\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[T2A]{fontenc}
\usepackage[ngerman,romanian,polish,english]{babel}



\usepackage{float}








\begin{document}

\title{Pneumocystis jirovecii pneumonia complicated a case of SARS-CoV-2
infection and multiple sclerosis after treatment with rituximab}



\author[1]{Mahmoud  Sadeghi Haddad Zavareh}%
\author[1]{Hamed  Mehdinezhad}%
\author[1]{Rahele  Mehraeen}%
\author[1]{Mohammad  Golparvar Azizi}%
\author[1]{Ali Tavakoli}%
\affil[1]{Babol University of Medical Science}%


\vspace{-1em}



  
  \date{June 13, 2024}


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





\selectlanguage{english}
\begin{abstract}
Immunodeficient patients are less prone to develop serious complications
of COVID-19 and cytokine storm. However, they are more likely to develop
opportunistic infections that can mimic the symptoms of the SARS-CoV-2.
we presented a 27-year-old male case of SARS-CoV-2, who was complicated
with Pneumocystis jirovecii pneumonia, following treatment with
rituximab.%
\end{abstract}%



\sloppy


\textbf{Introduction}

In December 2019, the viral infection outbreak in Wuhan, China became a
global pandemic that crossed borders and put the lives of populations in
danger, especially those with immunodeficiency (1). During these
challenging years and the management of COVID-19 disease, many questions
have arisen regarding immunomodulatory and immunosuppressive therapies,
especially, in patients with demyelinating disease (2). Given the
reduced immune responses, immunodeficient patients are less prone to
develop serious~complications of COVID-19 and cytokine storm. However,
they are more likely to develop opportunistic~infections that~can
mimic~the symptoms of SARS-CoV-2 infection (3).

Multiple sclerosis (MS), an autoimmune, demyelinating disease of the
central nervous system (CNS), is mainly linked to the reaction of CD4+ T
cells to the antigens of myelin membrane (4). Two previous randomized
clinical trials (RCTs), has demonstrated that rituximab, a monoclonal
anti-CD20 antibody, could be effective in primary progressive multiple
sclerosis (PPMS) and relapsing-remitting multiple sclerosis (RRMS) (5).
However, there are growing reports, introducing post-rituximab therapy
Pneumocystis~jirovecii~pneumonia~(PJP), in cases of systemic lupus
erythematosus, Wegener's granulomatosis, rheumatoid arthritis, lymphoma,
and humoral renal transplant rejection (6). Given the fact that
rituximab is a commonly used medication for the highly active forms of
MS, it is important to consider the possible risk of PJP in these
patients.

In the current study, we presented a case of COVID-19 infection, who was
complicated with PJP, following treatment with rituximab for RRMS.

\textbf{Case presentation}

A 27-year-old male patient with MS for the past 12 years has been
referred to our center with complaints of cough, dyspnea, body pain, and
fever, in April 2022. The patient was admitted to the hospital due to
cough with sputum, myalgia, fever, sweating, and frequent outpatient
treatment (the last appointment was about a week before hospitalization)
due to the exacerbation of previous myalgia, and the initiation of
cough, fever, and dyspnea. In June 2021, he was also hospitalized in
another center for 5 days with fever, cough, and dyspnea due to COVID-19
infection, and treated with remdesivir and glucocorticoid. Eventually,
he was this discharged, 24 hours after the termination of his fever.

He had also a previously-diagnosed RRMS for the past 12 years, which
resulted in neurological symptoms such as blurred vision, headaches and
paresthesia in the lower limbs. Due to the uncontrollable MS,
intravenous (IV) injections of rituximab (1gr per 6 month) was applied.
The last injection was in February 2022. He was also taking prednisolone
(5mg daily) for maintenance therapy and other medications such as
salmeterol plus fluticasone inhaler, montelukast, NAC, and aspirin.

On physical exam, his temperature was 38 \selectlanguage{ngerman}°C; blood pressure, 125/80
mmHg; respiratory rate, 17 breaths per min; pulse rate, 88 beats per
min; and oxygen saturation, 94\% (without any oxygen therapy). His fever
was during day, but the sweating was preferably overnight. He also had a
dyspnea that made him unable to walk (FCIII). The patient's cough
contained yellow sputum, and the body pain was responsive to analgesic.
He had symmetric chest wall movements and no crackles or wheezing was
detected. However, we could find rhonchi. There was no evidence of
organomegaly, tenderness, or rebound tenderness in the examination of
abdomen and it was not distended. In the neurological examination, no
abnormal findings were detected. His laboratory data on admission showed
an increased LDH (2061 U/L) along with increased levels of hepatic
biomarkers (Table 1). Moreover, the levels of CRP, ESR, and PCT were
higher than normal range. Transthoracic echocardiography (TTE) revealed
an increased pulmonary artery pressure (30 mmHg).

