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\begin{document}

\title{Acetaminophen-induced Stevens--Johnson syndrome with lethal lung injury:
A case report}



\author[1]{RYOTA NAKAMURA}%
\author[1]{Fumihiro Ochi}%
\author[1]{Toshiyuki Chisaka}%
\author[1]{Toshihiro Jogamoto}%
\author[1]{Mariko Eguchi}%
\affil[1]{Ehime University Graduate School of Medicine}%


\vspace{-1em}



  
  \date{June 07, 2024}


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\selectlanguage{english}
\begin{abstract}
Stevens--Johnson syndrome (SJS) with respiratory distress can lead to
fatal outcomes. However, there are a few reports of drug-induced lung
injury with diffuse alveolar damage caused by acetaminophen, the most
severe type. Here, we describe a fatal case of acetaminophen-induced SJS
in a child with irreversible lung lesions.%
\end{abstract}%



\sloppy


\textbf{Acetaminophen-induced Stevens--Johnson syndrome with lethal lung
injury: A case report}

Ryota Nakamura, MD\textsuperscript{1}; Fumihiro Ochi, MD,
PhD\textsuperscript{1,2}; Toshiyuki Chisaka, MD, PhD\textsuperscript{1};
Toshihiro Jogamoto, MD, PhD\textsuperscript{1}; Mariko Eguchi, MD,
PhD\textsuperscript{1}

\textsuperscript{1}Department of Pediatrics, Ehime University Graduate
School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan

\textsuperscript{2}Department of Pediatrics, Ehime Prefectural Niihama
Hospital, Hongo, Niihama, Ehime 792-0042, Japan

\textbf{Corresponding author:} Fumihiro Ochi

Postal address: Department of Pediatrics, Ehime Prefectural Niihama
Hospital, Hongo, Niihama, Ehime 792-0042, Japan

Email address: fmochi2000@yahoo.co.jp

Telephone number: +81-89-743-6161

\textbf{Co-corresponding author:} Mariko Eguchi

Postal address: Department of Pediatrics, Ehime University Graduate
School of Medicine

Shitsukawa, Toon, Ehime 791-0295, Japan

Email address: maeguchi@m.ehime-u.ac.jp

Telephone number: +81-89-960-5320

\textbf{DISCLOSURE STATEMENT}

The authors declare no conflicts of interest.

\textbf{ETHICS APPROVAL STATEMENT}

The authors are accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved. All procedures performed in
studies involving human participants were in accordance with the ethical
standards of the institutional and Declaration (as revised in 2013).
Written informed consent was obtained from the patient.

\textbf{KEY CLINICAL MESSAGE}

There are cases of acetaminophen-induced SJS in which lung injury
progresses rapidly and irreversibly, leading to fatal outcomes.

\textbf{ABSTRACT}

Stevens--Johnson syndrome (SJS) with respiratory distress can lead to
fatal outcomes. However, there are a few reports of drug-induced lung
injury with diffuse alveolar damage caused by acetaminophen, the most
severe type. Here, we describe a fatal case of acetaminophen-induced SJS
in a child with irreversible lung lesions.



\textbf{INTRODUCTION}

Stevens--Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are
serious systemic diseases with erythema multiforme of the skin and
mucosa and are characterized by a polymorphous vesicular and bullous
eruption with fever triggered by drug administration or
infection\textsuperscript{1}. SJS causes complications in many organs,
such as the liver, kidneys, and lungs, leading to treatment
difficulties\textsuperscript{1,2}. In particular, patients with
respiratory distress can require extended treatment or have fatal
outcomes\textsuperscript{2}. However, there are few reports of SJS with
lung lesions in children.

Acetaminophen is an antipyretic commonly used to relieve fever and
associated discomfort in children. A prospective cohort study suggested
that as many as 95\% of children were exposed to acetaminophen by the
age of 9 months\textsuperscript{3}. Although not adequately recognized,
acetaminophen is a drug that can easily cause SJS. Acetaminophen was
reported as one of the top five most frequently administered drugs
associated with SJS/TEN in Japan and the United
States\textsuperscript{4,5}. According to a recent review of cases of
SJS/TEN and SJS/TEN overlap suspected to be associated with
acetaminophen, 77.8\% received supportive and symptomatic care. Systemic
corticosteroids and intravenous immunoglobulin were administered to
69.4\% and 44.4\% of patients, respectively. The prognosis of these
patients was not poor, as all patients survived, although long-term
sequelae were available in only 13.9\%\textsuperscript{6}.

