United States

Background:
Glomerular diseases are commonly classified based on immune complex and complement deposition patterns. While classical and alternative complement pathways are well studied, the role of the lectin pathway (LP) in glomerular disease pathogenesis remains underexplored. Previous observations at our institute revealed C4d deposition in 20% of C3 glomerulonephritis (C3GN) and 50% of dense deposit disease (DDD), prompting further investigation into LP activation across various glomerular pathologies.
Methods:
In this prospective study (2020–2021), 39 consecutive kidney biopsies (native and transplant) with glomerular pathology were analyzed. Light microscopy (LM), IF, and electron microscopy (EM) were used for diagnosis. Routine immunofluorescence (IF) findings guided selection for additional immunofluorescent staining with C5b-9, C4d, MASP, MBL, and ficolin on OCT blocks stored at –80°C.
Results:
Lectin pathway activation was observed in 75% of membranous nephropathy (MN) cases, with higher prevalence in primary MN (72%). Early-stage MN showed stronger LP activation (80%) compared to late-stage disease. IgG4 predominance (16%) and co-dominance (58%) were frequently associated with LP activation. No correlation was found between LP activation and anti-PLA2R status. C3 tissue deposition was present in 75% of secondary and 28% of primary MN cases. In secondary MN, C3 tissue positivity correlated with low serum C3 in 75% of cases; this correlation was absent in primary MN.
IgA nephropathy (IgAN) showed no deposition of lectin pathway markers, although all cases exhibited strong C5b-9 deposition. C3 was deposited in 50% of IgAN cases without correlation to serum C3 levels. C4d was positive in 25% of IgAN. In complement-mediated MPGN, strong C3 and C5b-9 deposits were observed along capillary walls and mesangium, but no lectin pathway proteins were detected.
Other glomerular diseases including MPGN, FSGS, non-proliferative glomerulopathies, diabetic nephropathy, amyloidosis, chronic active antibody-mediated rejection (AMR), acute tubular injury (ATI), and thrombotic microangiopathy (TMA) showed no evidence of complement activation via the lectin pathway.
Conclusion:
Our study demonstrates consistent activation of the lectin pathway in primary membranous nephropathy, particularly in early stages, and links it to IgG4 deposition. LP activation is variable in secondary MN and lupus nephritis, but absent in IgAN, MPGN, FSGS, and other glomerulopathies. These findings suggest a potential pathogenic role for the lectin pathway in MN and underscore the therapeutic potential of complement-targeted interventions tailored to specific pathways.


2025 AMA Research Challenge – Member Premier Access

Lectin Pathway Activation in Glomerular Diseases: A Prospective Analysis of Native and Transplant Kidney Biopsies

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Objective: Pediatric asthma exacerbations are common emergencies seen in the emergency department (ED), with a high potential for decompensation. While it is known that substance use disorder (SUD) complicates management of pediatrics in the ED, little is known about how they influence outcomes in asthma exacerbations. This study aims to assess how a coexisting SUD diagnosis influences clinical outcomes in pediatric ED visits for asthma exacerbation.

Methods: We queried the deidentified TriNetX database to identify patients aged 11–21 who presented to the ED with asthma exacerbation between 01/01/2010 and 01/01/2025 (n=75,167). Patients with a documented SUD diagnosis within the last 1 year (n=5,712) were compared to patients who have never been diagnosed with SUD (n=69,455). Propensity score matching (PSM) was performed (1:1) based on age, sex, race, ethnicity, and common pediatric comorbidities. Risk ratios (RR) with 95% confidence intervals (CI) and p-values (<0.05 significant) were used to compare outcomes.

