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Sickle Cell Acute Pain Episodes: Lessons Learned from the Prematurely Halted PECARN STArT Trial

A faces pain-assessment sheet and a prepared syringe on an overbed tray table, with an adolescent patient resting on the stretcher behind, in a pediatric emergency department

Article reviewed: Morris CR, Hatabah D, Korman R, et al. Arginine therapy for sickle cell disease acute pain episodes: the STArT randomized clinical trial. JAMA. Published online August 19, 2026
DOI: 10.1001/jama.2026.13310  |  PubMed: PMID 42616542

A child with sickle cell disease arrives in your emergency department (ED) in an acute pain episode. In one of the largest US pediatric trials of a treatment for acute sickle cell pain, how long that crisis lasted varied far more between hospitals than it did between the study drug and placebo.

The PECARN STArT trial randomized 274 children and young adults with sickle cell acute pain episodes to IV arginine or saline placebo at 10 US children’s hospitals. Arginine, which targets the nitric oxide depletion that drives vaso-occlusion, did not shorten time to crisis resolution, and the trial was halted early for futility [1]. The more useful numbers are in site-level data. Median time to crisis resolution varied by as much as 61 hours between participating hospitals, and mean total parenteral opioid by as much as 3.0 mg/kg of based on morphine-equivalent calculations [1,3]. These are observational site differences. They may reflect analgesia and opioid-discontinuation practice, patient mix, and other institutional factors that the analyses can not distinguish.

Study Design

STArT was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted (2021-2024). Patients aged 3 to 21 years with sickle cell disease who presented to the ED with acute pain requiring parenteral opioids and hospital admission were randomized within 12 hours of their first IV opioid dose. Arginine was given as a 200 mg/kg loading dose followed by 100 mg/kg every 8 hours until discharge. Of 274 patients randomized, 271 received study drug, 129 arginine and 142 placebo. The primary outcome was time to crisis resolution, the interval from first study drug delivery to the last dose of parenteral opioid, and it is the outcome the US Food and Drug Administration prefers for regulatory approval in this population [1].

Results

Median time to crisis resolution was 60.8 hours with arginine versus 65.8 hours with placebo, an absolute difference of 7.2 hours favoring arginine with a confidence interval spanning benefit in either direction (95% CI, -21.6 to 35.9 hours). Total parenteral opioid use, pain scores, and hospital length of stay were similar between groups, and the arginine effect on time to crisis resolution did not differ significantly by chronic pain status. Serious adverse events did not differ and there were no deaths [1].

Three descriptive findings arose from the collected data:

  • Site variation. Median time to crisis resolution differed by up to 61 hours across the 10 hospitals, and mean total parenteral opioid by up to 3.0 mg/kg [1,3].
  • Delay to study drug. Study drug arrived a median of 8 hours after the first ED dose of IV opioid, and only 50.4% of participants had sought care within 24 hours of pain onset [1]. In 23 of 271 treated participants the last IV opioid had already been given before study drug arrived, producing a primary outcome of zero hours.
  • Chronic pain prevalence. 41% of participants met criteria for chronic sickle cell pain, including 34% of children younger than 12 years [1]. A single triage pain score means something different in a child who already has pain 15 or more days a month.

Build an Expedited Pain Plan in the Emergency Department

It is unclear why the wide variation in time to pain crisis resolution. The study was not designed to untangle the reasons, but in theory the causes are likely multifactorial and include: patient mix, underlying chronic pain, time spent in pain before arrival, institutional practices, and individual practitioner analgesia practices. That last one is something that you can act on today.

An expedited pain plan for a sickle cell acute pain episode

Consider administering intranasal fentanyl at triage, if  IV opioids are not readily available.

The American Society of Hematology 2020 recommendation is to assess the patient and administer analgesia within 1 hour of ED arrival, with reassessment every 30 to 60 minutes. It is a strong recommendation on low-certainty evidence [8].

Two cross-sectional PECARN studies describe what meeting those targets looks like. In a PECARN Registry analysis of 9233 ED visits for uncomplicated sickle cell pain at 12 children’s hospitals, a first opioid dose within 60 minutes of arrival was associated with lower odds of hospitalization (OR 0.84; 95% CI, 0.75-0.95). That association held even when the second dose fell outside 30 minutes (OR 0.85), and with a timely first dose the odds fell stepwise as the second-dose interval shortened: 0.78 within 60 minutes, 0.70 within 45, and 0.62 within 30 (95% CI, 0.52-0.75) [9]. Separately, among 400 children at 20 academic pediatric EDs in the US and Canada, only 19% received intranasal fentanyl, and those who did had nearly ninefold higher adjusted odds of discharge from the ED (adjusted OR 8.99; 95% CI, 2.81-30.56; P < .001) [10].

