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\begin{document}

\title{Fusobacterium nucleatum bacteremia with liver abscess following
administration of anti-COVID-19 vector-based vaccine}



\author[1]{Jiun-Ting Wu}%
\author[2]{Yung-Fa Lai}%
\author[2]{Chien-Tung  Chiu}%
\affil[1]{E-DA cancer Hospital}%
\affil[2]{E-DA Hospital}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\begin{abstract}
Immunization of the population through vaccination against COVID-19 is
recognized as a public health priority. The most difficult scientific
challenge for vaccines is the clinical safety and efficacy. We report a
patient presenting with Fusobacterium nucleatum bacteremia and liver
abscess formation following administration of anti-COVID-19
viral-vectored vaccine.%
\end{abstract}%



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\textbf{Introduction}

\emph{Fusobacterium} species are anaerobic, Gram-negative, rod-shaped,
adherent, non-motile and non-spore-forming bacteria.\emph{Fusobacterium
nucleatum} is an oral bacterium, commensal to the human oral cavity,
that plays a role in periodontal disease and colorectal
neoplasm\textsuperscript{1,2}.\emph{F. nucleatum} is a rare cause of
bacteremia; the annual reported incidence is 0.22--0.76 cases/100,000
population\textsuperscript{3,4}. Risk factors for \emph{F. nucleatum}
bacteremia include malignancy, older age, alcohol abuse,
immunosuppression, and dialysis; infection is often
hospital-acquired\textsuperscript{3}.

Immunization of the population through vaccination is recognized as a
public health priority against COVID-19. The clinical efficacy and
safety for vaccines against the novel coronavirus is the most difficult
scientific challenge at present. We report the case of a 67-year-old
man, an immunocompetent patient with \emph{F. nucleatum} bacteremia and
liver abscess formation following administration of the first dose of
anti-COVID-19 viral-vectored vaccine during the COVID-19 pandemic.

\textbf{Case history}

A 67-year-old physician with a past history of hypertension, allergic
rhinitis and hepatic hemagioma for 10 years received the first dose of
ChAdOx1nCov-19 vaccine on 2021/3/22. Three days later, he presented with
fever, up to 39\textsuperscript{o}C, combined with general soreness. He
took an acetaminophen tablet and his fever subsided completely. However,
fever up 39.3 with chills occurred on 3/31, and he was admitted for
detailed evaluation. Blood culture was done. Neither leukocytosis nor a
higher C-reactive protein (CRP) level was noted, and the Covid-19 PCR
was negative. The next day, his fever subsided and he was discharged.

However, he developed a fever, up to 38.5, 2 days after discharge.
Owing to persistent fever for 3 days, he subsequently visited the
infectious disease outpatient department and was admitted for further
evaluation. On admission, he had a temperature of 37.6, blood pressure
of 127/71 mmHg, and heart rate of 80 beats per minute. On physical
examination, he did not have a toxic appearance, but his tonsils had
erythematous enlargement. No neck lymphadenopathy was found. His chest
examination revealed clear breathing sounds, and a regular heart rhythm
without murmur. His abdominal examination revealed a soft abdomen
without rigidity or rebound, and no tenderness to palpation. There was
no lower extremity edema. His skin was intact without rashes. His white
blood cell count was 20.14\selectlanguage{ngerman}×10\textsuperscript{3}/\selectlanguage{greek}μ\selectlanguage{english}L (reference range
3.8--10.8\selectlanguage{ngerman}×10\textsuperscript{3}/\selectlanguage{greek}μ\selectlanguage{english}L) with 86.8\% neutrophils, hemoglobin
was 12.9 g/dL (reference range 12--15.5 g/dL), and platelet count was
246\selectlanguage{ngerman}×10\textsuperscript{3}/\selectlanguage{greek}μ\selectlanguage{english}L (reference range
150--450\selectlanguage{ngerman}×10\textsuperscript{3}/\selectlanguage{greek}μ\selectlanguage{english}L). His liver chemistries revealed
aspartate aminotransferase of 50 U/L, alanine aminotransferase of 60
U/L, and total bilirubin of 0.64 mg/dL. Meanwhile, a CRP level of 148.56
mg/L (reference range \textless{}5 mg/L) and procalcitonin C of 3.1
ng/ml (reference range \textless{}0.5 ng/mL) were found, which revealed
his inflammatory markers were significantly more elevated than during
the previous admission. His COVID-19 nasopharyngeal swab test was still
negative. Both abdominal echography and computed tomography of the
abdomen showed 4.5-cm abscesses at left lateral segment of the liver
(Figure 1). Blood cultures were obtained and he was given empiric
antibiotic treatment. The liver abscess was drained with a pigtail
catheter on the next day. The pus smear revealed Gram-negative bacilli.
Later, his blood cultures, which had been collected during the previous
admission, yielded\emph{Fusobacterium nucleatum} (\emph{F. nucleatum} ).
He then underwent a colonoscopy examination, which revealed
diverticulosis at the cecum and ascending colon. A dentist was consulted
and asymptomatic periodontitis was found.

The patient then received antibiotics with metronidazole and underwent
liver abscess drainage. His fever subsided completely and he was
discharged under a stable status. After 4 weeks of metronidazole
treatment, the patient was able to return to his normal daily life.

