Acute severe hepatitis outbreak in children: A perfect storm. What do we know, and what questions remain?

During the first half of 2022, the World Health Organization reported an outbreak of acute severe hepatitis of unknown aetiology (AS-Hep-UA) in children, following initial alerts from the United Kingdom (UK) where a cluster of cases was first observed in previously well children aged <6 years. Sporadic cases were then reported across Europe and worldwide, although in most countries incidence did not increase above the expected baseline. There were no consistent epidemiological links between cases, and microbiological investigations ruled out known infectious causes of hepatitis. In this review, we explore the evidence for the role of viral infection, superimposed on a specific host genetic background, as a trigger for liver pathology. This hypothesis is based on a high prevalence of Human Adenovirus (HAdV) 41F in affected children, together with metagenomic evidence of adeno-associated virus (Adeno-associated viruses)-2, which is a putative trigger for an immune-mediated liver injury. Roles for superantigen-mediated pathology have also been explored, with a focus on the potential contribution of SARS-CoV-2 infection. Affected children also had a high frequency of the MHC allele HLA-DRB1*04:01, supporting an immunological predisposition, and may have been vulnerable to viral coinfections due to disruption in normal patterns of exposure and immunity as a result of population lockdowns during the COVID-19 pandemic. We discuss areas of ongoing uncertainty, and highlight the need for ongoing scrutiny to inform clinical and public health interventions for this outbreak and for others that may evolve in future.

Clinical Outcome of Viral Respiratory Tract Infections in Hospitalized Adults in Norway: High Degree of Inflammation and Need of Emergency Care for Cases With Respiratory Syncytial Virus.

Background: The clinical features and outcomes of viral respiratory tract infections (RTIs) in adults have not been thoroughly studied, especially the respiratory syncytial virus (RSV) disease burden. It has become apparent that outbreaks of RSV in the elderly are associated with increased hospitalization rates. However, little data exists on the severity of such viral RTIs in adults, particularly the need for hospitalization, respiratory support and intensive care. Methods: We conducted a retrospective observational single-center study at Østfold Hospital Trust, Norway, during three winter seasons 2015-2018. Patients ≥18 years with either influenza A, influenza B, RSV A/B, human metapneumovirus, parainfluenza virus 1-4 or adenovirus detected in respiratory specimens were included, if they were hospitalized 14 days prior or following the detection date, with signs of RTI. Hospital records on treatment and outcome were investigated, as well as mortality of all causes up to 30 days from discharge. Results: Of the 1222 infection events that were included, influenza A was the most frequent virus detected (39%), while 179 infection events (14.6%) were due to RSV. Influenza B counted for 24% of the infection events, human metapneumovirus 13%, parainfluenza virus 9% and adenovirus 1%. Patients admitted with RSV more often suffered from COPD and congestive heart failure than patients with influenza A. In addition, RSV patients were overrepresented in the urgent response NEWS score (National Early Warning Score) category ≥5. RSV patients also showed signs of more severe inflammation, with WBC ≥11.1 × 109/L and CRP >100 mg/L, and they were more often treated with antibiotic agents during their hospital stay. However, we found no differences in the need for ICU admission or mortality. Conclusion: Patients with RSV had more often high values for markers of inflammation and elevated NEWS score when compared to patients hospitalized with other common respiratory viruses. Taken into account that they suffered more frequently from comorbidities like COPD, these patients needed hospitalization more urgently. These findings highlight the need for further investigations on RSV disease in adults and the elderly.

The incidence of infectious diseases and viruses other than SARS-CoV-2 amongst hospitalised children in Oslo, Norway during the Covid-19 pandemic 2020-2021.

Background: Measures to reduce spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during the Covid-19 pandemic 2020-2021 may impact other microbiological agents. We aimed to investigate the incidence of infectious diseases and the incidence of viruses other than SARS-CoV-2 amongst children at The Department of Paediatric and Adolescent Medicine, Oslo University Hospital, Norway during 2020-2021 compared to previous years. Methods: Data from April 1st 2020 - March 31st 2021 were compared to data from corresponding 12-months periods 2017-2020. ICD-10 infectious disease diagnoses were collected from the Hospital Diagnosis and Procedure Registry and results of virus PCR analyses of different specimens (mainly nasopharyngeal (NF) and faecal samples) were collected from the Laboratory System at the Department of Microbiology. Results: The number of hospital contacts with acute bronchiolitis, viral pneumonia, gastroenteritis and viral central nervous system infections were reduced by 90% (p<0.0001), 89% (p<0.0001), 74% (p<0.0001) and 78% (p<0.01), respectively. Respiratory syncytial virus (RSV), influenza virus A and B and Human metapneumovirus (HMPV) were almost completely absent during the pandemic period. The proportions of rhinovirus positive NF samples were 31.7% vs. 34.9% (p<0.05), but not significantly different for adenovirus. The proportions of positive faecal samples were 1% vs. 10% for adenovirus (p<0.00001) and 3.3% vs. 12% for norovirus (p<0.00001), but not significantly different for rotavirus. The proportions of enterovirus positive samples were 3.5% vs. 21.6% (p<0.00001). Conclusion: The incidence of several paediatric infectious diseases mainly of viral aetiology declined significantly during the Covid-19 pandemic. Some common respiratory viruses were almost completely absent.