Both studies are cross-sectional and neither establishes causality. Timeliness of the first dose is the more robust of the two signals, since it survived a late second dose.

Not All Pain is the Same

The STArT study enrolled acute pain episodes, defined by pain severe enough to need parenteral opioids. However, arginine specifically targets vaso-occlusion pain. The accompanying JAMA editorial argued that these are not the same thing: the term acute pain episode has become operationally synonymous with vaso-occlusive episode, yet acute pain in sickle cell disease also arises from neuropathic mechanisms, central sensitization, and musculoskeletal injury [2]. A trial that heterogeneously enrolls all of them dilutes the study population. Notably, 41% of the study participants had underlying chronic pain [1].

Can We Narrow the Patient Inclusion Criteria?

The editorial accompanying STArT argues for enrolling a more narrow subset of patients, focusing on objective markers rather than pain severity [2]:

  • Hypoxemia, worrisome for acute chest syndrome
  • Very high LDH with thrombocytopenia, reported in a small retrospective adult series as suggesting a severe vaso-occlusive subtype that prompted consideration of early intervention [6]
  • Acute kidney injury or acute liver injury, used the way organ dysfunction defines severity in sepsis trials
Trial design sidebar
Why the trial stopped early, and why that matters beyond arginine

STArT closed after 76.1% of target enrollment because conditional power for the primary outcome had fallen below 6%, even assuming the full 17-hour effect originally hypothesized. Futility stopping is not a safety signal, and it is not proof of no effect. It means the predicted chance of reaching the primary statistical result was low if enrollment continued, not zero [1].

The primary outcome measure is a possible culprit. Time to crisis resolution correlated with hospital length of stay, which can be shaped as much by institutional opioid discontinuation practice as by drug biology [1,2,7]. US stays have trended shorter over the last 25 years and are now brief: the editorial describes a contemporary median under 72 hours, and PECARN’s MAGiC trial reported a median under 56 hours [1,2,5]. A post hoc recalculation using STArT’s own variance estimates put the required sample size above 900 participants [1]. Morris et al note that phase 3 trials targeting acute sickle cell pain have so far failed to shorten either hospital length of stay or time to crisis resolution [1], despite the study drugs spanning four largely distinct mechanisms: inhaled nitric oxide in 2011 [11], IV magnesium in PECARN’s MAGiC trial in 2015[5], poloxamer 188 in 2021 [12], and rivipansel, an E-selectin antagonist, in 2023 [13]. Arginine is the fifth agent to move nothing on this family of endpoints. The authors now question the outcome measure itself.

Three levers are on the table. The first is to enroll patients with objective organ injury, where the endpoint can be adjudicated on an image or a laboratory value rather than on a clinician’s decision to stop an opioid infusion. Among 54 STArT participants who either had acute chest syndrome at presentation or developed it after randomization, mean time to crisis resolution was 108 hours with arginine versus 184 hours with placebo (29 vs 25 participants; P = 0.16; median difference 34 hours) [4]. Because acute chest syndrome status partly arose after randomization, this exploratory comparison cannot establish a treatment effect. The editorialists note that further detail from this cohort is awaited and would likely be informative [2]. The second is to change the outcome entirely. STArT captured 72-hour and 28-day ED return and rehospitalization as safety outcomes, and the editorialists argue these belong on the efficacy side, because the burden of sickle cell disease acute pain “may reside less in the duration of individual hospitalizations and more in the frequency of readmissions and ED revisits” [2]. The 28-day ED-return rates were 27.1% with arginine and 32.4% with placebo, and at a disease level return visits follow as many as 29% of initial ED encounters, with up to 28% of hospitalized children readmitted within 30 days [1]. The third lever is the design itself: the editorialists raise external control cohorts, or a crossover in which patients serve as their own controls, as ways to cut the participant numbers a conventional trial would need [2].

More From PECARN

Related papers worth a read:

Bottom Line

  • Arginine is not ready. Nothing in this STArT trial displaces supportive care, NSAIDs, and opioids for a sickle cell acute pain episode.
  • The 61-hour spread between hospitals was more than three times the trial’s originally hypothesized 17-hour treatment difference. How your department assesses and treats pain is part of what that spread reflects.
  • The American Society of Hematology recommends giving an analgesic dose within the first hour of ED arrival. Consider intranasal fentanyl at triage, while awaiting IV access.

