham, Andrew [Vis alle 7 forfattere av denne artikkelen] (2023). Safety of hypoxic red blood cell administration in patients with transfusion-dependent hematological malignancies: An interim analysis. Transfusion and Apheresis Science. ISSN 1473-0502. 62:103755(5), s. 1–4. doi: 10.1016/j.transci.2023.103755. Fulltekst i vitenarkiv Vis sammendrag

  Anemia is a common symptom of hematological malignancies and red blood cell (RBC) transfusion is the primary supportive treatment, with many patients becoming transfusion dependent. Hemanext Inc. (Lexington, MA, United States) has developed a CE mark certified device to process and store RBCs hypoxically – citrate-phosphatedextrose (CPD)/phosphate-adenine-glucose-guanosine-saline-mannitol (PAGGSM) RBCs, leukocytes-reduced (LR), O2/CO2 reduced – with the aim of improving RBC quality for transfusion. This interim analysis describes the first patients to receive hypoxic RBCs, administered as part of a pilot post-marketing study in Norway. The primary outcome was adverse events (AEs) within 24 h of transfusion initiation and overall up to 7 days ( ± 1 day) post-transfusion. Secondary outcomes included changes in hemoglobin levels post-transfusion. Five patients with hematological malignancies were included (80 % male, mean age 69.8 [SD ± 19.3] years). Prior to the study, patients had been receiving conventional RBC transfusions every two weeks. Patients received 2 units of hypoxic RBCs over 2 h without complication. One mild AE (rhinovirus) was reported two days post-treatment and was deemed unrelated to treatment. The mean ± SD pre-transfusion hemoglobin level was 7.7 ± 0.5 g/dL, evolving to 9.0 ± 0.9 g/dL following administration of hypoxic RBCs; an increase of 17 %. This interim analysis showed that transfusion with hypoxic RBCs processed with the CPD/PAGGSM LR, O2/CO2 reduced system was effective and well tolerated in patients with hematologic malignancies. The overall clinical program will assess whether the use of hypoxic RBCs can reduce transfusion interval versus conventional RBCs in patients requiring acute and chronic transfusions.

• Mirlashari, Mohammad Reza; Vetlesen, Annette; Nissen-Meyer, Lise Sofie Haug & Hetland, Geir (2023). Effects of storage on quality and function of acid-treated platelets with reduced HLA Class I surface expression. Transfusion Medicine. ISSN 0958-7578. 33(4), s. 329–336. doi: 10.1111/tme.12983. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background Refractory patients need to be provided with HLA‐matched platelets (PLTs), which require time‐consuming cross‐matching. Treatment of PLTs with citric acid leads to denaturation of the HLA Class I complexes without significant damage to the PLTs. HLA Class I depleted PLTs could alternatively be used to HLA‐matched PLTs for transfusion. These PLTs have verified normal function up to 4–6 h after acid treatment. Materials and Methods Buffy coat (BC) PLT concentrates were depleted of HLA Class I complexes by incubation in citric acid. The days after acid‐treatment, surface expression of HLA Class I complexes, CD62P and CD63 were determined by flow cytometry, in addition to viability and mitochondrial membrane potential (MMP). Thromboelastography (TEG) tested PLT functionality. Results Expression of HLA Class I complexes was reduced by 70%–75% in acid‐treated PLTs compared to untreated PLTs from day 1 through day 7. Controls and acid‐treated PLTs showed insignificant loss of MMP stored for 4 days. Analysis of the residual PLT activation and viability showed no significant differences for 4 days of storage. However, the residual PLT activation potential and viability were significantly decreased in acid‐treated PLTs and control PLTs after 7 days of storage. Acid treatment caused a significant decrease in the TEG variable, reaction time (R time), for acid‐treated PLTs as compared to control PLTs from days 1 through day 3. Conclusion Our data suggest that extended storage of acid‐treated PLTs is possible and will improve flexibility when planning for transfusion of patients with alloimmune PLT refractoriness caused by anti‐HLA‐antibodies.

• Mahmood, Faiza; Nissen-Meyer, Lise Sofie Haug; Hetland, Geir & Nentwich, Ivo (2023). Assessing IgE sensitization profiles to birch and timothy grass pollen allergens in birch pollen allergic blood donors using an oligoplex specific IgE assay. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 83(7), s. 444–447. doi: 10.1080/00365513.2023.2255972. Fulltekst i vitenarkiv Vis sammendrag

  IgE sensitization profiles to single birch allergens in birch-sensitized patients differ among European countries. The aim of this study was to determine the distribution of specific IgE antibodies to major and minor birch pollen allergens in a population of allergic Norwegian individuals by using a birch allergic blood donor population as a surrogate sample. Sixty blood donors were recruited and sampled based on birch allergy symptoms such as rhinitis, rhinoconjunctivitis and/or mild asthma in previous seasons. All sera were collected before start of the pollen season and tested using a line blot assay (Euroimmun AG, Lübeck, Germany) for IgE to birch and timothy pollen. Both extracts, single allergens, and cross-reacting carbohydrate determinants (CCD) were analysed. Only donors with specific IgE to birch and/or timothy grass were further evaluated. Specific IgE to birch pollen extract was found in 52 sera, and sensitization to timothy grass in 40 sera. Specific IgE to Bet v 1 was predominant in contrast to Bet v 4 which was absent. However, sensitization to the minor allergens Bet v 2 and 6 was always found together with high levels of IgE to Bet v 1. Subjects sensitized to the profilin Bet v 2 from birch were also sensitized to Phl p 12 from timothy grass. In conclusion, there was predominantly Bet v 1 sensitization in this cohort and low sensitization to minor allergens and cross-reactive allergens (Bet v 2, Bet v 4, Phl p 7 and Phl p 12).

• Hetland, Geir; Fagerhol, Magne Kristoffer; Dimova-Svetoslavova, Veselka Petrova; Mirlashari, Mohammad Reza; Nguyen, Nhan Trung & Lind, Andreas [Vis alle 9 forfattere av denne artikkelen] (2022). Inflammatory markers calprotectin, NETs, syndecan-1 and neopterin in COVID-19 convalescent blood donors. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 82(6), s. 481–485. doi: 10.1080/00365513.2022.2123387. Fulltekst i vitenarkiv Vis sammendrag

  Persisting inflammation has been discovered in lungs and other parenchymatous organs of some COVID-19 convalescents. Calprotectin, neutrophil extracellular traps (NETs), syndecan-1 and neopterin are general key inflammatory markers, and systemically enhanced levels of them may remain after the COVID-19 infection. These inflammatory markers were therefore measured in serum samples of 129 COVID-19 convalescent and 27 healthy blood donors or employees at Oslo Blood bank, Norway. Also antibodies against SARS-CoV-2 nucleocapsid antigen were measured, and timing of sampling and severity of infection noted. Whereas neopterin and NETs values remained low and those for syndecan-1 were not raised to statistically significant level, concentrations for calprotectin, as measured by a novel mixed monoclonal assay, were significantly increased in the convalescents. Antibodies against SARS-CoV-2 nucleocapsid antigen were elevated, but did not correlate with levels of inflammatory markers. Difference between the groups in only one biomarker makes evaluation of ongoing or residual inflammation in the convalescents difficult. If there is a low-grade inflammation, it would in that case involve neutrophils.

