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\begin{document}

\title{Chemotherapy-Induced Bone Marrow Suppression Complicated by Pyogenic
Liver Abscess: A Case of Endogenous Endophthalmitis and a Literature
Review}



\author[1]{Wei Jie Tao}%
\author[1]{Ying Gao}%
\author[1]{Jin Miao Wang}%
\author[1]{Shou Jun Wang}%
\author[1]{Ran Duan}%
\author[1]{Jie Hao}%
\affil[1]{Tianjin Union Medical Center Tianjin People's Hospital}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\selectlanguage{english}
\begin{abstract}
Objective: In this article, we review the clinical data of a case
involving chemotherapy-induced bone marrow suppression complicated by
pyogenic liver abscess, leading to endogenous endophthalmitis (EE). By
consulting the relevant literature, we comprehensively analyse and
summarise the information, ultimately offering diagnostic and
therapeutic insights for similar cases. Methods: This article presents
the case of a 65-year-old female patient with breast cancer who
developed bone marrow suppression during postoperative chemotherapy.
Imaging examinations revealed the presence of a pyogenic liver abscess,
and the patient subsequently experienced visual impairment. Following a
thorough examination, the diagnosis indicated secondary EE resulting
from a pyogenic liver abscess caused by Klebsiella pneumoniae. Upon
hospitalisation, the patient underwent treatment with granulocyte
colony-stimulating factor (G-CSF) to stimulate bone marrow
haematopoiesis and she also received comprehensive systemic
anti-infective therapy. Additionally, a pyogenic liver abscess drainage
procedure was performed, coupled with intravitreal injection of
antibiotics into the vitreous cavity of the affected eye. Results: After
comprehensive systemic and local treatments, the patient's laboratory
parameters normalised. The volume of the pyogenic liver abscess reduced
noticeably, allowing for the removal of the drainage tube. At the time
of discharge, there was a reduction in intraocular inflammation.
Nevertheless, complete loss of vision persisted in the affected eye.
Conclusion: In patients with bone marrow suppression following
chemotherapy, it is crucial to conduct liver imaging examinations to
promptly exclude the possibility of bacterial pyogenic liver abscess. To
prevent serious complications such as EE leading to blindness, timely
pyogenic liver abscess drainage procedures must be performed.
Administering antibiotics empirically for comprehensive systemic
anti-infective therapy, along with localised ocular treatment, is also
essential. This approach preserves vision as much as possible and
enhances the overall prognosis for patients%
\end{abstract}%



\sloppy


Chemotherapy-Induced Bone Marrow Suppression Complicated by Pyogenic
Liver Abscess: A Case of Endogenous Endophthalmitis and a Literature
Review

Wei Jie Tao\textsuperscript{1}, Ying Gao\textsuperscript{1}, Jin Miao
Wang\textsuperscript{1}, Shou Jun Wang\textsuperscript{1}, Ran
Duan\textsuperscript{1}, Jie Hao\textsuperscript{1}

1 Department of Breast and Thyroid surgery, Tianjin Union Medical Center
Tianjin People's Hospital No.190 Jieyuan Road,Hongqiao District,Tianjin
300121,P.R.China,Tianjin, CN 300121

Corresponding author : Jie Hao, Department of Breast and Thyroid
surgery, Tianjin Union Medical Center Tianjin People's Hospital

Email: haojie1215@126.com

\textbf{Abstract}

\textbf{Objective:} In this article, we review the clinical data of a
case involving chemotherapy-induced bone marrow suppression complicated
by pyogenic liver abscess, leading to endogenous endophthalmitis (EE).
By consulting the relevant literature, we comprehensively analyse and
summarise the information, ultimately offering diagnostic and
therapeutic insights for similar cases.

\textbf{Methods:} This article presents the case of a 65-year-old female
patient with breast cancer who developed bone marrow suppression during
postoperative chemotherapy. Imaging examinations revealed the presence
of a pyogenic liver abscess, and the patient subsequently experienced
visual impairment. Following a thorough examination, the diagnosis
indicated secondary EE resulting from a pyogenic liver abscess caused by
Klebsiella pneumoniae. Upon hospitalisation, the patient underwent
treatment with granulocyte colony-stimulating factor (G-CSF) to
stimulate bone marrow haematopoiesis and she also received comprehensive
systemic anti-infective therapy. Additionally, a pyogenic liver abscess
drainage procedure was performed, coupled with intravitreal injection of
antibiotics into the vitreous cavity of the affected eye.