References

  1. Morris CR, Hatabah D, Korman R, et al; Pediatric Emergency Care Applied Research Network (PECARN). Arginine therapy for sickle cell disease acute pain episodes: the STArT randomized clinical trial. JAMA. Published online August 19, 2026. PMID: 42616542. doi:10.1001/jama.2026.13310
  2. Anum SJ, Kanter J. Arginine treatment and sickle cell disease pain: a great STArT, but a hard end point. JAMA. Published online August 19, 2026. PMID: 42616535. doi:10.1001/jama.2026.14849
  3. Rees CA, Hatabah D, Korman R, et al; PECARN. Hospital variations in time-to-crisis-resolution among children and adolescents with sickle cell disease. Am J Hematol. 2026;101(1):206-212. PMID: 41190764. doi:10.1002/ajh.70129
  4. Morris CR, Ahmad F, Airewele G, et al. Sickle cell disease treatment with arginine therapy (STArT): results of a phase-3 randomized controlled trial. Blood. 2025;146(suppl 1):616. doi:10.1182/blood-2025-616
  5. Brousseau DC, Scott JP, Badaki-Makun O, et al. A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children. Blood. 2015;126(14):1651-1657. PMID: 26232172. doi:10.1182/blood-2015-05-647107
  6. Gardner K, Thein SL. Super-elevated LDH and thrombocytopenia are markers of a severe subtype of vaso-occlusive crisis in sickle cell disease. Am J Hematol. 2015;90(10):E206-E207. PMID: 26205137. doi:10.1002/ajh.24126
  7. Ataga KI. The challenge of clinical end points in sickle cell disease. Blood. 2023;142(24):2047-2054. PMID: 37890140. doi:10.1182/blood.2023021220
  8. Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4(12):2656-2701. PMID: 32559294. doi:10.1182/bloodadvances.2020001851
  9. Gwarzo I, Coleman KD, McKinley K, et al. Opioid timeliness in the emergency department and hospitalizations for acute sickle cell pain. JAMA Pediatr. 2025;179(11):1194-1202. PMID: 40892426. doi:10.1001/jamapediatrics.2025.2967
  10. Rees CA, Brousseau DC, Ahmad FA, et al; SCD Arginine Study Group and PECARN. Intranasal fentanyl and discharge from the emergency department among children with sickle cell disease and vaso-occlusive pain: a multicenter pediatric emergency medicine perspective. Am J Hematol. 2023;98(4):620-627. PMID: 36606705. doi:10.1002/ajh.26837
  11. Gladwin MT, Kato GJ, Weiner D, et al; DeNOVO Investigators. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA. 2011;305(9):893-902. PMID: 21364138. doi:10.1001/jama.2011.235
  12. Casella JF, Barton BA, Kanter J, et al. Effect of poloxamer 188 vs placebo on painful vaso-occlusive episodes in children and adults with sickle cell disease: a randomized clinical trial. JAMA. 2021;325(15):1513-1523. PMID: 33877274. doi:10.1001/jama.2021.3414
  13. Dampier CD, Telen MJ, Wun T, et al; RESET Investigators. A randomized clinical trial of the efficacy and safety of rivipansel for sickle cell vaso-occlusive crisis. Blood. 2023;141(2):168-179. PMID: 35981565. doi:10.1182/blood.2022015797
By |2026-08-28T00:00:21-07:00Aug 24, 2026|Heme-Oncology, Pediatrics, Tox & Medications|
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SAEM Clinical Images Series: Wilma, Take a Look at This!

A 2-year, 11-month-old female with a history of constipation was brought to the ED by her mother for abdominal pain. The mother noticed that the patient’s abdomen had been enlarging for months. When they visited the pediatrician several months ago, the pediatrician also noticed a mildly enlarged abdomen but the patient was asymptomatic at that time. She was well during the interval until more recently, the patient began to complain of persistent abdominal pain and would point to the epigastric area. The patient had two episodes of unprovoked, non-bloody, non-bilious vomiting the morning prior to the ED visit. The patient had been tolerating oral intake well, passing adequate urine, having normal bowel movements, and behaving at baseline. No associated fever, diarrhea, bloody stool, dysuria, hematuria, or weight loss.

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kidney

Vitals: Temp 97.9 °F (36.6 °C); BP 103/68; Pulse 121; RR 26; SpO2 99% on room air

Constitutional: Active, well-developed, and in no distress.

HEENT: Normocephalic and atraumatic. No scleral icterus. TMs intact, no erythema. No rhinorrhea, no erythema. Moist mucous membranes, oropharynx is clear, no exudates or erythema.

Cardiovascular: Normal rate, regular rhythm and normal heart sounds.