• Hetland, Geir; Fagerhol, Magne Kristoffer; Wiedmann, Markus; Søraas, Arne Vasli; Mirlashari, Mohammad Reza & Nissen-Meyer, Lise Sofie Haug [Vis alle 9 forfattere av denne artikkelen] (2022). Elevated NETs and Calprotectin Levels after ChAdOx1 nCoV-19 Vaccination Correlate with the Severity of Side Effects. Vaccines. 10(8). doi: 10.3390/vaccines10081267. Fulltekst i vitenarkiv Vis sammendrag

  ChAdOx1 nCoV-19 vaccination has been associated with the rare side effect; vaccine-induced immune thrombotic thrombocytopenia (VITT). The mechanism of thrombosis in VITT is associated with high levels of neutrophil extracellular traps (NETs). The present study examines whether key markers for NETosis, such as H3-NETs and calprotectin, as well as syndecan-1 for endotheliopathy, can be used as prognostic factors to predict the severity of complications associated with ChAdOx1 vaccination. Five patients with VITT, 10 with prolonged symptoms and cutaneous hemorrhages but without VITT, and 15 with only brief and mild symptoms after the vaccination were examined. Levels of H3-NETs and calprotectin in the vaccinated individuals were markedly increased in VITT patients compared to vaccinees with milder vaccination-associated symptoms, and a strong correlation (r ≥ 0.745, p &lt; 0.001) was found with severity of vaccination side effects. Syndecan-1 levels were also positively correlated (r = 0.590, p &lt; 0.001) in vaccinees to side effects after ChAdOx1 nCoV-19 vaccination. We hypothesize that the inflammatory markers NETs and calprotectin may be used as confirmatory tests in diagnosing VITT.

• Meroni, Pier Luigi; Croci, Stefania; Lonati, Paola Adele; Pregnolato, Francesca; Spaggiari, Lucia & Besutti, Giulia [Vis alle 15 forfattere av denne artikkelen] (2022). Complement activation predicts negative outcomes in COVID-19: The experience from Northen Italian patients. Autoimmunity Reviews. ISSN 1568-9972. 22:103232(1), s. 1–7. doi: 10.1016/j.autrev.2022.103232. Fulltekst i vitenarkiv Vis sammendrag

  Coronavirus disease 19 (COVID-19) may present as a multi-organ disease with a hyperinflammatory and prothrombotic response (immunothrombosis) in addition to upper and lower airway involvement. Previous data showed that complement activation plays a role in immunothrombosis mainly in severe forms. The study aimed to investigate whether complement involvement is present in the early phases of the disease and can be predictive of a negative outcome. We enrolled 97 symptomatic patients with a positive RT-PCR for SARS-CoV-2 presenting to the emergency room. The patients with mild symptoms/lung involvement at CT-scan were discharged and the remaining were hospitalized. All the patients were evaluated after a 4-week follow-up and classified as mild (n. 54), moderate (n. 17) or severe COVID-19 (n. 26). Blood samples collected before starting any anti-inflammatory/immunosuppressive therapy were assessed for soluble C5b-9 (sC5b-9) and C5a plasma levels by ELISA, and for the following serum mediators by ELLA: IL-1β, IL-6, IL-8, TNFα, IL-4, IL-10, IL-12p70, IFNγ, IFNα, VEGF-A, VEGF-B, GM-CSF, IL-2, IL-17A, VEGFR2, BLyS. Additional routine laboratory parameters were measured (fibrin fragment D-dimer, C-reactive protein, ferritin, white blood cells, neutrophils, lymphocytes, monocytes, platelets, prothrombin time, activated partial thromboplastin time, and fibrinogen). Fifty age and sex-matched healthy controls were also evaluated. SC5b-9 and C5a plasma levels were significantly increased in the hospitalized patients (moderate and severe) in comparison with the non-hospitalized mild group. SC5b9 and C5a plasma levels were predictive of the disease severity evaluated one month later. IL-6, IL-8, TNFα, IL-10 and complement split products were higher in moderate/severe versus non-hospitalized mild COVID-19 patients and healthy controls but with a huge heterogeneity. SC5b-9 and C5a plasma levels correlated positively with CRP, ferritin values and the neutrophil/lymphocyte ratio. Complement can be activated in the very early phases of the disease, even in mild non-hospitalized patients. Complement activation can be observed even when pro-inflammatory cytokines are not increased, and predicts a negative outcome.

• Mirlashari, Mohammad Reza; Vetlesen, Annette; Nissen-Meyer, Lise Sofie Haug; Naper, Christian; Tjønnfjord, Geir Erland & Njerve, Ida Unhammer [Vis alle 12 forfattere av denne artikkelen] (2021). HLA class I depletion by citric acid, and irradiation of apheresis platelets for transfusion of refractory patients. Transfusion. ISSN 0041-1132. 61(4), s. 1222–1234. doi: 10.1111/trf.16282. Fulltekst i vitenarkiv Vis sammendrag

  Background Patients can form antibodies to foreign human leukocyte antigen (HLA) Class I antigens after exposure to allogeneic cells. These anti‐HLA class I antibodies can bind transfused platelets (PLTs) and mediate their destruction, thus leading to PLT refractoriness. Patients with PLT refractoriness need HLA‐matched PLTs, which require expensive HLA typing of donors, antibody analyses of patient sera and/or crossmatching. An alternative approach is to reduce PLT HLA Class I expression using a brief incubation in citric acid on ice at low pH. Methods and Materials Apheresis PLT concentrates were depleted of HLA Class I complexes by 5 minutes incubation in ice‐cold citric acid, at pH 3.0. Surface expression of HLA Class I complexes, CD62P, CD63, phosphatidylserine, and complement factor C3c was analyzed by flow cytometry. PLT functionality was tested by thromboelastography (TEG). Results Acid treatment reduced the expression of HLA Class I complexes by 71% and potential for C3c binding by 11.5‐fold compared to untreated PLTs. Acid‐treated PLTs were significantly more activated than untreated PLTs, but irrespective of this increase in steady‐state activation, CD62P and CD63 were strongly upregulated on both acid‐treated and untreated PLTs after stimulation with thrombin receptor agonist peptide. Acid treatment did not induce apoptosis over time. X‐ray irradiation did not significantly influence the expression of HLA Class I complexes, CD62P, CD63, and TEG variables on acid treated PLTs. Conclusion The relatively simple acid stripping method can be used with irradiated apheresis PLTs and may prevent transfusion‐associated HLA sensitization and overcome PLT refractoriness.

• Mirlashari, Mohammad Reza; Vetlesen, Annette; Nissen-Meyer, Lise Sofie Haug; Stensland, Maria Ekman; Singh, Sachin Kumar & Nyman, Tuula Anneli [Vis alle 7 forfattere av denne artikkelen] (2021). Proteomic study of apheresis platelets made HLA class I deficient for transfusion of refractory patients. PROTEOMICS - Clinical Applications. ISSN 1862-8346. 15:e2100022(6), s. 1–8. doi: 10.1002/prca.202100022. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Refractoriness can occur after repeated platelet (PLT) transfusions because of alloimmunization to HLA class I antigens on transfused PLTs and generation of anti-HLA antibodies that bind to the foreign PLTs and initiate their destruction. Such refractoriness can be overcome by provision of HLA-matched PLTs from HLA typed donors. However, since the procedure is both expensive and time-consuming, an alternative approach is to deplete PLTs of HLA class I molecules by a brief treatment with citric acid, on ice. This is shown to be feasible without damaging PLT function. We used label free quantitative mass spectrometry (MS)-based proteomics to investigate the effect of acid treatment on apheresis PLTs for combatting immunologic PLT refractoriness. Experimental Design Proteomic analyses are undertaken using PLTs from seven apheresis concentrates, which were split in two with or without acid treatment. Results In total 1717 proteins in apheresis PLTs were quantified using proteomics. Data are available via ProteomeXchange with identifier PXD027893 . Of these, the amount of 80 proteins changed significantly after acid treatment, but overall there were not any major differences in proteomes between samples with and without acid treatment. Conclusions and Clinical Relevance In general, the changes of PLT proteins after treatment with citric acid were quite small and functionally safe. Hence, this result taken together with our previously published data indicates that acid treated PLTs can be used for treatment of patients with PLT refractoriness and opens up for a clinical trial.

