Introduction
Transfusion-related acute lung injury (TRALI) is a serious and potentially fatal syndrome characterized by the acute onset of hypoxemia and bilateral pulmonary edema, which occurs during or within 6 hours of blood product transfusion [ 1 ] . TRALI was first described in the early 1980s [ 1 ] , and since then emerged as a significant cause of transfusion-associated morbidity and mortality, despite advances in blood banking practices [ 1 ] . Epidemiological studies estimated the incidence of TRALI to be approximately 1 in 130 000 transfused blood products. However, this figure may vary depending on the definition used and the vigilance of reporting systems [ 1 , 2 ] .
The pathogenesis of TRALI is complex and multifactorial, involving both antibody-mediated and non-antibody-mediated mechanisms. The widely accepted “two-hit” model proposed that a first hit, such as underlying inflammation or a pre-existing pulmonary condition, primes the pulmonary vasculature. This is followed by a second hit, often involving donor-derived antibodies against recipient leukocytes or bioactive lipids accumulating in stored blood products, which leads to neutrophil activation, endothelial damage, and ultimately, pulmonary edema [ 3 ] . Several risk factors have been identified for TRALI, including older age, sepsis, recent surgery, underlying pulmonary disease, and malignancies [ 4 ] . Studies illustrated that patients with hematologic malignancies, like multiple myeloma (MM), may have an elevated baseline inflammatory state, which increases their susceptibility to TRALI [ 1 ] .
HIGHLIGHTS
The case demonstrates the diagnostic complexity of TRALI in a patient with multiple myeloma, emphasizing the challenge of distinguishing it from other post-transfusion complications such as TACO, allergic reactions, and infectious causes1.
The patient’s underlying hematologic malignancy and recent chemotherapy likely created a pro-inflammatory state, serving as the “first hit” in the two-hit model of TRALI pathogenesis, with the transfusion acting as the “second hit.”
Despite aggressive supportive management – including oxygen therapy, mechanical ventilation, and broad-spectrum antimicrobials – the patient experienced rapid clinical deterioration and fatal outcome, underscoring the severity of TRALI in immunocompromised individuals.
The report highlights the importance of early recognition and differentiation of TRALI from other causes of acute lung injury, as prompt diagnosis is critical for appropriate management and improving patient outcomes.
Preventive strategies, such as donor screening and the use of leuko-reduced blood products, are discussed as essential measures to reduce TRALI risk, especially in high-risk populations like those with hematologic malignancies.
Given the diagnostic challenges and potential severity of TRALI, it is crucial to enhance awareness and understanding of this condition among healthcare professionals [ 4 ] . In this report, we presented a complex case of TRALI in a patient with MM who developed acute respiratory distress following a whole blood transfusion for severe pancytopenia. We aimed to note the diagnostic complexities involved in recognizing TRALI, discuss key aspects of its pathophysiology and management. This study is compliant with the TITAN Guidelines 2025 [ 5 ] .
Case presentation
A 57-year-old woman with a history of multiple myeloma (MM) was admitted to the emergency department at Shohada Hospital, Tehran, Iran, due to severe mucositis. She had been undergoing treatment with alkylating agents for the past year and had experienced a fungal pulmonary infection 8 months prior, which was successfully treated.
Clinical findings
Upon admission, the patient presented with white patches on the inner aspect of her mouth (Fig. 1 ), consistent with oral thrush. Her vital signs were within normal limits, and her electrocardiogram (ECG) showed a normal sinus rhythm. Initial laboratory tests revealed pancytopenia, with a hemoglobin (Hb) level of 5 g/dL, a white blood cell (WBC) count of 2 × 10 9 /L with 1000 cells/μL absolute neutrophil count (ANC), and a platelet (Plt) count of 50 000/μL. All these assessments were performed at the arrival of patient.
