Background: Cytokine Release Syndrome (CRS) is a hyperinflammatory state triggered by immune therapies like CAR T-cell therapy and bispecific T-cell engagers (BiTEs). Characterized by excessive cytokine release, CRS often mimics infectious and inflammatory conditions, complicating diagnosis and treatment. Immunosuppressive therapies used for CRS further elevate the risk of secondary infections. Methods: A systematic search of PubMed and EMBASE was conducted using terms related to “cytokine release syndrome”, “cytokine storm”, “infections”, and “management”. Studies were included if they described infectious complications, diagnostic mimics, or therapeutic approaches related to CRS. Results: Of 19,634 studies, 2572 abstracts were reviewed. Infections occurred in up to 23% of patients post-CAR T therapy and 24% post-BiTE therapy. Pathogens included gram-positive and gram-negative bacteria, herpesviruses (e.g., CMV, HSV), fungi (e.g., Candida, Aspergillus), and parasites (e.g., Toxoplasma gondii). CRS mimics also included non-infectious inflammatory syndromes. Differentiation remains challenging, but cytokine profiling and biomarkers (e.g., ferritin, CRP, sIL-2Rα) may aid in diagnosis. Treatments included tocilizumab, corticosteroids, and empiric antimicrobials. Prophylactic strategies were inconsistently reported. Conclusions: Effective CRS management requires early recognition, differentiation from infectious mimics, and collaboration between oncology and infectious disease (ID) specialists. A multidisciplinary, collaborative, and structured approach, including dedicated ID input and pre-treatment evaluation, is essential for optimizing CRS management and patient outcomes.

Background/Objectives: Invasive pulmonary mold infections (IPMI) are critical complications in immunocompro-mised patients, contributing significantly to morbidity and mortality. Diagnosing pathogens like Aspergillus and Mucorales remains challenging due to non-specific clinical presentations and the limitations of traditional culture methods. This review provides an up-to-date synopsis of IPMI diagnostic tools, focusing on their diagnostic perfor-mance, turnaround time (TAT), and cost-effectiveness. Methods: We conducted a narrative review of current literature regarding clinical evaluation, radiographic findings (Computerized Tomography), invasive diagnostics (Bronchoalveolar Lavage and biopsy), and non-invasive assays, including next-generation sequencing (NGS) and volatile organic compounds (VOCs). Results: Chest CT remains a vital first step, though classic signs like the "halo" or "reversed halo" are neither sensitive nor specific. Traditional diagnostics are limited by low sensitivity and delayed results. While plasma microbial cell-free DNA (mcfDNA) NGS offers rapid TAT (24–48 hours) and high specificity, its suboptimal sensitivity for Aspergillus (< 50%) and high cost remain significant barriers. Investigational VOC "breath tests" show promising sensitivity (77%–96%) but lack standardization. Conclusions: Future research must prioritize the standardization of non-invasive microbiologic testing modalities, particularly those with rapid TAT such as bedside "breath tests" and high-throughput NGS. Furthermore, the de-velopment of clinical algorithms that balance cost-effectiveness with timely pathogen diagnosis based on the patient’s degree of immunosuppression is essential to improve survival in high-risk populations.

Invasive pulmonary mold infections (IPMIs) are critical complications in immunocompromised patients, contributing significantly to morbidity and mortality. Diagnosing pathogens like Aspergillus species (spp.) and the Mucorales remains challenging due to non-specific clinical presentations and the limitations of traditional culture methods. This review provides an up-to-date synopsis of IPMI diagnostic tools, focusing on their diagnostic performance, turnaround time (TAT), and cost-effectiveness. We conducted a narrative review of the current literature regarding clinical evaluation, radiographic findings, invasive diagnostics, and non-invasive assays, including next-generation sequencing (NGS) and volatile organic compounds (VOCs). Chest computerized tomography (CT) remains a vital first step, though classic signs like the “halo” or “reverse halo” are neither sensitive nor specific. Traditional diagnostics are limited by low sensitivity and delayed results. While plasma microbial cell-free DNA (mcfDNA) NGS offers rapid TAT (24–48 h) and high specificity, its suboptimal sensitivity for Aspergillus spp. (<50%) and high cost remain significant barriers. Investigational VOC “breath tests” show promising sensitivity (77–96%) but lack standardization. Future research must prioritize the standardization of non-invasive microbiologic testing modalities, particularly those with rapid TAT such as bedside “breath tests” and high-throughput mcfDNA NGS. Development of clinical algorithms that balance cost-effectiveness with timely pathogen diagnosis based on the patient’s degree of immunosuppression is essential to improve survival in high-risk populations.