\textbf{Results:} After comprehensive systemic and local treatments, the
patient's laboratory parameters normalised. The volume of the pyogenic
liver abscess reduced noticeably, allowing for the removal of the
drainage tube. At the time of discharge, there was a reduction in
intraocular inflammation. Nevertheless, complete loss of vision
persisted in the affected eye.

\textbf{Conclusion:} In patients with bone marrow suppression following
chemotherapy, it is crucial to conduct liver imaging examinations to
promptly exclude the possibility of bacterial pyogenic liver abscess. To
prevent serious complications such as EE leading to blindness, timely
pyogenic liver abscess drainage procedures must be performed.
Administering antibiotics empirically for comprehensive systemic
anti-infective therapy, along with localised ocular treatment, is also
essential. This approach preserves vision as much as possible and
enhances the overall prognosis for patients.

\textbf{Keywords:} Bone marrow suppression; Bacterial pyogenic liver
abscess; Endogenous endophthalmitis; Case report

\textbf{1 Background}

1.1 Chemotherapy-Induced Bone Marrow Suppression

In 2020, among new cancer cases worldwide, breast cancer officially
overtook lung cancer as the most prevalent form of cancer, accounting
for 11.7\% of all new cancer patients {[}1{]}. With continuous
improvements in tumour treatments, there are now numerous therapeutic
options for breast cancer. However, regardless of the chosen approach,
chemotherapy still holds a prominent position {[}2{]}. Over several
decades of development, chemotherapy drugs and regimens have continually
advanced. Now, they play a crucial role in prolonging patient survival
and enhancing their quality of life. However, various side effects from
chemotherapy should not be underestimated, with bone marrow suppression
being the most severe {[}3{]}. It mainly manifests as a reduction in red
blood cells, white blood cells, and platelets. Consequently, conditions
such as anaemia, infections, and bleeding may occur, resulting in
adjustments, interruptions, or delays in chemotherapy. In severe cases,
the patient's life may even be endangered. Studies have suggested that
the occurrence of bone marrow suppression is closely related to clinical
factors such as the chemotherapy drug type, combined or sequential
regimens, chemotherapy cycles, chemotherapy drug dosage and density
{[}4{]}, and even patient ethnicity {[}5{]}.

1.2 Bacterial Pyogenic Liver Abscess

Pyogenic liver abscess is the most common infectious disease that
affects the liver. The most prevalent form is bacterial pyogenic liver
abscess, which is caused by invasive bacterial infections and accounts
for approximately 80\% of all pyogenic liver abscesses. In recent years
in China and the Asia-Pacific region, there has been a gradual increase
in pyogenic liver abscess cases caused by Klebsiella pneumoniae, which
has replaced Escherichia coli as the primary pathogenic bacterium that
causes bacterial pyogenic liver abscess {[}6,7{]}. Clinical
manifestations of bacterial pyogenic liver abscess primarily include
fever, chills, and, in some cases, right upper abdominal pain, nausea,
vomiting, fatigue, weight loss, and jaundice. Clinical diagnosis relies
on a combination of the patient's symptoms, physical signs, inflammatory
indicators such as blood routine, C-reactive protein, or procalcitonin,
imaging examinations like abdominal ultrasound, CT, or MRI, as well as
results from blood and puncture fluid bacterial cultures. Treatment
options generally involve systemic anti-inflammatory therapy, ultrasound
or CT-guided percutaneous drainage of the pyogenic liver abscess, and
surgical intervention. Due to the potential for haematogenous
dissemination in the early stages, Klebsiella pneumoniae pyogenic liver
abscess (KPPLA) can easily lead to Klebsiella pneumoniae invasive
syndrome, which often involves the lungs, central nervous system, and
eyes {[}8,9{]}.