Results: After PSM (5,703 per cohort), within 0–1 day of ED presentation, adolescents with SUD were more likely to receive systemic corticosteroids (RR=1.23 [1.19–1.27]), inhaled beta-agonists (RR=1.32 [1.29–1.36]), and magnesium sulfate (RR=1.94 [1.72–2.19]; all p<0.001). They more frequently underwent chest X-ray (RR=1.46 [1.39–1.53]) and blood gas analysis (RR=2.33 [1.97–2.76]) and required CPAP (RR=2.40 [1.68–3.41]), sedation (RR=1.53 [1.31–1.77]), inpatient (RR=1.80 [1.56–2.07]), and ICU care (RR=1.47 [1.19–1.82]; all p<0.001). From 1 day to 1 month post-presentation, SUD patients showed higher risks of repeat asthma exacerbation (RR=1.43 [1.29–1.59]), ED revisits (RR=1.55 [1.41–1.69]), ICU admission (RR=2.07 [1.52–2.83]), acute respiratory failure (RR=2.12 [1.56–2.86]), pneumonia (RR=1.75 [1.33–2.31]), and SDOH code documentation (RR=1.79 [1.28–2.50]; all p<0.001).

Conclusion: Pediatric patients with SUD experience significantly greater resource utilization during ED visits for asthma exacerbations, including increased admissions, interventions, and diagnostic testing. These findings highlight the urgent need for integrated, multidisciplinary care strategies that address the complex medical and behavioral health needs of this vulnerable population.


Substance Use Disorder and Emergent Asthma Exacerbation in Adolescents

Title
Advanced Lung Adenocarcinoma in a Non-Smoker: Unravelling Diagnostic Challenges with Immunohistochemistry and Atypical Marker Profiles
Introduction
Lung adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC), increasingly diagnosed in non-smokers. In these patients, vague symptoms and misleading tumor markers often delay diagnosis. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), commonly associated with gastrointestinal malignancies, may be elevated in lung cancer, complicating workup. This case illustrates how immunohistochemistry (IHC) enabled diagnostic clarity in a non-smoker with metastatic disease and atypical biochemical features.
________________________________________
Case Presentation
A 75-year-old non-smoking male presented with fatigue, anorexia, weight loss, and a chronic cough. Laboratory evaluation revealed elevated CEA (60.4 ng/mL) and CA 19-9 (763.3 U/mL). PET-CT showed a right middle lobe lung mass with mediastinal lymphadenopathy and liver metastases.
Due to elevated GI tumor markers and liver involvement, a gastrointestinal primary was initially suspected. Liver lesion biopsy revealed poorly differentiated carcinoma. IHC showed strong positivity for CK7, TTF-1, NAPSIN-A, and CK19; focal positivity for CDX2; and negativity for CK20 and HepPar1 — confirming primary lung adenocarcinoma. The patient received Pemetrexed and Carboplatin. Molecular testing was not completed before therapy. He deteriorated and was transitioned to palliative care.
________________________________________
Discussion
This case highlights how tumor marker elevation and metastatic pattern can obscure the diagnosis of lung adenocarcinoma, particularly in non-smokers. CA 19-9 and focal CDX2 positivity initially suggested gastrointestinal origin. However, robust expression of TTF-1 and NAPSIN-A confirmed pulmonary origin, emphasizing the diagnostic utility of IHC in metastatic disease of uncertain origin.
Focal CDX2 staining has been documented in poorly differentiated lung adenocarcinomas, and its presence should not outweigh the significance of lung-specific markers. The reliance on tumor markers alone risks misclassification, especially when imaging patterns are nonspecific.
Moreover, non-smokers frequently harbor actionable driver mutations like EGFR or ALK. Unfortunately, molecular profiling was delayed, precluding timely personalized therapy. This reflects a common clinical gap where real-world constraints limit access to targeted options. The case underscores the value of integrating molecular diagnostics early, particularly in patients likely to benefit from targeted agents.
________________________________________
Conclusion
When clinical and biochemical indicators are incongruent, comprehensive IHC can guide accurate diagnosis. In advanced lung adenocarcinoma, especially in non-smokers, early molecular profiling is essential. This case exemplifies the importance of timely, integrated diagnostics to inform optimal, individualized care.