Pulmonary: Breath sounds normal. No wheezing, no stridor, no decreased breath sounds. Normal effort, no acute respiratory distress.

Abdomen: Protuberant, distended abdomen with mild generalized tenderness to palpation. Rigid mass palpated in the upper right quadrant. Normal bowel sounds are heard.

Genitourinary: Normal anatomy. No hernias visualized, no erythema.

Skin: No jaundice or rashes visualized.

Neurological: Awake and alert. No focal deficits present.

CBC: No leukocytosis, leukopenia, anemia, or thrombocytopenia.

CMP: Electrolytes, kidney, and liver function tests were within normal limits.

The most common pediatric renal malignancy is a Wilms tumor, also known as nephroblastoma. It is an embryonal tumor due to disrupted nephrogenesis. It affects approximately 1 in 10,000 children with the median age of onset being 3.5 years (1). The most common chief complaint is abdominal pain, as in this case.

Here a large homogenous mass initially appears to be projecting from the liver, but it can also be seen protruding out of the right kidney. Pediatric abdominal organs commonly overlap so it is essential to note the origination of a mass, primarily for surgical planning. If ultrasound imaging is equivocal, CT is the next best step in differentiating the mass origination. Here, a 12 cm x 9.5 cm x 9 cm mass was noted to originate from the right kidney. If the mass becomes big enough, patients can present with vomiting due to the direct compression of the alimentary tract, such as in this case. Other presenting signs and symptoms may be fever, hypertension, anemia, hematuria, or dysuria (2).

In the US, the National Wilms Tumor Study Group recommends primary nephrectomy followed by a chemotherapy regimen that is tailored to the individual patient and tumor staging. With modern multidisciplinary management, curative therapy is achievable in approximately 90% of affected patients (2). This patient had a successful nephrectomy performed by general surgery and initiated chemotherapy on the medical floor. The patient was eventually discharged home with pediatric oncology follow-up.

Take-Home Points

  • Think of pediatric malignancy if the patient presents with chronic abdominal distention and pain.
  • Pediatric abdominal structures commonly overlap. Knowing the origination of an abdominal mass is essential for surgical planning. If ultrasound is equivocal, CT imaging is the next best step.
  • The definitive management of a Wilms tumor is a multidisciplinary approach, with primary nephrectomy followed by a tailored chemotherapy regimen as the gold-standard treatment in the US.

  1. Spreafico F, Fernandez CV, Brok J, Nakata K, Vujanic G, Geller JI, Gessler M, Maschietto M, Behjati S, Polanco A, Paintsil V, Luna-Fineman S, Pritchard-Jones K. Wilms tumour. Nat Rev Dis Primers. 2021 Oct 14;7(1):75. doi: 10.1038/s41572-021-00308-8. PMID: 34650095.
  2. Sonn G, Shortliffe LM. Management of Wilms tumor: current standard of care. Nat Clin Pract Urol. 2008 Oct;5(10):551-60. doi: 10.1038/ncpuro1218. PMID: 18836464.
  3. Leslie SW, Sajjad H, Murphy PB. Wilms Tumor. 2023 May 30. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 28723033.

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Copyright

Images and cases from the Society of Academic Emergency Medicine (SAEM) Clinical Images Exhibit at the 2023 SAEM Annual Meeting | Copyrighted by SAEM 2023 – all rights reserved. View other cases from this Clinical Image Series on ALiEM.

By |2024-10-28T09:46:11-07:00Oct 28, 2024|Heme-Oncology, Pediatrics, Renal, SAEM Clinical Images|
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SAEM Clinical Images Series: A Blistery Mystery

blister

A 76-year-old female presented with a lingering cough and an oral lesion to the left lower cheek. She reported ten days of improving flu-like symptoms but had a persistent cough and nasal congestion. On the day of presentation, she developed a painful, intermittently bleeding “blood blister” to the left lower cheek that had increased in size, as well as new red spots on her arms and legs. She reported no recent trauma or history of similar lesions in the past.

Vitals: 98.3°F; HR 85; BP 178/89; RR 16; SpO2 98% on RA

HENT: Blood-filled pocket to the left lower vestibule

Skin: Diffuse petechial rash to extremities

CBC: Hb 13.6, Plt 6, WBC 10.3

PT: 12.2

INR: 1.05

PTT: 33

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder caused by autoantibodies against platelet antigens. It is thought to be due to IgG directed against platelet membrane glycoprotein GPIIb/IIIa, leading to platelet destruction. Common inciting events include viral infections, autoimmune diseases, or immunodeficiency syndromes [1]. Patients typically present with bleeding or nonspecific symptoms such as fatigue or generalized weakness. The severity of bleeding can range from petechiae, purpura, and epistaxis, to (very rarely) life-threatening hemorrhage. It is important to perform a thorough skin and oral exam to evaluate for petechial rashes or mucosal bleeding. Initial diagnostics include a CBC which will show isolated thrombocytopenia, as well as hemolysis labs to exclude alternative etiologies.

