Massih et al.
Egyptian Pediatric Association Gazette
(2022) 70:22
https://doi.org/10.1186/s43054-022-00113-2
Egyptian Pediatric
Association Gazette
Open Access
REVIEW
Revisiting the overlooked role of recycled
sewage water in high-income countries
in adenoviral outbreaks such as the “2022
pediatric hepatitis’ outbreak”
Antoine Abdel Massih1,2* , Aya Kamel3, Ali Mohamed Zaki4, Ayten Aboudeif4, Clara Emad3, Dina Ramadan4,
Hanya Gaber3, Harvey Bastorous4, Mehraiel Shaker4, Nancy Salah4, Nourhan Hany4, Nur El‑Mestkawy3,
Rana Adel Naguib Sawiris4, Rana Mamdouh3, Sandy Atalla3, Sara Abozeid3, Sarah Ismail Ghazi4,
Steven A. Youssef4, Youssef ElMaghraby4, Zainab Khudhair3, Rafeef Hozaien3, Nadine El Husseiny5,6 and
Meryam El Shershaby3
Abstract
Background: On the 5th of April 2022, cases of adenovirus‑induced hepatitis were reported in Scotland and then
reached multiple parts of the world. While adenovirus normally presents with diarrhea, vomiting, and fever, these
novel cases also resulted in the development of fulminant hepatitis in non‑immunocompromised cases.
Main body: The responsible pathogen “Adenovirus 41” is an enterovirus. Enteroviruses are spread by the fecal‑oral
route and are resistant to drying. As such, they predominate in sewage water. Hepatitis is normally restricted to poorer
countries, yet this new wave seems to be confined to mostly high‑income countries in Europe and the USA. These
countries treat and recycle a higher percentage of sewage water. We also propose that the fulminant nature of this
strain could be due to either a cross‑species mutation or the general decrease in trained immunity post‑COVID‑19
lockdown.
Short conclusion: Evidence strongly suggests that the link between these new hepatitis cases is recycled sewage
water. This should warrant further investigations on the origin of this outbreak by re‑visiting the role of recycled sew‑
age water in causing such outbreak.
Keywords: Adenovirus 41, Recycled sewage water, Unknown hepatitis cases, COVID‑19
Background
A global surge of inexplicable hepatitis cases came into
light on April 5, 2022, with the first cases reported in
Scotland (1). The number of cases has since progressively
risen all over the world. It is attributed to enteric adenovirus type 41 and presented with diarrhea, vomiting, and
*Correspondence: antoine.abdelmassih@kasralainy.edu.eg
2
Cardiac Sciences’ department, Pediatric Cardiology Division, Sheikh Khalifa
Medical City, Abu Dhabi, UAE
Full list of author information is available at the end of the article
fever in children. It had not previously led to the development of fulminant hepatitis in non-immunocompromised cases [1].
To date, twelve European countries have reported
cases. Intriguingly, the countries belong predominantly
to the high-income category (according to the World
bank). Fifty-five cases have been recorded from around
the European Union/European Economic Area (EU/EE)
as of April 27, 2022. The countries in question are Austria, Belgium, Denmark, France, Germany, Italy, Ireland,
Norway, Poland, Romania, Spain, and the Netherlands.
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Massih et al. Egyptian Pediatric Association Gazette
(2022) 70:22
The cases started showing symptoms in early to midMarch and some tested positive for adenovirus [2].
UK
Since the last report on April 25, active case-finding
investigations have uncovered 34 confirmed cases, bringing the overall number of cases to 145, 128 of which originated in England. Fortunately, no deaths have occurred.
(2) Four cases were reported in Ireland in children
between the ages of 2 and 11. (3) In Scotland, 13 cases
were confirmed, with a median age of 3.9. All 13 children
were hospitalized at the time of publishing, and three of
them required liver transplant assessment. One of the
children received a successful transplant, while five of the
thirteen patients are being treated in the hospital [3].
Denmark
Denmark reported five instances in children under the
age of ten and one in children above ten. There have been
no deaths or need for liver transplants in the cases [2].
Italy
Italy had 17 cases across various Italian regions. They
suspected eight cases and nine are yet to be classified.
The ages of the cases have not been confirmed, but all
children are under 16 years of age. One case required a
liver transplant [2].