Reference #1: Travis WD, Brambilla E, Burke AP, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. IARC; 2015.

Reference #2: Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for lung cancer patients. Arch Pathol Lab Med. 
2018;142(3):321–346. doi:10.5858/arpa.2017-0388-CP
Reference #3: Saad RS, Ghorab Z, Khalifa MA, et al. CDX2 as a marker in the differential diagnosis of gastrointestinal adenocarcinomas. 
Am J Clin Pathol.2004;121(3):351–359. doi:10.1309/Y6A14HCKUJYHCEHJ


Advanced Lung Adenocarcinoma in Non-Smoker: Unraveling Diagnostic Challenges with Immunohistochemistry and Atypical Marker Profiles

Background
Long-duration spaceflight exposes astronauts to immense physical and psychological stress, potentially impairing neurocircuitry and motor coordination. Recent literature has revealed decreased density in several white matter tracts associated with motor control and coordination alongside well-established deficits in coordinative function post-spaceflight. Virtual reality (VR) could potentially be used to monitor and enhance neurocognitive resilience in space environments. This project involved conducting a literature review, creating a study design, and submitting a NASA grant to fund a VR training program that will be implemented during a future space mission in October 2025.
Methods
We have designed and implemented a VR training program with several games capturing pupillometry, eye tracking, and body kinematic data to test various aspects of cognitive control and psychomotor function. Performance data will be collected by the REACT Neuro VR System through biometric sensors and task analytics. Evaluation will involve outcome measures including ocular dynamics, oculo-motor coordination, accuracy, and reaction time, to compare baseline assessments with post-spaceflight outcomes. Overall task performance will be based on the number of difficulty levels successfully passed. Additionally, astronauts will undergo specialized MRI imaging to quantify white matter changes and associate them with VR metrics.
Results
Preliminary activities include literature synthesis and grant preparation, building a robust framework for this project. Anticipated results, as demonstrated in a test cohort of Air Force C-17 pilots earlier this year, include detection of early psychomotor decline after high-altitude flight and new evidence for the use of VR training to preserve motor coordination and strength in the astronaut population.
Conclusion
This VR analysis program provides a new method for neurocognitive monitoring during spaceflight. It may also support the role of neuroplasticity in psychomotor changes observed after spaceflight. Limitations include small participant sample sizes and delays between spaceflight and MRI imaging, while future directions involve scaling this program to larger cohorts and integrating more neurofeedback metrics. After demonstrating REACT Neuro’s potential to track and rehabilitate coordinative and cognitive deficits in astronauts, we see incredible potential for translating these techniques to patients with similar ailments in the general population.

Virtual Reality Training for Neurocognitive Monitoring in Astronauts

Introduction:
Thalassemia trait generally has minimal clinical impact, but physiologic changes during pregnancy may increase the risk of anemia, transfusion, and hypertensive disorders. Prior evidence is limited and often conflicting. This study evaluated pregnancy outcomes among women with thalassemia trait using a large, multicenter database.
Methods:
We conducted a retrospective cohort study using data from the TriNetX US Collaborative Network. Females aged 18–45 with ICD-10 codes indicating pregnancy (Z33.1, O00–O9A, Z34, Z3A) were included. Patients with pregnancy and coexisting thalassemia minor (D56.3) formed the thalassemia cohort (n = 19,369), while those without a thalassemia diagnosis (D56) comprised the control cohort (n = 5,471,214). Propensity score matching (1:1) balanced age, race/ethnicity, and comorbidities including obesity, smoking, hypertension, and type 2 diabetes. The index event was defined as the earliest date meeting criteria for both pregnancy and thalassemia minor (exposed) or pregnancy alone (controls). Outcomes within one year included anemia, blood transfusion, preeclampsia/eclampsia, cesarean section, venous thromboembolism (VTE), heart failure, preterm delivery, intrauterine growth restriction (IUGR), and intrauterine fetal demise (IUFD). Risk ratios (RR) with 95% confidence intervals (CI) were calculated.
Results:
After matching, 38,488 patients (19,244 per cohort) were analyzed. Thalassemia trait was associated with increased risks of anemia (RR 3.09, 95% CI 2.94–3.25), transfusion (RR 1.65, 95% CI 1.41–1.94), preeclampsia/eclampsia (RR 1.57, 95% CI 1.49–1.65), cesarean delivery (RR 1.47, 95% CI 1.38–1.56), preterm delivery (RR 1.39, 95% CI 1.26–1.53), and IUGR (RR 1.96, 95% CI 1.72–2.23), all p < 0.001. VTE risk was also higher (RR 2.05, 95% CI 1.40–3.01, p < 0.001).
Conclusion:
Thalassemia trait in pregnancy was associated with greater rates of anemia, transfusion, and adverse maternal and fetal outcomes. These findings highlight the need for tailored peripartum care and close multidisciplinary monitoring in this population.

