ST合剤（TMP-SMX）って、特にニューモシスチス肺炎の予防・治療で大活躍ですよね。ただ、皮疹・血球減少・肝障害などの副作用もそれなりに経験する薬だと思います。

ST合剤による薬剤性肺障害でARDSをきたすこともあり、その定義が提案されています。

Definition and Clinical Evaluation for Trimethoprim-Sulfamethoxazole Severe Acute Respiratory Failure

Miller J, Khan H, Mino-Kenudson M, Taylor M, Shih A, Goldman J. published online ahead of print, 2023 Jul 14. Crit Care Med.

Objectives: Trimethoprim-sulfamethoxazole (TMP-SMX)-associated severe acute respiratory distress syndrome (ARDS) has gone underrecognized. We propose the first disease definition and clinical evaluation for a novel adverse drug reaction (ADR) based on a series of recently identified rare cases of life-threatening ADRs.

Design: A retrospective study was conducted. All medical records were evaluated. Available pathology samples were sent to Massachusetts General for clinical consultation. Blood samples from surviving patients were obtained and human leukocyte antigen (HLA) analysis was performed by the Children’s Mercy Hospital Genomic Center and Vanderbilt University Medical Center.

Setting: U.S. ICUs, 1996-2021.

Patients: Nineteen young patients (10-37) were identified. Patients were previously healthy, with no preexisting pulmonary disease, no other cause for respiratory failure, and no chronic history of smoking/vaping.

Interventions: None.

Measurements and main results: Through our retrospective analysis, we analyzed clinical characteristics associated with TMP-SMX. Pathology samples were reviewed, and HLA analysis was performed on available samples by the study team or as standard of care at treatment hospitals in some cases. In 19 critically ill patients, we identified a pattern of severe respiratory failure requiring ICU admission, mechanical ventilation, and frequent extracorporeal membrane oxygenation use. We describe the first three-part clinical diagnosis and evaluation strategy: 1) Clinical definition: Unexplained severe respiratory failure in a patient receiving greater than or equal to 6 days of TMP-SMX at treatment dose (not prophylaxis). TMP-SMX ARDS is a diagnosis of exclusion. 2) Genetic association: One hundred percent of currently available TMP-SMX respiratory failure patient genomic data, (n = 11) have been carriers of both HLA-B*07:02 and HLA-C*07:02 alleles. HLA allele evaluation could be considered in patients with suspected TMP-SMX respiratory failure. 3) Lung pathology: A unique pulmonary pathologic pattern of lung injury termed diffuse alveolar injury with delayed epithelialization has been observed in these cases. In suspected cases, surgical lung biopsy early in the clinical course could be considered.

Conclusions: TMP-SMX is a commonly prescribed antibiotic. However, we find it imperative to share this relatively rare but life-threatening condition with clinicians as the mortality rate approaches 40%.

PMID: 37449964

25年間で19例なので、稀とはいえ1〜2年に1例とそれなりに多いですね。死亡率は他のARDSと同様で40%に達するようです。合剤なのでTMPとSMXのどちらが原因なのか、あるいは両者が合わさることで起こるのかなど、まだ分からないことは多いです。

結局のところ除外診断ですが、他疾患の除外というのは「悪魔の存在証明」と同じく難しい。症例によっては外科的肺生検（あるいはクライオ肺生検）を検討しても良いかもしれません。病理的にはdiffuse alveolar injury with delayed epithelialization（DAIDE）というパターンが特徴のようです（DAIDEについてはPMID: 28696778）。

遺伝的には、解析症例の全員にHLA-B*07:02とHLA-C*07:02がみられています。日本人では、アレル頻度はそれぞれ5.6%と12.7%で、これらのアレルを持つA*24:02–C*07:02–B*07:02–DRB1*01:01が3番目に多い（3.7%）ハプロタイプでした（PMID: 25789826）。ちなみにHLA-B*13:01はアジア人のST合剤の重症薬疹（severe cutaneous adverse reaction; SCAR）に関連しているようです（PMID: 32791162）。

よく使う薬だからこそ比較的まれな副作用も頭に入れておきたいですね。