To the Editor,

The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality worldwide. Driven by findings of high-quality randomized trials, management of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has developed rapidly over the past year [1]. Although these trials justifiably focused on preventing severe disease in general patients, their benefits might not apply to some immunodeficient patients at high risk for recurrence of persistent infection. Prolonged Covid-19 is a developing issue for patients with lymphoma or immune deficiency [2]. Several reports described persistent SARS-CoV-2 replication with severe symptoms in immunocompromised patients, including those with lymphoma [3, 4]. This population is at increased risk of persistent SARS-CoV-2 infection, severe outcomes, and mortality due to COVID-19 [5]. Host genomic evolution and viral escape phenomena may potentially occur in patients with primary immunodeficiency due to prolonged relapse of SARS-CoV-2-related infection [6]. Clark et al. reported that SARS-CoV-2 evolution in an immunocompromised host shows neutralization escape mechanisms [7]. As an underlying defect in the immune response of patients with haematological malignancies, the lack of B-cell precursors is the main reason for continuing viral replication and defective viral clearance [8]. Furthermore, immune system deficiencies occurring following anti-CD20 monoclonal antibody treatment can slow development of neutralizing antibodies after administration of two doses of mRNA vaccines against SARS-CoV-2 [9]. Thus, highly efficacious antiviral therapies are urgently needed for these patients. Furlan et al. noted that therapeutic strategies combining immunotherapy with prolonged antiviral treatment may be decisive in patients with B cell immunodeficiencies [10]. Although rapid viral elimination with combined antiviral and antibody-based therapy might preclude further evolution, no optimal, decisive strategy is currently available for patients with persistent infection that allows clinicians to sustain viral clearance, determine optimal timing to stop treatment, and prevent virus reactivation. Some reports discuss RT-PCR cycle threshold (Ct) values and specific antibodies that indicate prolonged COVID-19 infection and responses to vaccines, but none address use of both indicators for treatment [11, 12].

From February 2022, we introduced a novel treatment combining antiviral and neutralizing antibody-based therapies with monitoring of spike-specific antibody and Ct values as indicators of viral load for immunocompromised patients with persistent COVID-19 infection. Knowledge of specific immune responses to antibody-based therapy in immunosuppressed patients is important, and well-validated quantitative PCR that correlates with both viral culture titres and Ct values may help in clarifying infectious viral shedding, guiding treatments, and assessing outcomes [11]. We examined these titre values at least twice weekly. Monitoring of spike-specific antibody response and Ct values during treatment allowed us to evaluate effects of antivirals and neutralizing antibody-based therapies and determine when to end treatment.

In an immunosuppressed COVID-19 patient taking tacrolimus hydrate and mycophenolate mofetil following kidney transplantation, we administered remdesivir as antiviral therapy on day 1 along with sotrovimab as neutralizing antibody-based therapy (Fig. 1). We continued remdesivir while monitoring spike-specific antibody response, viral load, and Ct values. Because the latter two values did not improve, we changed to nirmatrelvir/ritonavir antiviral therapy, following which these values improved to treatment level. After the patient’s viral load stopped rising without antiviral therapy and antibody response was maintained, the patient was removed from isolation and discharged on day 23. We applied this treatment strategy to 10 immunosuppressed COVID-19 patients who currently or previously received immunosuppressive agents for their disease (Table 1). In 5 patients, we switched from initial remdesivir to other antiviral therapy during treatment because viral load and Ct values remained unchanged or worsened. In the other 5 patients who responded well to remdesivir, we terminated it only after confirming that viral load and Ct values reached target levels. All patients were removed from isolation after confirmation that viral load, Ct values, and antibody titres had not worsened since end of treatment. No patient suffered relapse of the viral infection.

Table 1 Immunosuppressed patients with COVID-19 completing treatment without relapse of the viral infection
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As limitations, first, although the progression of SARS-CoV-2 infectious viral shedding and specific immune responses by this treatment are understandable, criteria for frequency of measuring spike-specific antibody and Ct values remain unknown. Second, long-term data on potential viral relapse is unknown. Third, administration of antiviral drugs at above-normal prescription limits based on frequent test results could increase long-term drug and hospitalization costs. Fourth, because the sample size is small, results should be interpreted cautiously. More rigorous research including randomization and larger sample size is needed. Nevertheless, our novel strategy may offer potentially successful treatment for immunocompromised patients with persistent COVID-19.

Fig. 1
figure 1

The graph shows the clinical course of a COVID-19 patient taking tacrolimus hydrate and mycophenolate mofetil as immunosuppressive therapy following kidney transplantation. The round circle indicates viral load, the square indicates Ct value, and the triangle indicates the spike-specific antibody

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