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

Abstract

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%.

Trimethoprim-sulfamethoxazole-induced lung injury: a case report

“…TMP-SMX-induced lung injury has been reported to manifest as hypersensitivity pneumonitis, acute fibrinous OP, and interstitial lung disease ( 2 - 4 ). Cases with similar clinical presentation and course to our patient, in particular the phenotype of TMP-SMX-induced ARDS associated with extensive pneumomediastinum and pneumothorax, have been reported ( 5 - 9 , 34 ). Majority of these cases have early air leaks even prior to intubation, as in our case, which appears to be a notable feature of patients with TMP-SMX-associated ARDS ( 9 ).…”

“…Cases with similar clinical presentation and course to our patient, in particular the phenotype of TMP-SMX-induced ARDS associated with extensive pneumomediastinum and pneumothorax, have been reported ( 5 - 9 , 34 ). Majority of these cases have early air leaks even prior to intubation, as in our case, which appears to be a notable feature of patients with TMP-SMX-associated ARDS ( 9 ). In the largest case series to date, Miller et al reported 19 previously healthy children and young adults who developed severe acute respiratory failure associated with TMP-SMX ( 9 ).…”

“…Majority of these cases have early air leaks even prior to intubation, as in our case, which appears to be a notable feature of patients with TMP-SMX-associated ARDS ( 9 ). In the largest case series to date, Miller et al reported 19 previously healthy children and young adults who developed severe acute respiratory failure associated with TMP-SMX ( 9 ). While patients were slightly older (median age 17 years old), the timeline of exposure, symptoms, and illness course bore striking similarity to our patient ( 6 , 9 ).…”

“…In the largest case series to date, Miller et al reported 19 previously healthy children and young adults who developed severe acute respiratory failure associated with TMP-SMX ( 9 ). While patients were slightly older (median age 17 years old), the timeline of exposure, symptoms, and illness course bore striking similarity to our patient ( 6 , 9 ). In Miller et al ’s case series, 84% of patients required extracorporeal membrane oxygenation (ECMO), 6 of 19 patients underwent lung or heart/lung transplant and a third of the survivors had mild restrictive lung disease on pulmonary function tests performed at a mean of 16 months post-discharge ( 9 ).…”

“…Well recognized side effects include cytopenia and severe cutaneous adverse reactions (SCARs) such as Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) ( 1 ). TMP-SMX-induced lung toxicity in adults and children is rare, with reports of hypersensitivity pneumonitis, acute fibrinous organizing pneumonia (OP), interstitial lung disease and acute respiratory distress syndrome ( 2 - 9 ).…”