Herein, we describe a fatal case of acetaminophen-induced SJS in a child
with irreversible lung lesions.

\textbf{CASE REPORT}

A 6-year-old boy with fever was suspected of having \emph{Mycoplasma
pneumoniae} infection and was prescribed acetaminophen and
clarithromycin in the clinic 7 days before admission. He had no previous
medical or family history. In addition, there was no history of drug
allergy or exposure to suspected drugs before disease onset. At night,
erythema multiform appeared on the patient's face and trunk. Three days
before admission, he was diagnosed with SJS at a general hospital based
on skin findings. Although he was administered prednisolone (2.0
mg/kg/day), his erythema gradually expanded and developed dyspnea. The
patient was transferred to our hospital for further intensive care.

Upon admission, his vital signs were as follows: body temperature, 37.3
\selectlanguage{ngerman}°C; blood pressure, 86/52 mmHg; heart rate, 86 beats/min; respiratory
rate, 36 breaths/min; and oxygen saturation, 90\% with
O\textsubscript{2} at 8 L/min via an oxygen mask with a reservoir bag.
Retractions appeared immediately below the neck and under the breast.
Subcutaneous emphysema was observed in the cervical and supraclavicular
fossae. Chest examination revealed coarse crackles, decreased breathing
sounds, and bilateral expiratory wheezing. No hyperemia or erosion was
found in the conjunctiva of the eyeball, bloody scabs were found on the
lips, and no redness or erosion was found in the oral cavity. The body
surface area of blisters or erosions was less than 10\%, and that of
erythema was 25\% (\textbf{Fig. 1A} ). Laboratory examination further
revealed the following findings: white blood cell, 5,800 /\selectlanguage{greek}µ\selectlanguage{english}L
(neutrophils 69.6\%, lymphocytes 19.3\%, and eosinophils 0\%); red blood
cells, 482\selectlanguage{ngerman}×10\textsuperscript{4} /\selectlanguage{greek}µ\selectlanguage{english}L; hemoglobin 13.2 g/dL; platelet,
35.2\selectlanguage{ngerman}×10\textsuperscript{4} /\selectlanguage{greek}µ\selectlanguage{english}L; total-bilirubin, 7.0 mg/dL; aspartate
aminotransferase, 304 U/L; alanine aminotransferase, 372 U/L; lactate
dehydrogenase, 614 U/L; ferritin, 615 ng/mL; soluble interleukin-2
receptor, 779 U/mL; Krebs von den Lungen 6 (KL-6), 953 U/mL; and
antinuclear antibody titer, 1:40. The drug lymphocyte stimulation test
(DLST) was positive for acetaminophen (H-thymidine, 905 cpm; stimulation
index, 274\%) and negative for clarithromycin (H-thymidine, 226 cpm;
stimulation index, 114\%). \begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}Moreover, the loop-mediated isothermal
amplification (LAMP) assay for \emph{M. pneumoniae} was negative, and
there was no increase in antibody titer. Chest radiography revealed
subcutaneous emphysema, bilateral mediastinal emphysema, and decreased
permeability in the bilateral middle and lower lung fields (\textbf{Fig.
1B} ).

Based on these findings, we diagnosed severe SJS due to acetaminophen
with mediastinal/subcutaneous emphysema. We also administered high-dose
immunoglobulin (0.5 g/kg/day, for 5 days) and methylprednisolone pulse
therapies (1 g/day for 3 days/week), resulting in an improvement in the
eruption. However, his respiratory failure persisted, and the chest CT
showed a ground-glass-like shadow (\textbf{Fig. 1C} ). We diagnosed
acute respiratory distress syndrome (ARDS), and cyclosporine (3.0
mg/kg/day) was added to the treatment regimen on day 9. Artificial
respiration with tracheal intubation was initiated on day 13. Persistent
progressive respiratory failure, veno-venous extracorporeal membrane
oxygenation, and plasmapheresis were introduced on day 44. On day 51,
left hemopneumothorax developed, and thoracoscopic hemostasis and lung
biopsy were performed. Pathological examination of the pulmonary tissue
revealed the diffuse alveolar injury, confirming the diagnosis of
diffuse alveolar damage (DAD) (\textbf{Fig. 1D} ). Although we performed
various multidisciplinary treatments, his lung lesions showed poor
treatment responsiveness, and he died on day 90.