1.3 Endogenous Endophthalmitis

Endogenous endophthalmitis (EE), also known as metastatic
endophthalmitis, is a severe, vision-threatening intraocular infection
caused by pathogenic bacteria in the bloodstream that penetrate the
blood-ocular barrier and enter the intraocular environment. As the most
serious complication of KPPLA, EE has an incidence rate of approximately
4.5\% {[}10,11{]}. In its early stages, EE lacks distinct characteristic
features, making initial diagnosis challenging and often leading to
misdiagnosis. The progression of EE is rapid and the prognosis remains
poor, even in cases that receive timely treatment {[}12{]}. Severe cases
often lead to blindness and sometimes require enucleation of the eye. In
this article, we review the clinical data of a patient who was admitted
to our hospital with chemotherapy-induced bone marrow suppression
combined with pyogenic liver abscess resulting in EE. A comprehensive
analysis is provided based on the patient's case and the relevant
literature.

\textbf{2 Medical Records}

2.1 Brief Summary of the Medical Condition

The patient was a 65-year-old female with no history of diabetes or
liver disease. She underwent a modified radical mastectomy for a
malignant tumour in the left breast on July 4, 2023. Postoperative
pathology (left breast) revealed high-grade ductal carcinoma in situ
with focal microinvasion. Of the 25 axillary lymph nodes that were
examined, one exhibited cancer metastasis (1/25). Immunohistochemistry
results were ER (-), PR (-), HER-2 (3+), Ki67 (+, approximately 40\%),
pT2N1M0, Stage IIB. The postoperative adjuvant therapy plan included
four cycles of AC (pirarubicin + cyclophosphamide) chemotherapy followed
by sequential THP (Abraxane + trastuzumab + pertuzumab) chemotherapy and
targeted therapy. After the third cycle of chemotherapy, the patient
experienced a persistent high fever for about a week, reaching a maximum
of 39 . Self-administered antipyretic medications did not alleviate the
fever, so she sought emergency medical attention at our hospital. The
laboratory tests revealed: white blood cell count:
1.3\selectlanguage{ngerman}×10\textsuperscript{9}/L, absolute neutrophil count:
0.66×10\textsuperscript{9}/L, neutrophil percentage: 85.30\%, absolute
lymphocyte count: 0.57×10\textsuperscript{9}/L, platelet count:
102×10\textsuperscript{9}/L, C-reactive protein: 245.20 mg/L, alanine
aminotransferase (ALT): 53 U/L, aspartate aminotransferase (AST): 117
U/L, gamma-glutamyl transferase (GGT): 140 U/L. Consequently, she was
admitted to the hospital on September 21, 2023, for further treatment
with a provisional diagnosis of ''chemotherapy-induced bone marrow
suppression''.

2.2 Auxiliary Examinations

Following admission, an abdominal CT scan was performed. It revealed a
nodule in the right lobe of the liver, raising suspicion of pyogenic
liver abscess. A subsequent enhanced liver MRI disclosed two nodules in
the VI segment of the liver, with the larger one exhibiting multiple
septations and a diameter of approximately 3 cm, indicative of a liver
abscess (Figure 1). On the second day of hospitalisation, the patient
reported blurred vision and pain in the left eye. Ophthalmologists were
consulted, and the results of a visual acuity examination indicated OD
0.8+ and OS 0.6-. Examination of the fundus in the left eye revealed
conjunctival congestion, a transparent cornea, numerous dust-like
keratic precipitates (KP) in the endothelium, a deep anterior chamber,
positive Tyndall phenomenon, a round pupil with 3 mm diameter, delayed
light reaction, failure of the lower part of the iris to enter the
anterior chamber, and positive tenderness in the upper and lower
eyelashes. The intraocular pressure was OD 13.5 mmHg and OS 14.2 mmHg.
Moreover, an ocular ultrasound exposed vitreous opacities in the left
eye (Figure 3). The provisional diagnosis was left iridocyclitis, and
symptomatic treatment with prednisolone acetate eye drops was initiated.
However, after two days, the patient's symptoms worsened, leading to
loss of vision in the left eye with purulent discharge. Upon
re-examination, ophthalmologists detected mild redness and swelling in
the left eyelid, conjunctival congestion and oedema, mild corneal
oedema, and increased KP (+++). The anterior chamber was deep with
flocculent exudation, while the pupil was not well-rounded, with a
diameter of 5 mm, no light reaction, and posterior synechiae.
Additionally, the lens was cloudy and no fundus details could be
visualised. The intraocular pressure was OD 11.9 mmHg and OS 23.4 mmHg.
An orbital CT scan (Figure 4) revealed slight swelling of the soft
tissue in the upper eyelid on the left side and exophthalmos of the left
eyeball. Subsequently, we made a diagnosis of left endophthalmitis with
orbital infection.

