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\begin{document}

\title{Tocilizumab-induced Cytomegalovirus Colitis in a Patient with COVID-19}



\author[1]{Mohamad  Khatib}%
\author[1]{Karimulla  Shaik}%
\author[1]{Amna  Ahmed}%
\author[1]{Mohammad Alwraidat}%
\author[1]{Ahmed soliman Mohamed}%
\author[1]{mohamed aboukamar}%
\author[1]{Abdulqadir Nashwan}%
\affil[1]{Hamad Medical Corporation}%


\vspace{-1em}



  
  \date{May 10, 2024}


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\selectlanguage{english}
\begin{abstract}
Cytomegalovirus (CMV) infection exists in 50-80\% of the world's
population in clinically undetected form due to their immunocompetent
status. Here we report a case of a 42-year-old COVID-19 patient with no
past medical history, who received tocilizumab, which led to a massive
lower gastrointestinal bleeding not responded to medical management.%
\end{abstract}%



\sloppy


\textbf{Key Clinical Message}

The authors urge clinicians to observe the early signs of lower
gastrointestinal bleeding and perforation associated with tocilizumab
treatment in patients with COVID-19. On-time recognition and performance
of exploratory laparotomy with double-barrel colostomy are effective
life-saving measures.

\textbf{Background}

Cytomegalovirus (CMV) is a double-stranded deoxyribonucleic acid virus
belonging to the Herpesviridae family. \textsuperscript{1} It is more
commonly seen in individuals with immunosuppressive diseases, including
inflammatory bowel disease (IBD), hematological malignancy, organ
transplantation, acquired immunodeficiency syndrome (AIDS), or therapies
such as cancer, and corticosteroids. \textsuperscript{2} However, most
of the CMV-related infections in immunocompetent individuals go
undetected, \textsuperscript{3} and presented as fever, sometimes with
pancytopenia. Diarrhea (watery and bloody in severe cases) may begin to
develop as an inflammatory response. Ulcerative changes can be seen when
the colon tissue affected by CMV.

Subsequently, inflammatory polyps may develop, which, rarely, may cause
colon obstruction. Severe inflammation and vasculitis may lead to bowel
perforation~and~peritonitis due to ischemia and transmural necrosis.
\textsuperscript{4} We describe a case of COVID-19 pneumonia on
immunosuppressive treatment presenting with lower gastrointestinal
bleeding due to CMV colitis confirmed by histopathology.

\textbf{Case Report}

A 42-year-old gentleman with no past medical history admitted to our
intensive care unit (ICU) with a laboratory-confirmed case of COVID-19,
requiring non-invasive ventilation (NIV). He developed spontaneous
pneumothorax, for which chest drain placed. One day after his admission
he was intubated and pronned for deterioration of his oxygen levels and
PaO2/FiO2 ratios (\emph{Figure 1} ). For possible cytokine storm in view
of high ferritin levels and persistent fever patient received IL-6
inhibitor (Tocilizumab 400 mg Once) 3 days after admission to ICU.

His course was complicated by upper gastrointestinal bleeding (melena)
with a drop in hemoglobin by one gram on day nine, Gastroenterology team
managed him conservatively, as the melena subsided. Almost 22 days after
admission, he re-developed bleeding per rectum again (hematochezia),
with a drop in hemoglobin from 9 gm/dl to 6 gm/dl, this time he was
hemodynamically unstable, requiring nor adrenaline vasopressor support
and multiple blood product transfusions. Esophagogastroduodenoscopy did
not show active bleeding or altered blood from upper esophageal
sphincter to level-D3 part of the duodenum, and only clear biliary
secretions were found.

Colonoscopy performed with a difficulty till the splenic flexure, the
colon was filled with blood clots and fresh bleed was noted around the
colon circumferentially and the scope could not be passed further due to
poor visibility due to blood clots, the procedure was abandoned,
hemostasis not achieved due to not identifiable active bleeder.

A computed tomography (CT) angiogram was done for identifying the cause
of bleeding and for possible angioembolization. No bleeder could be
identified, and the only positive finding was mural thickening with
intramural axial hemorrhage involving the splenic flexure and proximal
part of the descending colon (\emph{Figure 2} ). In view of
hemodynamical instability, a team of multi-disciplinary surgeons decided
to take him for lifesaving emergency laparotomy.

