Alemtuzumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that binds to CD52, a superficial marker expressed on most mature lymphocytes, leading to a severe depletion of peripheral blood lymphocytes (T and B cells, especially CD4⁺) for a period of several months or longer, dose-depending. For the last years it has been used for the treatment of relapsing-remitting multiple sclerosis and it was prior approved for the treatment of B-cell chronic lymphocytic leukemia [1],[2]. The incidence of symptomatic CMV reactivation in patients with leukemia treated with Alemtuzumab has ranged from 5% to 30% [3]. The risk of reactivation of latent herpesvirus infection like cytomegalovirus (CMV) is increased by therapy that affects cellular immunity, such as Alemtuzumab and several opportunistic infections such as CMV reactivation have been reported in post-marketing case series [4],[5],[6],[7].

We report the case of a patient with MS who had an asymptomatic CMV reactivation after starting Alemtuzumab posing a therapeutic dilemma.

A 37-year-old lady presented in 2008 with a clinical picture of ataxia, diplopia, and left hemi-sensory loss. Magnetic resonance imaging and cerebrospinal fluid were consistent with MS. The patient reported a previous episode of diplopia in 2001. In 2008, she started treatment with subcutaneous interferon beta-1a but the treatment was stopped because of intolerance and then she began Glatiramer acetate. Despite that, she had breakthrough disease and the treatment was switched to Natalizumab in 2009. John Cunningham virus seropositivity led to Natalizumab interruption in 2013 and the patient started Fingolimod. In 2018, she had two relapses under Fingolimod and treatment with Alemtuzumab was considered. At that time, the patient was evaluated at the Infectious Diseases outpatient clinic. Under Fingolimod the patient presented lymphopenia grade 2 (710 cells/μL). At first in Infectious Diseases consultation the patient had no constitutional nor respiratory symptoms. She was screened for CMV which revealed a prior contact with the agent (IgM negative, IgG positive), with undetectable plasma CMV DNA by polymerase chain reaction (PCR) assay. Human immunodeficiency virus (HIV) serology was negative.

The patient started a 6-week Fingolimod washout period with lymphocyte recovery (1434 cells/μL with 474 CD4⁺ T-cells/μL). Afterwards, the patient started the standard dose of 12 mg daily for 5 days of Alemtuzumab. During the Alemtuzumab infusion, methylprednisolone was prescribed (1 g per day i.v. for 5 days). On the first day of infusion, the patient initiated anti-herpesvirus prophylaxis with acyclovir 200 mg twice daily and anti-Pneumocystis jirovecii and Listeria monocytogenes prophylaxis with trimethoprim-sulfamethoxazole 960 mg tree times per week.

Pre-emptive therapy for prevention of CMV infection guided by CMV-DNA detection and on a symptom-based approach was chosen. The patient repeated laboratorial work-up after one month of Alemtuzumab infusion and a severe lymphopenia was found (106 cells/μL) with a decrease in CD4⁺ T-cell count to 6 cells/μL and an increase of CMV plasma viral load to 10.604 copies/mL. The patient did not show any signs nor symptoms compatible with a viral syndrome or with end-organ disease. She had also an ophthalmological evaluation which excluded CMV retinitis.

An asymptomatic CMV reactivation was assumed and an antiviral regimen was initiated with valganciclovir 900 mg twice daily for 21 days after which CMV viral load was undetectable. Valganciclovir was then adjusted for a prophylactic dose (900 mg/day) that was maintained until three months after Alemtuzumab infusion. Cytomegalovirus viral load remained undetectable during this period which led to prophylaxis suspension. At that time, the laboratorial work-up showed a grade 2 lymphopenia (630 cells/μL with 35 CD4⁺ T-cells/μL).

At one-year follow-up the patient did not develop any clinical symptoms and at least two additional CMV viral DNA PCR tests were performed and were negative.

It was decided to delay the second Alemtuzumab cycle in the COVID-19 pandemic scenario according to international recommendations

Cytomegalovirus is one of the most relevant pathogens when dealing with immunocompromised patients, including solid organ or hematopoietic cell transplant recipients, HIV-infected patients, and patients treated with immunomodulating drugs for other indications, such as Alemtuzumab for MS treatment [8],[9],[10].