• Hetland, Geir; Johnson, Egil; Bernardshaw, Soosaipillai & Grinde, Bjørn (2020). Can medicinal mushrooms have prophylactic or therapeutic effect against COVID-19 and its pneumonic superinfection and complicating inflammation? Scandinavian Journal of Immunology. ISSN 0300-9475. 93(1), s. 1–12. doi: 10.1111/sji.12937. Fulltekst i vitenarkiv Vis sammendrag

  Medicinal mushrooms have documented effects against different diseases, including infections and inflammatory disorders. The related Basidiomycota Agaricus blazei Murill (AbM), Hericium erinaceus (HE), and Grifola frondosa (GF) have been shown to exert antimicrobial activity against viral agents, Gram‐positive and Gram‐negative bacteria, and parasites in vitro and in vivo. Since the mechanism is immunomodulatory and not antibiotical, the mushrooms should be active against multi‐drug resistant microbes as well. Moreover, since these Basidiomycota also have anti‐inflammatory properties, they may be suited for treatment of the severe lung inflammation that often follows COVID‐19 infection. An AbM‐based mushroom extract (Andosan™), also containing HE and GF, has been shown to significantly reduce bacteraemia and increase survival in mice with pneumococcal sepsis, and to improve symptoms and quality of life in IBD patients via an anti‐inflammatory effect. Hence, such mushroom extracts could have prophylactic or therapeutic effect against the pneumonic superinfection and severe lung inflammation that often complicates COVID‐19 infection. Here, we review antimicrobial and anti‐inflammatory properties of AbM, HE and GF mushrooms, which could be used for the battle against COVID‐19.

• Hetland, Geir; Tangen, Jon-Magnus; Mahmood, Faiza; Mirlashari, Mohammad Reza; Nissen-Meyer, Lise Sofie Haug & Nentwich, Ivo [Vis alle 9 forfattere av denne artikkelen] (2020). Antitumor, Anti-inflammatory and Antiallergic Effects of Agaricus blazei Mushroom Extract and the Related Medicinal Basidiomycetes Mushrooms, Hericium erinaceus and Grifola frondosa: A Review of Preclinical and Clinical Studies. Nutrients. 12(5), s. 1–19. doi: 10.3390/nu12051339. Fulltekst i vitenarkiv Vis sammendrag

  Since the 1980s, medicinal effects have been documented in scientific studies with the related Basidiomycota mushrooms Agaricus blazei Murill (AbM), Hericium erinaceus (HE) and Grifola frondosa (GF) from Brazilian and Eastern traditional medicine. Special focus has been on their antitumor effects, but the mushrooms’ anti-inflammatory and antiallergic properties have also been investigated. The antitumor mechanisms were either direct tumor attack, e.g., apoptosis and metastatic suppression, or indirect defense, e.g., inhibited tumor neovascularization and T helper cell (Th) 1 immune response. The anti-inflammatory mechanisms were a reduction in proinflammatory cytokines, oxidative stress and changed gut microbiota, and the antiallergic mechanism was amelioration of a skewed Th1/Th2 balance. Since a predominant Th2 milieu is also found in cancer, which quite often is caused by a local chronic inflammation, the three conditions—tumor, inflammation and allergy—seem to be linked. Further mechanisms for HE were increased nerve and beneficial gut microbiota growth, and oxidative stress regulation. The medicinal mushrooms AbM, HE and GF appear to be safe, and can, in fact, increase longevity in animal models, possibly due to reduced tumorigenesis and oxidation. This article reviews preclinical and clinical findings with these mushrooms and the mechanisms behind them.

• Fagerhol, Magne Kristoffer; Johnson, Egil; Tangen, Jon-Magnus; Hollan, Ivana; Mirlashari, Mohammad Reza & Nissen-Meyer, Lise Sofie Haug [Vis alle 7 forfattere av denne artikkelen] (2020). NETs Analyzed by Novel Calprotectin-Based Assays in Blood Donors, and Patients With Multiple Myeloma or Rheumatoid Arthritis. A Pilot Study. Scandinavian Journal of Immunology. ISSN 0300-9475. 91(5), s. 1–5. doi: 10.1111/sji.12870. Fulltekst i vitenarkiv Vis sammendrag

  Two novel enzyme-linked immunosorbent assays (ELISAs), designed to detect complexes containing DNA, leucocyte calprotectin and S100A12 proteins, were generated for improved specificity and rapid measurement of neutrophil extracellular traps (NETs). The assays were applied on plasma and serum samples from blood donors for establishment of reference values, and from patients with multiple myeloma (MM) or rheumatoid arthritis (RA) in order to examine putatively increased values in the two different inflammatory conditions. Although NETs were hardly detectable in healthy individuals, NET levels were as expected highly and statistically significantly increased in RA patients. The detection of statistically significantly increased NET levels in MM is a novel finding.

• Mahmood, Faiza; Hetland, Geir; Nentwich, Ivo; Mirlashari, Mohammad Reza; Ghiasvand, Reza & Nissen-Meyer, Lise Sofie Haug (2019). Agaricus blazei-Based Mushroom Extract Supplementation to Birch Allergic Blood Donors: A Randomized Clinical Trial. Nutrients. 11(10), s. 1–15. doi: 10.3390/nu11102339. Fulltekst i vitenarkiv Vis sammendrag

  Since Agaricus blazei Murill (AbM) extract reduced specific IgE and ameliorated a skewed Th1/Th2 balance in a mouse allergy model, it was tested in blood donors with self-reported, IgE-positive, birch pollen allergy and/or asthma. Sixty recruited donors were randomized in a placebo-controlled, double-blinded study with pre-seasonal, 7-week, oral supplementation with the AbM-based extract AndosanTM. Before and after the pollen season, questionnaires were answered for allergic rhino-conjunctivitis, asthma, and medication; serum IgE was measured, and Bet v 1-induced basophil activation was determined by CD63 expression. The reported general allergy and asthma symptoms and medication were significantly reduced in the AbM compared to the placebo group during pollen season. During the season, there was significant reduction in specific IgE anti-Bet v 1 and anti-t3 (birch pollen extract) levels in the AbM compared with the placebo group. While the maximal allergen concentrations needed for eliciting basophil activation before the season, changed significantly in the placebo group to lower concentrations (i.e., enhanced sensitization) after the season, these concentrations remained similar in the AndosanTM AbM extract group. Hence, the prophylactic effect of oral supplementation before the season with the AbM-based AndosanTM extract on aeroallergen-induced allergy was associated with reduced specific IgE levels during the season and basophils becoming less sensitive to allergen activation.

• Johnson, Egil; Therkelsen, Stig Palm; Nentwich, Ivo; Nissen-Meyer, Lise Sofie Haug & Hetland, Geir (2019). IgE-sensitization to food and inhalant allergens in IBD patients compared with normal blood donors at Oslo University Hospital, Norway. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 54(9), s. 1107–1110. doi: 10.1080/00365521.2019.1663445. Fulltekst i vitenarkiv
• Tangen, Jon-Magnus; Holien, Toril; Mirlashari, Mohammad Reza; Misund, Kristine & Hetland, Geir (2017). Cytotoxic Effect on Human Myeloma Cells and Leukemic Cells by the Agaricus blazei Murill Based Mushroom Extract, Andosan™. BioMed Research International. ISSN 2314-6133. 2017. doi: 10.1155/2017/2059825. Fulltekst i vitenarkiv Vis sammendrag

  Agaricus blazei Murill is an edible mushroom of the Basidiomycetes family, which has been found to contain a number of compounds with antitumor properties, such as proteoglycans and ergosterol. In the present investigation, we show that the commercial mushroom product Andosan, which contains 82.4% Agaricus blazei Murill, together with medicinal mushrooms Hericium erinaceus (14.7%) and Grifola frondosa (2.9%), has a cytotoxic effect on primary myeloma cells, other myeloma cell lines, and leukemia cell lines in vitro. Although the exact content and hence the mechanisms of action of the Andosan extract are unknown, we have found in this investigation indications of cell cycle arrest when myeloma cell lines are cultivated with Andosan. This may be one of the possible explanations for the cytotoxic effects of Andosan.

