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\begin{document}

\title{Bilateral lung transplantation for rapidly progressive interstitial lung
disease associated with clinically amyopathic dermatomyositis followed
by posterior reversible encephalopathy}



\author[1]{qiao gu}%
\author[1]{mengyuan diao}%
\author[1]{wei hu}%
\author[2]{man huang}%
\author[1]{zhu ying}%
\affil[1]{Hangzhou First People's Hospital}%
\affil[2]{Zhejiang University School of Medicine Second Affiliated Hospital}%


\vspace{-1em}



  
  \date{May 16, 2024}


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\selectlanguage{english}
\begin{abstract}
A 36-year-old woman with RP-ILD and lung fibrosis secondary to CADM who
was treated for 31 days with venovenous extracorporeal membrane
oxygenation (V-V ECMO) as a rescue utility and bridge to bilateral lung
transplantation.After surgery She fell into a coma due to posterior
reversible encephalopathy syndrome (PRES).%
\end{abstract}%



\sloppy


\textbf{1 Introduction}

Clinically amyopathic dermatomyositis (CADM) is defined as the presence
of typical cutaneous manifestations of dermatomyositis (DM) along with
absent or minimal muscle weakness in DM{[}1{]}. Population-based data
suggest that CADM occurs in approximately 20\% of all adult DM
cases{[}2{]}, and the incidence of CADM is estimated to be 2.08 per 1
million persons{[}3{]}. Patients with CADM have an increased risk of
interstitial lung disease (ILD), and especially severe cases are
complicated by life-threatening rapid progressive ILD (RP-ILD){[}4{]},
emphasizing the necessity and significance of early recognition and
management of the disease. ILD more frequently occurs in patients with
CADM and positive anti-melanoma differentiation-associated gene 5
(anti-MDA5) antibody, and these patients are more likely to progress to
RP-ILD and refractory acute respiratory failure and often have a poorer
prognosis than those with negative anti-MDA5 antibody{[}5{]}.

For RP-ILD patients with critical hypoxemia or respiratory acidosis
despite conventional therapies, particularly that accompanied by other
respiratory complications, venovenous extracorporeal membrane
oxygenation (VV-ECMO) may be a perfect choice. The treatment is
sometimes a bridge to recovery, but limited options exist for CADM
patients with refractory hypoxemia who fail to wean from ECMO{[}6{]}.
However, with no lung transplant consideration, using ECMO in such cases
has been felt to be ``bridge to nowhere''{[}7{]} due to the limited
treatment response and overall options. The immunosuppressants used
after transplants inevitably introduce complications; posterior
reversible encephalopathy syndrome (PRES) is a common complication that
manifests as various neurological symptoms{[}8{]}. Tacrolimus, an
important immunosuppressive drug for organ transplantation patients, is
a major risk factor for PRES{[}9{]}.

Here, we present the case of a female with CADM complicated by severe
RP-ILD managed with VV-ECMO. Due to refractory respiratory failure,
bilateral lung transplantation was eventually performed, but the patient
ultimately developed posterior reversible encephalopathy syndrome.

\textbf{2 Case Report}

A 36-year-old previously healthy female visited a local hospital
presenting with cough and fever. She had undergone induction of labor
for a stillborn fetus 2 months earlier and subsequently noticed erythema
on her face, accompanied by cough, but no phlegm. Allergic disease was
considered, and antiallergic treatment was given, but her symptoms did
not improve. Her condition was then managed with oral prednisolone for
10 days, and the facial erythema and cough disappeared. The patient's
clinical course is shown in Figure 1.

On admission, the patient showed no cutaneous and muscular
manifestations. Computed tomography (CT) of the chest showed bilateral
ground glass opacities (Figure 2A). Anti-MDA5 antibody was not measured
because there was no consideration of CAMD and ILD. After receiving
antibiotic therapy for 12 days, the patient's status did not improve and
worsened in later stages; the clinical manifestations were shortness of
breath and dyspnea. CT of the chest showed bilateral pulmonary patchy
infiltrates, and interstitial pneumonia was considered (Figure 2B).
Shortly thereafter, the patient presented with acute hypoxemic
respiratory failure (PaO2/FiO2: 68 mmHg), and intubation and mechanical
ventilation were subsequently performed 3 days after admission. Using
next-generation sequencing (NGS) of the bronchoalveolar lavage fluid
(BLF) sample and cultured isolates from the patients, \emph{Pseudomonas
aeruginosa, Stenotrophomonas maltophilia} and\emph{Pneumocystis
jirovecii} were found. Sulfamethoxazole (SMZ) was added for the
treatment of pneumocystis pneumonia (PCP) caused by \emph{Pneumocystis
jirovecii} . The patient' s respiratory status continued to deteriorate,
and mediastinal emphysema and subcutaneous emphysema developed 4 days
after invasive ventilation.

