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\begin{document}

\title{Staphylococcus aureus subcapsular splenic abscess and associated empyema
in the setting of tocilizumab therapy: A case report}



\author[1]{Audrey Lee}%
\author[1]{Yi Tong Aw}%
\affil[1]{Canberra Hospital}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\textbf{Title}

\emph{Staphylococcus aureus} subcapsular splenic abscess and associated
empyema in the setting of tocilizumab therapy: A case report

\textbf{Key Clinical Message}

We report a case of \emph{Staphylococcus aureus} subcapsular splenic
abscess and associated empyema after recent commencement of tocilizumab,
masquerading as musculoskeletal pain. This highlights the importance of
considering unusual underlying infections in patients on tocilizumab.

\textbf{Introduction}

Tocilizumab is an anti-interleukin-6 (IL-6) receptor monoclonal antibody
used in the management of rheumatoid arthritis.\textsuperscript{1} It is
effective at decreasing disease activity and improving function, and is
used as monotherapy or in combination with other disease-modifying
anti-rheumatic drugs.\textsuperscript{1} However, tocilizumab increases
the risk of serious infections,\textsuperscript{2,3} which can present
atypically for patients on tocilizumab -- such as having mild clinical
features despite disseminated infection,\textsuperscript{4} or having
disproportionately low or normal C-reactive protein
(CRP).\textsuperscript{5} We present a previously unreported case
of\emph{Staphylococcus aureus} subcapsular splenic abscess with
associated empyema in the setting of recent commencement of tocilizumab
therapy.

\textbf{Case presentation}

A 56-year-old woman presented to hospital with progressively worsening
left upper quadrant and flank pain, which had persisted following a
mechanical rotational injury to the thoracic spine sustained four weeks
prior. This was initially diagnosed as musculoskeletal pain secondary to
injury by her general practitioner, however her symptoms continued to
worsen despite resting and avoiding further mechanical aggravation.

Her medical history was significant for seronegative rheumatoid
arthritis, for which she took leflunomide 10 mg daily and methotrexate
20 mg weekly with folic acid supplementation for the last two years, and
prednisolone at a stable dose 2.5 mg daily. She had also been commenced
on subcutaneous tocilizumab 162 mg weekly, three months prior by her
rheumatologist.

She also had a recurrent Bartholin cyst infection for the preceding six
weeks, from which microbiological swab samples taken had cultured
methicillin-sensitive \emph{Staphylococcus aureus} (MSSA)\emph{.} This
had been managed by her general practitioner with short courses of
amoxicillin-clavulanic acid -- including most recently a five-day
course, completed two weeks prior to presentation. Her immunosuppressive
therapy was withheld for the preceding two weeks but she continued low
dose prednisolone.

She did not report any adverse reaction to amoxicillin-clavulanic acid
and had also tolerated this previously for other indications. She did
not have any known allergies. She did not start any new herbal or over
the counter medications, or prescribed medications, except for
tocilizumab.

She did not have any urinary symptoms, other infective symptoms, nor a
history of renal stones or gallstones. She did not have any prior
history of immunodeficiency, hyposplenism, diabetes mellitus,
endocarditis or other recent systemic infection. She did not have any
history of intravenous drug use, excessive alcohol use, prostheses or
implants. She did not have any significant or severe infections in the
preceding two years while taking methotrexate and leflunomide.

On examination, she was febrile but haemodynamically stable. She had
left upper quadrant abdominal tenderness and guarding on palpation, and
reduced breath sounds with dullness on percussion over the left lung
base. She did not have any new rashes, arthralgia or active
tenosynovitis. Blood investigations revealed elevated inflammatory
markers with a CRP of 286.2 mg/L and neutrophilia of 10.17 x
10\textsuperscript{9}/L. Her renal function was normal with no
electrolyte derangement. Her liver function tests were unremarkable.