2.3 Treatment and Prognosis

After admission, the patient received intravenous ceftazidime for
injection (0.2 g Q12H) for anti-inflammatory therapy and subcutaneous
injections of granulocyte colony-stimulating factor (G-CSF) (200 \selectlanguage{greek}μ\selectlanguage{english}g QD)
to stimulate bone marrow haematopoiesis. Following the confirmation of a
pyogenic liver abscess, on September 26, 2023, the patient underwent a
CT-guided pyogenic liver abscess drainage procedure under local
anaesthesia. Bacterial cultures of both blood and pyogenic liver abscess
puncture fluid confirmed the presence of Klebsiella pneumoniae. Based on
the sensitivity results, the antibiotic was switched to intravenous
imipenem (1 g Q8H). After one week of treatment, the patient's body
temperature returned to normal. Besides, a re-examination of the
laboratory parameters showed all values within the normal range: white
blood cell count: 5.8\selectlanguage{ngerman}×10\textsuperscript{9}/L, absolute neutrophil
count: 4.34×10\textsuperscript{9}/L, neutrophil percentage: 74.70\%,
absolute lymphocyte count: 1.2×10\textsuperscript{9}/L, platelet count:
300×10\textsuperscript{9}/L, C-reactive protein: 6.87 mg/L, ALT: 35 U/L,
AST: 30 U/L, GGT: 40 U/L. A follow-up abdominal CT scan revealed a
significant reduction in the volume of the pyogenic liver abscess
cavity, with a diameter of approximately 1 cm (Figure 2). After the
endophthalmitis diagnosis, ophthalmologists performed intravitreal
injections of vancomycin with a concentration of 10 mg/ml and a total
volume of 0.1 ml (1 mg). There were three treatment cycles with an
average interval of 4 days. During this period, vitrectomy was
recommended, but the patient declined. Following systemic and local
treatment, the patient's intraocular infection gradually improved.
However, ultimately, permanent blindness occurred in the left eye. The
liver drainage tube was removed one month after placement. After
discharge, the patient refused to continue chemotherapy due to concerns
about further adverse reactions. Currently, the patient is undergoing
regular targeted therapy with the HP regimen and no serious adverse
reactions have occurred.

\textbf{3 Discussion}

As a crucial component in cancer treatment, chemotherapy plays a vital
role in eliminating tumour cells. However, it also exerts a significant
cytotoxic effect on normal, rapidly dividing cells, particularly
haematopoietic cells. This often leads to chemotherapy-induced bone
marrow suppression, resulting in a reduced number of white blood cells
and platelets, which lowers the overall immune response in patients.
Tumour presence, chemotherapy, and compromised systemic immunity are
common predisposing factors for bacterial pyogenic liver abscess. In
China, Klebsiella pneumoniae is the predominant pathogen that causes
bacterial pyogenic liver abscess {[}13,14{]}. The primary route of
infection is through the intestines. As a normal inhabitant of the human
gastrointestinal tract, Klebsiella pneumoniae can translocate to the
portal vein or bile ducts, causing infection and resulting in Klebsiella
pneumoniae pyogenic liver abscess (KPPLA) when the immune defences in
the body are compromised. There is a high likelihood of KPPLA
haematogenous spread, which poses a risk of invasive infections in other
organs, especially with hypervirulent Klebsiella pneumoniae (hvKP)
{[}15,16{]}. The abundant capsule polysaccharides on the surface allow
the bacteria to evade phagocytosis by macrophages and neutrophils in the
bloodstream, as well as resist serum complement bactericidal activity.
In patients with chemotherapy-induced bone marrow suppression, the
significant decrease in white blood cells and neutrophils makes them
more susceptible to systemic dissemination of Klebsiella pneumoniae,
which can potentially penetrate the blood-ocular barrier and enter the
vitreous cavity. The vitreous, an avascular tissue rich in water and
proteins, provides an ideal environment for bacterial growth and
nutrition. Once infected, the vitreous is prone to the formation of
infectious foci, leading to the occurrence of EE. Currently,
chemotherapy-induced bone marrow suppression and KPPLA can be
successfully treated in most cases, but the prognosis for EE is
generally poor. EE can rapidly cause permanent irreversible visual
impairment {[}17{]}, especially when associated with hvKP infection and
the optimal treatment window is missed. Indeed, hvKP infections can lead
to irreversible retinal photoreceptor cell damage within 48 hours of
ocular tissue infection. Reports indicate that 57.8\% of eyes affected
by EE ultimately lose light perception, while 26.8\% require removal to
eradicate the infection {[}18{]}.

