Emerging, re-emerging and/or atypically behaving infectious diseases.

The 3rd millennium started with an outbreak of severe acute respiratory syndrome (SARS) caused by the coronavirus SARS CoV-1, identified in late February 2003 in China, and then spreading in almost all continents. That was just the beginning of a series of outbreaks and epidemics determined by several emerging, re-emerging and/or atypically behaving infectious agents. Just a few years after SARS CoV-1 we have witnessed the first influenza pandemic of the 21st century due to the outbreak of a swine-derived influenza A virus (H1N1) that spread quickly and was declared a full-scale pandemic from the World Health Organisation (WHO) in June 2009. After the 2014–2016 rapidly evolving outbreak of Ebola in the West African subregion, we have now entered the present era of coronavirus-SARS-CoV-2, a virus sharing more than 70% genetic similarity to SARS-CoV-1, at the origin of COVID-19. To complicate matters, the persistence of Covid-19 has facilitated the rise of a number of common diseases which had been suppressed by social restrictions during the pandemic peaks and are now coming back along with the return to pre-lockdown life. Changes in contact patterns since early 2020 have, indeed, affected not only the number of outbreaks but also the regular seasonal cycles of diseases such as the seasonal flu/influenza.1 The 2020 and 2021 winter flu season was among the mildest reported in terms of deaths and/or hospitalizations. Instead, many cases were registered in February and continued to go up into the spring and summer as Covid restrictions and adoption of non-pharmaceutical interventions were alleviated.2 The current 2022–23 flu season has been marked by unprecedented unpredictability and a higher-than-usual volume of cases.3 Most of these diseases have often emerged also in new and peculiar ways. As paediatricians, we are called upon as small children are those who do appear more involved, likely because of their missed age-related opportunities to acquire antibodies against common viruses.1 Similarly to the seasonal influenza, also respiratory syncytial virus (RSV) seemed to disappear in 2020–2021. However, it come back with an irregular viral behaviour during the off-season spring and summer of last year overfilling many children's hospitals during fall adding to influenza and COVID this year with a so called “tripledemic” phenomenon. Small children have been the target also of a multi-country increased incidence of invasive Group A Streptococcus infection,4 and, in India, this age group has been victim of an infectious disease with a still debated aetiology, known as “tomato flu”. On top of the above scenarios of emerging and re-emerging, prevalently viral, irregularly behaving infectious diseases, beginning late 2021, and peaking in April 2022 in the UK, multiple clusters of severe non-A to E acute hepatitis have been documented worldwide in otherwise healthy young children. As of September 14, 2022, approximately 1296 probable cases have been reported from 37 countries/regions, of which approximately 55 required or received liver transplantation and 29 died.5 Although several etiopathogenetic and/or contributing factors have been called into question, the exact cause of this serious disease is still debated (hence, its name Childhood Severe Acute Hepatitis of Unknown Origin, AHUO). (Figure 1). The parallel silent outbreaks of adenovirus type F 41, a virus which has been found alone or accompanied by a variety of other common viruses in more than half of the AHOU cases, appear to represent more and more a major culprit. In a pre-Covid retrospective study this virus generally deemed responsible of benign, self-limiting illnesses with flu-like and gastrointestinal mild symptoms, has been found to provoke also a previously oversighted frequent mild liver injury which were also occasionally severe in particular when associated with a diverse coinfecting virus.6 The obvious question arises therefore why Adenovirus is now involved in so many simultaneous worldwide outbreaks of severe hepatitis in healthy children during this Covid period. The article by Irena Ilic and Milena Ilic appearing in this issue of Acta Paediatrica7 is particularly welcome because of their accurate review. The Authors are to be commended as they succeeded in focusing clearly on those which presently appear the most relevant epidemiological characteristics of the disease and individuating several related open questions needing urgent answers (Table 1). Regarding the etiological agents, although the most possible causes were also keenly considered, few more considerations regarding Adenovirus and its inclusion within the SARS-CoV-2 related immune debt/gap model may warrant further emphasis. No matter what, SARS-CoV-2 appears in