Patients with life-threatening bleeding should be treated emergently with platelet transfusions, IVIG, and steroids. In all other cases, management decisions should be made in conjunction with Hematology. In general, those with mild/moderate bleeding and platelets <20,000/μL should be treated with a steroid course, with IVIG or platelet transfusions in special circumstances only [3]. Patients who receive any treatment or have diagnostic uncertainty should be admitted.

Take-Home Points

  • Immune thrombocytopenia is an acquired isolated thrombocytopenia that can be a primary disorder or secondary to viral illness, autoimmune syndrome, or immunodeficiency disease.
  • Patients typically present with minor bleeding and nonspecific symptoms such as fatigue, or, rarely, severe hemorrhage. Perform a thorough skin and oral exam to evaluate for petechial rashes or mucosal bleeds.
  • Life-threatening bleeding should be treated immediately with platelet transfusions, IVIG, and steroids. Treatment for mild/moderate bleeding is more nuanced. Consult Hematology early to guide management.

  • Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: pathogenic and clinical diversity. Blood. 2009 Jun 25;113(26):6511-21. doi: 10.1182/blood-2009-01-129155. Epub 2009 Apr 24. PMID: 19395674; PMCID: PMC2710913.
  • Neunert C, Terrell DR, Arnold DM, Buchanan G, Cines DB, Cooper N, Cuker A, Despotovic JM, George JN, Grace RF, Kühne T, Kuter DJ, Lim W, McCrae KR, Pruitt B, Shimanek H, Vesely SK. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019 Dec 10;3(23):3829-3866. doi: 10.1182/bloodadvances.2019000966. Erratum in: Blood Adv. 2020 Jan 28;4(2):252. PMID: 31794604; PMCID: PMC6963252.
  • Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817. doi:10.1182/bloodadvances.2019000812

Copyright

Images and cases from the Society of Academic Emergency Medicine (SAEM) Clinical Images Exhibit at the 2023 SAEM Annual Meeting | Copyrighted by SAEM 2023 – all rights reserved. View other cases from this Clinical Image Series on ALiEM.

By |2024-09-28T21:40:15-07:00Oct 11, 2024|Heme-Oncology, SAEM Clinical Images|
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SAEM Clinical Images Series: Blue is Bad

66 year-old-male with a history of type 2 diabetes and hypertension presented as a transfer for rapid progression of lower extremity pain, swelling, and blue-purple discoloration of the entire limb with concern for a possible necrotizing infection. His symptoms began earlier in the day and progressed over just a few hours. He had no known thromboembolic risk factors.

MSK: Swollen, tender, and blue/purple-colored right lower extremity

Complete Blood Count (CBC): WBC 8.7; Hb 15; Hct 45; Plt 172

Glucose: 472

Severe venous thromboembolism (VTE), also known as Phlegmasia Cerulea Dolens, which means “painful blue inflammation”, is commonly seen with a unilateral exquisitely tender, swollen, and bluish/purple-colored lower extremity.

Phlegmasia Cerulea Dolens has a high amputation rate secondary to venous gangrene or compartment syndrome. If no pulse is noted on exam, a high suspicion for compartment syndrome must be maintained.

Take-Home Points

  • Phlegmasia Cerulea Dolens is a rare ischemic complication of massive venous thromboembolism with amputation and mortality rates as high as 50% and 40% respectively.
  • Phlegmasia Cerulea Dolens tends to affect the iliofemoral segment of the lower extremities and is commonly associated with malignancy.
  • The preferred imaging modality is doppler ultrasound. Management includes limb elevation, IV fluids, and either systemic anti-coagulation, catheter-directed thrombolysis, and/or thrombectomy.

