TO THE EDITOR
Cytomegalovirus (CMV) is a common herpesvirus that is carried asymptomatically by most healthy individuals throughout their lives[1]. CMV was first described in the early 1900s but was not isolated until 1957[2]. CMV makes up one of the most common perinatal diseases in the world, affecting between 0.5% and 1.0% of newborns annually[3]. Immunocompetent individuals rarely develop symptoms, but patients with compromised immune systems due to human immunodeficiency virus, organ transplants, or underdeveloped immune systems, such as in newborns, can be at fatal risk for complications resulting from CMV[4].
CMV activation significantly impacts mortality, morbidity, and organ incorporation in organ transplant[5]. CMV reactivation commonly causes pneumonia and gastrointestinal disease and eventually leads to end-organ damage and death.[6] Patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) are often evaluated for CMV and CMV infection is detected in 25%-40% of patients developing CMV[7]. CMV precautions for patients undergoing allo-HSCT include measuring viral load (VL), strict adherence to guidelines, and the use of prophylactic antivirals[8]. Despite its widespread prevalence among allo-HSCT patients, the same strict guidelines, diagnostic criteria, and close monitoring are limited in autologous hematopoietic stem cell transplantation (AHSCT) due to the believed decreased risk of CMV reactivation and faster immune system recovery[9].
Despite the more limited occurrence of CMV in AHSCT patients, recent studies have demonstrated a significant mortality rate due to the variability in screening guidelines and VL thresholds, especially compared to the stringent guidelines that exist with allo-HSCT patients[10]. In a targeted case study, Zhou et al[11] described six patients who received AHSCT treatment and were previously CMV seropositive. Five of the patients suffered fatal post-surgical complications related to CMV issues, including underlying infection, hemorrhaging, and ophthalmic loss. With more proactive treatment, including a presurgical screening for CMV serological presence and a more tailored therapy given these results to limit the use of T-cell depleting monoclonal antibodies and corticosteroids, these patients could have had an earlier detection of the complications and an earlier intervention, potentially yielding improved clinical results[11]. This risk may be particularly underestimated in specific AHSCT patient subgroups, especially in patients who undergo T-cell-depleting therapies due to the removal of CMV-specific immunity and delayed immune system reconstitution[12]. Ben Moussa et al[13] found that another at risk subgroup was based on sex, with women suffering from CMV reactivation at nearly two times the rate of men, though further work needs to be done to verify the true difference in CMV reactivation between sexes and the true mechanism of action.
Alexander et al[14] surveyed multiple AHSCT facilities worldwide and found core differences in the screening and care provided to patients. Pre-surgical serological testing was performed in only 91% of facilities, and only 82% of centers monitored patients with autoimmune diseases for CMV reactivation after AHSCT. The length of follow-up varied among patients post-treatment: 95% of centers followed out to day 100 (d100), 52% to day 180 (d180), and 27% to day 365 (d365)[14].
