Sudden Conjunctivitis, Lymphopenia, and Rash Combined With Hemodynamic Changes (SCoRCH) After Trimethoprim-Sulfamethoxazole Use

Key Points

Question

What are the mucocutaneous findings and clinical features of an increasingly recognized hypersensitivity reaction associated with hemodynamic changes after trimethoprim-sulfamethoxazole (TMP-SMX) use?

Findings

This case series study of 7 patients describes the sudden onset of generalized sunburn-like erythema, conjunctivitis, and facial and acral edema, hemodynamic changes, and end-organ dysfunction after recent exposure to TMP-SMX.

Meaning

Given that the mucocutaneous and clinical features of TMP-SMX hypersensitivity reaction are distinct from those of other drug reactions and are potentially life-threatening, we propose the syndrome be identified as SCoRCH to refer to sudden conjunctivitis, lymphopenia, and rash combined with hemodynamic changes.

Abstract

Importance

Trimethoprim-sulfamethoxazole (TMP-SMX) hypersensitivity reaction, ranging from circulatory shock to aseptic meningitis and respiratory failure, is a potentially life-threatening condition with dermatologic relevance.

Objective

To describe the mucocutaneous findings and clinical features of TMP-SMX hypersensitivity reaction.

Design, Setting, and Participants

This was a retrospective case series study of 7 patients who developed a characteristic rash, hemodynamic changes, and end-organ dysfunction after treatment with TMP-SMX at a large university hospital system during January 2013 to March 2022.

Exposures

Treatment with TMP-SMX within 2 weeks of the reaction.

Main Outcome and Measures

Descriptions of the condition, including the demographic information of the affected population, the reaction timeline, and mucocutaneous and clinical features.

Results

The cohort comprised 7 patients (median [range] age, 20 [15-66] years; 4 female and 3 male). The most common mucocutaneous findings were generalized sunburn-like erythema without scale, conjunctivitis, and mild facial and acral edema. Three patients had previous exposure to TMP-SMX and developed symptoms in 1 day or less, while those without prior exposure presented from 4 to 11 days after drug initiation. Among the 7 patients, 6 had fever, 7 had hypotension, and 7 had tachycardia. All patients had lymphopenia and evidence of end-organ dysfunction with either kidney or liver involvement. Median (range) time to resolution was 72 (48-96) hours.

Conclusions and Relevance

This retrospective case series indicates that SCoRCH (sudden conjunctivitis, lymphopenia, and rash combined with hemodynamic changes) should be considered in the differential diagnosis of patients presenting with acute generalized sunburn-like erythema, conjunctivitis, systemic symptoms, and hemodynamic changes in the setting of recent TMP-SMX use.

This retrospective case series study of 7 patients describes the characteristic symptoms of a potentially life-threatening hypersensitivity reaction to trimethoprim-sulfamethoxazole SCoRCH, or sudden conjunctivitis, lymphopenia, and rash combined with hemodynamic changes.

Introduction

Hypersensitivity reactions (HSRs) with hemodynamic changes have been described after administration of trimethoprim-sulfamethoxazole (TMP-SMX).¹Various names exist for this reaction, including TMP-SMX induced circulatory shock, and atypical, unusual, anaphylactic-like, or severe shock-like reaction to TMP-SMX.^1,2 This systemic reaction was initially described in patients with HIV.However, recent reports have demonstrated that this reaction to TMP-SMX can occur in patients who are not infected with HIV.^1,2 Although this reaction appears to be a distinct entity from other drug HSRs, the dermatologic features are not well described in the literature. This study assesses a cohort that developed rash, hemodynamic changes, and end-organ dysfunction after exposure to TMP-SMX and describes the mucocutaneous findings and other clinical features.

Methods

This retrospective case series study was reviewed and approved by the institutional review board of the University of Texas Southwestern Medical Center (No. STU 032016-024), which granted a waiver of informed consent. The reporting guideline for case series was followed.

The inpatient dermatology registry for University of Texas Southwestern Medical Center−affiliated hospitals was used to identify patients from January 2013 to March 2022. The registry includes medical record numbers, diagnoses, and case descriptions for all inpatient dermatology consultations. Patients with recent TMP-SMX exposure who developed cutaneous findings consistent with previous reports of this HSR as well as hemodynamic changes or the presence of fever, tachycardia, tachypnea, and/or end-organ dysfunction were included. Patients likely to have other HSRs, such as a drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) were excluded. When clinically indicated, infectious causes were ruled out by a negative result to a blood culture and/or viral testing.