A small bowel enterotomy was done at the suspicious site of bleeding; GI
team passed the colonoscope to locate bleeding; no evidence of bleed
found up to three meters of small bowel and enterotomy closed. Left
hemicolectomy was done in view of the high suspicious site of bleeding
at the splenic flexure, both the loops of large bowel brought out as
functional transverse colon and descending mucous fistula as
double-barrel stoma performed. Histopathology report confirmed CMV
colitis with colonic perforation, for which he was started on
Ganciclovir therapy 220 mg once daily for 4 days. Intime recognition and
timely performance of life-saving surgery helped our patient survival;
we continued for ganciclovir 440 mg every 12 hours for a total of 3
weeks, the patient has been tracheostomized and stepped down to the
inpatient ward with a functional colostomy.

\textbf{Discussion}

CMV infections are becoming more prevalent in immunocompetent
patients.\textsuperscript{5} Recently, with the outbreak of Coronavirus
disease (COVID-19), many studies have suggested that COVID-19 may
activate dysregulated host immune responses, where interleukin-6 (IL-6)
levels are elevated in cases of severe COVID-19, so the anti-IL-6 such
as tocilizumab may be beneficial. \textsuperscript{6} however, the
available evidence still not conclusive that tocilizumab is beneficial
to patients with severe COVID-19 and not yet recommended for routine
clinical guidelines.

Al-Omari et al. noted that the risk factors such as the
immunocompromised, mechanical ventilation, sepsis were found to be
strongly associated with CMV. In contrast, the use of corticosteroids,
blood transfusion and stress were weakly associated. They found no
association with risk factors such as age, gender, disease severity
scores, and active malignancy. \textsuperscript{7}

It demonstrates an organ-specific tropism within the body affecting
mainly hemopoietic stem cells and parenchymal connective tissue. As per
the systemic review done by Rafailidis et al., in immunosuppressed
patients with tissue-invasive (TI) CMV, the gastrointestinal tract is
the most commonly affected and comprises almost 30\% of the
disease.\textsuperscript{5} CMV lesions may be present throughout the
gastrointestinal tract, from the oral cavity to the rectum. However,
colon involvement is the most common, comprising up to 94\% of
cases.\textsuperscript{8-10} For viral reactivation in the
immunocompetent, critical illness is a major predisposing factor for
developing TI-CMV disease. \textsuperscript{11}

Endoscopic findings of CMV colitis, like ulcers and inflammation, are
similar to UC exacerbation. Biopsies that reveal CMV inclusion bodies in
the pathological specimen may be the only way to distinguish between IBD
and CMV. The presence of CMV infection in our patient was diagnosed only
based on the presence of inclusion bodies. Biopsy with
Immunohistochemistry using monoclonal antibodies against CMV antigens is
now considered the gold standard. \textsuperscript{12} The
characteristic Owl's eye inclusion bodies are highly specific for
CMV.\textsuperscript{13} CMV colitis and IBD closely mimics each other
in their clinical, endoscopic and histological appearance. Therefore, it
is crucial to avoid misdiagnosis and mismanagement, keeping in mind the
high morbidity associated with it.

\textbf{Conclusion}

This case highlights the importance of keeping a high suspicion and
diagnosing the pathology at the earliest to treat and control the
disease in these critically ill patients. Though they may be
immunocompetent and with no risk factors prior to admission to the ICU,
they become vulnerable and the risk of developing primary/latent CMV
infection is high. A timely diagnosis can prevent prolonged ICU and
hospital stay. It also warrants judicious use of corticosteroids and
other immunomodulatory drugs like tocilizumab in critically ill
patients. In the present Scenario, while treating patients with COVID-19
with the use of immunosuppressive therapy should be justified while
being alert for signs and symptoms of CMV reactivation. Early
recognition of CMV infection and initiation of early treatment will
prevent life-threatening bleeding and mortality.