Computerised Tomography (CT) of the abdomen revealed findings concerning
for a subcapsular splenic abscess and a left-sided empyema (Figure 1).
These findings were new compared to a CT performed four weeks prior at
the time of the original injury.

Splenic abscess drainage was performed under ultrasound guidance,
revealing frank pus with heavy growth of MSSA. Video assisted
thoracoscopy (VATS) and washout of the left-sided empyema and pleural
effusion was performed, with MSSA again isolated on two pleural biopsy
specimens. Blood cultures were negative for any growth. A transthoracic
echocardiogram was normal with no evidence of vegetations or valvular
abnormalities. A nuclear medicine bone scan did not demonstrate any
evidence of focal osteomyelitis.

\textbf{Outcome and follow-up}

The patient was diagnosed with a MSSA subcapsular splenic abscess and
associated empyema, in the context of being immunosuppressed and
recently commencing tocilizumab. Following the identification of MSSA,
the patient was changed from empirical antibiotic treatment with
intravenous amoxicillin-clavulanic acid to intravenous flucloxacillin
monotherapy. There was subsequently a good biochemical and clinical
response with normalisation of neutrophilia and a slow downtrend in the
CRP to 27 mg/L, after three weeks of intravenous antibiotic therapy and
source control with splenic abscess drainage and VATS washout. She was
discharged home on oral flucloxacillin monotherapy to complete a
four-week total course of antibiotic therapy and made a full recovery.
Tocilizumab was ceased, and leflunomide and methotrexate were withheld
on discharge in the context of infection, with ongoing follow-up planned
with her rheumatologist.

\textbf{Discussion}

Tocilizumab has been associated with both atypical and delayed
presentations of infections.\textsuperscript{5} Atypical presentations
of common conditions in patients on tocilizumab include case reports of
pneumonia with absence of fever and disproportionately normal or mildly
elevated biochemical markers.\textsuperscript{5} Delayed presentations
of severe infection have also been reported in patients on tocilizumab,
with case reports of disseminated \emph{Staphylococcus
aureus}bacteraemia associated with epidural abscess, polyarticular
septic arthritis, and empyema.\textsuperscript{4} Other unusual
presentations include re-activation of latent tuberculosis presenting as
fulminant sepsis with splenic abscess two weeks after initiating
tocilizumab.\textsuperscript{6} An increased risk of fungal
co-infections and reports of invasive fungal disease have also been
observed in patients after a single dose of tocilizumab for the
management of COVID-19.\textsuperscript{7,8}

We present a case of \emph{Staphylococcus aureus} subcapsular splenic
abscess and associated left-sided empyema in the setting of tocilizumab.
Using ``tocilizumab'' and ``splenic abscess'' search terms on PubMed and
Google Scholar, there was a single case report of splenic abscess in
context of reactivated tuberculosis.\textsuperscript{6} There were no
previously reported cases of non-mycobacterial splenic abscess
associated with tocilizumab therapy, and hence this would be the first
reported case to the best of our knowledge.

In this clinical case, we hypothesise the formation of splenic abscess
was by haematogenous seeding from transient but
uncaptured\emph{Staphylococcus aureus} bacteraemia in the context of
antibiotic therapy suppression, with the recurrent Bartholin cyst
infection being the likely primary source of infection. The left sided
empyema/pleural effusion with biopsy-proven pleural infection, was
likely a continuation of the adjacent splenic abscess
\emph{Staphylococcus} infection through the presence of otherwise
clinically-insignificant congenital diaphragmatic
defects,\textsuperscript{9} given the similar radiological appearance
(Figure 1). While the rotational injury of the spine which prompted the
patient's presentation may have coincidentally caused concurrent
musculoskeletal pain in her left upper quadrant and flank, it is likely
to be a red herring in the setting of the splenic abscess being the more
plausible cause for progressively worsening pain. The significant
immunosuppressive regimen of leflunomide, methotrexate and tocilizumab
likely contributed to the development of the atypical infection and
delayed presentation, due to the patient having a markedly suppressed
ability to mount an immune response and hence remaining relatively
asymptomatic during the early stages of infection. However, we postulate
that this atypical presentation was in particular due to the recent
commencement of tocilizumab -- given the patient had previously
tolerated methotrexate and leflunomide for two years prior without
developing significant infections.