France
France reported two cases in children younger than 10
years old. Both cases had severe acute hepatitis, but neither required liver transplantation [2].
Page 2 of 5
Wisconsin. Alabama declared the most cases among the US
states, 9; all of whom tested positive for adenovirus [5].
Table 1 shows the details of cases and their need for
liver transplantation.
As mentioned earlier, most of the cases have tested
positive for adenovirus 41. Adenovirus 41 is known to
grow in sewage water. High-income countries rely on
recycled sewage water to fight water scarcity; therefore,
we hypothesize that recycled sewage water is incriminated in this outbreak. We will also discuss the theories
behind the fulminant nature of the observed hepatitis
despite occurring in immunocompetent hosts.
Main body
Enteric adenoviruses, predominant in sewage water?
There are 47 serotypes of human adenoviruses (hADV)
divided into six subgenera (A-F). The “F” subgenera
include enteric adenoviruses type 40 and 41 that cause
gastroenteritis. These types constitute the second most
important cause of infantile gastroenteritis. They mostly
affect children under two, causing diarrhea in 4–17%.
Clinically, the infection appears as vomiting, watery diarrhea, mild dehydration, and low-grade fever; a specific
symptom is a protracted diarrhea [6].
Adenoviruses enter the body through the mouth, the
nasopharynx, or the conjunctiva. Because of the extended
shedding of viruses in feces, fecal-oral transmission
accounts for most adenovirus infections in young children. Adenovirus infections of the nose, throat, and eyes
Table 1 Overview of cases of the number of unknown hepatitis
cases and their need for liver transplantation until the 27th of
April 2022
Countries
Number of Number of
cases
deaths
Number of patients
requiring liver
transplantation
Austria
2
0
0
Spain
Belgium
2
0
0
Not much information is available about the cases in
Spain. The last report by the CDC on 23 April 2022 stated
that there were 13 cases in Spain. The need for a hepatic
transplant, mortalities, and hospitalization information
has not been revealed [2].
England
128
0
10
France
2
0
0
Germany
1
0
0
Ireland
4
0
0
Italy
17
0
1
Israel
12
0
0
USA
Netherlands
4
0
3
Among 24 states, 109 cases have been reported in the USA,
14% need liver transplants, and nine require hospitalization.
Five deaths were reported, but the states have not yet been
revealed. The cases were reported in Alabama, Arizona,
California, Colorado, Delaware, Florida, Georgia, Idaho,
Illinois, Indiana, Louisiana, Michigan, Minnesota, Missouri, North Carolina, North Dakota, Nebraska, New York,
Ohio, Pennsylvania, Tennessee, Texas, Washington, and
Norway
2
0
0
Poland
1
0
0
Romania
1
0
0
Scotland
13
0
3
Spain
13
1
0
USA
109
5
15
Totals
311
6
32
Israel
Only 12 cases have been reported and are all hospitalized, and no further information is available [4].
Abbreviations: USA United States of America
Massih et al. Egyptian Pediatric Association Gazette
(2022) 70:22
are linked to insufficiently treated swimming pool water.
They survive longer in water and are resistant to drying;
therefore, contaminated inanimate surfaces may play a
substantial role in viral transmission [7].
The pathogenic viruses are discharged into the environment through treated and untreated wastes (sewage
water may undergo three levels of treatment: primary,
secondary, and tertiary) [8]. A study measured the adenovirus level in surface water, wastewater, and combined
sewer overflows (CSOs) using PCR. Adenoviruses were
consistently present in sewage and were occasionally
detected in rivers receiving sewage effluents. Unfortunately, PCR cannot determine the viability of the virus.
Virus detection is also not attempted until after the
outbreak, inhibiting prophylactic measures that could
decrease outbreak severity [9].
Adenoviruses are also resistant to deactivation via
monochromatic UVC light and monochloramines. These
treatments have minimal effects on the viral structural
proteins because the infectivity of adenoviruses does not
heavily depend on its DNA being fully intact—what the
above treatments target. However, the virus can be inactivated by free chlorine and full-spectrum sunlight. The
extent of inactivation of the human adenoviruses correlates to the damage to the protein structures of the virus
as it seems to readily repair DNA damage caused by
UVC, explaining the infectivity of said treatment [10].