Results

The case series cohort comprised 7 patients, (median [range] age, 20 (15-66) years; 4 female and 3 male; race and ethnicity will not be reported owing to small sample size and no consent for most patients), all of whom were adolescents or young adults except 1 (Table 1). Indications for TMP-SMX treatment included infection (5 of 7 patients), hidradenitis suppurativa (1 of 7), and Pneumocystis jiroveci pneumonia prophylaxis (1 of 7); mucocutaneous features included generalized sunburn-like erythema without scale (7 of 7), conjunctivitis (4 of 7), facial edema (4 of 7), and acral edema or erythema (3 of 7); and none had mucosal erosions (Figure). Other symptoms included pruritus (3 of 7), headache (4 of 7), sore throat (3 of 7), nausea and/or vomiting (4 of 7), and abdominal pain (2 of 7). Two patients had either mild respiratory symptoms or abnormal findings on chest radiography. Table 1 includes additional findings of test for infectious causes. A skin biopsy specimen from 1 patient demonstrated sparse superficial perivascular dermatitis with rare eosinophils. Six patients received topical corticosteroids; none received systemic steroids. One patient required vasopressors and 2 patients were admitted to the intensive care unit. The median (range) time to resolution after discontinuing TMP-SMX use was 72 (48-96) hours.

Table 1. Characteristics of 7 Patients With SCoRCH, Disease Management, and Outcomes.

Patients characteristic				Mucocutaneous findings	Clinical characteristics					Acute kidney injury	Abnormal transaminases	Management and outcomes			TTR, h
Age, decade	Indication for TMP-SMX	TTO	Prior exposure		Temp, °C	BP, min	HR, max	Absolute lymphocyte count (109/L)	Absolute neutrophil count (109/L)			Infectious disease cultures/tests	Differential diagnosis	Treatment
60s	Urinary tract infection	1 d	Yes, 14-d course	Generalized erythema, conjunctivitis	37.4	82/51	122	0.57	6.3	Yes	No	Blood, urine, influenza, RSV, COVID-19	VFS, AGEP, DRESS, SSSS, TSS	Topical corticosteroid	48
20s	Hidradenitis suppurativa	9 d	No	Generalized erythema, facial edema, lymphadenopathy	39.6	70/38	140	0.57	1.4	No	Yes	Blood, urine, fungal, influenza, AFB, CSF	DRESS, viral exanthem	Supportive care	72
20s	Otitis media	<2 h	Yes, 7-d course	Generalized erythema, conjunctivitis, facial edema, acral edema, lymphadenopathy	39.4	84/37	138	0.31	2.5	Yes	No	Blood, urine	SJS-TEN, DRESS, Kawasaki disease, scarlet fever	Topical corticosteroid	96
20s	PJP prophylaxis	11 d	No	Generalized erythema, coalescing erythematous maculopapular rash, conjunctivitis, facial edema, lymphadenopathy	39.5	86/47	124	0.24	1.9	No	Yes	Blood, urine, fungal, influenza, CMV, EBV, fungal antigens, AFB	SJS-TEN, DRESS, viral exanthem, Kawasaki disease	Topical corticosteroid, required vasopressor	96
10s	Paronychia	4 d	No	Coalescing erythematous maculopapular rash, facial edema, feet erythema	39.4	105/46	116	0.75	0.5	No	Yes	Blood, CMV, EBV, COVID-19	DRESS, viral exanthem	Topical corticosteroid	48
10s	Postsurgery infection	7 d	No	Generalized erythema, lymphadenopathy	40.5	109/52	157	0.36	0.6	No	Yes	Blood	DRESS, TSS	Topical corticosteroid	72
10s	Postsurgery infection	<8 h	Yes, 10-d course	Generalized erythema, conjunctivitis, acral edema, erythema	39.3	91/50	118	0.23	12.8	Yes	Yes	Blood, urine, respiratory viral panel, COVID-19	AGEP, TSS	Topical corticosteroid	72

Abbreviations: AFB, acid fast bacilli; AGEP, acute generalized exanthematous pustulosis; BP, blood pressure (measured as millimeters of mercury); CMV, cytomegalovirus; CSF, cerebrospinal fluid; DRESS, drug reaction with eosinophilia and systemic symptoms; EBV, Epstein-Barr virus; HR, heart rate (measured as beats per minute); PJP, Pneumocystis jiroveci pneumonia; RSV, respiratory syncytial virus; SCoRCH, sudden conjunctivitis, lymphopenia, and rash combined with hemodynamic changes; SJS-TEN, Stevens-Johnson syndrome and toxic epidermal necrolysis; SSSS, staphylococcal scalded skin syndrome; temp, maximum temperature; TMP-SMX, trimethoprim-sulfamethoxazole; TSS, toxic shock syndrome; TTO, time to onset; TTR, time to resolution; VFS, vancomycin flushing syndrome.

Figure. Dermatologic Features of Sudden Conjunctivitis, Lymphopenia, and Rash Combined With Hemodynamic Changes (SCoRCH) in Patients of Differing Skin Pigmentation .