This case emphasises the importance of considering infection as a
differential diagnosis for common presentations such as suspected
musculoskeletal pain in patients who are on tocilizumab. Additionally,
given tocilizumab inhibits IL-6 mediated production of
CRP,\textsuperscript{5} a normal CRP may be unreliable for excluding
infection. Conversely, elevation in CRP in the setting of active
tocilizumab therapy may be a marker of severe disseminated infection --
as exemplified by the present case. As the availability and use of
tocilizumab increases, it is increasingly important for clinicians to
have a high index of suspicion for delayed presentations of unusual
infections in patients on tocilizumab therapy, including those who
present with otherwise common presentations such as suspected
musculoskeletal pain.

\textbf{References}

1. Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid
arthritis. \emph{Cochrane Database of Systematic Reviews} .
2010;(7)doi:10.1002/14651858.CD008331.pub2

2. Pawar A, Desai RJ, Solomon DH, et al. Risk of serious infections in
tocilizumab versus other biologic drugs in patients with rheumatoid
arthritis: a multidatabase cohort study. \emph{Annals of the Rheumatic
Diseases} . 2019;78(4):456-464. doi:10.1136/annrheumdis-2018-214367

3. Campbell L, Chen C, Bhagat SS, Parker RA, \selectlanguage{ngerman}Östör AJK. Risk of adverse
events including serious infections in rheumatoid arthritis patients
treated with tocilizumab: a systematic literature review and
meta-analysis of randomized controlled trials. \emph{Rheumatology} .
2010;50(3):552-562. doi:10.1093/rheumatology/keq343

4. Nguyen MT, Pødenphant J, Ravn P. Three cases of severely disseminated
Staphylococcus aureus infection in patients treated with
tocilizumab.\emph{BMJ Case Reports} . 2013;2013:bcr2012007413.
doi:10.1136/bcr-2012-007413

5. Berman M, Ben-Ami R, Berliner S, et al. The Effect of Tocilizumab on
Inflammatory Markers in Patients Hospitalized with Serious Infections.
Case Series and Review of Literature. \emph{Life} . 2021;11(3):258.

6. Reisinger AC, Hermann J, Vagena FR, Hackl G, Eller P. Tuberculosis
sepsis after tocilizumab treatment. \emph{Clinical Microbiology and
Infection} . 2020;26(11):1493-1494. doi:10.1016/j.cmi.2020.05.030

7. Peng J, Fu M, Mei H, et al. Efficacy and secondary infection risk of
tocilizumab, sarilumab and anakinra in COVID-19 patients: A systematic
review and meta-analysis. \emph{Reviews in Medical Virology} .
2022;32(3):e2295. doi:https://doi.org/10.1002/rmv.2295

8. Pettit NN, Nguyen CT, Mutlu GM, et al. Late onset infectious
complications and safety of tocilizumab in the management of
COVID-19.\emph{Journal of Medical Virology} . 2021;93(3):1459-1464.
doi:https://doi.org/10.1002/jmv.26429

9. Lidid L, Valenzuela J, Villarroel C, Alegria J. Crossing the barrier:
when the diaphragm is not a limit. \emph{AJR Am J Roentgenol} .
2013;200(1):W62-70.

\textbf{Figure}\selectlanguage{english}
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\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
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\textbf{Figure 1: CT image of the chest/abdomen demonstrating a 51 mm x
40 mm x 49 mm hypodense lesion with peripheral enhancement consistent
with a subcapsular splenic abscess (blue arrow) and left-sided
moderate-volume loculated pleural effusion with peripheral enhancement
in keeping with an associated empyema (red arrow).}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

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