In clinical practice, patients often experience bone marrow suppression
after chemotherapy. The severity of bone marrow suppression ranges from
Grade 0 to Grade IV and is classified according to the Common
Terminology Criteria for Adverse Events (CTCAE) version 5.0 from the
National Cancer Institute (NCI). In this case, the patient underwent
three cycles of AC chemotherapy, resulting in Grade III bone marrow
suppression. KPPLA lesions are typically solitary and predominantly
located in the right lobe of the liver. They are possibly associated
with the large volume and rich blood supply of the right liver lobe.
Clinical manifestations primarily include fever and chills, and
diagnosis is typically based on blood tests and imaging examinations
such as colour ultrasound and CT. EE often affects a single eye, with
similar incidence rates in both the left and right eyes {[}11{]}.
Initial symptoms of EE are mild and inconspicuous, and they are often
overlooked by physicians, who frequently misdiagnose EE as
iridocyclitis, acute necrotising retinitis, or panuveitis. However, the
condition progresses rapidly, leading to blurred vision accompanied by
ocular pain in the affected eye. Additionally, severe cases may exhibit
purulent discharge. Diagnosis is made according to the patient's medical
history, symptoms, signs, ocular auxiliary examinations, microbial
bacterial cultures from intraocular specimens, and rapid identification
of bacterial species through PCR testing of aqueous humour and vitreous
samples.

Currently, there are no documented cases in the domestic or
international literature of chemotherapy-induced bone marrow suppression
combined with pyogenic liver abscess leading to EE. Since this article
represents the first report of such a case, there is no consensus
regarding the diagnosis and treatment of patients with similar
conditions. In clinical practice, treatment approaches predominantly
involve systemic and local interventions {[}20,21{]}. Systemic
treatments encompass both recovery therapy for bone marrow suppression
and anti-inflammatory measures. Febrile neutropenia (FN), which is the
most prevalent type of bone marrow suppression, is typically addressed
by stimulating bone marrow haematopoiesis using haematopoietic growth
factors. Additionally, granulocyte colony-stimulating factors (G-CSF)
are commonly employed in clinical settings, including short-acting
recombinant human G-CSF (rhG-CSF) and long-acting pegylated recombinant
human G-CSF (PEG-rhG-CSF). Both of these growth factors have been proven
to be effective in preventing FN {[}22{]}. In systemic anti-inflammatory
treatment, the initial step usually involves the empirical selection of
antibiotics that are sensitive to Klebsiella pneumoniae {[}23{]}.
Klebsiella pneumoniae strains normally produce beta-lactamases and are
generally susceptible to third- and fourth-generation cephalosporins,
fluoroquinolones, aminoglycosides, and carbapenems. Antibiotic choices
should be guided by bacterial culture and sensitivity results, with
appropriate adjustments. Following infection control, a de-escalation
treatment strategy is necessary. The patient in this study initially
received ceftazidime but subsequently transitioned to the more sensitive
imipenem. After achieving improved infection control, she returned to
ceftazidime. It is crucial to note that for patients with a history of
diabetes, strict blood sugar control is essential during systemic
treatment. Elevated blood sugar levels may compromise the phagocytic
function of white blood cells {[}24{]}, disrupt vascular permeability,
breach the blood-ocular barrier, facilitate bacterial dissemination in
the bloodstream, and aggravate symptoms of EE, potentially affecting
both eyes. Furthermore, attention should be directed towards digestive
symptoms such as nausea, vomiting, and diarrhoea, which are commonly
associated with chemotherapy. Ensuring the overall nutritional status of
the patient, correcting hypoalbuminaemia, anaemia, and electrolyte
imbalances, and enhancing the immune response of the body are essential
elements of care.