\textbf{Abbreviations}

CMV: Cytomegalovirus

COVID-19: Coronavirus disease

IBD: Inflammatory bowel disease

AIDS: Acquired immunodeficiency syndrome

ICU: Intensive care unit

IL-6: Interleukin 6

\textbf{Declarations}

\textbf{Ethics approval and consent to participate}

The article describes a case report. Therefore, no additional permission
from our Ethics Committee was required.

\textbf{Consent for publication}

The consent for publication was obtained.

\textbf{Availability of data and material}

All data generated or analyzed during this study are included in this
published article.

\textbf{Competing interests}

The authors declare that they have no competing interests.

\textbf{Funding}

This study was not funded.

\textbf{Authors' contributions}

MYK, KSS, AAA, MAA, AJN, ASM: Data Collection, Literature Search,
Manuscript Preparation

All authors read and approved the final manuscript

\textbf{Acknowledgments}

We thank the patient for allowing us to share his case. Open Access
funding provided by the Qatar National Library

\textbf{References}

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Detection of human cytomegalovirus DNA, RNA, and antibody in normal
donor blood. \emph{Journal of Infectious
Diseases.}1995;171(4):1002-1006.

2. Nakase H, Herfarth H. Cytomegalovirus colitis, cytomegalovirus
hepatitis and systemic cytomegalovirus infection: common features and
differences. \emph{Inflammatory intestinal diseases.} 2016;1(1):15-23.

3. Rawlinson W, Scott G. Cytomegalovirus: a common virus causing serious
disease. \emph{Australian family physician.} 2003;32(10):789.

4. Kram HB, Shoemaker WC. Intestinal perforation due to cytomegalovirus
infection in patients with AIDS. \emph{Diseases of the colon \&
rectum.}1990;33(12):1037-1040.

5. Rafailidis PI, Mourtzoukou EG, Varbobitis IC, Falagas ME. Severe
cytomegalovirus infection in apparently immunocompetent patients: a
systematic review. \emph{Virology journal.} 2008;5(1):47.

6. Coomes EA, Haghbayan H. Interleukin-6 in COVID-19: a systematic
review and meta-analysis. \emph{MedRxiv.} 2020.

7. Al-Omari A, Aljamaan F, Alhazzani W, Salih S, Arabi Y.
Cytomegalovirus infection in immunocompetent critically ill adults:
literature review. \emph{Annals of intensive care.} 2016;6(1):110.

8. Fakhreddine AY, Frenette CT, Konijeti GG. A practical review of
cytomegalovirus in gastroenterology and
hepatology.\emph{Gastroenterology research and practice.} 2019;2019.

9. Jacob S, Zayyani NR. Cytomegalovirus colitis masquerading as rectal
malignancy in an immunocompetent patient. \emph{Indian Journal of
Pathology and Microbiology.} 2015;58(1):80.

10. Lee C-Y, Chen Y-H, Lu P-L. Reactivated cytomegalovirus proctitis in
an immunocompetent patient presenting as nosocomial diarrhea: a case
report and literature review. \emph{BMC Infectious
Diseases.}2017;17(1):113.

11. Osawa R, Singh N. Cytomegalovirus infection in critically ill
patients: a systematic review. \emph{Critical Care.} 2009;13(3):R68.

12. Niv E, Ovadia B, Groisman G, Kopelman Y. CMV-Induced Severe Colonic
Stricture in an Adult Crohn's Disease Patient. \emph{Digestive Diseases
and Sciences.} 2020:1-4.

13. Malik A, Vaze R, Buckshaw R, Nellis E, Shah H. A Case of CMV Colitis
Seen in DRESS: 1571. \emph{American Journal of
Gastroenterology.}2019;114(2019 ACG Annual Meeting Abstracts):S875-S876.

\par\null

\emph{Figure 1} : Shows bilateral consolidation of lung, Endotracheal
tube, Nasogastric tube (NG Tube) right IJV (Internal jugular vein)
Central venous catheter.

\emph{Figure 2} : Mural thickening with intramural axial hemorrhage
involving the splenic flexure of the colon.\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Fig-2/Fig-2}

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\textbf{Hosted file}

\verb`Fig 2.docx`  available at \url{https://authorea.com/users/313565/articles/476198-tocilizumab-induced-cytomegalovirus-colitis-in-a-patient-with-covid-19}

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