VV-ECMO via the right internal jugular and right femoral vein
cannulation was initiated on ventilator day 4, and she was then referred
to the ECMO center. Laboratory investigations revealed that serum
anti-Ro-52 was positive via ELISA, and serum ferritin (SF) was
significantly higher without elevated serum muscle enzymes. NGS of BLF
also showed \emph{Pneumocystis jirovecii} and \emph{Acinetobacter
baumannii} ; thus, antibiotic therapy and SMZ were continued.
Considering the COVID-19 epidemic in China, the patient received a
nucleic acid test for COVID-19, but the result was negative. CT of the
chest showed bilateral pulmonary extensive infiltrates and lobular
interstitium thickness, and pulmonary fibrosis was considered (Figure
2C). CT of the head was normal (Figure 3A), and the patient was
conscious after withdrawal of the sedative. Although lung protective
ventilation, recruitment maneuver and prone position ventilation were
implemented, she did not tolerate attempts to wean from ECMO within 28
days of ECMO. She required continuous sedation and analgesia because of
patient-ventilator asynchrony.

Therefore, a decision was made to place the patient on the lung
transplant waitlist, and she was subsequently transferred to the
transplantation center for lung transplant evaluation. Anti-MDA5
antibody was tested by ELISA, and the result was positive. Based on
these findings, the patient was diagnosed with CADM and ILD. At 31 days
of ECMO, the patient underwent a successful sequential double lung
transplant and received tacrolimus as an immunosuppressive regimen after
the transplant. Her explant pathology showed extensive consolidation of
lung tissue and pulmonary interstitial fibrosis (Figure 4). The
patient's respiratory status gradually improved, and CT of the chest
showed bilateral pulmonary scattered infiltration (Figure 2D), which was
improved compared with previous imageological diagnosis. ECMO was weaned
successfully 3 days after transplant, and the patient's oxygenation
status did not deteriorate with ventilator support. The patient's state
of consciousness deteriorated, and she presented with coma. Head CT
showed bilateral parieto-occipital low-density lesions, which were
considered to be due to PRES (Figure 3B). Since the condition was
considered to be related to immunosuppressive agents, tacrolimus was
suspended for 1 day, and the dosage was gradually reduced to 0.5 mg/day,
after which the patient's consciousness returned. Unfortunately, the
patient developed a disturbance of consciousness once more after
hemodynamic instability, which may be related to implant infection;
consciousness did not return after active treatment. After 14 days of
lung transplant, the patient declined further treatment for financial
reasons and was discharged.

\textbf{3 Discussion}

CADM typically presents with characteristic cutaneous manifestations of
classic dermatomyositis without muscle involvement; almost all patients
with CADM present at least one characteristic skin lesion{[}1{]}. In our
present case, because of the absence of traditional muscle findings and
atypical skin lesions after hospitalization, the diagnosis of CADM can
be a challenge. In this case, facial erythema was noticed after
induction of labor for a stillborn fetus, and the symptom vanished after
oral prednisone administration. Meanwhile, the patient presented with no
myalgia, and her creatine kinase level was normal during subsequent
hospitalization.

Patients with CADM are often combined with ILD. It is known that RP-ILD
is more common in the CADM subset. The patient initially presented with
interstitial pneumonia and then developed refractory respiratory failure
very quickly. Despite maximum respiratory support and the corresponding
treatment, the patient's status was aggravated continuously with a
life-threatening hypoxemia. The mechanism of onset of RP-ILD is
ill-informed; reports have suggested that the condition is highly
correlated with CADM and MDA5 antibody positivity{[}10{]}. High SF has
been shown to be another important indicator of poor prognosis of RP-ILD
in CADM. The SF levels are reported to be higher with positive anti-MDA5
antibody than with negative anti-MDA5 antibody and higher in
nonsurvivors than in survivors{[}11{]}. Furthermore, anti-Ro-52 is also
a risk factor for ILD in CAMD{[}12{]}. The patient experienced
pneumomediastinum and pneumothorax with the development of CADM and
RP-ILD. Pneumomediastinum has also been reported to be more common in
CAMD patients with positive anti-MDA5 antibody than in patients with
negative anti-MDA5 antibody{[}13{]}. These reports indicate that our
patient had a high anti-MDA5 antibody titer, a high anti-Ro-52 antibody
titer, a high ferritin level, and the complications of pneumomediastinum
and pneumothorax, all of which indicated the diagnosis of clinically
amyopathic dermatomyositis and showed a poor prognosis.