Etiology of viral respiratory tract infections in hospitalized adults, and evidence of the high frequency of prehospitalization antibiotic treatment in Norway.

BACKGROUND AND AIMS: Respiratory tract infections (RTIs) cause considerable morbidity and mortality in all age groups, but the epidemiology and role of several of the viral RTIs in the adult and elderly patients are still unclear, as is the extent of prehospitalization antibacterial drug use in this population. METHODS: We conducted a three-year (2015-2018) observational study of viral RTIs in hospitalized patients in a 500-bed hospital in Southeastern Norway, including all patients ≥18 years with RTI symptoms where one of the following viral agents was detected in a respiratory specimen (Seegene Allplex): Influenza A/B, RSV A/B, human metapneumovirus (hMPV), adenovirus and parainfluenza virus 1-4. Viral findings, demographical data, and information on prehospital antibiotic prescriptions were recorded. RESULTS: In 1182 patients 1222 viral infection events occurred. The mean patient age was 69.6 years, and 53% were females. Influenza virus A/B (63%), RSV A/B (15%) and hMPV (13%) were the most common agents detected. The proportional burden of influenza A H1 was found to be relatively high (65%) in the age groups <69 years, compared to older patients (P = .001, chi-square).As many as 20% of the patients had been treated with antibiotics prior to admission, with the lowest rate for influenza A H3 group at 17% (P = .036, chi-square), and highest for the RSV group at 28% (P = .004, chi-square).Oseltamivir was prescribed prior to hospitalization in only 3 cases (0.2%). CONCLUSIONS: We found a high rate of prehospital antibiotic prescription in adults hospitalized with viral RTIs, warranting better stewardship programs to tackle the increasing antibiotic resistance problem.

Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial.

BACKGROUND: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. OBJECTIVE: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. DESIGN: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). SETTING: 23 hospitals in Norway. PATIENTS: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. INTERVENTION: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). MEASUREMENTS: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. RESULTS: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. LIMITATION: The trial had no placebo group. CONCLUSION: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19. PRIMARY FUNDING SOURCE: National Clinical Therapy Research in the Specialist Health Services, Norway.

Increased interleukin-6 and macrophage chemoattractant protein-1 are associated with respiratory failure in COVID-19.

In SARS-CoV-2 infection there is an urgent need to identify patients that will progress to severe COVID-19 and may benefit from targeted treatment. In this study we analyzed plasma cytokines in COVID-19 patients and investigated their association with respiratory failure (RF) and treatment in Intensive Care Unit (ICU). Hospitalized patients (n = 34) with confirmed COVID-19 were recruited into a prospective cohort study. Clinical data and blood samples were collected at inclusion and after 2-5 and 7-10 days. RF was defined as PaO2/FiO2 ratio (P/F) < 40 kPa. Plasma cytokines were analyzed by a Human Cytokine 27-plex assay. COVID-19 patients with RF and/or treated in ICU showed overall increased systemic cytokine levels. Plasma IL-6, IL-8, G-CSF, MCP-1, MIP-1α levels were negatively correlated with P/F, whereas combinations of IL-6, IP-10, IL-1ra and MCP-1 showed the best association with RF in ROC analysis (AUC 0.79-0.80, p < 0.05). During hospitalization the decline was most significant for IP-10 (p < 0.001). Elevated levels of pro-inflammatory cytokines were present in patients with severe COVID-19. IL-6 and MCP-1 were inversely correlated with P/F with the largest AUC in ROC analyses and should be further explored as biomarkers to identify patients at risk for severe RF and as targets for improved treatment strategies.

Parvovirus B19 DNAemia in pregnant women in relation to perinatal death: A nested case-control study within a large population-based pregnancy cohort.