First, we were highly suspicious of infections; thus, we began empiric
treatment with ceftriaxone. However, due to persistent fever, the
suspicion of nosocomial infections, the progression of pulmonary
lesions, and reduced oxygen saturation, we began treatment with
piperacillin + tazobactam, vancomycin, and levofloxacin. Nevertheless,
patient's fever did not stop after the aforementioned empiric treatment
and his conditions got worse. Therefore, we were highly suspicious of
opportunistic infections such as Cytomegalovirus, tuberculosis (TB),
pulmonary aspergillosis, and Pneumocystis jirovecii.

We also considered the probability of infection in other sites. Thus,
echocardiography and abdominal and pelvic ultrasonography were performed
and revealed to be normal. Accordingly, bronchoalveolar lavage (BAL)
fluid was obtained through bronchoscopy and was assessed for infections.
In the case of TB, both BAL smear and RT-PCR were negative.
Aspergillosis was also excluded due to a negative level of galactomannan
in the BAL. However, RT-PCR demonstrated that COVID-19 infection was
still remained (cycle threshold of 27). Further, the cytological
assessment of BAL fluid showed no evidence of malignancy.
Pneumomediastinum and pneumothorax were also excluded on the CT scan
images. In figure 1, the patient's CT scan findings were demonstrated,
on admission day, right before bronchoscopy, discharge day, and 3 months
later.

On the 12\textsuperscript{th} day, his conditions worsened and he was
admitted to the intensive care unit, due reduced oxygen saturation
(SpO\textsubscript{2} = 88\%), and treatment was switched to linezolid
and imipenem. At this time, the result of BAL fluid, tested for
Pneumocystis jirovecii by RT-PCR, turned out to be positive. Therefore,
we started trimethoprim-sulfamethoxazole (treatment of choice for PCP)
and dexamethasone. Following the treatment, his conditions improved and
the levels of PCT and CRP decreased. He was discharged in May 2022.

\textbf{Discussion}

Respiratory viral infections can put patients in the risk of secondary
infections, especially by bacterial and fungal organisms (7). In a
previous study, about 30\% of SARS-CoV-2 infected cases were at the risk
of developing secondary pneumonia without a known reason (8). In fact,
SARS-CoV-2 infection can interfere with the immune system and its
balance; therefore, it may result in an increased risk of fungal
infections such as invasive candidiasis, pulmonary aspergillosis, and
Pneumocystis jirovecii (9). Given the fact that Pneumocystis
pneumonia~(PCP) and COVID-19 may have similar and common clinical
features such as profound hypoxemia and bilateral multifocal
infiltrates, coinfection with PJP could be missed, especially in those
with life-threatening forms of COVID-19 infection. Hence, it seems wise
to apply additional diagnostic workup for PJP in severe COVID-19
patients, especially in the presence of clinical features that support
coinfection, like cystic formations on chest CT scan and an increased
level of lactate dehydrogenase, even if there were no risk factors for
PJP (10).

It seems that immunosuppression plays an important role in the
association of COVID-19 and PCP. Although impaired immune balance may be
useful in the context of COVID-19 severity, due to the reduced immune
respond and inflammation, which are related to the severity of
manifestations, it is also a chief risk factor for the occurrence of PCP
(11). In that case, preexisting immunodeficiency (e.g. HIV- or
drug-induced) could increase the risk of COVID-19 and PJP coinfection.
Importantly, it might be observed in those who are not included in the
known risk groups, which could be a result of severe COVID-19-induced
lymphopenia or immunosuppressive therapy (12).

PJP has two morphological forms in its life cycle, including cystic and
trophic forms. It is an infection usually identified in patient with
impaired T cell immunity, particularly
CD4\textsuperscript{+}lymphopenia. Unfortunately, severe COVID-19
infection is associated with severely diminished levels of
CD4\textsuperscript{+} cells (9), which makes these patients highly
susceptible to PJP. Moreover, COVID-19 infection could result in
conditions like acute respiratory distress syndrome, which requires
immunosuppressive therapies (e.g. corticosteroids), a familiar risk
factor for developing PCP (9).

\textbf{Conclusion}

SARS-CoV-2 infection can interfere with the immune system and its
balance; therefore, it may result in an increased risk of fungal
infections such as invasive candidiasis, pulmonary aspergillosis, and
PJP. In the current study, we presented a case of COVID-19 infection,
who was complicated with PJP, following treatment with rituximab for
RRMS. We hope this article helps clinicians consider causes other than
COVID-19, especially opportunistic infections such as PJP, in patients
with respiratory symptoms and fever.