Primary diagnostic evaluation
Given her history of pulmonary infection, a chest radiograph and computed tomography (CT) scan were performed instantly at the first hour of patient’s admission, both displaying no obvious pathology (Fig. 2 ). Moreover, sputum and blood tests and culture, and Covid-19 test was also performed to rule out pneumonia causes after radiology evaluations. Severe mucositis was suspected to be caused by leukopenia and opportunistic infections. The gram staining results from the ulcer’s smear demonstrated that the patient had oral candidiasis. So, treatment with nystatin drops and oral fluconazole capsules was initiated.
Transfusion-related complications
Afterward, to address patient’s severe pancytopenia, the patient received three units of whole blood. However, 4 hours post-transfusion, she developed a sudden onset of dyspnea, tachycardia (110 bpm), tachypnea (33 breaths/min), hypoxemia (oxygen saturation: 75%), and hypotension (BP: 85/50 mmHg). Her body temperature remained normal. Supportive oxygen therapy was initiated instantly, and auscultation revealed decreased breath sounds with diffuse rales bilaterally. An urgent chest CT angiography illustrated diffuse bilateral consolidation and ground-glass opacities (Fig. 3 ).
Further management and outcome
After patient’s symptoms appearance, cardiac causes were ruled out, as there were no signs of peripheral edema or elevated jugular venous pressure. The ECG was normal, and transthoracic echocardiography revealed preserved ventricular function. Sputum, blood, and COVID-19 tests, which were performed before blood transfusion, were negative for infectious causes (such as viral, bacterial, and fungal causes). However, empirical antibiotic therapy with meropenem, vancomycin, and acyclovir was initiated before cultures and COVID-19 test results get ready. Despite aggressive management, including inotropic support and mechanical ventilation, the patient’s condition deteriorated, and she succumbed to her illness.
Clinical discussion
TRALI is a rare but severe complication of blood transfusion, characterized by acute hypoxemia and non-cardiogenic pulmonary edema occurring within 6 hours of transfusion in the absence of other risk factors for acute lung injury (ALI) [ 6 ] . Although the incidence of TRALI has decreased with modern blood bank precautions, it still poses a diagnostic challenge due to its clinical similarity to other transfusion-associated adverse events, such as transfusion-associated circulatory overload (TACO), allergic reactions, cardiac complications, and infectious processes [ 6 ] .In our case, a 57-year-old woman with MM developed acute respiratory distress and bilateral pulmonary infiltrates 4 hours after receiving a whole blood transfusion. Her presentation fulfilled the revised 2019 diagnostic criteria for Type II TRALI, which includes new-onset ALI within 6 hours of transfusion in patients with pre-existing risk factors, such as hematologic malignancy or systemic inflammation [ 7 ] . The patient’s hematologic malignancy and recent chemotherapy likely contributed to a pro-inflammatory state, acting as the “first hit” in TRALI pathogenesis, with transfusion being the “second hit.” The “second hit” was likely triggered by transfused donor plasma containing leukocyte antibodies or bioactive lipids, leading to pulmonary neutrophil activation, endothelial damage, and capillary leak [ 8 , 9 ] . This aligns with previous literature indicating that hematologic malignancies are high-risk phenomenon for TRALI, though recent studies suggest that malignancies do not heighten the risk unless accompanied by transfusion or systemic inflammation [ 10 , 11 ] . As a result, this case reinforces the need for increased clinical suspicion of TRALI in patients with hematologic malignancies and consideration of both patient- and transfusion-related factors in risk evaluations. Notably, the accurate differentiation of TRALI from TACO was essential. While both conditions can manifest with respiratory distress, hypoxia, and radiographic evidence of pulmonary edema, TACO is characterized by signs of circulatory overload, including elevated jugular venous pressure, peripheral edema, hypertension, and cardiomegaly on chest imaging, as well as a favorable response to diuretic therapy [ 12 ] . In our patient, clinical examination illustrated no evidence of volume overload. Additionally, transthoracic echocardiography illustrated normal left ventricular function without signs of cardiac decompensation, which makes TACO unlikely.
Allergic and anaphylactic transfusion reactions were also considered, as they typically present with cutaneous signs such as urticaria, flushing, or pruritus, and may involve respiratory symptoms including wheezing or bronchospasm [ 13 ] . Our patient exhibited none of these features.