• Therkelsen, Stig Palm; Hetland, Geir; Lyberg, Torstein; Lygren, Idar & Johnson, Egil (2016). Cytokine Levels After Consumption of a Medicinal Agaricus blazei Murill-Based Mushroom Extract, AndoSan™ , in Patients with Crohn's Disease and Ulcerative Colitis in a Randomized Single-Blinded Placebo-Controlled Study. Scandinavian Journal of Immunology. ISSN 0300-9475. 84(6), s. 323–331. doi: 10.1111/sji.12476. Fulltekst i vitenarkiv
• Therkelsen, Stig Palm; Hetland, Geir; Lyberg, Torstein; Lygren, Idar & Johnson, Egil (2016). Effect of a medicinal agaricus blazei murill- based mushroom extract, andosan™, on symptoms, fatigue and quality of life in patients with ulcerative colitis in a randomized single-blinded placebo controlled study. PLOS ONE. 11(3). doi: 10.1371/journal.pone.0150191. Fulltekst i vitenarkiv Vis sammendrag

  Background Ingestion of AndoSan™, based on the mushroom Agaricus blazei Murill, has previously been shown to exhibit anti-inflammatory effects because of reduction of pro-inflammatory cytokines in healthy individuals and patients with ulcerative colitis. In this randomized single-blinded placebo controlled study we examined whether intake of AndoSan™also resulted in clinical effects. Methods and Findings 50 patients with symptomatic ulcerative colitis were block-randomized and blinded for oral daily intake of AndoSan™or placebo for the 21 days’ experimental period. The patients reported scores for symptoms, fatigue and health related quality of life (HRQoL) at days 0, 14 and 21. Fecal calprotectin and general blood parameters were also analyzed. In the AndoSan™group (n = 24) symptoms improved from baseline (day 0) to days 14 and 21, with respective mean scores (95% CI) of 5.88 (4.92–6.83), 4.71 (3.90–5.52) (p = 0.002) and 4.50 (3.70–5.30) (p = 0.001). Corresponding improved mean scores (±SD) for total fatigue were 16.6 (5.59), 14.1 (4.50) (p = 0.001) and 15.1 (4.09) (p = 0.023). These scores in the placebo group (n = 26) were not improved. When comparing the two study groups using mixed model statistics, we found significant better scores for the AndoSan™-patients. HRQoL for dimensions bodily pain, vitality, social functioning and mental health improved in the AndoSan™group. There were no alterations in general blood samples and fecal calprotectin. Conclusions Beneficiary effects on symptoms, fatigue and HRQoL from AndoSan™consumption were demonstrated in this per-protocol study, supporting its use as a supplement to conventional medication for patients with mild to moderate symptoms from ulcerative colitis. The patients did not report any harms or unintended effects of AndoSan™in this study. Trial Registration ClinicalTrials.gov NCT01496053

• Therkelsen, Stig Palm; Hetland, Geir; Lyberg, Torstein; Lygren, Idar & Johnson, Egil (2016). Effect of the medicinal agaricus blazei murill-based mushroom extract, andosantm, on symptoms, fatigue and quality of life in patients with Crohn's disease in a randomized single-blinded placebo controlled study. PLOS ONE. 11:e0159288(7). doi: 10.1371/journal.pone.0159288. Fulltekst i vitenarkiv Vis sammendrag

  Background Ingestion of AndoSanTM, based on the mushroom Agaricus blazei Murill, has previously shown an anti-inflammatory effect through reduction of pro-inflammatory cytokines in healthy individuals and patients with Crohn’s disease (CD). In this randomized singleblinded placebo-controlled study we examined whether intake of AndoSanTM also resulted in clinical effects. Methods and Findings 50 patients with symptomatic CD were randomized for oral daily consumption of Ando-SanTM or placebo for a 21-day experimental period, in this per-protocol study. Patients reported validated scores for symptoms, fatigue and health related quality of life (HRQoL) at days 0, 14 and 21. Fecal calprotectin and general blood parameters were also analyzed. In the AndoSanTM group (n = 25) symptoms improved from baseline (day 0) to days 14 and 21, with respective mean scores (95% CI) of 5.52 (4.64–6.40), 4.48 (3.69–5.27) and 4.08 (3.22–4.94) (p<0,001). We found significant improvements in symptom score for both genders in the AndoSanTM group, and no significant changes in the placebo (n = 25) group. There were however no significant differences between the groups (p = 0.106), although a marginal effect in symptom score for men (p = 0.054). There were comparable improvements in physical, mental and total fatigue for both groups. HRQoL versus baseline were at day 21 improved for bodily pain and vitality in the AndoSanTM group and for vitality and social functioning in the placebo group. No crucial changes in general blood samples and fecal calprotectin were detected. Conclusions The results from this single-blinded randomized clinical trial shows significant improvement on symptoms, for both genders, in the AndoSanTM group, but no significant differences between the study groups. The results on fatigue, HRQoL, fecal calprotectin and blood samples were quite similar compared with placebo. The patients did not report any harms or unintended effects of AndoSanTM. CD patients with mild to moderate symptomsmay have beneficiary effects of AndoSanTM as a safe supplement in addition to conventional medication. Trial Registration ClinicalTrials.gov NCT01496053

• Hetland, Geir; Eide, Dag Markus; Tangen, Jon-Magnus; Haugen, Mads Haugland; Mirlashari, Mohammad Reza & Paulsen, Jan Erik (2016). The Agaricus blazei-Based Mushroom Extract, Andosan™, Protects against Intestinal Tumorigenesis in the A/J Min/+ Mouse. PLOS ONE. 11(12). doi: 10.1371/journal.pone.0167754. Fulltekst i vitenarkiv Vis sammendrag

  Background The novel A/J Min/+ mouse, which is a model for human Familial Adenomatous Polyposis (FAP), develops spontaneously multiple adenocarcinomas in the colon as well as in the small intestine. Agaricus blazei Murill (AbM) is an edible Basidiomycetes mushroom that has been used in traditional medicine against cancer and other diseases. The mushroom contains immunomodulating β-glucans and is shown to have antitumor effects in murine cancer models. Andosan™ is a water extract based on AbM (82%), but it also contains the medicinal Basidiomycetes mushrooms Hericeum erinaceus and Grifola frondosa. Methods and findings Tap water with 10% Andosan™ was provided as the only drinking water for 15 or 22 weeks to A/J Min/+ mice and A/J wild-type mice (one single-nucleotide polymorphism (SNP) difference), which then were exsanguinated and their intestines preserved in formaldehyde and the serum frozen. The intestines were examined blindly by microscopy and also stained for the tumor-associated protease, legumain. Serum cytokines (pro- and anti-inflammatory, Th1-, Th2 -and Th17 type) were measured by Luminex multiplex analysis. Andosan™ treated A/J Min/+ mice had a significantly lower number of adenocarcinomas in the intestines, as well as a 60% significantly reduced intestinal tumor load (number of tumors x size) compared to control. There was also reduced legumain expression in intestines from Andosan™ treated animals. Moreover, Andosan™ had a significant cytotoxic effect correlating with apoptosis on the human cancer colon cell line, Caco-2, in vitro. When examining serum from both A/J Min/+ and wild type mice, there was a significant increase in anti-tumor Th1 type and pro-inflammatory cytokines in the Andosan™ treated mice. Conclusions The results from this mouse model for colorectal cancer shows significant protection of orally administered Andosan™ against development of intestinal cancer. This is supported by the finding of less legumain in intestines of Andosan™ treated mice and increased systemic Th1 cytokine response. The mechanism is probably both immuno-modulatory and growth inhibition of tumor cells by induction of apoptosis.

