\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{A case of COVID-19 masquerading as presumed Trastuzamab induced
subclinical cardiotoxicity}



\author[1]{Amy Maree Clark}%
\author[1]{Liza Thomas}%
\author[2]{Anita Boyd}%
\affil[1]{The University of Sydney Faculty of Medicine and Health}%
\affil[2]{Westmead Private Hospital}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
A 48-year-old woman was diagnosed with right-sided Grade 2 invasive
breast carcinoma. Prior to initiation of chemotherapy, transthoracic
echocardiogram (TTE) demonstrated normal systolic function with left
ventricular ejection fraction (LVEF) 64\% and global longitudinal strain
(GLS) 21\%. Following adjuvant chemotherapy with four cycles of
anthracycline, twelve cycles of Paclitaxel, and two cycles of
Trastuzamab chemotherapies, TTE demonstrated reduction in LVEF to 56\%
and GLS of -18\% (14\% relative reduction compared to baseline). Further
investigation revealed recent symptomatic COVID-19 infection coinciding
with functional impairment and decision was made to continue Trastuzumab
therapy without cardioprotective agents. Subsequent TTE demonstrated
improved systolic function, indicating the importance of taking history
of significant viral infections during chemotherapy standard of care.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

The ongoing Coronavirus disease 2019 (COVID-19) global pandemic has
resulted in over six million deaths worldwide.\textsuperscript{1} In
addition to primary acute respiratory symptoms, COVID-19 has been
demonstrated to have multisystem
involvement.\textsuperscript{2}Cardiovascular system manifestations
include thrombosis, acute coronary syndrome, arrhythmias, myocarditis,
and evidence of subclinical myocardial dysfunction, with increased risk
of mortality observed following myocardial injury.\textsuperscript{3}
Cardiac resonance imaging (CMR) provides the highest diagnostic accuracy
for acute myocarditis, however speckle tracking echocardiography (STE)
derived strain analysis offers a more pragmatic alternative. STE
examination has demonstrated sub-clinical myocardial involvement of
patients with only mild/ moderate COVID-19 symptoms.\textsuperscript{4}

\textbf{Case Report:}

A 48-year-old woman was diagnosed with right sided Grade 2 invasive
breast carcinoma (no special type (NST), oestrogen receptor/
progesterone receptor (ER/PR) negative and human epidermal growth factor
receptor 2 (HER2) positive), in April 2021. She had received adjuvant
chemotherapy with four cycles of anthracycline, twelve cycles of
Paclitaxel, and two cycles of Trastuzamab chemotherapies, to be followed
by bilateral mastectomy and adjuvant radiation and on-going Trastuzumab.
Prior to the initiation of chemotherapy, a transthoracic echocardiogram
(TTE) demonstrated normal left ventricular (LV) systolic function, with
LV ejection fraction (LVEF) of 64\% with a global longitudinal strain
(GLS) of -21\% (Figure 1, A). She had routine cardiac surveillance as is
clinical practice at our centre with a repeat TTE (August 2021) after
anthracycline therapy and prior to commencement of Trastuzamab (Figure
1, B). This demonstrated LVEF of 59\% with GLS of -19\% (9\% relative
reduction in GLS compared to baseline). As is standard of care, a TTE is
performed at 3 monthly intervals after commencement of Trastuzumab. Her
next routine 3 monthly TTE (November 2021) demonstrated a further
reduction in LVEF to 56\% and GLS of -18\% (14\% relative reduction
compared to baseline (TTE measurements were repeated by an experienced
and independent sonographer and verified by the consulting
cardiologist), triggering review by a cardiologist (Figure 1, C). There
was no significant change in blood pressure, heart rate, LV volumes, LA
volume or E/e' over this period.

At cardiologist review, the patient reported no cardiovascular symptoms,
in particular no dyspnoea, fatigue, or pedal oedema. She mentioned that
she had COVID-19 infection (although having been vaccinated prior (x 2
doses) in late September 2021 and had mild -- moderate symptoms of
dyspnoea and fatigue for approximately three weeks, though she denied
any chest pain or palpitations., she did not have any blood tests (for
cardiac biomarkers), require hospitalisation, and did not receive
specific antiviral therapy. On examination, she had a heart rate of 60
bpm, was normotensive with a blood pressure of 124/78 mmHg, with normal
heart sounds, no murmurs or rubs. Electrocardiogram showed sinus rhythm
with normal axis, and non-specific T wave inversion in leads III and
aVF.

The patient had an asymptomatic drop in LVEF of 9\% and 14\% relative
reduction in LV GLS compared with her baseline study whilst on
Trastuzumab, and therefore met criteria for commencement of
cardioprotective therapy (angiotensin-converting enzyme inhibitor +/-
Beta blocker therapy). However, given the history of COVID infection in
the interim with resolution of symptoms subsequently, a decision was
made to continue with Trastuzumab therapy with TTE surveillance after
further two cycles of Trastuzamab, without initiation of
cardioprotective therapy.

At follow up, the patient reported no further symptoms and did not have
dyspnoea or fatigue. Her TTE in January 2022 demonstrated improved LVEF
of 59\% and GLS of -19\% (Figure 1, D). She has subsequently continued
Trastuzumab with standard clinical surveillance, without commencement of
cardioprotective agents.