\textbf{DISCUSSION}

SJS/TEN is caused by a type IV-c delayed hypersensitivity reaction to
infections or drugs\textsuperscript{7}. SJS/TEN is defined as a
widespread vesiculobullous rash with epidermal sloughing, necrosis, and
mucous membrane involvement, typically in the eyes, oral cavity, and
skin. SJS/TEN were classified according to the extent of the detached
and detachable epidermis, expressed as a percentage of the total body
surface area (TBSA) (SJS: \textless{}10\% TBSA; SJS-TEN overlap:
10--30\% TBSA; and TEN: \textgreater{}30\% TBSA)\textsuperscript{8}.
Mucosal and eye inflammation are present in 90\% and 60\% of cases,
respectively. Severe cases culminate in corneal scarring, respiratory
distress syndrome, pneumonia, and respiratory
failure\textsuperscript{9}.

According to the United States Food and Drug Administration Adverse
Event Reporting System database, the top five most frequently
administered drugs associated with SJS/TEN are valdecoxib, lamotrigine,
phenytoin, acetaminophen, and furosemide\textsuperscript{5}. In
contrast, allopurinol, loxoprofen, acetaminophen, carbamazepine, and
lamotrigine are the frequent causes of SJS in Japan\textsuperscript{4}.

In our case, we initially suspected that it was caused by an infectious
agent, such as mycoplasma, or was induced by drugs such as acetaminophen
and clarithromycin. However, the LAMP assay of \emph{M. pneumoniae} was
negative, and the DLST against acetaminophen was positive; thus,
acetaminophen was considered to be the cause.

SJS caused by acetaminophen tended to be more predominant in the younger
groups aged 0--19 years old, with a median time to onset of 2
days\textsuperscript{4}. The time to onset was only 1 day in the present
case, which is consistent with a previous report. However, the present
case was followed by a more rapid and serious course than that of the
previous reports on acetaminophen-related SJS. Therefore, early and
aggressive therapeutic interventions are required, as in this case.

A recent review of cases of SJS/TEN associated with acetaminophen
summarized a total of 36 patients described in 29 previously published
reports\textsuperscript{6}. TEN, SJS, and SJS/TEN overlap were diagnosed
in 24 (66.7\%), 10 (27.8\%), and 2 (5.6\%) patients, respectively. Of
these 36 patients, 28 (77.8\%) received supportive and symptomatic care.
Systemic corticosteroids were administered to 25 patients (69.4\%), and
intravenous immunoglobulin was administered to 16 patients (44.4\%). The
prognosis of these patients was not poor, as all patients survived
according to the reports, although long-term sequelae were available
only in five patients (13.9\%)\textsuperscript{6}.

Reports in the United States have shown that the SJS mortality rate was
4.8\% in adults\textsuperscript{10} and 0\% in
children\textsuperscript{11}. Predictors of mortality risk in pediatric
SJS include the presence of renal failure, sepsis, epilepsy, bacterial
infections, and malignant diseases\textsuperscript{11}. According to
this criterion, the mortality risk was not high in our case. Although
the patient's skin and mucosal lesions improved with immunosuppressive
therapy, the lung injury did not improve despite intensive treatment.
Accordingly, we considered that the severity of lung injury might also
affect the prognosis of SJS, with a profound impact on mortality.
Additional clinical studies with larger numbers of patients are needed
to determine whether a pulmonary impairment is a risk factor.

In adults, 37.8\% of patients with SJS/TEN may require mechanical
ventilation in the acute phase\textsuperscript{12}. Pathologically,
epidermal sloughing of the bronchial epithelium was observed by
fiberoptic bronchoscopy in 27\% of SJS/TEN cases, and those with
positive pathological findings showed early pulmonary complications in
the acute phase, with a high rate of fatal outcome\textsuperscript{13}.
Although fiberoptic bronchoscopy could not be performed in our case,
pathological findings of pulmonary tissue in the lung biopsy revealed
DAD. There are few reports of drug-induced lung injury caused by
acetaminophen and even fewer reports of DAD caused by acetaminophen. DAD
is the most severe type of drug-induced lung injury, requiring high-dose
steroid therapy early after diagnosis\textsuperscript{14}. However,
there are many unresponsive cases to treatment, and the prognosis of
patients with DAD is poor. Our patient was diagnosed with DAD based on
CT and pathological findings and was refractory to various drug
treatments.

In conclusion, there are cases of acetaminophen-induced SJS in which
lung injury progresses rapidly and irreversibly, leading to fatal
outcomes.

\textbf{AUTHORSHIP CONTRIBUTION}

R. N. participated in the management of the patient, obtained clinical
data, drafted the initial manuscript, and revised the manuscript. F. O.
helped in conceptualizing and drafting the manuscript. T. C., T. J., and
M. E. critically reviewed and revised the manuscript. All authors have
read and approved the final manuscript.