Pregnancy Outcomes in Women with Thalassemia Trait: A Multi-Center Cohort Study

Background
Hexapod external fixators are used for fracture treatment, deformity correction, and limb lengthening. Although they are very powerful tools, they pose several challenges including their size, pin track infections, and patient physical and mental discomfort.. Therefore, any intervention minimizing the time spent in the frame is desirable. 
In the setting of fractures, controlled micro-motion has demonstrated greater circumferential callus formation and greater mechanical strength compared to rigid fixation. Historically, controlled “accordion” motion at the fracture or osteotomy site has been utilized to promote healing. We have utilized an automated hexapod to provide ongoing mechanical stimulation during deformity correction and/or lengthening. We report on the early results in this case series.
Methods
We queried an IRB approved database for all patients who underwent deformity correction or lengthening with a hexapod external fixator from May 2020 to June 2025. Demographic data as well as treatment parameters were recorded. 
Results
Seven patients were included in our study. Two of these patients had double level osteotomies, totaling nine corrections for this study. Three patients had lengthening ranging from 1.0 - 3.7 cm. The mean time in the external fixator was 190.3 days. Ultimately seven out of seven osteotomies healed with 2 additional osteotomies still in treatment. There was one patient with an unplanned return to the operating room for inadequate frame stability and early conversion to internal fixation. 
Conclusion
The use of HEF with automated mechanical stimulation has potential to assist with healing and bony union. It is difficult to compare results with the existing literature, but these encouraging findings warrant further research to refine these methods and compare its efficacy against alternative techniques. 


A Case Series of Automated Mechanical Stimulation in a Hexapod External Fixator

Background
Respiratory Syncytial Virus (RSV) is a leading cause of morbidity and hospitalization in infants and young children. Although prophylactic agents such as Nirsevimab and maternal Abrysvo vaccination have become available, their real-world effectiveness and equitable uptake across pediatric populations remain unclear. Prior research has largely focused on trial settings, leaving gaps in understanding how these interventions perform in heterogeneous clinical environments, particularly in high-risk and racially diverse groups. This study aimed to evaluate RSV-confirmed lower respiratory tract infection (LRTI) incidence, hospitalization, and secondary outcomes across developmental risk factors, care settings, prophylaxis strategies, and racial/ethnic groups.

Methods
We performed a retrospective observational analysis of 12,414 pediatric bronchiolitis encounters within a single health system. Patients were stratified by prophylaxis status (Nirsevimab, Abrysvo, combined, or untreated), age, gestational age, APGAR scores, race/ethnicity, and care setting. Outcomes included RSV-confirmed LRTI, hospitalization, wheeze, otitis media, and antibiotic use. Proportions were compared using chi-square and z-tests; risk projections estimated the impact of prophylaxis hesitancy. Analyses were conducted in R (v4.4.1).