Furthermore, cardiogenic pulmonary edema, resulting from myocardial infarction or heart failure, was excluded due to the absence of cardiac symptoms, normal ECG and echocardiogram results. There were also no elevations in cardiac biomarkers to suggest ischemic injury.
Importantly, the patient’s initial chest imaging showed no abnormalities. Fever was absent, inflammatory markers did not suggest sepsis, and cultures from blood and sputum were negative. Additionally, COVID-19 PCR testing returned negative. The rapid onset of respiratory distress post-transfusion, in the absence of preceding signs of infection, further supported TRALI over infectious causes (Table 1 ).
Table 1
Characteristics of differential diagnoses of transfusion-related acute lung injury (TRALI)
a Transfusion-associated circulatory overload. b B-type natriuretic peptide. c N-terminal proBNP. d Jugular vein distention. This table was designed based on Cho et al study [ 14 ] .
| TRALI | TACO a | Infectious causes (sepsis/bacterial contamination) | Allergic causes (allergic/anaphylactic reactions) | |
| Onset time | Within 6 hours of transfusion (usually acute) | Usually within 1–2 hours of transfusion | Can occur during or shortly after transfusion | Usually immediate or during transfusion |
| Pathophysiology | Non-cardiogenic pulmonary edema caused by neutrophil activation, endothelial damage | Cardiogenic (hydrostatic) pulmonary edema due to volume overload | Infection due to bacterial contamination, septic shock possible | Hypersensitivity to donor plasma proteins or allergens |
| Clinical presentation | Acute respiratory distress, hypoxemia (SpO2 < 90%), dyspnea, tachypnea, fever, hypotension, cyanosis, sometimes transient leukopenia | Respiratory distress, hypertension, elevated central venous pressure, distended neck veins, peripheral edema, tachycardia | Fever, chills, rigors, hypotension, possible septic shock | Urticarial rash, itching, bronchospasm, laryngeal edema, hypotension |
| Blood pressure | Hypotension common | Hypertension common | Hypotension common in severe sepsis | Hypotension common especially in anaphylaxis |
| Chest auscultation | Pulmonary crackles, minimal findings | Rales, crackles, possible S3 gallop | Variable, may have crackles | Wheezing, bronchospasm |
| Chest X-ray findings | Bilateral pulmonary infiltrates, non-cardiogenic pulmonary edema (no cardiomegaly) | Bilateral pulmonary infiltrates with enlarged cardiac silhouette, Kerley B lines | Possible bilateral infiltrate if ARDS/sepsis develops | Usually normal; no infiltrates |
| Pulmonary artery wedge pressure (PAWP) | Normal or low (<18 mmHg) | Elevated (>18 mmHg) | Variable, often elevated in septic shock | Normal |
| Central venous pressure (CVP) | Normal or unchanged | Elevated | Variable | Normal |
| BNP b or NT-proBNP c levels | Normal or low BNP (<100–200 pg/mL) | Elevated BNP (>500–1200 pg/mL) | Variable, may be elevated in septic shock | Normal |
| Fluid status | No signs of circulatory overload | Positive fluid balance, volume overload signs | Variable, may have fluid shifts due to capillary leak | Normal |
| Response to diuretics | Minimal or no improvement | Significant improvement | Variable | Not applicable |
| Leukocyte count | Transient leukopenia observed in some cases | No leukopenia | Leukocytosis or leukopenia depending on infection phase | No specific leukocyte change |
| Fever | Often present | Usually absent or unchanged | Common, prominent | Sometimes present (especially with anaphylaxis) |
| Additional signs | Absence of volume overload signs such as JVD d | Jugular venous distension, peripheral edema | Positive blood cultures with same organism as transfused product | Urticarial rash, angioedema, bronchospasm |
| Laboratory tests | May detect donor anti-HLA or anti-HNA antibodies; exclusion of other ALI risk factors | Elevated BNP/NT-proBNP, signs of volume overload on labs | Positive blood cultures, elevated inflammatory markers | Elevated serum tryptase or positive basophil activation test (BAT) |
| Management implication | Supportive care, oxygen, mechanical ventilation if needed; no role for diuretics or corticosteroids | Diuretics effective; careful fluid management; oxygen support | Antibiotics, supportive care for sepsis | Antihistamines, corticosteroids, epinephrine for anaphylaxis |
Overall, despite aggressive supportive measures – including oxygen therapy, mechanical ventilation, and broad-spectrum antibiotics – the patient deteriorated rapidly, which underscores the severity of TRALI in immunocompromised patients. Management remains largely supportive, including immediate termination of transfusion and provision of oxygen therapy or mechanical ventilation, as needed. Although no specific pharmacologic treatments have been established, ongoing research continues to explore anti-inflammatory and immunomodulatory therapies [ 12 ] .