\textbf{Discussion:}

Myocardial dysfunction and heart failure secondary to cancer therapy
(cardiotoxicity) is an important cause of patient morbidity and
mortality in cancer survivors.\textsuperscript{5} Anthracycline-induced
cardiotoxicity has a cumulative, dose dependant, and non-reversible
presentation with cellular apoptosis. Myocardial dysfunction and/ or
heart failure can be delayed for a number of years due to compensatory
mechanisms.\textsuperscript{5} The highly effective treatment of
monoclonal antibody Trastuzumab for HER2 positive breast cancer
demonstrates partially reversible acute myocardial dysfunction with
immediate improvements in left ventricular ejection fraction (LVEF)
following Trastuzumab cessation, however with an ongoing subclinical
reduction of LV GLS.\textsuperscript{5, 6}

Prevention and management of cancer therapy induced cardiotoxicity is
important for long term patient outcomes and requires screening, risk
stratification, and ongoing monitoring as
strategies.\textsuperscript{7}Baseline cardiac assessment should include
medical history, electrocardiography, cardiac imaging with determination
of systolic, diastolic, and subclinical dysfunction with strain
analysis, and/ or troponin assessment.\textsuperscript{5} Cardiac
imaging is typically performed with TTE with evaluation of LVEF and GLS,
where a reduction in LVEF by \textgreater{}10\% to below 55\% or a GLS
relative reduction of 11-15\% from baseline are indicative of
cardiotoxicity.\textsuperscript{7} Follow-up cardiac imaging is
recommended at the completion of anthracycline therapy, and then every 3
months during Trastuzumab treatment.\textsuperscript{5} Minimising risk
of cardiotoxicity includes anthracycline dose modification and
sequential administration of anthracyclines and
Trastuzumab.\textsuperscript{7}

Acute myocardial dysfunction has also been described in patients
following infection with COVID-19, with reduction in GLS an independent
indicator of COVID-19 related death.\textsuperscript{4, 8} Impairment
has been demonstrated in both LVEF and GLS in an apical sparing pattern
typical of a reverse-stress/ Takotsubo
cardiomyopathy.\textsuperscript{9} The prevalence of myocardial
dysfunction following COVID-19 infection in the wider population remains
unknown, however there is 20 -- 30\% reported myocardial involvement in
hospitalised patients.\textsuperscript{10} Conflicting reports have been
presented regarding improvement of LVEF and GLS following COVID-19
recovery, which may indicate a need for ongoing monitoring and/or
administration of cardioprotective agents.\textsuperscript{8, 9}

Myocardial dysfunction is a recognised sequela of both cancer therapy
related cardiac dysfunction and COVID-19 infection. In this case our
patient demonstrated myocardial dysfunction during Trastuzamab therapy,
albeit following a COVID-19 infection. Recovery was observed in the
course of ongoing Trastuzamab treatment without administration of
cardioprotective agents, indicating a probable subclinical myocarditis
following COVID-19 infection. This indicates the importance of taking a
history of prior COVID-19 infection, or indeed other significant viral
infections that may alter LV function, in patients undergoing
chemotherapy, with ongoing TTE surveillance.

Word count 1106

\textbf{References:}

1. Center JHUoMCR. COVID-19 dashboard by the Center for Systems Science
and Engineering (CSSE) at Johns Hopkins University (JHU) 2022 {[}June
21, 2022{]}. Available from: https://coronavirus.jhu.edu.

2. Shao H, Ghaly HSA, Varamini1 P. Coronavirus disease 2019: An overview
of the complications and management. ITPS. 2021;4(1):1-28.

3. Giustino G, Pinney SP, Lala A, Reddy VY, Johnston-Cox HA, Mechanick
JI, et al. Coronavirus and cardiovascular disease, myocardial injury,
and arrhythmia: JACC~focus~seminar. J Am Coll Cardiol.
2020;76(17):2011-23.

4. St\selectlanguage{ngerman}öbe S, Richter S, Seige M, Stehr S, Laufs U, Hagendorff A.
Echocardiographic characteristics of patients with SARS-CoV-2 infection.
Clin Res Cardiol. 2020;109(12):1549-66.

5. Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, et
al. Expert consensus for multimodality imaging evaluation of adult
patients during and after cancer therapy: a report from the American
Society of Echocardiography and the European Association of
Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging.
2014;15(10):1063-93.

6. Stoodley P, Tanous D, Richards D, Meikle S, Clarke J, Hui R, et al.
Trastuzumab-induced cardiotoxicity: The role of two-dimensional
myocardial strain imaging in diagnosis and management. Echocardiography.
2012;29(6):E137-E40.

7. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano
R, Galderisi M, et al. 2016 ESC Position Paper on cancer treatments and
cardiovascular toxicity developed under the auspices of the ESC
Committee for Practice Guidelines: The Task Force for cancer treatments
and cardiovascular toxicity of the European Society of Cardiology (ESC).
Eur J Heart Fail. 2017;19(1):9-42.

8. Lassen MCH, Skaarup KG, Lind JN, Alhakak AS, Sengeløv M, Nielsen AB,
et al. Echocardiographic abnormalities and predictors of mortality in
hospitalized COVID\selectlanguage{english}-19 patients: the ECHOVID\selectlanguage{english}-19 study. ESC Heart Fail.
2020;7(6):4189-97.

9. Chao CJ, DeValeria PA, Sen A, Lee H, Pedrotty DM, Patel B, et al.
Reversible cardiac dysfunction in severe COVID\selectlanguage{english}-19 infection, mechanisms
and case report. Echocardiography (Mount Kisco, NY). 2020;37(9):1465-9.

10. Haryalchi K, Olangian\selectlanguage{english}-Tehrani S, Asgari Galebin SM, Mansour\selectlanguage{english}-Ghanaie
M. The importance of myocarditis in Covid\selectlanguage{english}-19. Health Sci Rep.
2022;5(1):e488-n/a.

\textbf{Hosted file}

\verb`Case report figures.docx`  available at \url{https://authorea.com/users/500005/articles/580907-a-case-of-covid-19-masquerading-as-presumed-trastuzamab-induced-subclinical-cardiotoxicity}

\selectlanguage{english}
\FloatBarrier
\end{document}