INTRODUCTION: Parvovirus B19 (B19V) is the infectious cause of exanthema infectiosum. In Europe around 40% of pregnant women are susceptible to infection. Having small children at home is the main risk factor for contracting an infection during pregnancy. The association between B19V-infection and perinatal death is not yet settled. The aims of the study were to estimate the association between maternal parvovirus B19 infection in pregnancy and perinatal death, and to assess the significance of a positive B19V PCR in pregnancy. MATERIAL AND METHODS: The study population consists of women included in the Norwegian Mother and Child Cohort Study, a prospective population-based pregnancy cohort of nearly 100 000 women. Blood samples were obtained during weeks 17-18 in pregnancy (M1), at birth, and in umbilical cord blood. Within participants in the pregnancy cohort, 138 cases of perinatal death and 1350 controls with live-born children were included in a nested case-control study. Samples were analyzed with B19V serology and B19V PCR according to a predefined test algorithm. For cases, medical records and laboratory results from hospitals were combined with the results of B19V serology and PCR. The reported causes of perinatal death were categorized using the classification system: Causes Of Death and Associated Conditions (CODAC). RESULTS: The B19V seroconversion rates were 9.8% for cases and 6.8% for control mothers. The odds ratio for maternal B19V infection in cases compared with controls was 1.28 (95% CI 0.35-4.70), adjusted for age, parity, body mass index and tobacco use. B19V-PCR-positive samples were detected at weeks 17-18 of gestation in both cases and controls. The proportion of positive samples was similar in cases and controls, 24% and 28.2%, respectively. Mothers with PCR-positive M1 samples transmitted B19V vertically in 9.1% of cases and in 11.9% of the controls. Of all perinatal deaths, 53% were attributed to placental pathology or unknown causes. CONCLUSIONS: B19V PCR positivity was high and similar in both cases and controls. In our study B19V DNAemia was not seen to be associated with fatal outcome of pregnancy. The clinical significance of B19V DNA detection during pregnancy is uncertain. Caution is needed when diagnosing a B19V infection based only on B19V DNAemia.

Rotavirus detection in bulk stool and rectal swab specimens in children with acute gastroenteritis in Norway.

BACKGROUND: Bulk stool specimens are traditionally used for rotavirus detection but may be challenging to obtain from young children. Immediate and easy sampling may however be required in different situations, such as outbreak investigation. OBJECTIVES: We assessed the diagnostic performance of rectal swabs compared to bulk stools for the detection of rotavirus by Enzyme Immunoassay (EIA) and multiplex semi-nested reverse transcription PCR (semi-nested RT-PCR) in children recruited through active hospital-based surveillance of acute gastroenteritis in Norway. STUDY DESIGN: We obtained 265 paired bulk stool and rectal swab specimens from children under 5 years of age hospitalized with acute gastroenteritis (AGE). Both types of specimens were analyzed for rotavirus by EIA and semi-nested RT-PCR. In addition, VP6-spesific real-time PCR was used to evaluate the detection performance in the two specimen types. RESULTS: Concordant results were obtained in 257 (97%) paired specimens by EIA and in 248 (94%) pairs by semi-nested RT-PCR. Results of VP6-specific real-time PCR obtained from 100 pairs of specimens showed concordance in 91% of the pairs. Sensitivity and specificity for rectal swab specimens were 95% and 100% by EIA; 95% and 92% by semi-nested RT-PCR, respectively. CONCLUSION: Both EIA and semi-nested RT-PCR showed a high accuracy, and rectal swab specimens are appropriate for rotavirus diagnosis and may be used as an alternate specimen type when collection of bulk stool is not feasible.

Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment.

Cancer patients are often encouraged to receive seasonal influenza vaccination. The monoclonal antibody rituximab is widely used in treatment of non-Hodgkin lymphoma. This results in a prolonged depletion of normal B cells, which might impair humoral responses. The aim of the present study was to investigate whether lymphoma patients undergoing rituximab-containing treatment regimens or having received such regimens within the past 6 months were able to mount protective antibody responses to the influenza A(H1N1) 2009 virus vaccine Pandemrix during the 2009 "swine flu" pandemic. Contrary to the control group, where 82% responded adequately to the vaccine, none of the 67 patients achieved protective antibody titers, suggesting that lymphoma patients receiving rituximab-containing regimens might not benefit from this vaccine. It is important that doctors who care for such patients are aware that they may fail to respond not only to the influenza vaccine, but also to other common vaccines.

[HIV/AIDS--from lethal syndrome to chronic disease]. / Fra dødelig syndrom til kronisk sykdom.

BACKGROUND: At its discovery in 1981, AIDS was a fatal syndrome that rapidly led to death. Combination treatment with at least three drugs has radically improved the prognosis. MATERIAL AND METHODS: The study includes all HIV-patients controlled at the Department of Infectious Diseases, Ullevål University Hospital from 1982 to 2005. Development of immune deficiency, morbidity and causes of death were registered prospectively. Possible connections between death and HIV-infection and treatment were evaluated. RESULTS: 1632 patients were followed at our department. 32 % of these patients have died. The number of patients who died annually during the 5 years from 1986 to 1990 was 47 % and this was reduced to 11 % in 2001 - 05. Many patients still die because they either present too late for treatment or have received insufficient treatment. 22 patients have died during the last 10 years irrespective of starting treatment with at least 3 antiretroviral drugs: 7 died from cancers, 6 from treatment failure, one from unknown cause and 8 from other causes. The 6 patients who died from treatment failure had very low CD4 counts and serious opportunistic infections that could not be treated effectively at the time of diagnosis. INTERPRETATION: Patients who start and adhere to treatment with 3 HIV-medications have a good prognosis, but they may still have an increased risk of non-AIDS defining cancers and cardiovascular disease. HIV/AIDS has become a chronic disease with a good prognosis.