Preventive strategies have remarkably diminished TRALI incidence in recent years. These include the use of male-only plasma donors, screening for anti-HLA and anti-HNA antibodies in donors, and the adoption of leuko-reduced blood components, particularly in high-risk populations such as patients with hematologic malignancies [ 15 , 16 ] .
This case report was limited by its single-patient scope, absence of advanced biomarker analysis or post-mortem studies limits the understanding of the underlying pathophysiology. The empirical antimicrobial regimen administered to our patient (meropenem, vancomycin, and acyclovir) may not include specific coverage for Pneumocystis jirovecii or Aspergillus species, which are important considerations in high-risk neutropenic hosts. Future institutional guideline updates may address these gaps to optimize management of similar cases. Notably, limitations in blood bank resources resulted in the use of whole blood transfusions rather than leuko-reduced blood components, which are preferred to reduce transfusion-related complications. Additionally, delays in diagnostic testing, including microbiological and radiological assessments, constrained timely differentiation of TRALI from other potential transfusion reactions or infectious etiologies. Such resource and infrastructure constraints are common in many settings and underscore the real-world barriers to optimal care in patients with hematologic malignancies requiring transfusion support. Recognition of these systemic challenges is essential for contextualizing management decisions and for guiding improvements in clinical protocols and health system capacity.
Conclusion
This case underscores the diagnostic challenges and clinical severity of TRALI, especially in patients with hematologic malignancies like multiple myeloma. Early recognition and supportive care are critical for managing this life-threatening complication. Future studies should focus on identifying specific biomarkers for TRALI, exploring preventive strategies such as improved donor screening protocols, and evaluating novel therapeutic approaches to reduce its impact. Large-scale research is also needed to enhance understanding and improve outcomes for high-risk populations.
Footnotes
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Published online 14 August 2025
Contributor Information
Mehdi Yousefipour, Email: mehdiypm@gmail.com.
Amirreza Heidarian, Email: arh14042025@gmail.com.
Ethical statement
Ethics committee review was not needed for this case report.
Consent
Written informed consent was achieved from the legal guardians of patient for publication of this case report and accompanying images. A copy of the written informed consent is available for review by the Editor-in-Chief of this journal on request.
Sources of finding
None.
Conflicts of interest disclosure
The authors declare no competing interests.
Author contributions
All the authors participated in the study’s conceptualization and design. A.H. and M.Y. was responsible for data collection and figure design. M.S.T. and A.H. analyzed and reported the radiographic findings. A.H. and M.S.T. wrote the initial draft, with all authors contributing revisions and feedback. M.Y. edited the manuscript. A.H. also oversaw the study. All the authors reviewed and approved the final version.
Research registration unique identifying number (UIN)
Name of the registry: RESEARCH REGISTRY. Unique identifying number or registration ID: researchregistry 11161. Hyperlink to the registration (must be publicly accessible): https://www.researchregistry.com/browse-the-registry#home/ .
Guarantor
Amirreza Heidarian.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Data availability
The data supporting the findings of this study are available within the manuscript. Additional details can be obtained by contacting the corresponding author.
References
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Associated Data
Data Availability Statement
The data supporting the findings of this study are available within the manuscript. Additional details can be obtained by contacting the corresponding author.