ECMO provides temporary cardiopulmonary support in patients with severe
but potentially reversible cardiac and/or respiratory failure
unresponsive to maximal conventional management. While it does not
reverse the underlying lung disease, it acts as a bridge to recovery by
offering patients more time for treatment therapies to take effect. It
can also reduce ventilator-induced lung injury and oxygen toxicity
caused by mechanical ventilation, which can add further damage to
already damaged lungs. Last, chronic systemic disease or refractory
end-stage pulmonary disease, which was resistant to conventional
therapy, was considered a contraindication to ECMO in the past.
Pulmonary interstitial fibrosis associated with RP-ILD in CAMD is a rare
indication for lung transplantation. However, ECMO can provide
additional time for these patients who are being considered for lung
transplant, and there are some reports of lung transplantation for
RP-ILD{[}14{]}. In the course of this patient, lung protective
ventilation strategy, lung recruitment maneuver and prone position were
all performed to support ECMO, but pulmonary interstitial fibrosis
gradually occurred, and the patient did not tolerate attempts to wean
from ECMO. Our case indicated that ECMO has shown to be a valid rescue
therapy in acute refractory respiratory failure secondary to RP-ILD and
made further diagnosis and treatment possible. Although this patient did
not completely recover her health at the end, ECMO added time to make an
accurate diagnosis and offered the patient the opportunity for a lung
transplantation.

Tacrolimus, a calcineurin inhibitor, is an effective immunosuppressive
agent for the prevention of organ transplant rejection. However, PRES is
a rare and serious neurologic complication of tacrolimus. Temporary
cessation of tacrolimus and gradual reduction of the dosage may be
effective strategies for managing PRES. However, these managements
include risks of reducing immunosuppression, thereby leading to acute
rejection. In our case, the strategy is to suspend tacrolimus for one
day and gradually reduce the dosage to 0.5 mg/day. The patient's
neurological symptoms improved, and signs of acute rejection were
absent.

In conclusion, when patients experience RP-ILD for no apparent reason,
CADM should be considered, especially in patients who are positive for
anti-MDA5 and anti-Ro-52 antibody and have a high ferritin level and
complications of pneumomediastinum and pneumothorax. ECMO should be
considered as a supportive therapy and initiated early in patients in
acute respiratory failure secondary to RP-ILD since it could provide a
true opportunity to improve survival for such a rare disease and its
potentially deadly complications. In cases of refractory respiratory
failure and pulmonary fibrosis, lung transplant may be an option. PRES
is not very common, but more attention should be paid to the patients
who are using immunosuppression drugs. Our findings suggest that
temporary cessation of tacrolimus and dosage reduction may be effective
management strategies for PRES. The results of our case are frustrating,
but more experience and further studies are needed to evaluate the true
value of this method.

\textbf{Conflict Of Interest}

None declared.

\textbf{Author Contributions}

Qiao,Mengyuan and Ying conceived and planned the case report. Qiao and
Mengyuan carried out the clinical procedure for this case report.
Qiao,Mengyuan and Ying took the lead in writing the manuscript and
preparing the first and final draft. All authors provided critical
feedback and helped shape the research, analysis and manuscript.

\textbf{Consent Statement}

Patient provided written consent for publication of this case report. It
is available upon request.

\textbf{Funding}

There are no funders to report for this submission.

\textbf{References:}

{[}1{]} Concha J, Tarazi M, Kushner CJ, Gaffney RG, Werth VP. The
diagnosis and classification of amyopathic dermatomyositis: a historical
review and assessment of existing criteria. Br J Dermatol 2019; 180:
1001-1008.

{[}2{]} Ortiz-Santamaria V, Babot A, Ferrer C. Anti-MDA5-positive
dermatomyositis: an emerging entity with a variable clinical
presentation. SCAND J RHEUMATOL 2017; 46: 509-511.