  • Bazan HA, Reiner E, Sumpio B. Management of bilateral phlegmasia cerulea dolens in a patient with subacute splenic laceration. Ann Vasc Dis. 2008;1(1):45-8. doi: 10.3400/avd.AVDcr07002. Epub 2008 Feb 15. PMID: 23555338; PMCID: PMC3610218.
  • Chaochankit W, Akaraborworn O. Phlegmasia Cerulea Dolens with Compartment Syndrome. Ann Vasc Dis. 2018 Sep 25;11(3):355-357. doi: 10.3400/avd.cr.18-00030. PMID: 30402189; PMCID: PMC6200621.
  • Gardella L, Faulk J. Phlegmasia Alba And Cerulea Dolens. 2022 Oct 3. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 33085284.
  • Said A, Sahlieh A, Sayed L. A comparative analysis of the efficacy and safety of therapeutic interventions in phlegmasia cerulea dolens. Phlebology. 2021 Jun;36(5):392-400. doi: 10.1177/0268355520975581. Epub 2020 Nov 25. PMID: 33236674.
  • Schroeder M, Shorette A, Singh S, Budhram G. Phelgmasia Cerulea Dolens Diagnosed by Point-of-Care Ultrasound. Clin Pract Cases Emerg Med. 2017 Mar 13;1(2):104-107. doi: 10.5811/cpcem.2016.12.32716. PMID: 29849409; PMCID: PMC5965407.

Copyright

Images and cases from the Society of Academic Emergency Medicine (SAEM) Clinical Images Exhibit at the 2023 SAEM Annual Meeting | Copyrighted by SAEM 2023 – all rights reserved. View other cases from this Clinical Image Series on ALiEM.

By |2023-09-14T13:02:29-07:00Sep 25, 2023|Heme-Oncology, SAEM Clinical Images|
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SAEM Clinical Images Series: An Ominous Umbilical Lesion

umbilical

A 54-year-old male with a past medical history of atrial flutter and alcohol use disorder presents with an umbilical wound that has been bothering him for approximately six months. There is no history of trauma, prior infection, or umbilical surgery. There is intermittent mild pain and irritation that occurs randomly. No drainage or bleeding. He admits to picking at the wound regularly. He denies fever, chills, nausea, generalized abdominal pain, diarrhea, constipation, dysuria, and hematuria. The patient drinks four or more alcoholic beverages daily and has a long-standing history of tobacco use.

 

Vitals: BP 105/73; HR 70; RR 16; SpO2 97% on room air; Temp 36.1°C

Constitutional: Appears stated age, resting comfortably, well-appearing.

Abdominal: Soft, flat, non-tender.

Skin: Umbilical wound characterized by a peripheral eschar and a central area of hyperpigmented and crusted tissue overlying an area of whiteish moist tissue that was uncovered by gentle cleansing. No surrounding erythema and no areas of fluctuance. No active drainage or malodor.

None available.

Sister Mary Joseph (SMJ) nodule is a rare cutaneous metastasis of gastrointestinal or genitourinary primary malignancies to the umbilicus [1,3]. They are typically firm, painful, indurated, and irregularly shaped, with sizes typically less than 2 cm [1]. They can be ulcerated or necrotic with variable presence of discharge ranging from purulent to serous or serosanguinous [1]. Sister Mary Joseph nodules typically arise late in disease and portend a poor prognosis [1]. Most primary malignancies are adenocarcinomas (75%), and pancreatic cancers represent approximately 9% of umbilical metastases [1]. Mean survival of patients with SMJ nodules is less than 12 months, and less than three in those with pancreatic primaries [1]. Prognosis is slightly less bleak if the SMJ nodule is the only metastatic site [1]. Sister May Joseph Dempsey was a nun and surgical assistant to Dr. William Mayo, the surgeon who developed the approach to umbilical hernia repair and the first to identify the connection between abdominopelvic cancers and umbilical nodules [2,3].

Abdominal CT imaging.

Our patient was discharged on the initial visit with wound care instructions. He returned to the Emergency Department two months later and was admitted for atrial flutter with rapid ventricular response and acute on chronic congestive heart failure. During that visit, the patient had a CT chest/abdomen/pelvis that demonstrated likely a pancreatic tail adenocarcinoma with metastasis to the peritoneal and abdominal walls. The patient declined any further intervention.

Take-Home Points

  • Sister Mary Joseph nodules are umbilical metastases from abdominopelvic primary malignancies.
  • Recognition of their features on clinical exam can lead to a more rapid diagnosis.
  • Prognosis is grim with an average survival of less than one year.