A, Conjunctivitis without substantial erythema or involvement of palpebral conjunctiva in a Black adolescent male patient with SCoRCH. B, Conjunctivitis in a White adult male patient with SCoRCH. C, Confluent, sunburn-like erythema involving the chest and abdomen without scale in the same Black patient. D, Generalized, confluent, sunburn-like erythema of head, neck, chest, and trunk without scale in the same White patient.

Discussion

Severe reactions to TMP-SMX use—many cases with almost immediate onset after re-exposure—have been characterized in the literature as fever, conjunctivitis, rash, hemodynamic changes, and systemic manifestations that ranged from aseptic meningitis to respiratory failure.^1,3,4,5 Although reports describe “a warm, erythematous rash,” mucocutaneous findings are not well-characterized.¹In the present study cohort, dermatologic features included generalized sunburn-like erythema, conjunctivitis, and mild facial and acral edema. Although nondermatological journals most commonly describe patients in shock, only 1 patient in this study cohort met shock criteria and required use of vasopressors.

The timing of 4 to 11 days in patients with no prior exposure to TMP-SMX and rapid onset after a rechallenge to TMP-SMX suggests delayed-type hypersensitivity. Although the pathophysiologic features of the reaction are not completely characterized, a previous case described an abrupt rise in interleukin-6 (IL-6) following controlled rechallenge to TMP-SMX.⁶ Given the role of IL-6 in the septic response, downstream cytokine activation may trigger endothelial barrier dysfunction and vasodilation, contributing to the hypotension, generalized erythema, conjunctivitis, and facial and acral edema seen in this reaction. Elevation of IL-6 has also been described in TMP-SMX−induced aseptic meningitis, with reports of rash, hypotension, and similar time to onset and resolution as the reaction presented in the present study.³ Additionally, a similar constellation of mucocutaneous symptoms and rapid onset after rechallenge have been reported in a patient with TMP-SMX−induced respiratory failure and in several patients who had prominent respiratory symptoms that were described as “TMP-SMX anaphylactoid reactions.”^4,5 Although none of the patients in our study cohort experienced respiratory failure, 2 patients had either pulmonary symptoms or abnormal findings on chest radiography. Likewise, although 4 patients reported experiencing headache, none were diagnosed with aseptic meningitis—only 1 patient had symptoms severe enough to warrant lumbar puncture. As such, the overlap of symptoms and rapid onset following re-exposure suggests that these 3 TMP-SMX HSRs (TMP-SMX−induced circulatory shock, aseptic meningitis, respiratory failure) may be on a spectrum with shared pathophysiology, risk factors, and severity.

Although the present study described TMP-SMX−associated cases, the literature has reports of other drugs that caused similar reactions. Notably, a report of sulfasalazine-induced HSR described a case with similar cutaneous and systemic features, characterized by rapid onset of symptoms after rechallenge.⁷ Abacavir HSR and this novel TMP-SMX reaction share many clinical features (Table 2). Furthermore, there are cases of HSR after abacavir, azathioprine, and ibuprofen use presenting with abrupt fever, hemodynamic changes, diffuse erythema, and conjunctivitis within hours of rechallenge.^8,9,10 Although 75% of the azathioprine-related HSRs represent drug-induced neutrophilic dermatoses, patients with presentations similar to this reaction have been described.^10,12Additionally, reports of ibuprofen-induced aseptic meningitis contain descriptions of similar mucocutaneous findings and hypotension on presentation, further supporting the possibility that these HSRs may be part of a spectrum.¹¹ To characterize this novel HSR through the constellation of dermatologic and clinical features, we propose the acronym SCoRCH, an abbreviation for sudden conjunctivitis, lymphopenia, and rash combined with hemodynamic changes.

Table 2. Clinical Reaction Pattern of Cutaneous Adverse Drug Reactions.