{[}3{]} Bendewald MJ, Wetter DA, Li X, Davis MD. Incidence of
dermatomyositis and clinically amyopathic dermatomyositis: a
population-based study in Olmsted County, Minnesota. Arch Dermatol 2010;
146: 26-30.

{[}4{]} Mukae H, Ishimoto H, Sakamoto N, Hara S, Kakugawa T, Nakayama S
et al.. Clinical differences between interstitial lung disease
associated with clinically amyopathic dermatomyositis and classic
dermatomyositis. CHEST 2009; 136: 1341-1347.

{[}5{]} Motegi SI, Sekiguchi A, Toki S, Kishi C, Endo Y, Yasuda M et
al.. Clinical features and poor prognostic factors of anti-melanoma
differentiation-associated gene 5 antibody-positive dermatomyositis with
rapid progressive interstitial lung disease. EUR J DERMATOL 2019; 29:
511-517.

{[}6{]} Lee YJ, Kim DJ, Kim JS, Lee JH, Lee CT, Jheon S et al..
Experience and results with VV-ECMO for severe acute respiratory
failure: weaning versus nonweaning. ASAIO J 2015; 61: 184-189.

{[}7{]} Abrams DC, Prager K, Blinderman CD, Burkart KM, Brodie D.
Ethical dilemmas encountered with the use of extracorporeal membrane
oxygenation in adults. CHEST 2014; 145: 876-882.

{[}8{]} Chen S, Hu J, Xu L, Brandon D, Yu J, Zhang J. Posterior
Reversible Encephalopathy Syndrome After Transplantation: a Review. MOL
NEUROBIOL 2016; 53: 6897-6909.

{[}9{]} Dhar R. Neurologic Complications of Transplantation. NEUROCRIT
CARE 2018; 28: 4-11.

{[}10{]} Li J, Liu Y, Li Y, Li F, Wang K, Pan W et al.. Associations
between anti-melanoma differentiation-associated gene 5 antibody and
demographics, clinical characteristics and laboratory results of
patients with dermatomyositis: A systematic meta-analysis. J DERMATOL
2018; 45: 46-52.

{[}11{]} Gono T, Sato S, Kawaguchi Y, Kuwana M, Hanaoka M, Katsumata Y
et al.. Anti-MDA5 antibody, ferritin and IL-18 are useful for the
evaluation of response to treatment in interstitial lung disease with
anti-MDA5 antibody-positive dermatomyositis. Rheumatology (Oxford) 2012;
51: 1563-1570.

{[}12{]} Gan YZ, Zhang LH, Ma L, Sun F, Li YH, An Y et al.. Risk factors
of interstitial lung diseases in clinically amyopathic dermatomyositis.
Chin Med J (Engl) 2020: 644-649.

{[}13{]} Bakhshaee M, Jokar MH, Mirfeizi Z, Atabati E, Tarighat S.
Subcutaneous Emphysema, Pneumomediastinum and Pneumothorax in a Patient
with Dermatomyositis. Iran J Otorhinolaryngol 2017; 29: 113-116.

{[}14{]} Said SA, Okamoto T, Sakanoue I, Unai S, Budev M, Akindipe O et
al.. Lung Transplant for Patient with Idiopathic Pneumonia Syndrome. ANN
THORAC SURG 2020.

\textbf{Figure legends}

Figure 1. Clinical course of the patient. A, Stage 1: From pathogeny to
intubation. B, Stage 2: ECMO stage. C, Stage 3: Transplant and
posttransplant stages.

Figure 2. Computed tomography (CT) image of the chest. A, CT of the
chest shows bilateral ground glass opacities 9 days before intubation.
B, CT of the chest shows bilateral pulmonary patchy infiltrates, which
was considered as interstitial pneumonia 3 days before intubation. C. CT
of the chest shows bilateral pulmonary extensive infiltrates and lobular
interstitium thickness, which was considered as pulmonary fibrosis 23
days after ECMO. D, CT of the chest showed bilateral pulmonary scattered
infiltration 3 days after lung transplantation.

Figure 3. Computed tomography (CT) image of the head. A, CT of the head
is normal at the ECMO stage. B, CT of the head shows bilateral
parieto-occipital low-density lesions at day 3 after transplantation.

Figure 4. Microscopic examination of the explanted lung
(hematoxylin-eosin stain, \selectlanguage{ngerman}× 50) shows extensive consolidation of lung
tissue and pulmonary interstitial fibrosis.\selectlanguage{english}
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