• Berven, Lise; Karppinen, Pernille Kristensen; Hetland, Geir & Samuelsen, Anne Berit C. (2015). The polar high molecular weight fraction of the agaricus blazei murill extract, andosan™, reduces the activity of the tumor-associated protease, legumain, in RAW 264.7 cells. Journal of Medicinal Food. ISSN 1096-620X. 18(4), s. 429–438. doi: 10.1089/jmf.2014.0018. Fulltekst i vitenarkiv
• Therkelsen, Stig Palm; Hetland, Geir; Johnson, Egil & Nentwich, Ivo (2015). AndosanTM-an anti-allergic and anti-inflammatory ingredint prepared from Agaricus blazei Mushroom. Journal of Clinical & Cellular Immunology. 6(2), s. 1-10–1-10. doi: 10.4172/2155-9899.1000320. Fulltekst i vitenarkiv
• Tangen, Jon-Magnus; Tierens, Anne; Caers, Jo; Binsfeld, Marilene; Olstad, Ole Kristoffer & Siebke, Anne-Marie [Vis alle 9 forfattere av denne artikkelen] (2015). Immunomodulatory Effects of the Agaricus blazei Murrill-Based Mushroom Extract AndoSan in Patients with Multiple Myeloma Undergoing High Dose Chemotherapy and Autologous Stem Cell Transplantation: A Randomized, Double Blinded Clinical Study. BioMed Research International. ISSN 2314-6133. doi: 10.1155/2015/718539. Fulltekst i vitenarkiv
• Hetland, Geir; Tangen, Jon-Magnus & Tryggestad, Anne Merete Aaland (2014). Stimulation of human monocytic cells by the medicinal mushroom Agaricus blazei Murill induces expression of cell surface markers associated with activation and antigen presentation. Applied Scientific Reports. ISSN 2054-9903. doi: 10.7243/2054-9903-1-1. Fulltekst i vitenarkiv
• Hetland, Geir; Tryggestad, Anne Merete Aaland; Espevik, Terje & Ryan, Liv (2013). The medicinal mushroom Agaricus blazei Murill promotes NF-B activation via stimulation of TLR2 and inhibits its activation via TLR4. Journal of Pharmaceutical and Biomedical Sciences. ISSN 2230-7885. 29, s. 753–761. doi: 10.1182/blood.v116.21.3904.3904. Fulltekst i vitenarkiv
• Hetland, Geir; Johnson, Egil; Eide, Dag Markus; Grinde, Bjørn; Samuelsen, Anne Berit C. & Wiker, Harald G (2013). Antimicrobial effects of beta-glucans and pectin and of the Agaricus blazei-based mushroom extract, AndoSanTM. Examples of mouse models for pneumococcal-, fecal bacterial-, and mycobacterial infections. I Mendez-Vilas, A. (Red.), Microbial pathogens and strategies for combating them: science, technology and education. Formatex Research Center. ISSN 9788494213403. s. 889–898. Fulltekst i vitenarkiv
• Johnson, Egil; Førland, Dag T.; Hetland, Geir; Sætre, Karin Lisbeth; Olstad, Ole Kristoffer & Lyberg, Torstein (2012). Effect of AndoSan (TM) on expression of adhesion molecules and production of reactive oxygen species in human monocytes and granulocytes in vivo. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 47(8-9), s. 984–992. doi: 10.3109/00365521.2012.660544. Fulltekst i vitenarkiv
• Førland, Dag T.; Johnson, Egil; Sætre, Karin Lisbeth; Lyberg, Torstein; Lygren, Idar & Hetland, Geir (2011). Effect of an Extract Based on the Medicinal Mushroom Agaricus blazei Murill on Expression of Cytokines and Calprotectin in Patients with Ulcerative Colitis and Crohn's disease. Scandinavian Journal of Immunology. ISSN 0300-9475. 73(1), s. 66–75. doi: 10.1111/j.1365-3083.2010.02477.x. Fulltekst i vitenarkiv
• Hetland, Geir; Johnson, Egil; Lyberg, Torstein & Kvalheim, Gunnar (2011). The Mushroom Agaricus blazei Murill Elicits Medicinal Effects on Tumor, Infection, Allergy, and Inflammation through Its Modulation of Innate Immunity and Amelioration of Th1/Th2 Imbalance and Inflammation. Advances in Pharmacological Sciences. ISSN 1687-6334. doi: 10.1155/2011/157015. Fulltekst i vitenarkiv
• Førland, Dag T.; Johnson, Egil; Tryggestad, Anne Merete Aaland; Lyberg, Torstein & Hetland, Geir (2010). An extract based on the medicinal mushroom Agaricus blazei Murill stimulates monocyte-derived dendritic cells to cytokine and chemokine production in vitro. Cytokine. ISSN 1043-4666. 49(3), s. 245–250. doi: 10.1016/j.cyto.2009.09.002. Fulltekst i vitenarkiv
• Bertelsen, Randi Jacobsen; Instanes, Christine; Granum, Berit; Carlsen, Karin C. Lødrup; Hetland, Geir & Carlsen, Kai-Håkon [Vis alle 8 forfattere av denne artikkelen] (2010). Gender differences in indoor allergen exposure and association with current rhinitis. Clinical and Experimental Allergy. ISSN 0954-7894. 40(9), s. 1388–1397. doi: 10.1111/j.1365-2222.2010.03543.x. Fulltekst i vitenarkiv
• Ellertsen, Linda Kathrine & Hetland, Geir (2009). An extract of the medicinal mushroom Agaricus blazei Murill can protect against allergy. Clinical and Molecular Allergy. 7. doi: 10.1186/1476-7961-7-6. Fulltekst i vitenarkiv
• Ellertsen, Linda Kathrine; Storla, Dag G; Diep, Lien M; Brokstad, Karl A; Wiker, Harald G & Hetland, Geir (2009). Allergic sensitisation in tuberculosis patients at the time of diagnosis and following chemotherapy. BMC Infectious Diseases. 9. doi: 10.1186/1471-2334-9-100. Fulltekst i vitenarkiv Vis sammendrag

  Background It is still a matter of debate whether there is an association between infection with Mycobacterium tuberculosis (M. tuberculosis) and allergy. Previously, we have shown higher levels of specific IgE to different inhalant allergens and total IgE in tuberculosis (TB) patients compared to controls. The objectives of this study were to evaluate a possible change in allergic sensitisation after successful TB treatment and to confirm the finding of our previous study of enhanced allergic sensitisation in TB patients compared to controls in a more controlled setting. Additionally, we wanted to determine the cytokine profile in the same groups and finally to evaluate the association between the presence of Bacillus Calmette-Guérin vaccination (BCG) scar and allergic sensitisation among the controls. Methods Sera were analysed for specific IgE to inhalant allergens (Phadiatop) and total IgE by the use of ImmunoCAP 1000 (Pharmacia Diagnostics). Thirteen different cytokines were also analysed in the sera by multiplex bead immunoassay (Luminex 100, Luminex Corporation), and clinical symptoms of allergy and BCG scar were reported in a questionnaire. Results A reduction in levels of specific and total IgE were observed after successful TB treatment. TB patients also had higher levels of specific and total IgE compared to healthy controls. Both interleukin (IL)-6 and interferon (IFN)γ were higher in TB patients compared to healthy controls. The levels of IL-6 were reduced after successful TB treatment. The presence of a BCG scar was associated with a reduced risk of developing allergic sensitisation. Conclusion We observed a reduced level of allergic sensitisation after successful TB treatment. TB patients seem to be more allergically sensitised than healthy controls, confirming our previous finding. Furthermore, we observed an inverse association between allergic sensitisation and visible BCG scar, which adds additional support to the hygiene hypothesis.