  1. Vekariya P, Daneti DB, Senthamizh Selvan K, Verma SK, Hamide A, Mohan P. Sister Mary Joseph Nodule as an Initial Presentation of Pancreatic Adenocarcinoma. ACG Case Rep J. 2020 Aug 25;7(8):e00453. doi: 10.14309/crj.0000000000000453. PMID: 32903972; PMCID: PMC7447472.
  2. Palazzi DL, Brandt ML. Care of the umbilicus and management of umbilical disorders. UpToDate. Updated August 27, 2021. Accessed January 2, 2022. https://www.uptodate.com/contents/care-of-the-umbilicus-and-management-of-umbilical-disorders?search=sister%20mary%20joseph%20nodule&source=search_result&selectedTitle=2~6&usage_type=default&display_rank=2#H25.
  3. Tso S, Brockley J, Recica H, Ilchyshyn A. Sister Mary Joseph’s nodule: an unusual but important physical finding characteristic of widespread internal malignancy. Br J Gen Pract. 2013 Oct;63(615):551-2. doi: 10.3399/bjgp13X673900. PMID: 24152477; PMCID: PMC3782795.

Copyright

Images and cases from the Society of Academic Emergency Medicine (SAEM) Clinical Images Exhibit at the 2021 SAEM Annual Meeting | Copyrighted by SAEM 2021 – all rights reserved. View other cases from this Clinical Image Series on ALiEM.

By |2023-01-02T02:15:58-08:00Jan 9, 2023|Gastrointestinal, Heme-Oncology, SAEM Clinical Images|
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SAEM Clinical Images Series: Dermatology Deserving a Deeper Dive

A 22-year-old female without significant past medical history presented to the Emergency Department (ED) for a progressive rash for the past six months. She had initially complained of dry and peeling skin on bilateral hands and feet and had multiple ED and dermatology encounters where topical steroids, acyclovir, and methotrexate were prescribed with no improvement. The rash continued to progress with worsening pain and inability to flex fingers secondary to lesions and scabbing at the joints. The patient also developed painful sores in her mouth primarily involving the tongue. More concerningly, she had lost 60 pounds since the onset of the rash and mouth lesions which she attributed to the inability to eat due to significant pain. Otherwise, she denied systemic symptoms, exposures, new medications, or previous illnesses.

paraneoplastic

Vitals: Within normal limits

HEENT: Swelling, erythema, and mild desquamation of the tongue mucosa with adherent white discharge present. Lesions are limited to the surface of the tongue with no buccal involvement.

Cardiovascular/Respiratory: Heart sounds within normal limits. Bilateral breath sounds without wheezes, rales, or rhonchi.

Abdomen: Soft, non-tender and non-distended.

Skin: The patient was noted to have desquamated, scabbing and oozing lesions on bilateral palms and fingers, soles of the feet, and web spaces between toes. The patient had no observable vesicles/bullae, or target lesions. Negative Nikolsky sign.

Complete Blood Count (CBC): Mild anemia, stable from baseline.

Basic Metabolic Panel (BMP): Within normal limits.

CT Abdomen/Pelvis with contrast (relevant findings only): Large solid right retroperitoneal mass lobulated in contour with heavy coarse calcifications measuring 21.2 x 8.5 x 10.4 cm, traversing the right hemidiaphragm and extending to the right lower mediastinum. The diaphragm itself is asymmetrically thickened as compared with the contralateral left side with a small volume of adjacent retroperitoneal fluid and there is extension into the right neural foramina.

The diagnosis of paraneoplastic pemphigus (PNP) was made after skin biopsy along with the constellation of findings including desquamating cutaneous lesions, painful mucosal erosions, and large retroperitoneal mass concerning for malignancy. Skin biopsy findings in this case include a distinct suprabasilar cleft, apoptotic keratinocytes, eosinophilic spongiosis, and superficial perivascular lymphocytic infiltrate with scattered eosinophils. Focally, there was full-thickness necrosis of the epidermis and dermis.

Patients with concern for PNP without known malignancy require a full neoplastic workup. In this case, a biopsy of the retroperitoneal mass and subsequently full resection was notable for Castleman’s disease, a rare lymphoproliferative disorder. PNP is an often fatal paraneoplastic mucocutaneous blistering disease that is most commonly caused by various lymphoproliferative disorders including non-Hodgkin’s lymphoma, chronic lymphocytic leukemia (CLL), and Castleman’s disease. It is an extremely rare condition with an unknown incidence rate. The mucosal erosions present are a requirement for the diagnosis. It typically presents as an erosive stomatitis involving the tongue and is characteristically chronic, progressive, and painful. These lesions are the initial disease manifestation in almost one-half of patients with PNP and often lead to malnutrition secondary to pain with attempts at oral intake. The cutaneous lesions in the disease are widely variable in morphology and can present with tense or flaccid bullae, as well as inflammatory papules or plaques.

