Cytomegalovirus Infections in Hematopoietic Stem Cell Transplant: Moving Beyond Molecular Diagnostics to Immunodiagnostics
Abstract
:1. Introduction
1.1. CMV in HSCT
1.2. CMV Diagnosis
1.3. CMV Management Strategies in HSCT
1.4. CMV Immune Reconstitution and Immune Monitoring in HSCT
2. Role of Genetic Polymorphism
3. Method for Immune Monitoring
4. Utility of Immune Monitoring in HSCT
5. Functional Immune Monitoring
6. Immune Reconstitution in Haploidentical HSCT
7. Pre-Transplant Immune Monitoring
8. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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S. No. | Diagnostic Test |
---|---|
1. | Serology: Antibody detection of anti-CMV immunoglobulin (IgM and IgG), does not indicate active viral replication. |
2. | Viral culture: Isolation of virus from multiple samples, including whole blood, plasma, sterile body fluids, urine, and biopsy using tissue cultures that use human embryonic fibroblast cells. However, detection of CMV in culture only indicates the presence of the virus or shedding of the virus and does not confirm active CMV disease. Moreover, these methods are time-consuming, lack sensitivity, and are rarely used nowadays. |
3. | Histopathology: Histopathology is the gold standard for the diagnosis of tissue-invasive CMV disease by detecting cytomegalic cells and viral-specific inclusion bodies in a tissue biopsy specimen but requires invasive procedures like bronchoscopy or endoscopy to obtain a tissue sample. |
4. | Antigen detection: This involves the detection of pp65 in peripheral blood leucocytes by using specific fluorescently labelled monoclonal antibodies in peripheral blood polymorph nuclear leukocytes. This technique is sensitive, specific, and quantitative. The antigen detection can also be used for monitoring therapeutic response. However, being labour-intensive is not used widely. |
5. | Molecular assay: PCR is highly sensitive as it can detect minute amounts of nucleic acid in various clinical samples, determine viral load, and can be used for therapeutic monitoring. |
Studies | Study Design | Study Population | CMV Cell-Mediated Immune Assessment | Method for CMV Assessment | Results |
---|---|---|---|---|---|
Chemaly et al., React Study, 2020 [36] | Multicentric 13 centers USA, Canada, UK, Sweden | 241 adult patients (>18 years) Allogenic HSCT R+ | Pre-transplant: d = 14, Post-transplant: d +14, +28, every 15 d up to 6 months | CMV pp65 and IE1-specific ELISPOT assay | CMV-CMI, independent predictor of CS-CMVi (p = 0.04) CMV-CMI low in patients who experienced CS-CMVi (94%), and high CMV-CMI has less CS-CMVi (p < 0.0001) |
Seo et al., 2021 [37] | Australia | 52 pediatric patients Allogenic HSCT D+/R− status: 45 D−/R− status: 4 D−/R− status: 3 | Pre-transplant: once Post-transplant: 1, 2, 3, 4, 5, 6, 9, 12 months Monitoring terminated when CMV-CMI recovered at two consecutive evaluations | CMV pp65 and IE1-specific ELISpot assay | Pre-HSCT CMV-specific CMI > 5 SFC/2 × 105 cells significant predictive factor CMV-CMI recovery post-HSCT, but not CS-CMVi; Recovery of CMV-CMI > 50 SFC/2 × 105 cells Post-HSCT protective factor for CS-CMVi (aOR = 0.13; 95% CI = 0.22–0.71) |
Lilleri et al., 2012 [24] | Italy | 131 adult and pediatric patients Allogenic HSCT D+/R+ status: 51 D−/R+ status: 38 D+/R− status: 42 | Post-transplant— monthly until day 180, then every 3 months until the detection of CMV-specific CD4+ and CD8+ T cells | Flow cytometric analysis for CMV-specific CD4+ and CD8+ T cells producing IFN-γ and IL-2 | In the absence of GvHD, virus-specific T cell immune response remained stable after recovery, and the patients did not require treatment for CMV reactivation after achieving protective immunity |