Clinical impact
CMV reactivation can have a significant impact, particularly as AHSCT becomes a primary treatment modality for a range of autoimmune diseases, including lymphomas. A national study performed in Korea found that CMV reactivation affected about 6.5% of patients who underwent hematopoietic stem cell transplantation, the third most common opportunistic infection in the study[15]. Patients diagnosed with CMV reactivation suffer from a variety of different CMV complications that target various organ systems. Fatal complications usually result from issues related to end-organs. A common CMV complication is the presence of CMV pneumonia, a condition that was found in one study by Konoplev et al[10] to have a fatality rate of 31%. Antiviral prophylaxis is common in both allo-HSCT and AHSCT, but differences in treatment duration and screening practices can affect patient outcomes, particularly in cases of delayed CMV reactivation. While prophylaxis treatment and d100 screening methods are more common, the lack of late-term screening can allow compounding VL and yield significant complications much further from the treatment[16]. While Ben Moussa et al[13] noted primarily CMV reactivations within the d100 period among the patients in their study, a study done by Husain et al[17] demonstrated that delayed acting CMV reactivation in transplant patients occurred over three months to up to 2 years later, an almost 30% occurrence, further demonstrating the type of issues that can strike patients with the lack of detailed clinical guidelines to determine a screening schedule or how often follow-up should be administered. Results from this study bring into question if d100 is an appropriate stopping point for CMV screening or if further testing is beneficial for patients, especially given the high variability that was found in various surgical settings including length of continued follow-up for testing, with only 27% of surgical centers following patients to d365[14]. Limited research is present in studying delayed CMV reactivation in AHSCT patients, but research in allogenic-HSCT recipients establish the real and dangerous risk of CMV reactivation after d100 when most testing ends, with reactivation occurring in approximately 60% of seropositive patients and 10% of seronegative patients, and of those being delayed (termed in this case to be after d100) approximately 7.2% of the time[18,19]. Based off of these results, movement of the centralized guidelines to d365 would be more advisable, helping to save a significant amount of patients and allowing higher standards of more rigorous testing to be applied to patients who are seropositive pre-transplant[20]. Additional clinical tools are also present to help with pre- and post-surgical treatment for patients with AHSCT; Jakharia et al[21] discuss the use of CMV cell-mediated immunological assays to help individualize treatment for immune reconstitution in patients at-risk for issues arising from surgery; however, the lack of detailed guidelines still limits the effectiveness and usefulness of the application of such clinical tools into practice.
The need for centralized guidelines for CMV reactivation complications in AHSCT is extremely necessary and should be organized arranged on pertinent characteristics that determine CMV reactivation susceptibility. Ben Moussa et al[13] establish that VL monitoring is essential to early detection and treatment of CMV reactivation, with results demonstrating that VL greater than 150 IU/mL demonstrated occurrence of CMV reactivation in patients before generally climbing to a median at 1300 IU/mL. Ben Moussa et al[13] also found that within the patient cohort tested, the initial media VL post-transplant was elevated for patients that suffered CMV-related fatalities, close to 2400 IU/mL, necessitating specific antiviral medications. The testing and adoption of universal guidelines for VL measurements are medically necessary to allow patients the ability to survive the CMV reactivation complication, with thresholds needed for initial measurements as well as for when specific antiviral medications need to be introduced to prevent further complications. Additional attention should be given to at-risk patient subgroups, for example: Patients that test seropositive during the pre-transplant process, a subgroup in which CMV reactivation occurs 60% of the time according to Stern et al[18]. Such subgroups would benefit from an extended CMV testing schedule and a more thorough monitoring regimen. Ben Moussa et al[13] also highlights the importance of adoption of prophylactic antiviral medications, another centralized guideline that should be evaluated and adopted for improved patient safety.
CONCLUSION
CMV reactivation is a well-known complication that affects many immunosuppressed patients worldwide. Among them are those who receive hematopoietic stem cell transplantation. Although commonly evaluated pre- and post-surgically in allo-HSCT, the same clinical guidelines, VL thresholds, and clinical evaluations have not been applied in AHSCT. Although the prevalence of CMV reactivation is much lower in AHSCT, its impact is evident in both mortality and graft incorporation success rates. Screening and follow-up are typically done close to the AHSCT procedure, but patients with delayed CMV reactivation can result in vastly increased VL that can be detected and allow for early intervention with a centralized guideline and threshold for patient safety[8]. Centralized guidelines are not only medically necessary, but are paramount to the safety of patients in a complication of AHSCT that has been historically marginalized. The development of universal VL thresholds for CMV reactivation so that providers can effectively identify at-risk patients, give specific antivirals to those who need it based on VL, and also help all patients through the adoption of prophylactic antiviral medication should be a priority moving forward. Such standardized guidelines and safety thresholds can also be effectively applied to patient subgroups that are at a higher risk for CMV reactivation such as T-cell-depleting therapy patients, to effectively manage procedural complications and prevent any potential ramifications from excess care[12,13]. CMV reactivation remains a serious threat to patients going through both allogenic and AHSCT and should be treated as such.