Alemtuzumab produces a pronounced depletion of circulating immune cells which is related with a temporally increased susceptibility toward infections, especially those that depend on T-cells control, such as viral infections (including CMV). An immune state similar to the one caused by an advanced human immunodeficiency virus infection is induced and the spectrum of infectious agents to account for is similar to the ones that occur on severe quantitative T-cell defect linked to acquired immunodeficiency syndrome associated with HIV infection [2].

Cytomegalovirus end-organ disease was common in advanced HIV infection, typically occurring with CD4⁺ T-cell count of 100 cells/mm. Cytomegalovirus infection can affect multiple organs, the most common clinical manifestations being related to the underlying immunosuppression. In HIV infection the most common manifestation is retinitis and in hemopoietic stem cell transplantation is gastrointestinal disease [9],[10].

Our patient had a rapid CD4⁺ T-cell depletion (6 cells/μL) one month after Alemtuzumab infusion accounting as a risk factor for CMV reactivation.

Asymptomatic CMV infection is defined as CMV replication without signs or symptoms of disease. Cytomegalovirus disease is defined as CMV infection accompanied by clinical signs and symptoms [10]. We considered this case to be an asymptomatic CMV infection because the patient had CMV viral replication with no symptoms nor evidence of end-organ disease.

Cytomegalovirus retinitis should be excluded by a formal ophthalmological examination, as happened in our case, since it may be clinically silent and the patient may not report symptoms.

The two main strategies for CMV prevention are prophylaxis (a CMV anti-viral drug such as valganciclovir is initiated as soon as the immunomodulating drug is introduced in order to prevent infection) and pre-emptive therapy (CMV viral load is monitored during treatment and if there is an elevation, prophylaxis is started).

Pre-emptive therapy is effective in the prevention of CMV disease development, preventing the exposure to the side effects of prophylaxis. However the need to perform routine diagnostic evaluation (mainly DNACMV) in order to identify the moment of CMV reactivation imposes a tight follow-up of the patient and may become more expensive than prophylaxis [2].

Currently there are no formal guidelines regarding an attitude towards CMV reactivation when dealing with MS patients treated with Alemtuzumab. While guidelines exist for other pathologies where Alemtuzumab is used, as for chronic lymphocytic leukemia or solid organ and hematopoietic cell transplantation, in the case of MS the Alemtuzumab dose is lower, used in monotherapy and for a shorter period of time.

Cytomegalovirus disease in MS patients is infrequent, with only scarce case reports [4],[5],[6],[7]. However a study in MS patients treated with anti-CD52 drugs reported several opportunistic infections, mainly CMV reactivations (48%) that was defined by detectable viremia (>85 copies/mL on serum) regardless of signs of CMV disease, most of these occurring early after drug infusion in the first month after treatment, which the authors found to be related with considerable decrease of the lymphocytes counts (total and CD4⁺ T-cells) [10]. Pre-emptive monitoring with PCR is not warranted in MS patients receiving Alemtuzumab, as opposed to what is proposed in hematological patients, but it may be an option [1],[2]. The PCR assay is a quantitative test and the combination of viral load in the initial phase of infection and the rate of increase in viral load may help to identify patients at risk for CMV disease and also to monitor responses to antiviral therapy if initiated. This could prevent initial prophylaxis with no clear indication and possible side effects. We choose a PCR assay also because is available in our center.

Based on the lack of evidence to choose a prophylactic strategy we decided to monitor the patient for the development of CMV replication. We performed a viral load testing prior to and one month after Alemtuzumab infusion. Because CMV viremia was detected, we initiated anti-viral treatment with valganciclovir to prevent progression to disease. There are no established cut off values to definitely differ active CMV infection (which requires treatment) from asymptomatic viral replication with no clinical significance, particularly for MS patients. We assumed CMV reactivation concerning there was an important increase of CMV viral load (10.604 copies/mL) comparing with the baseline value.

In conclusion, the use of Alemtuzumab imposes clinical and laboratorial specific approaches regarding CMV prophylaxis and guidelines considering MS patients are scarce. A pre-emptive approach for CMV reactivation among MS patients on Alemtuzumab may be plausible, but randomized studies are needed. Like other authors, we suggest that CMV serology should be determined prior to Alemtuzumab treatment and the plasma or whole-blood CMV viral load should be monitored in the first two months after Alemtuzumab infusion, when CMV reactivation risk appears to be higher. More studies are needed to establish if a pre-emptive approach to CMV in MS patients has an impact in the outcome of these patients.