\textbf{REFERENCES}

1. Hasegawa A, Abe R. Recent advances in managing and understanding
Stevens-Johnson syndrome and toxic epidermal necrolysis.
\emph{F1000Res}2020; 9: F1000 Faculty Rev-612.

2. Shanbhag SS, Chodosh J, Fathy C, et al. Multidisciplinary care in
Stevens-Johnson syndrome. \emph{Ther Adv Chronic Dis} 2020; DOI:
10.1177/2040622319894469.

3. Morton SMB, Atatoa Carr PE, Grant CC, et al. Cohort profile: growing
up in New Zealand. \emph{Int J Epidemiol.} 2013; 42(1): 65-75.
DOI:10.1093/ije/dyr206

4. Abe J, Umetsu R, Mataki K, et al. Analysis of Stevens-Johnson
syndrome and toxic epidermal necrolysis using the Japanese Adverse Drug
Event Report database. \emph{J Pharm Health} 2016; 2: 14.

5. Abe J, Mataki K, Umetsu R, et al. Stevens-Johnson syndrome and toxic
epidermal necrolysis: The Food and Drug Administration adverse event
reporting system, 2004--2013. \emph{Allergol Int.} 2015; 64: 277--9.

6. Milosavljevi\selectlanguage{polish}ć \selectlanguage{english}MN, Pej\selectlanguage{polish}č\selectlanguage{english}i\selectlanguage{polish}ć \selectlanguage{english}AV, Milosavljevi\selectlanguage{polish}ć \selectlanguage{english}JZ. A review of published
cases of Stevens-Johnson syndrome and toxic epidermal necrolysis
associated with the use of acetaminophen. \emph{Cutan Ocul
Toxicol.}2021; 40(3): 280-292. DOI: 10.1080/15569527.2021.1942896.

7. Lee\begin{CJK}{UTF8}{gbsn}　\end{CJK}\selectlanguage{english}QU. Hypersensitivity to antipyretics: pathogenesis, diagnosis,
and management.

\emph{Hong Kong Med J.} 2017 ;23(4):395-403. DOI: 10.12809/hkmj166186.

8. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of
cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and
erythema multiforme. \emph{Arch Dermatol.} 1993; 129: 92-96.

9. Borchers AT, Lee JL, Naguwa SM, et al. Stevens-Johnson syndrome and
toxic epidermal necrolysis. \emph{Autoimmun Rev.} 2008; 7: 598-605.

10. Hsu DY, Brieva J, Silverberg NB, et al. Morbidity and Mortality of
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in United States
Adults. \emph{J Invest Dermatol} 2016; 136: 1387-97.

11. Hsu DY, Brieva J, Silverberg NB, et al. Pediatric Stevens-Johnson
syndrome, and toxic epidermal necrolysis in the United States. \emph{J
Am Acad Dermatol} 2017; 76: 811-7. e4.

12. Beck A, Cooney R, Gamelli RL, et al. Predicting mechanical
ventilation and mortality: early and late indicators in Steven-Johnson
syndrome and toxic epidermal necrolysis. \emph{J Burn Care Res} 2016;
37: e47-e55.

13. Lebargy F, Wolkenstein P, Gisselbrecht M, et al. Pulmonary
complications in toxic epidermal necrolysis: a prospective clinical
study. \emph{Intensive Care Med} 1997; 23: 1237-1244.

14. Kubo K, Azuma A, Kanazawa M, et al. Consensus statement for the
diagnosis and treatment of drug-induced lung injuries. \emph{Respir
Investig} . 2013; 51: 260-277.

\textbf{FIGURE LEGEND}

Figure 1. (A) Skin findings upon admission. Dark red erythema was
observed from both lower eyelids to the neck, and erosion with bloody
scabs was observed on the lips. Blisters and erythema with crusting were
scattered from the neck to the upper navel. (B) Chest X-ray showed
subcutaneous emphysema, bilateral mediastinal emphysema, and decreased
permeability in the bilateral middle and lower lung fields. (C) Chest CT
showed ground glass-like shadows in both lung fields, and the area only
below the pleura was spared. (D) Pathological findings of lung tissue
(hematoxylin-eosin staining, \selectlanguage{ngerman}×400). Collagen fibers proliferate in
highly thickened vesicles, fibroblast proliferation in the airspace,
extensive granulomatous scarring with interstitial fibrosis, and
post-bleeding changes were observed.\selectlanguage{english}
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