Reaction and TTO	Mucocutaneous findings	Associated signs and symptoms	Hemodynamic changes	Hematologic abnormalities	End-organ dysfunction	TTR	Additional notes
SCoRCH 1,2,3,5,8,9,10,11
4-11 d; <1 d if prior exposure	Generalized sunburn-like erythema, mild facial and acral edema, conjunctivitis	Fever, sore throat, headache, GI symptoms, respiratory symptoms	Yes	Lymphopenia	Liver, kidney, lung	48-96 h	Other causative agents may be abacavir, azathioprine, ibuprofen; spectrum may also include aseptic meningitis, ARDS. Cases in adolescents, patients with autoimmune/HIV+
Abacavir hypersensitivity 8
8 d-6 wk; <1 d if rechallenge	In 60% of cases. “maculopapular rash,” urticaria, diffuse erythema, or targetoid lesions	Fever, sore throat, GI symptoms, myalgia, respiratory symptoms	Yes	Leukopenia, anemia, thrombocytopenia	Liver, kidney, lung	48-96 h	Associated with HLA-B*57:01. Rechallenge may result in rash, respiratory failure, circulatory shock
Azathioprine hypersensitivity 10,12
1-4 wk; <1 d if rechallenge	Neutrophilic dermatoses in 75% cases; nonspecific rash with urticaria, purpura, or diffuse erythema	Fever, GI symptoms, myalgia	Yes	Leukocytosis	Liver, kidney	5 d	Rechallenge can result in shock and respiratory failure. Cases reported in patients with autoimmune disease, IBD
Anaphylaxis
Min-h	Erythema, urticaria, angioedema	Respiratory distress, abdominal upset, anxiety, pruritus	Yes	None	Lung	24-48 h	None
Non-IgE−mediated urticaria or VFS
Min-h	Generalized erythema or flushing primarily of upper body, urticaria	Pruritus, chest tightness. No fever	Rare	None	None	Min-h	Infusion-related. Coadministration of other direct mast cell degranulators increases risk. Improves with infusion rate decrease and prophylaxis
DRESS 13
2-8 wk	Morbilliform rash, erythroderma, facial edema, purpura	Fever, pruritus, lymphadenopathy	Rare	Eosinophilia >0.7 × 109/L, neutrophilia, atypical lymphocytosis	Liver, kidney, lung, heart, pancreas	Wk-mo	Higher incidence in some HLA haplotypes; chronic autoimmune sequelae
AGEP 13,14,15
1-11 d	Intertriginous erythema, nonfollicular sterile pustules, postpustular desquamation	Fever, pruritus	Rare	Neutrophilia, mild eosinophilia	Liver, kidney, lung	2 Wk	Recessively inherited mutation in IL-36RN gene; cases without pustules exist
SJS-TEN 13
4-28 d	Confluent erythema, atypical target lesions, blisters, skin detachment, Nikolsky sign, mucositis	Fever, skin pain, influenza-like symptoms	Yes	Lymphopenia, anemia	Liver, kidney, GI tract	Weeks	Higher incidence in patients with HIV+, malignant neoplasms, some HLA haplotypes; long-term sequelae

Abbreviations: AGEP, acute generalized exanthematous pustulosis; ARDS, acute respiratory distress syndrome; DRESS, drug reaction with eosinophilia and systemic symptoms; GI, gastrointestinal; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; IBD, inflammatory bowel disease; min-h, minutes to hours; SCoRCH, sudden conjunctivitis, lymphopenia, and rash combined with hemodynamic changes; SJS-TEN, Stevens-Johnson syndrome and toxic epidermal necrolysis; TTO, time to onset; TTR, time to resolution; VFS, vancomycin flushing syndrome.

When considering the clinical pattern of this reaction, SCoRCH can be differentiated from other severe drug reactions, such as anaphylaxis, non-IgE mediated urticaria or vancomycin flushing syndrome, DRESS, AGEP, and SJS-TEN, by clinical features, timing, and duration (Table 2). Notably, the sudden onset of symptoms within hours of oral rechallenge was a unique feature of this reaction that is not common in other drug reactions apart from AGEP and type 1 HSRs.¹³ Although subtle presentations of AGEP with generalized erythema, minimal pustules, and hemodynamic changes have been described, results of skin biopsies demonstrate typical features of AGEP.^14,15 Although only 1 patient in the cohort underwent a skin biopsy, the nonspecific findings on histopathologic evaluation may have helped to exclude other drug reactions. Lastly, the differential diagnosis included eruptions seen in viral infections, toxin-mediated syndromes, Kawasaki disease, and COVID-19 multiorgan inflammatory syndrome. These diagnoses were ruled out in most patients through infectious disease testing as well as rapid resolution without immunomodulatory treatment.

Limitations

Limitations of this study include its retrospective nature, limited sample size, lack of standardized testing to rule out alternative causes in all patients, and absence of data supporting the mechanism of SCoRCH. It is possible that SCoRCH includes a wider range of mucocutaneous features not described among this study cohort. Further research is needed to confirm other causative drugs and to determine whether the spectrum of the reaction may include TMP-SMX-induced aseptic meningitis and TMP-SMX-induced acute respiratory failure. Future directions include translational studies to characterize the pathophysiologic features and to identify genetic risk factors including human leukocyte antigen associations.

Conclusions

This retrospective case series examined severe HSRs to TMP-SMX with hemodynamic changes and end-organ dysfunction and described mucocutaneous findings from a dermatologic perspective. We propose the acronym SCoRCH for this syndrome. In patients presenting with acute generalized erythema, conjunctivitis, systemic symptoms, and hemodynamic changes after TMP-SMX use, clinicians should consider SCoRCH in their differential diagnosis.