• Johnson, Egil; Førland, Dag T.; Sætre, Lisbeth; Bernardshaw, S; Lyberg, Torstein & Hetland, Geir (2009). Effect of an Extract Based on the Medicinal Mushroom Agaricus blazei Murill on Release of Cytokines, Chemokines and Leukocyte Growth Factors in Human Blood Ex Vivo and In Vivo. Scandinavian Journal of Immunology. ISSN 0300-9475. 69(3), s. 242–250. doi: 10.1111/j.1365-3083.2008.02218.x. Fulltekst i vitenarkiv
• Ellertsen, Linda Kathrine; Hetland, Geir & Løvik, Martinus (2008). Specific IgE to respiratory allergens and IgG antibodies to Toxoplasma gondii and Streptococcus pneumoniae in norwegian military recruits. Scandinavian Journal of Immunology. ISSN 0300-9475. 67(5), s. 496–500. doi: 10.1111/j.1365-3083.2008.02090.x. Fulltekst i vitenarkiv
• Hetland, Geir; Johnson, Egil; Lyberg, Torstein; Bernardshaw, Soosaipillai; Tryggestad, AMA & Grinde, Bjørn (2008). Effects of the Medicinal Mushroom Agaricus blazei Mutill on Immunity, Infection and Cancer. Scandinavian Journal of Immunology. ISSN 0300-9475. 68, s. 363–370. doi: 10.1111/j.1365-3083.2008.02156.x. Fulltekst i vitenarkiv
• Rydjord, Britt; Haanes, Jan Vilis; Strømsnes, Hege; Granum, Berit; Bolle, Roald & Nystad, Wenche [Vis alle 7 forfattere av denne artikkelen] (2008). Mould-specific immunoglobulin antibodies quantified by flow cytometry reflect mould exposure in Norwegian children. Clinical and Experimental Allergy. ISSN 0954-7894. 38(3), s. 430–437. doi: 10.1111/j.1365-2222.2007.02905.x. Fulltekst i vitenarkiv
• Hetland, Geir; Johnson, Egil; Lyberg, T; Bernardshaw, S; Tryggestad, AMA & Grinde, Bjørn (2008). Effects of the medicinal mushroom Agaricus blazei murill on immunity, infection and cancer. Scandinavian Journal of Immunology. ISSN 0300-9475. 68, s. 363–370. doi: 10.1111/j.1365-3083.2008.02156.x. Fulltekst i vitenarkiv
• Rydjord, Britt; Namork, Ellen; Nygaard, Unni Cecilie; Wiker, Harald G. & Hetland, Geir (2007). Quantification and characterisation of IgG binding to mould spores by flow cytometry and scanning electron microscopy. Journal of Immunological Methods (JIM). ISSN 0022-1759. 323(2), s. 123–131. doi: 10.1016/j.jim.2007.04.001. Fulltekst i vitenarkiv
• Ellertsen, Linda Kathrine; Hetland, Geir; Johnson, E. & Grinde, Bjørn (2006). Effect of a medicinal extract from Agaricus blazei Murill on gene expression in a human monocyte cell line as examined by microarrays and immuno assays. International Immunopharmacology. ISSN 1567-5769. 6(2), s. 133–143. doi: 10.1016/j.intimp.2005.07.007. Fulltekst i vitenarkiv Vis sammendrag

  Extracts from the edible mushroom Agaricus blazei Murill (AbM) are used extensively as a non-prescription remedy against cancer, infections, and immune related diseases. The presumed effect is to activate certain parts of the immune system. In order to investigate the effect, we examined the changes of gene expression caused by the extract on a human monocyte cell line (THP-1). Changes in the levels of mRNA transcripts were measured using 35 k microarrays, and the changes in select cytokine gene products by immuno assays. Lipopolysaccharide (LPS) was included for comparison. Both AbM and LPS had drastic effects on gene expression. Genes related to immune function were selectively up-regulated, particularly proinflammatoric genes such as the interleukins IL1B and IL8. Although most genes induced by AbM were also induced by LPS, AbM produced a unique profile, e.g., as to a particular increase in mRNA for the cytokines IL1A, CXCL1, CXCL2 and CXCL3, as well as PTGS2 (cyclooxygenase2).

• Grinde, Bjørn; Hetland, G. & Johnson, E. (2006). Effects on gene expression and viral load of a medicinal extract from Agaricus blazei in patients with chronic hepatitis C infection. International Immunopharmacology. ISSN 1567-5769. 6(8), s. 1311–1314. doi: 10.1016/j.intimp.2006.04.005. Fulltekst i vitenarkiv Vis sammendrag

  Extracts from the mushroom Agaricus blazei Murill (AbM) are used extensively as a non-prescription remedy against cancer and infections, including hepatitis. We previously demonstrated a potent immunomodulating effect of a particular preparation on monocytes in vitro, and a protective effect on bacterial infections in mice. Here we report the effect on gene expression in peripheral blood cells from four chronic hepatitis C patients, using global (29 k) oligo-based, single channel microarrays. The viral load was slightly, but not significantly, decreased after 1 week of AbM treatment. The cytokine genes most strongly induced in vitro were not induced in vivo. The more notable changes in mRNA levels were related to genes involved in the G-protein coupled receptor signalling pathway, in cell cycling, and in transcriptional regulation. The results suggest that the beta-glucans of the extract, which presumably are responsible for cytokine induction, did not readily enter the blood, while other components, such as substances proposed to have anticancer effects, were active in the blood

• Bernardshaw, Soosaipillai; Hetland, Geir; Grinde, Bjørn & Johnson, Egil (2006). An extract of the mushroom Agaricus blazei Murill protects against lethal septicemia in a mouse model of fecal peritonitis. Shock. ISSN 1073-2322. 25(4), s. 420–425. doi: 10.1097/01.shk.0000209526.58614.92. Fulltekst i vitenarkiv
• Ellertsen, Linda Katrine; Wiker, Harald G; Egeberg, NT & Hetland, Geir (2005). Allergic sensitization in tuberculosis and leprosy patients. International Archives of Allergy and Immunology. ISSN 1018-2438. 138(3), s. 217–224. doi: 10.1159/000088722. Fulltekst i vitenarkiv Vis sammendrag

  BACKGROUND: A negative association has been observed between infections and allergy in several studies. The aim of the present study was to examine whether tuberculosis and leprosy patients have more or fewer allergies than healthy individuals. METHOD: Sera from tuberculosis patients, leprosy patients and healthy controls were analysed by ELISA and Pharmacia Unicap for serological markers for allergy and mycobacterial infection. The serological markers for allergy were total IgE, specific IgE using Phadiatop and specific IgE to the dust mite allergen Dermatophagoides pteronyssinus 1 (Der p 1). Serological markers for mycobacterial infections included specific IgG to a mixture of bacille Calmette-Guerin culture filtrate antigens, to purified mannose-capped lipoarabinomannan (manLAM) and to purified secreted antigen 85B. RESULTS: Both tuberculosis and leprosy patients had significantly higher levels of total IgE than controls. Furthermore, a significantly higher level of specific IgE (Phadiatop) was also found in the tuberculosis patients compared with controls. A similar result, but not statistically significant, was observed for the leprosy group. Specific IgG to antigen 85B and to manLAM was found to be significantly higher in both tuberculosis and leprosy patients compared with controls. In addition, leprosy patients had significantly more IgG to the BCG culture filtrate antigen than controls. CONCLUSIONS: The results indicate that patients with mycobacterial infections have allergic sensitisation more frequently compared with healthy controls. This is seemingly in contrast with the notion that there is a negative association between allergy and infection ('hygiene hypothesis'). However, since only one in ten of those infected with Mycobacterium tuberculosis will develop the disease, patients with active mycobacterial disease represent a selected group. A similar relationship applies for leprosy. It is conceivable that those predisposed to allergy are less resistant to mycobacterial infections.