Results
RSV-confirmed LRTI incidence was significantly lower among infants who received Nirsevimab versus untreated infants (1.8% vs. 3.3%, p < 0.001), and also lower in combined prophylaxis groups versus untreated. Abrysvo alone showed a non-significant reduction (2.2% vs. 3.3%). Infants <12 months and those born prematurely experienced the highest RSV burden, while APGAR scores showed limited predictive value. Although RSV incidence did not significantly differ across racial or ethnic groups (~8.6–8.8%), American Indian/Alaska Native and Black children had notably lower prophylaxis uptake, highlighting inequities in preventive care access. A risk projection suggested that a 20% prophylaxis declination rate could result in approximately 3 additional RSV cases per 1,000 high-risk infants, and up to 6 among preterm infants.

Conclusion
In this real-world cohort, Nirsevimab and combined prophylaxis were associated with significantly reduced RSV-confirmed LRTI incidence. Findings underscore the importance of equitable prophylaxis access and addressing hesitancy, particularly among high-risk and historically underserved populations. Standardized testing, expanded surveillance, and targeted outreach are critical to maximizing the public health benefits of RSV prevention.

Evaluating RSV Burden and Prophylaxis Outcomes Across Pediatric Risk Groups: Real World Evidence from a Multi-Domain Analysis

Paraconduit hernias are a rare but recognized complication that can arise after esophagectomy with gastrointestinal reconstruction. It involves the herniation of intra-abdominal organs into the thoracic cavity through a defect adjacent to the esophageal conduit, typically at the hiatus. Unlike typical hiatal hernias, this type occurs alongside the reconstructed conduit rather than through the original hiatus, often leading to symptoms affecting quality of life. While mesh is commonly used in standard hiatal hernia repairs, its application in paraconduit hernia repair is
less studied, with limited evidence guiding its safety or long-term outcomes. The mesh technique typically includes reduction of the hernia and placement of a synthetic or composite mesh fixed securely around the conduit to prevent recurrence and preserve function. This study aims to fill the gap in evidence by examining real-world outcomes and perioperative characteristics of patients undergoing mesh repair for paraconduit hernias, focusing on effectiveness, recurrence, and prognosis

Surgical Revision of Paraconduit Hiatal Hernia (PCHH) Mesh Repair Following Esophagectomy: A Case-Based Review

Abstract Title: A Stepwise Diagnostic Approach to MINOCA with Microvascular Obstruction: The Utility of Cardiac MRI
Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) accounts for approximately 5–7% of acute myocardial infarctions (MI) and presents a diagnostic challenge due to its heterogeneous etiologies. It is a descriptive, working diagnosis that requires: (1) fulfillment of the universal definition of acute MI (a 20% change in cardiac troponin with one value above the 99th percentile and evidence of ischemia); (2) absence of obstructive coronary artery disease on angiography (major epicardial vessel stenosis ≤50%); and (3) no overt alternative cause for the acute presentation. In 2019, the American Heart Association emphasized an exhaustive diagnostic approach and endorsed cardiac magnetic resonance imaging (MRI) to confirm myocardial injury, differentiate ischemic from non-ischemic patterns, and assist in narrowing etiologies when angiography is non-revealing.
Case Presentation: A 74-year-old male with hypertension, prior deep vein thrombosis, and suspected thrombophilia on chronic warfarin presented with non-radiating, midsternal, 2/10 acute chest pain. Electrocardiogram showed lateral ST-elevation with reciprocal inferior ST-depression. These findings, in conjunction with an elevated troponin I level of 11.5 ng/mL (normal: <0.04 ng/mL), were consistent with acute coronary syndrome (ACS). Thus, the patient was indicated for invasive coronary angiography, which revealed non-obstructive coronary arteries. The finding of non-obstructed coronary arteries, in addition to ACS symptoms, led to the working diagnosis of troponin-positive non-obstructive coronary arteries (TpNOCA). Thus, cardiac MRI was performed, and indicated an acute transmural MI with microvascular obstruction (MVO) in the left anterior descending artery vascular territory. These findings, along with non-ischemic cardiac and extracardiac causes being ruled out, led to a revised diagnosis of MINOCA. The patient was managed with guideline-directed medical therapy and discharged in stable condition. 
Discussion: This case highlights a rare presentation of transmural MI with MVO in the absence of obstructive coronary disease and underscores the importance of working through the stepwise diagnostic process, from initial suspicion of acute coronary syndrome, to TpNOCA, and ultimately to MINOCA. Cardiac MRI was pivotal in confirming ischemic myocardial injury, ruling out alternative diagnoses, and guiding appropriate management. The patient’s chronic warfarin therapy for suspected thrombophilia may have contributed to spontaneous thrombolysis. Recognition of spontaneous thrombolysis as a mechanism for MINOCA emphasizes the value of a structured diagnostic algorithm combining clinical evaluation, angiography, and advanced imaging.