Take-Home Points

  • In patients with a progressive rash involving the oral mucosa that have failed multiple outpatient regimens and have findings concerning for possible systemic involvement, dermatology consultation, tissue biopsy, and body imaging are often needed to confirm a diagnosis of complicated disease processes such as paraneoplastic pemphigus (PNP).
  • Significant unintentional weight loss may be due to a variety of reasons stemming from one unifying etiology. In this case, our patient had both mouth pain limiting oral intake as well as a lymphoproliferative disorder.

  • Anhalt GJ, Kim SC, Stanley JR, Korman NJ, Jabs DA, Kory M, Izumi H, Ratrie H 3rd, Mutasim D, Ariss-Abdo L, et al. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med. 1990 Dec 20;323(25):1729-35. doi: 10.1056/NEJM199012203232503. PMID: 2247105.
  • Kaplan I, Hodak E, Ackerman L, Mimouni D, Anhalt GJ, Calderon S. Neoplasms associated with paraneoplastic pemphigus: a review with emphasis on non-hematologic malignancy and oral mucosal manifestations. Oral Oncol. 2004 Jul;40(6):553-62. doi: 10.1016/j.oraloncology.2003.09.020. PMID: 15063382.

Copyright

Images and cases from the Society of Academic Emergency Medicine (SAEM) Clinical Images Exhibit at the 2021 SAEM Annual Meeting | Copyrighted by SAEM 2021 – all rights reserved. View other cases from this Clinical Image Series on ALiEM.

By |2023-01-02T04:44:30-08:00Jan 2, 2023|Dermatology, Heme-Oncology, SAEM Clinical Images|
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SAEM Clinical Images Series: ‘Tis Not the Season to be Wheezing

wheezing

A 2-year-old male with a history of solitary kidney presented with greater than one month of daily coughing, wheezing, and decreased appetite. The patient was previously seen by his primary care physician after three weeks of symptoms where he was prescribed albuterol as needed for viral bronchospasm. The patient’s wheezing did not improve after two weeks of albuterol treatment so a chest x-ray was ordered. The patient’s mother denied any fevers, vomiting, diarrhea, weight changes, or night sweats.

Vitals: BP 131/60; Pulse 148; Temp 36.7 °C (98.1 °F) (Axillary); Resp 28; Wt 15.7 kg (34 lb 9.8 oz); SpO2 95%

General: Alert; well appearing

HEENT: Pupils equally reactive to light; moist mucous membranes; nares with normal mucosa without discharge

Cardiovascular: Regular rate; regular rhythm; normal S1, S2; no murmur noted; distal pulses 2+

Pulmonary: Good aeration throughout all lung fields; clear breath sounds bilaterally; prolonged expiratory phase; stridor with agitation

Abdomen: Soft; non-tender; non-distended

White blood cell (WBC) count: 56.1/uL (Blasts 58%)

Platelets: 288/uL

Uric acid: 8.3 mg/dL

LDH: 2231 iU/LD

D-Dimer: 3.22 ug/mL

Fibrinogen: 463 mg/dL

Bronchospasm, bronchiolitis, viral infection, pneumonia, foreign body aspiration, space-occupying lesion, vocal cord dysfunction, cardiac dysfunction, and acute chest in patients with sickle cell disease.

The radiograph shown demonstrates a mediastinal mass. This patient was ultimately diagnosed with T-cell acute lymphoblastic leukemia. T-ALL can present with fatigue, fevers, weight loss, easy bleeding/bruising, paleness, or a mediastinal mass. Mediastinal masses found on chest x-ray require further evaluation to determine the diagnosis, location, and treatment. If malignancy is suspected, an oncology referral and bone marrow sample will be necessary.

Take-Home Points

  • In patients with first-time wheezing that does not improve with bronchodilator therapy, consider alternative diagnoses and further evaluation.
  • A mediastinal mass is found at the time of diagnosis in 10% to 15% of children with acute lymphoblastic leukemia.

  • Steuber, P (2021). Overview of common presenting signs and symptoms of childhood cancer.UpToDate. Retrieved January 2, 2021.2.
  • Juanpere, S., Cañete, N., Ortuño, P., Martínez, S., Sanchez, G., & Bernado, L. (2013). A diagnostic approach to the mediastinal masses. Insights into imaging, 4(1), 29–52.https://doi.org/10.1007/s13244-012-0201-0

Copyright

Images and cases from the Society of Academic Emergency Medicine (SAEM) Clinical Images Exhibit at the 2021 SAEM Annual Meeting | Copyrighted by SAEM 2021 – all rights reserved. View other cases from this Clinical Image Series on ALiEM.

By |2022-11-06T10:12:53-08:00Nov 21, 2022|Heme-Oncology, Pediatrics, Pulmonary, SAEM Clinical Images|
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