• Instanes, Christine; Hetland, Geir; Berntsen, Sveinung; Løvik, Martinus & Nafstad, Per (2005). Allergens and endotoxin in settled dust from day-care centers and schools in Oslo, Norway. Indoor Air. ISSN 0905-6947. 15(5), s. 356–362. doi: 10.1111/j.1600-0668.2005.00381.x. Fulltekst i vitenarkiv Vis sammendrag

  Allergy to indoor allergens can cause frequent and severe health problems in children. Because little is known about the content of allergens in the indoor environments in Norway, we wanted to assess the levels of cat, dog and mite allergens in schoolsand day-care centers in Oslo. Allergen levels in dust samples from 155 classrooms and 81 day-care units were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. Additionally, we measured the levels of endotoxin in 31 day-care units, using the limulus amebocyte lysate test. Most of the dust samples contained detectable amounts of cat and dog allergens. In mattress and floor dust (day-care centers), and curtain and floor dust (schools) the median Fel d 1 levels were 0.17, 0.002, 0.02 and 0.079 mu g/m(2), while the median Can f 1 levels were 1.7, 0.03, 0.1 and 0.69 mu g/m(2), respectively. Levels of cat and dog allergens in school floor dust were associated with the number of pupils with animals at home. Incontrast,<1% of the samples had measurable levels of the mite allergen Der p 1. Moreover, the levels of endotoxin tended to be higher in dust from floors (1.4 ng/m(2)) compared with that from mattresses (0.9 ng/m(2)).

• Rydjord, Britt; Hetland, Geir & Wiker, Harald G (2005). Immunoglobulin G antibodies against environmental moulds in a Norwegian healthy population shows a bimodal distribution for Aspergillus versicolor. Scandinavian Journal of Immunology. ISSN 0300-9475. 62(3), s. 281–288. Fulltekst i vitenarkiv Vis sammendrag

  doi:10.1111/j.1365-3083.2005.01672.x --- Immunoglobulin G (IgG) antibodies against moulds related to indoor dampness problems are used as biomarkers to indicate exposure. In the present study, we evaluated the frequency of mould exposure in an adult healthy population by examining levels of mould-specific IgG antibodies in Norwegian blood donors. Using enzyme-linked immunosorbent assay, 106 blood donor sera were analyzed for IgG antibodies to Aspergillus versicolor, Penicillium chrysogenum, Cladosporium herbarum, Stachybotrys chartarum and Fusarium oxysporum. The levels of specific IgG antibodies to P. chrysogenum, C. herbarum and S. chartarum correlated (r = 0.46-0.62). Responses to A. versicolor were considerably stronger than to the other moulds, and another 996 blood donor sera were analyzed for IgG antibodies to this mould. Women had significantly higher levels of specific IgG antibodies to A. versicolor than men. The concentration of A. versicolor-specific IgG antibodies showed a non-Gaussian, bimodal distribution profile, in which 12.5% were defined as positive to exposure. This suggests that significant mould exposure in a healthy population can be calculated from mean + 1SD. Western blotting analyses showed that antibody responses to A. versicolor were largely directed against carbohydrate antigens of unknown saccharides.

• Ormstad, Heidi & Hetland, Geir (2005). Adjuvant effects of B-glucan in a mouse model for allergy. I Young, Shih-Houng & Castranova, Vincent (Red.), Toxicology of 1 - 3-Beta-Glucans. Glucans as a Marker for Fungal Exposure. Taylor & Francis. ISSN 9780429215285. s. 127–142. Fulltekst i vitenarkiv Vis sammendrag

  The polyglucose 1→3-β-D-glucan is a major structural component of the cell wall of yeast and fungi. We have studied the adjuvant activity of different β-glucans on the response to the model allergen ovalbumin (OA), using the popliteal lymph node (PLN) assay in Balb/c mice. The adjuvant activity on local cellular response was determined by measuring the weight, cell number, and proliferation of the extracted PLNs. The levels of OA-specific IgE, IgG1 (Th2 response) and IgG2a (Th1 response) in serum were measured by enzyme-linked immunoabsorbent assay (ELISA). Taken together, our results show that whereas β-glucan had little effect on the local inflammatory response, it revealed a strong adjuvant activity on the systemic allergic immune response in a mouse model. This supports the reported observations that inhaled β-1,3-glucan is an enhancer and inducer of allergic disease in man.

• Hetland, Geir; Granum, Berit; Groeng, Else-Carin & Løvik, Martinus (2001). Leptin does not influence the IgE response to ovalbumin in mice. Clinical Immunology. ISSN 1521-6616. 101(1), s. 8–11. Fulltekst i vitenarkiv
• Ormstad, Heidi; Groeng, Else-Carin; Løvik, Martinus & Hetland, Geir (2000). The fungal cell wall component b-1,3-glucan has an adjuvant effect on the allergic response to ovalbumin in mice. Journal of Toxicology and Environmental Health, Part A. ISSN 1528-7394. 61, s. 55–67. doi: 10.1080/00984100050116780. Fulltekst i vitenarkiv
• Hetland, G.; Samuelsen, A.B; Løvik, M.; Paulsen, B.S; Aaberge, Ingeborg Aase S. & Groeng, E.C [Vis alle 7 forfattere av denne artikkelen] (2000). Protective effect of Plantago major L. Pectin polysaccharide against systemic Streptococcus pneumoniae infection in mice. Scandinavian Journal of Immunology. ISSN 0300-9475. 52(4), s. 348–355. Fulltekst i vitenarkiv
• Hetland, Geir; Ohno, N; Aaberge, Ingeborg Aase S. & Løvik, Martinus (2000). Protective effect of beta-glucan against systemic Streptococcus pneumoniae infection in mice. FEMS Immunology and Medical Microbiology. ISSN 0928-8244. 27(2), s. 111–116. Fulltekst i vitenarkiv

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• Hetland, Geir; Biedron, Rafal; Hetland, Aleksander & Badmaev, Vladimir (2014). AndoSanTM: An Optimal Biological Response Modifier and Health Promoting Ingredient Prepared from Agaricus blazei Mushroom. Nova Science Publishers. ISBN 9781631171307. 71 s. Fulltekst i vitenarkiv

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• Nissen-Meyer, Lise Sofie Haug; Ezligini, Farshid; Bergerud, Unni E.; Holtan, Anders; Akkøk, Cigdem Ahaein & Danilova, Elena [Vis alle 7 forfattere av denne artikkelen] (2022). Blod og beredskap. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 142(11), s. 942–942. doi: 10.4045/tidsskr.22.0494. Fulltekst i vitenarkiv
• Hetland, Geir (2014). Kan den immunmodulerende soppen Agaricus blazei brukes mot multi-resistente infeksjoner? Fulltekst i vitenarkiv
• Hetland, Geir (2014). An extract of the medicinal mushroom Agaricus blazei Murill can protect against allergy. Fulltekst i vitenarkiv Vis sammendrag

  Agaricus blazei Murill (AbM) is an edible Brazilian mushroom that has been used in traditional medicine for a range of diseases. It has been shown to have anti-infection and anti-tumor properties in the mouse, which are due to induction of Th1 responses. On the other hand, IgE-mediated allergy is induced by a Th2 response. Since according to the Th1/Th2 paradigm an increased Th1 response may promote a reduced Th2 response, the aim was to examine whether AbM had antiallergy effects. A mouse model for allergy was employed, in which the mice were immunized s.c. with the model allergen ovalbumin (OVA). Additionally, the animals were given a mushroom extract, AndoSan, mainly (82%) containing AbM, but also Hericium erinaceum (15%) and Grifola frondosa (3%), or PBS p.o. either a day before or 19 days after the immunization. The mice were sacrificed on day 26, and anti-OVA IgE (Th2 response) and IgG2a (Th1 response) antibodies were examined in serum and Th1, Th2 and Treg cytokines in spleen cells cultures. It was found that the AndoSan extract both when given either before or after OVA immunization reduced the levels of anti-OVA IgE, but not IgG2a, in the mice. There was a tendency to reduced Th2 relative to Th1 cytokine levels in the AndoSan groups.