A Stepwise Diagnostic Approach to MINOCA with Microvascular Obstruction:
The Utility of Cardiac MRI

Hereditary hemochromatosis (HH) is a 
genetic disorder characterized by iron 
overload, which can lead to elevated 
liver enzymes, increased ferritin and 
transferrin saturation. The condition is 
associated with a heightened risk of 
liver and metabolic complications, 
including fatigue, joint pain, abdominal 
pain and endocrinopathies. 
Emerging preclinical data suggest that 
GLP-1 receptor agonists (GLP-1RAs) 
may improve hepatic inflammation and 
iron metabolism in HH.

Beyond Phlebotomy: Tirzepatide for Iron Overload in Hereditary Hemochromatosis

Background
COVID-19 has been associated with a broad range of neuropsychiatric sequelae, including new-onset psychosis, mood episodes, depression, anxiety, and cognitive impairment. These symptoms can develop during active infection or emerge in the weeks that follow. The underlying causes are likely multifactorial involving neuroinflammation, immune response, direct CNS effects, and psychosocial stressors. Patients with chronic psychiatric illnesses may be especially susceptible to decompensation but reports of COVID-19 related psychiatric decline in inpatient psychiatric settings remain limited.
Case Presentation
A 59 year old female with schizoaffective disorder, bipolar type, and polysubstance use was admitted for psychosis and catatonia. She initially was stabilized on sublingual buprenorphine, Invega Sustenna, and Ativan. By hospital day 27, she was discharge ready and denied hallucinations, suicidality or depressive symptoms. Shortly after stabilization, she endorsed symptoms of diarrhea, no URI symptoms, and subsequently tested positive for COVID-19. Following the positive COVID-19 PCR test, she was placed in isolation and was monitored for additional symptoms. Serial antigen tests 5 and 7 days after were negative. Within days of the initial positive test, she exhibited acute decompensation characterized by increased paranoia, auditory and visual hallucinations, disorganized behavior, and mania. Despite being on therapeutic doses of antipsychotic medications, she became increasingly labile, exhibited disorganized behavior, and made illogical statements. Management was complicated by suspected akathisia, bradycardia limiting propranolol use, and side effects from Lithium which was discontinued and replaced by Valproic acid for manic symptoms. Trial of Olanzapine was begun but was insufficient. On day 55, Clozapine was initiated due to persistent psychosis and mania. Despite concerns about subjective akathisia, she tolerated the initial titration, and mirtazapine was initiated for adjunctive management of akathisia and mood symptoms. The patient remains hospitalized under close psychiatric monitoring, with ongoing management focused on titration of clozapine and adjunctive pharmacologic support.
Discussion
This case highlights the risk of psychiatric destabilization in patients with severe mental illness following COVID-19 infection, even in the absence of severe respiratory symptoms. Management was further complicated by medication side effects and the need for antipsychotic regimen adjustments during an acute medical illness. Furthermore, careful medical management and early recognition of psychiatric relapse are critical in patients susceptible to COVID-19 in the inpatient psychiatric setting.


Next from 2025 AMA Research Challenge – Member Premier Access

Substance Use Disorder and Emergent Asthma Exacerbation in Adolescents