Sewage water re‑use is a hallmark of high‑income
countries, is it a coincidence?
Western Europe reuses 16% of its treated wastewater,
while MENA reuses 15%. Western Europe has the highest rate of treating wastewater (86%) compared to Saharan Africa and South Asia (16%). High-income countries
treat 74% of their wastewater compared to 4% treatment
in the low-income countries; wastewater treatment
increases proportionately with a country’s income.
For instance, in Europe, 71% of industrial wastewater produced is treated, while in Latin America, only
20% undergoes treatment. In the Middle East and North
Africa (MENA), 51% of industrial wastewater undergoes
treatment. African countries lack financial resources
for wastewater development which is a constraint on
wastewater management. All 32 of the 48 countries in
sub-Saharan Africa had no available data neither on
wastewater production or treatment.
In six member countries (Germany, Latvia, Luxembourg, the Netherlands, Austria, and Sweden) and Switzerland, and the UK, the proportion of the population
connected to secondary treatment plants has increased
further than 95%. On the other side of the scale, less than
one in two households are connected to at least secondary urban sewage treatment facilities in Cyprus, Malta,
Page 3 of 5
Romania, and Croatia (all 2018 data). Over the period
shown, some countries have succeeded in significantly
expanding the scope of wastewater treatment; for instance,
Hungary (29.8 to 80.4%) and Slovenia (12.3 to 68.9%) [11].
Almost 90% of wastewater in Israel is treated, most
of it in agricultural irrigation 18,000 WWTPs, and millions of kilometers of pipes. The majority of wastewater is
reused in Israel, while Europe recycles merely 60%. They
are aiming to recycle the entire volume in the future [12].
We can deduct from the above that it is considerable
overlap between the distribution of cases of this new
outbreak and the percentage of reliance on recycled or
treated sewage water. This might signify that the use of
recycled sewage water, as mentioned might be implicated
in the observed outbreak [12].
Why is the observed cases fulminant?
Enteric adenoviruses can induce a mild hepatitis illness.
The occurrence of more fulminant forms of hepatitis is
linked to a state of immunocompromise. According to
the ongoing reports, affected patients were not suffering
from any concurrent immunodeficiency or under treatment by immunosuppressive medications. The hygiene
theory has gained popularity in justifying the fulminant
nature of hepatitis observed in this outbreak [13, 14].
COVID‑19 and the hygiene theory
The COVID-19 pandemic induced a worldwide lockdown to decelerate the spread of the SARS-CoV-2 virus.
While this was crucial to limit the spread of SARSCOV2, it deleteriously altered the seasonal trends of viral
infections. As a case in point, Maison et al. recorded an
unusual surge of both Rota and Noroviruses post lockdown. Furthermore, during the lockdown, some non-respiratory infections increased as seen by the exacerbation
of dengue reported in Singapore [15].
This could be justified by the hygiene hypothesis and the
absence of trained immunity. The hygienic precautions
implemented alongside the lockdown reduced exposure to
pathogens diminishing the stimulation of the nonspecific
immune system and altering the balance of commensal
microorganisms [16]. The limitation of the functional interaction of the immune system is evident by the unexpected
increase of RSV cases showing similar viral genotypes as
those diagnosed in previous years post lockdown in Greece.
Similar findings were found in Australia where the seasonal
RSV peaks exceeded that of previous years [17, 18].
At the genetic level, this can be corroborated by studies showing that socially isolated mice and other species
show a downregulation of anti-viral genes. Moreover, the
sedentary lifestyle, confounded with the unhealthy diets
attributed to the limited income found during the pandemic-induced economic crisis, led to a higher prevalence
Massih et al. Egyptian Pediatric Association Gazette
(2022) 70:22
of obesity, which affects the immune system. Evidence
suggests that this unhealthy lifestyle may have upset the
microbiota and adversely impacted the production of
antibodies already showing “inexperienced” responses to
foreign antigens in children compared to adults [19].
The mutated strain theory
Another hypothesis for fulminant hepatitis occurring in
this outbreak is that a mutated strain of ADV 41 could have
acquired augmented virulence allowing it to induce more
liver damage. Interestingly, we found two reports dating
back to 2011 and 2013 describing similar illnesses in monkeys and marmosets by a mutated strain of ADV [20, 21].