• Josefsen, Dag; Hetland, Geir; Fløisand, Yngvar; Holte, Harald & Kvalheim, Gunnar (2013). The use of Plerixafor in hard-to-mobilize lymphoma and multiple myeloma patients not only provide sufficient numbers of Pbpcs to proceed to high dose therapy, but also have a positive impact on survival. Blood. ISSN 0006-4971. Fulltekst i vitenarkiv
• Josefsen, Dag; Hetland, Geir; Fløisand, Yngvar; Holte, Harald & Kvalheim, Gunnar (2013). The use of Plerixafor in hard-to-mobilize lymphoma and multiple myeloma patients not only provide sufficient numbers of Pbpcs to proceed to high dose therapy, but also have a positive impact on survival. Fulltekst i vitenarkiv
• Hetland, Geir; Tangen, Jon-Magnus; Tryggestad, Anne Merete Aaland; Dyrhaug, Marianne & Kvalheim, Gunnar (2013). The medicinal mushroom Agaricus blazei Murill activates NF-KB via TLR2 in monocytic cells, activates MDDC and induces expansion of CD56+HSC but not other progenitor HSC in vitro. Bone Marrow Transplantation. ISSN 0268-3369. 48, s. S521–S521. Fulltekst i vitenarkiv
• Josefsen, Dag; Hetland, Geir; Blystad, Anne Kirsti; Fløisand, Yngvar & Kvalheim, Gunnar (2013). Successful use of plerixafor in hard to mobilize patients: following high dose therapy all patients developed fast and sustained engraftment with durable clinical responses. Bone Marrow Transplantation. ISSN 0268-3369. 48, s. S522–S522. Fulltekst i vitenarkiv
• Hetland, Geir; Tangen, Jon-Magnus; Tierens, Anne; Kvalheim, Gunnar; Osnes, Liv T. N. & Tjønnfjord, Geir Erland (2013). The Agaricus blazei-based mushroom extract, AndosanTM,has immuno-suppressive and anti-inflammatory effects when used as supplement to multiple myeloma patients receiving high-dose chemotherapy and autologous bone marrow transplantation. Fulltekst i vitenarkiv
• Josefsen, Dag; Hetland, Geir; Blystad, Astrid; Fløisand, Yngvar & Kvalheim, Gunnar (2013). SUCCESSFUL USE OF PLERIXAFOR IN HARD TO MOBILIZE PATIENTS - FOLLOWING HIGH DOSE THERAPY ALL PATIENTS DEVELOPED FAST AND SUSTAINED ENGRAFTMENT WITH DURABLE CLINICAL RESPONSES. Cytotherapy. ISSN 1465-3249. 15(4), s. S24–S24. Fulltekst i vitenarkiv
• Hetland, Geir; Tangen, Jon-Magnus; Tryggestad, Anne Merete Aaland; Dyrhaug, Marianne & Kvalheim, Gunnar (2013). THE MEDICINAL MUSHROOM AGARICUS BLAZEI MURILL ACTIVATES NF-kappa B VIA TLR2 IN MONOCYTIC CELLS, INDUCES EXPANSION OF CD56+BUT NOT OTHER HSC, AND ACTIVATION OF HUMAN MONOCYTE-DERIVED DC IN VITRO. Cytotherapy. ISSN 1465-3249. 15(4), s. S36–S36. Fulltekst i vitenarkiv
• Josefsen, Dag; Hetland, Geir; Holte, Harald & Kvalheim, Gunnar (2012). Up-front use of plerixafor combined with chemotherapy and G-CSF in hard-to-mobilise lymphoma patients gives a satisfactory yield of CD34 cells within 1-2 days of apheresis and shows a sustained engraftment following high-dose therapy. Bone Marrow Transplantation. ISSN 0268-3369. 47, s. S238–S239. Fulltekst i vitenarkiv
• Hetland, Geir; Tryggestad, Anne Merete Aaland; Espevik, Terje; Ryan, Liv; Tangen, Jon-Magnus & Johnson, Egil [Vis alle 7 forfattere av denne artikkelen] (2010). The medicinal and antitumour mushroom, agaricus blazei murill, activates NF-KB via TLR2 in monocytic cells and induces expression of cell surface markers and production of cytokines in human monocyte-derived dendritic cells (MDDC) in vitro. European Journal of Cancer. ISSN 0959-8049. 8(5), s. 65–65. Fulltekst i vitenarkiv
• Hetland, Geir; Tryggestad, Anne Merete Aaland; Espevik, Terje; Ryan, Liv; Tangen, Jon-Magnus & Johnson, Egil [Vis alle 7 forfattere av denne artikkelen] (2010). The Medicinal and Antitumor Mushroom, Agaricus Blazei Murill, Activates NF-kappa B Via TLR2 but Not TLR4 In Monocytic Cells, and Stimulates Monocyte-Derived Dendritic Cells (MDDC) to Increased Cell Surface Marker Expression and Cytokine Production, and May Thus Have Adjuvant Effect In MDDC Cancer Vaccines. Blood. ISSN 0006-4971. 116(21), s. 1594–1594. Fulltekst i vitenarkiv
• Førland, Dag T.; Johnson, Egil; Tryggestad, Anne Merete; Lyberg, Torstein & Hetland, Geir (2009). The edible mushroom Agaricus blazei Murill stimulates monocyte-derived dendritic cells (MDDC) to cytokine production in vitro. Fulltekst i vitenarkiv
• Førland, Dag T.; Hetland, Geir; Lyberg, Torstein; Sætre, Lisbeth; Lygren, Idar & Johnson, Egil (2009). Oral intake of an extract based on the medicinal mushroom agaricus blazei murill alters levels of fecal calprotectin and pro-inflammatory cytokines in patients with ulcerative colitis and crohn’s disease. Fulltekst i vitenarkiv
• Vegarud, Gerd; Devold, Tove Gulbrandsen; Hetland, Geir & Jonassen, Christine (2006). Geitmelk, hoppemeløk og helseeffekter. Fulltekst i vitenarkiv Vis sammendrag

  Fremlegging av resulater fra geitmelksprosjekt ved fagmøte på Ullevål sykehus.

• Hetland, G.; Rydjord, Britt; Svenningsen, V. & Wiker, H. G. (2006). Immunoglobulin G antibodies against environmental moulds in a Norwegian healthy population shows a bimodal distribution for Aspergillus versicolor. Vox Sanguinis. ISSN 0042-9007. 91, s. 73–73. Fulltekst i vitenarkiv
• Ellertsen, Linda Kathrine & Hetland, Geir (2009). The relationship between allergy and microbial exposure. Epidemiological and experimental studies. Unipub forlag. ISSN 9788280725684. Fulltekst i vitenarkiv
• Rydjord, Britt & Hetland, Geir (2008). Mould-specific IgG antibodies, mould exposure and airway symptoms. Unipub forlag. ISSN 9788280724632. Fulltekst i vitenarkiv

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