fact to play or having played some relevant role. Ilic and Ilic appraisal provide several arguments that -put together- overall tend to support the hypothesis that the periods of reduced infectious exposure due to the previous rigid isolation associated with the COVID pandemic, after the aperture has resulted in an immunity gap in children leading to an increased susceptibility to/severity of one or more infectious agents.1 Past or present infection with SARS-CoV-2 might result in an altered host response to generally benign infectious agents, resulting in more severe inflammation damaging the liver in relation with the Adenovirus infection found in most reported series of severe AHUO, and in agreement with recent reports of an increasing circulation of Adenovirus in several countries, In some cases HAdV-F40/41 has been detected in patients having the same sequences from wastewater (F41 lineage 2b) and patients' homologous genome sequences.8 Most of the UK children presenting with severe AHUO the adenoviral infection was accompanied by an adeno-associated virus 2 (AAV2) in the liver. Much interestingly, these patients were also carriers of the DRB1*04:01 HLA allele, an immune phenotype typical of some autoimmune diseases. This supports the hypothesis that a specific genetic background of an immunological predisposition is probably at the basis of an exaggerated inflammatory response responsible for the viral acute liver damage. It has also been suggested the possible role of a multisystem inflammatory syndrome resulting from T-cell immune activation triggered by a superantigen motif contained inside the spike protein of SARS-CoV-2. As the Covid virus may persist in the gastrointestinal tract, superantigens released from the damaged mucosal barrier might increase the susceptibility to an unusual even more severe liver damage from Adenovirus alone or accompanied by other pathogens which have a similar intestinal tropism. Regarding the involvement of other possible causes, for mycotoxins or the administration of paracetamol, fluconazole which has been found to be excessive in some cases there is no effective evidence that they are associated with the disease.9 Last but not least, the greater awareness per se along with the post-COVID pandemic increased surveillance of public health issues, might have contributed to make diagnosis of some outbreaks more common. In other words, AHUO could not really be more common than in the past, but it's that more attention is being paid to it. In all cases, as for some other post-COVID conditions, also AHUO seems to be experiencing a spontaneous decrease so that some national surveillance systems are lowering their guard. Since the late autumn the major international health agencies have not presented new official statistics. Based on the CDC data on persons who are under investigation in the US the most recent document of the American Academy of Paediatrics, however, has reported that as of January 18, 2023, there have been no additional deaths reported since February 2022, and the proportion of patients requiring liver transplants has gone down from 15 percent to 9 percent since May 5.10 After the above considerations being made, one can agree that the present emergence of new epidemics is part of a never-ending and mostly cyclical phenomenon. The COVID epidemic in a naïve population has been followed by the development of herd/vaccine immunity, the subsequent disappearance of the epidemic, the gradual loss of immunity, and peaks of reappearance. As recommended by investigators of the European Paediatric Association/Union of National European Paediatric Societies and Associations, in any case, further studies are warranted to determine the potential for synergistic and antagonistic interactions of the various pathogens with SARSCoV-2 and their impact on the severity of clinical presentations or circulatory patterns when social distancing measures are mitigated. Hopefully, all this will allow for the establishment of appropriate prevention programs by public health systems and the acquisition of appropriate skills by us paediatricians to adequately address possible future epidemiological variations of even those which are considered the most common infectious diseases.11 In this context, the morbidity of the (putatively Adenovirus-linked) severe AHOU which at this moment, is tending to decrease, should not be ignored. As a disease with an aetiology and pathogenesis that remain unclear, no one knows when and where other outbreaks of this hepatitis will occur again in the future. Should the AHUO reappear, early diagnosis and prompt referral to centers with available liver transplantation facilities are in any case crucial due to possible deaths caused by the liver failure.12 There is no conflict of interest regarding this manuscript.