\textbf{Author contributions}

\textbf{MSHZ and HM} : treating the patient, collecting the medical
history, helped with manuscript writing and revision. \textbf{RM} :
report of CT scan images and helped with manuscript writing.\textbf{MGA}
: collecting the medical history and helped with manuscript writing and
revision. \textbf{ATP} : collecting the medical history, writing the
main part of the paper, and revising the content of manuscript.

\textbf{Acknowledgments}

We truly appreciate the patient and his family.

\textbf{Data availability statement}

The Data supporting the findings of this study are available upon
request from the corresponding author and with permission from Babol
University of Medical Sciences, Babol, Iran.

\textbf{Conflict of interest disclosure}

The authors declare no conflict of interest.

\textbf{Ethics statement}

For publication of this article, we obtained written informed consent
from the patient to release any potentially identifiable data.

\textbf{References}

1. Reder AT, Centonze D, Naylor ML, Nagpal A, Rajbhandari R, Altincatal
A, et al. COVID-19 in Patients with Multiple Sclerosis: Associations
with Disease-Modifying Therapies. CNS Drugs. 2021;35(3):317-30.

2. Paybast S, Shahrab F, Hejazi SA. Recurrence of COVID-19 in a Patient
With NMO Spectrum Disorder While Treating With Rituximab: A Case Report
and Review of the Literature. Neurologist. 2021;26(6):281-3.

3. Tehrani S, Kashefizadeh A, Ziaie S, Keyvanfar A. Case report:
Pneumonia in a patient with combined variable immunodeficiency (CVID):
COVID-19 or Pneumocystis Pneumonia? Frontiers in Medicine. 2022:353.

4. Segal BM. The Diversity of Encephalitogenic CD4+ T Cells in Multiple
Sclerosis and Its Animal Models. J Clin Med. 2019;8(1).

5. Salzer J, Svenningsson R, Alping P, Novakova L, Björck A, Fink K, et
al. Rituximab in multiple sclerosis: A retrospective observational study
on safety and efficacy. Neurology. 2016;87(20):2074-81.

6. Tsai MJ, Chou CW, Lin FC, Chang SC. Pneumocystis jiroveci pneumonia
in patients with systemic lupus erythematosus after rituximab therapy.
Lupus. 2012;21(8):914-8.

7. Schauwvlieghe A, Rijnders BJA, Philips N, Verwijs R, Vanderbeke L,
Van Tienen C, et al. Invasive aspergillosis in patients admitted to the
intensive care unit with severe influenza: a retrospective cohort study.
Lancet Respir Med. 2018;6(10):782-92.

8. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features
of patients infected with 2019 novel coronavirus in Wuhan, China.
Lancet. 2020;395(10223):497-506.

9. Jeican, II, Ini\selectlanguage{romanian}șca P, Gheban D, T\selectlanguage{polish}ă\selectlanguage{english}b\selectlanguage{polish}ă\selectlanguage{english}ran F, Alua\selectlanguage{romanian}ș M, Trombitas V, et
al. COVID-19 and Pneumocystis jirovecii Pulmonary Coinfection-The First
Case Confirmed through Autopsy. Medicina (Kaunas). 2021;57(4).

10. Menon AA, Berg DD, Brea EJ, Deutsch AJ, Kidia KK, Thurber EG, et al.
A Case of COVID-19 and Pneumocystis jirovecii Coinfection. Am J Respir
Crit Care Med. 2020;202(1):136-8.

11. Laurence J. Why Aren't People Living with HIV at Higher Risk for
Developing Severe Coronavirus Disease 2019 (COVID-19)? AIDS Patient Care
STDS. 2020;34(6):247-8.

12. Szyd\selectlanguage{polish}ł\selectlanguage{english}owicz M, Matos O. Pneumocystis pneumonia in the COVID-19
pandemic era: similarities and challenges. Trends Parasitol.
2021;37(10):859-62.

Figure 1: a) on admission day CT scan, there were multilobal bilateral
patchy consolidations, ground glass opacities and interlobular septal
thickening, with peripheral and peri-bronchovascular distribution.
``Crazy paving'' is the dominant feature at right upper lobe; b) CT scan
right before bronchoscopy showed increased consolidations, ground glass
opacities and crazy paving in the same manner at multiple lung segments;
c and d) on discharge day CT scan, there were decreased consolidations
and change to ground glass opacities and crazy paving appearance at the
same involved segments. There was also evidence of ``reverse halo'' in
several segments and progression to fibrotic changes predominantly at
lung bases, as parenchymal and sub pleural bands; e) CT scan image, 3
months after discharge.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-1/figure-1}

\end{center}
\end{figure}

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