\textbf{Discussion:}

\emph{Fusobacterium} species are Gram-negative anaerobic bacilli which
are normally a constituent of the oropharynx, gastrointestinal tract,
and female genital flora. Overall, \emph{Fusobacterium} species are a
rare cause of bacteremia, accounting for \textless{} 0.001\% of all
bacteremia and \textless{} 1\% of anaerobic bacteremia cases among
adults\textsuperscript{5}. \emph{Fusobacterium} bacteremia generally
affects males more than females\textsuperscript{6,7}, with the primary
infection source typically being the respiratory tract, abdomen, or
pelvis\textsuperscript{6,8}. With respect to the hepatic abscesses
associated with \emph{Fusobacterium} species, oropharyngeal disease or
intestinal sources of infections including diverticulitis have been
postulated as the potential initial portal of entry\textsuperscript{7}.
Our patient had periodontal disease, but no evidence of oropharyngeal
infections was noted.

Was this bacteremia event a coincidence or a complication related to
vaccination? \emph{F. nucleatum} is an adhesive bacterium. It can
co-aggregate with various microbial species in the oral cavity, and
plays a key role in dental plaque formation\textsuperscript{7,9}. In
healthy individuals, there is an established homeostasis between
immunity and oral cavity microorganisms that do not cause diseases. Once
disseminated outside the oral cavity and under dysbiosis, \emph{F.
nucleatum} induces exacerbated inflammation, thus turning into a
pathogen\textsuperscript{10,11}. Regulatory T cells (Tregs) have been
known to act on the balance of immunopathogenesis of periodontal
lesions. When Tregs function was inhibited, it increased alveolar bone
loss and inflammatory cell migration, and as such, the tissue damage
associated with periodontitis was noted\textsuperscript{12}.
Furthermore, \emph{F. nucleatum} stimulates Toll-like receptor 4
(TLR4)-mediated inflammatory responses in the placentas of pregnant
mice, causing fetal demise. Suppression of inflammation protects the
fetuses, even in the presence of bacterial
colonization\textsuperscript{13}. However, the exact molecular
immunological pathway against \emph{F. nucleatum} is not fully
understood. Therefore, we supposed that our patient experienced both
wanted and unwanted immunogenicity and the disruption of symbiont status
after vaccination, which led to \emph{F. nucleatum} bacteremia.

Fever developed off and on in our patient about 1 week after
vaccination. All laboratory data initially showed no abnormality, and he
was treated as having an adverse effect post-vaccination. Then, on day 3
of his second admission, the blood culture that was obtained during his
first hospitalization grew \emph{F. nucleatum} . The Oxford AstraZeneca
chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19, has appeared to
be effective and safe for SARS-CoV-2 immunization\textsuperscript{14}.
The incidence of objectively measured fever was low in the 18--55 years
standard-dose group (12 {[}24\%{]} of 49), and no fevers were recorded
in either the 56--69 years or older standard-dose groups within 7 days
after the prime vaccination with ChAdOx1 nCoV-19\textsuperscript{14}.
Therefore, the diagnosis of systemic adverse reactions post-vaccination
should be determined carefully by a clinical physician, especially fever
occurrence during an unexpected period among the elderly patient group.

During the COVID-19 pandemic, the normal processes of clinical inference
and diagnosis were disrupted and delayed treatment of bacteremia has
been noted\textsuperscript{15}. Although \emph{F. nucleatum} bacteremia
associated with coronavirus disease was reported recently during the
COVID-19 pandemic\textsuperscript{16}, to the best of our knowledge,
this is the first case report of \emph{F. nucleatum} bacteremia with
hepatic abscess in an immunocompetent patient post-anti-COVID-19 vaccine
administration. The exact relationship between host immunological
reaction and the pathogenesis of bacteremia is difficult to identify at
present, so further research is needed to elucidate this interaction.

\textbf{Authorship}

\textbf{AUTHOR CONTRIBUTIONS}

\textbf{Jiun-Ting Wu:contributed to the literature search, and wrote
the manuscript}

\textbf{Yung-Fa Lai:provided the concept and design of this report}

\textbf{Chien-Tung Chiu:} \textbf{qualified the patient's image}

\textbf{All authors approved the final version of the manuscript.}

\textbf{Ethical approval}

The patient gave permission and informed consent for the publication of
this case report.

\textbf{Funding source:}

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

\textbf{ACKNOWLEDGEMENT}

NA. Published with written consent of the patient.

\textbf{Conflict of Interest Statement}

The authors have no conflicts of interest to disclose.

\textbf{References:}

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Genome Sequence and Analysis of the Oral Bacterium
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Bacteriology. 2002;184(7):2005-18.

2. Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M,
Strauss J, et al. Fusobacterium nucleatum infection is prevalent in
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3. Afra K, Laupland K, Leal J, Lloyd T, Gregson D. Incidence, risk
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5. Dorsher CW, Rosenblatt JE, Wilson WR, Ilstrup DM. Anaerobic
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6. Anne-Marie B, Fran, xe, ois L, Patrick D, xe, et al. Fusobacterium
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7. Huggan PJ, Murdoch DR. Fusobacterial infections: Clinical spectrum
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8. Goldberg EA, Venkat-Ramani T, Hewit M, Bonilla HF. Epidemiology and
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9. Rickard AH, Gilbert P, High NJ, Kolenbrander PE, Handley PS.
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10. Brennan CA, Garrett WS. Fusobacterium nucleatum - symbiont,
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11. de Andrade KQ, Almeida-da-Silva CLC, Coutinho-Silva R. Immunological
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14. Ramasamy MN, Minassian AM, Ewer KJ, Flaxman AL, Folegatti PM, Owens
DR, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine
administered in a prime-boost regimen in young and old adults (COV002):
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2020;396(10267):1979-93.

15. Miyagami T, Uehara Y, Harada T, Watari T, Shimizu T, Nakamura A, et
al. Delayed treatment of bacteremia during the COVID-19 pandemic.
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