Nesher et al. [38] | USA | 63 adult patients Allogeneic HSCT D+/R+ status: 41 D−/R+ status: 22 | Pre-transplant Post-transplant d 30 (±7 d), d 60 (±7 d), and d 100 (±14 d) | CMV-specific IE-1 and pp65 antigens ELISpot assay | Thresholds (50 spots/250,000 cells for IF-1; 100 spots /250,000 cells for pp65) identified patients who were protected against CMV infection CMV-specific ELISpot response above the determined thresholds only significant factor for preventing CMV reactivation (aHR—0.21; 95% confidence interval, p = 0.046) |
Tey et al., 2013 [34] | Australia | 41 adult patients (>18 years) Allogenic HSCT D+/R− status: 14 D−/R− status: 24 D−/R− status: 3 | Post-transplant weekly between 3 and 14 weeks, 6 and 12 months | CMV-specific peptides pp65, IE1, epitopes from pp50, IE2 and gB; QuantiFERON CMV assay | The median time to stable CMV-specific immune reconstitution was 59 days, incidence of CMV reactivation lower in patients who developed this than those who did not (27% versus 65%; p = 0.031) Failure to reconstitute CMV-specific immunity soon after the onset of CMV viremia associated with higher peak viral loads (5685 copies/mL versus 875 copies/mL; p = 0.002) |
Naik et al. [39] | USA | 23 pediatric patients >2 years Allogenic HSCT | Pre-transplant: once Post-transplant: 1, 2, 3, 4, 5, 6, 9, 12 months | CMV pp65, IE1-specific IFNg ELISpot Longitudinal assessment of CD3+ T cells by FACS | Recipients with CD3+ counts >300 cells/microL exhibited potent functionally protective levels of CMV-directed T cell activity (defined as >30 antigen-specific SFCs/5 × 105), rapidly cleared viral reactivation |
Lee et al. [35] | Republic of Korea | 33 pediatric patients Allo-HSCT D+/R+ status: 16 D+/R− status: 7 D−/R− status: 2 | Baseline at 4 weeks post-HSCT Every time with CMV antigenemia (pp65) till the end of CMV treatment, 7 d after CMV antigenemia becomes negative | QuantiFERON CMV assay | Patients who had positive QF-CMV results after CMV reactivation had no recurrent infections thereafter, patients with indeterminate or negative results had recurrent CMV infections. Established CMV-specific T cell immunity following initial CMV infection to prevent recurrent CMV infection episodes |
1 | Predict CMV reactivation |
2 | Shorten the duration of pre-emptive therapy |
3 | Predict those who could clear the virus spontaneously |
4 | Predict those who could contract an end-organ disease |
5 | Predict recurrent CMV reactivation following the first reactivation episode |
6 | To determine the need for adoptive T cell therapy |
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Gupta, C.; Mundan, N.G.; Das, S.; Jawed, A.; Dar, S.A.; Dailah, H.G. Cytomegalovirus Infections in Hematopoietic Stem Cell Transplant: Moving Beyond Molecular Diagnostics to Immunodiagnostics. Diagnostics 2024, 14, 2523. https://doi.org/10.3390/diagnostics14222523
Gupta C, Mundan NG, Das S, Jawed A, Dar SA, Dailah HG. Cytomegalovirus Infections in Hematopoietic Stem Cell Transplant: Moving Beyond Molecular Diagnostics to Immunodiagnostics. Diagnostics. 2024; 14(22):2523. https://doi.org/10.3390/diagnostics14222523
Chicago/Turabian StyleGupta, Chhavi, Netto George Mundan, Shukla Das, Arshad Jawed, Sajad Ahmad Dar, and Hamad Ghaleb Dailah. 2024. "Cytomegalovirus Infections in Hematopoietic Stem Cell Transplant: Moving Beyond Molecular Diagnostics to Immunodiagnostics" Diagnostics 14, no. 22: 2523. https://doi.org/10.3390/diagnostics14222523
APA StyleGupta, C., Mundan, N. G., Das, S., Jawed, A., Dar, S. A., & Dailah, H. G. (2024). Cytomegalovirus Infections in Hematopoietic Stem Cell Transplant: Moving Beyond Molecular Diagnostics to Immunodiagnostics. Diagnostics, 14(22), 2523. https://doi.org/10.3390/diagnostics14222523