Local treatment mostly focuses on managing the KPPLA infection and
addressing the eye affected by EE. Since KPPLA is the primary source of
EE infection, local liver puncture drainage is a crucial intervention
for directly eliminating the cause and controlling the spread of
infection {[}25{]}. For infected lesions with a diameter greater than 3
cm and good liquefaction, percutaneous pyogenic liver abscess puncture
drainage under ultrasound or CT guidance is usually performed. Compared
to surgical treatment, puncture drainage is safer, more convenient, and
results in minimal trauma. As a result, it is more widely accepted by
patients. In cases with multiple abscess lesions, clinicians adopt a
sequential approach that addresses the larger abscesses before the
smaller ones. After puncture, imaging follow-ups are usually conducted
weekly to assess changes in abscess volume and identify new pyogenic
liver abscesses or liquefied lesions. If there are new abscesses, repeat
puncture may be necessary. In this study, the patient received a
follow-up abdominal CT one month after catheter placement. The scan
revealed a significant reduction in the pyogenic liver abscess cavity
with no new lesions, so the drainage tube was removed. Surgical
treatment should be considered in cases where puncture drainage proves
ineffective and there is a high risk of abscess rupture, or if rupture
has already occurred and has led to pleurisy, peritonitis, or concurrent
biliary tract diseases.

In the treatment of EE, the blood-ocular barrier limits the
effectiveness of intravenous antibiotic administration. It results in
low drug concentrations within the eye, making it difficult to achieve
positive therapeutic outcomes. Therefore, it is crucial to administer
local ocular treatment, which includes vitrectomy and intraocular drug
injection into the vitreous cavity. In contrast to subconjunctival
injection, topical eye drops, or systemic antibiotics, intraocular drug
injection effectively maximises drug concentrations within the vitreous
cavity. Clinically, antibiotics with favourable intraocular penetration
and a broad spectrum are commonly utilised, including vancomycin,
ceftazidime, amikacin, fluoroquinolones, and others, as well as
combinations of these drugs, as necessary. Ideally, drug injection
should be conducted within 48 hours of the onset of eye discomfort
symptoms. While intraocular drug injection effectively eliminates
pathogenic bacteria in the vitreous cavity, its impact on lesions under
the retina is limited. Hence, when deemed necessary, vitrectomy is
performed to thoroughly clear lesions under the retina, enhance the
intraocular environment, restore retinal function, reduce the risk of EE
recurrence, and prevent serious complications {[}26{]}. In our case,
given her compromised overall health, severe intraocular inflammation,
and elevated surgical risks, the patient declined surgical intervention
and opted solely for intraocular drug injection. Although the
intraocular infection was successfully controlled using this approach,
the patient experienced permanent vision loss in the affected eye.

\textbf{4 Conclusion}

In summary, for postoperative breast cancer patients requiring
chemotherapy, a careful risk evaluation for bone marrow suppression
should be conducted before initiating chemotherapy. For patients
undergoing chemotherapy regimens with a moderate-to-high risk of FN,
regardless of the treatment goal (cure, survival extension, or
improvement of disease-related symptoms), the prophylactic use of G-CSF
should be considered. Regular blood examinations should also be
performed during chemotherapy and if bone marrow suppression is
detected, timely corrective treatment is necessary. For febrile
patients, a comprehensive abdominal CT or ultrasound examination should
be conducted after chemotherapy to rule out the possibility of bacterial
pyogenic liver abscess. KPPLA-induced EE is a clinically atypical
infectious disease characterised by rapid progression and a poor
prognosis. In patients with a confirmed KPPLA diagnosis, timely systemic
anti-infective treatment should be administered. If necessary, pyogenic
liver abscess puncture and drainage should also be performed.
Additionally, routine fundus examination should be conducted regularly
{[}19,27{]}. Early diagnosis and treatment are essential to preserve
vision, improve prognosis, and prevent serious adverse consequences such
as blindness or enucleation due to EE.

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