A catastrophic outbreak of fulminant pneumonia and
hepatitis was documented in a confined colony of New
World titi monkeys of the Callicebus genus at the California National Primate Research Center (CNPRC). One
third of the monkeys got infected, and 83% of them died.
Virochip was used to identify a unique and highly divergent adenovirus as the source. Clinical and serological
evidence further demonstrated that this virus infected a
CNPRC researcher and a family member. Thus, researchers revealed the possibility of adenovirus cross-species
infection [12]. Furthermore, SqMAdV-1, a novel adenovirus discovered in immunocompromised squirrel monkeys,
has fatal effects in species aside from its natural host [20].
Page 4 of 5
In 2011, an experiment was conducted to show crossspecies TMAdV infection of marmosets. An acute mild
respiratory disease, associated with a rise in virus-specific neutralizing antibody titers, was generated by the
nasal administration of a cell cultured-adapted TMAdV
strain into three marmosets [21].
Reports circulated of fulminant hepatitis in a Japanese
aquarium afflicting otariids; presenting with symptoms of
diarrhea which acutely progressed to low spirits and death
after 3 days. Available data suggest that increased aspartate
aminotransferase, alanine aminotransferase, necrotic hepatitis, and eosinophilic intranuclear inclusion bodies [22].
Conclusion
The reported cases of adenovirus-induced hepatitis
are mainly circulating in high-income countries. Given
the pattern of survival of adenovirus in sewage water,
its resistance to inactivation by ultraviolet rays and the
increasing reliance of high-income countries on recycled sewage water for drinking water and for irrigation
of crops, and it is advisable to test the possible incrimination of recycled sewage water in such outbreak. If the
suggested hypothesis is proven true, recycling of sewage
water should take into consideration resistant pathogens
such as adenoviruses.
Figure 1 summarizes the points discussed in this article.
Fig. 1 Can be sewage water recycling be implicated in the unknown hepatitis outbreak. Abbreviations: ADV41, adenovirus 41; COVID‑19,
coronavirus disease 2019
Massih et al. Egyptian Pediatric Association Gazette
(2022) 70:22
Abbreviations
ADV: Adenovirus; CDC: Center for disease control; COVID‑19: Coronavirus
disease 2019; CSO: Combined sewer overflows; DNA: Deoxyribonucleic acid;
EU: European Union; PCR: Polymerase chain reaction; SARS‑COV‑2: Severe
acute respiratory syndrome 2; SqADV: Squirrel adenovirus; TMADV: Titi‑
monkey adenovirus; UK: United Kingdom; USA: United States of America; UVC:
Ultraviolet‑C.
Page 5 of 5
8.
9.
10.
11.
Acknowledgements
To the families of my wonderful students who did a magic work raising such
great minds and souls.
Authors’ contributions
AA, MES, and HG contributed to the conception of the idea. AA, AK, AMZ,
AAD, CE, DR, HG, HB, MS, NS, NH, NM, RS, RM, SA, SA, SIG, SAY, YEM, ZK, RH, NH,
and MES contributed equally to drafting and revision of the manuscript. The
authors read and approved the final manuscript.
12.
13.
14.
15.
Funding
This research received no specific grant from any funding agency, commercial
or not‑for‑profit sectors.
Availability of data and materials
Not applicable
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Pediatric Department, Pediatric Cardiology Unit, Cairo University Children
Hospital, Faculty of Medicine, Cairo University, Kasr Al Ainy Street, Cairo 12411,
Egypt. 2 Cardiac Sciences’ department, Pediatric Cardiology Division, Sheikh
Khalifa Medical City, Abu Dhabi, UAE. 3 Student and Internship research
program (Research Accessibility Team), Faculty of Medicine, Cairo University,
Cairo, Egypt. 4 Student and Internship research program (Research Acces‑
sibility Team), Faculty of Medicine, New Giza University, Giza, Egypt. 5 Faculty
of Dentistry, Cairo University, Cairo, Egypt. 6 Pixagon Graphic Design Agency,
Cairo, Egypt.
Received: 25 May 2022 Accepted: 26 July 2022
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