Persistent SARS-CoV-2 Infection in an Immunocompromised Host Treated Successfully With the Japanese Herbal Medicine, Mao-to: A Case Report

Introduction

Persistent coronavirus disease 2019 (COVID-19) among immunocompromised patients, such as those with B-cell deficiencies or HIV, and those who have undergone solid-organ transplantation, is an important clinical challenge [1]. COVID-19 guidelines [2]recommend treatment with nirmatrelvir/ritonavir, molnupiravir, or remdesivir for people at risk of severe COVID-19, or ensitrelvir for mild-to-moderate COVID-19. Remdesivir is highly recommended in mild and moderate cases, with corticosteroids or baricitinib and remdesivir in severe cases. However, the duration of these treatments is limited to ≤10 days, and there is minimal consensus on the treatment of infection persisting beyond 10 days. In most healthy individuals, the clearance of infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is expected within 9 days. However, persistent infection has been identified in some patients, particularly those who are immunocompromised. Although persistent COVID-19 is frequently observed in immunocompromised patients, the treatment is challenging. Persistent COVID-19 causes multiple problems; for patients, these include persistent fever and pneumonia symptoms; for hospitals, the increased potential for further viral transmission. Additionally, SARS-CoV-2 has been reported to accelerate mutation and evolve within the host, raising concerns for public health [1].

Previously, we reported a case in which a 20-day extended course of nirmatrelvir/ritonavir was used successfully to treat persistent COVID-19 [3]. While this treatment was highly effective, the monetary costs were high. For example, an extended course (20 days) of nirmatrelvir/ritonavir costs approximately 400 000 JPY ($2700 USD). Thus, exploring more cost-effective treatment options is crucial.

The Japanese herbal medicine “Kampo” has been widely used in various medical fields. Although reports suggest potential efficacy against COVID-19, there is no consensus on using “Kampo” to treat COVID-19 [4,5]. In this report, we present a case in which the patient did not respond to guideline-based treatments. Mao-to (Ma-huang-tang), a traditional “Kampo” medicine, was used to reduce the SARS-CoV-2 load and successfully improved the patient’s COVID-19 symptoms.

Case Report

A 62-year-old man (height: 174.5 cm; weight: 71.3 kg) underwent 12 courses of obinutuzumab, an anti-cluster of differentiation-20 (anti-CD20) antibody, for follicular lymphoma, and achieved remission 5 years ago. His past medical history included follicular lymphoma, thyroid tumor, and cough variant asthma. He subsequently became infected with SARS-CoV-2, and the clinical course is shown in Figure 1. On day 1, he developed a fever and visited a physician, where he was diagnosed with COVID-19 pneumonia based on a positive antigen test and an infiltrative shadow in the right lung on X-ray images (Figures 2A, 3A). Computed tomography (CT) revealed focal ground-glass opacities in the right lower lung. Remdesivir and dexamethasone were administered intravenously for 3 days, with improvement. However, on day 17, a fever of 40°C recurred, and he visited another hospital. He was diagnosed with persistent COVID-19, and oral molnupiravir was administered on day 18 for 5 days. However, the fever persisted, and he visited his physician again on day 29. X-rays and CT revealed worsening bilateral lung infiltrates (Figure 2B, 3B). He was subsequently treated with remdesivir and methylprednisolone; however, the fever persisted. On day 43, extensive bilateral ground-glass opacities were found on chest CT (Figures 2C, 3C), and he was referred to our hospital on the same day. At our examination, he had a fever of 38.3°C and peripheral oxygen desaturation (91% on room air). Additionally, the SARS-CoV-2 polymerase chain reaction (PCR) cycle threshold (Ct) value was 31, suggesting a relatively low viral load, as measured using the GeneXpert System GX-IV (Cepheid, Sunnyvale, CA, USA). Based on the clinical interpretation criteria used in our institution, Ct values greater than 40 are considered negative. The CT findings were consistent with an organizing pneumonia/nonspecific interstitial pneumonia pattern. From these findings, we diagnosed bacterial pneumonia and/or organizing pneumonia following COVID-19. Initially, we prescribed oral levofloxacin 500 mg/day for the bacterial pneumonia from days 43 to 49. However, due to the lack of clinical and radiological improvement, bacterial infection was considered less likely, and treatment was switched to prednisolone 35 mg (0.5 mg/kg) from days 49 to 55 for organizing pneumonia. However, the fever and lung opacities persisted. On day 55, the SARS-CoV-2 PCR Ct value worsened to 24.9, and chest X-rays showed worsening lung infiltrates (Figure 2D). Because low serum immunoglobulin levels were also identified (480 mg/dL), we changed the diagnosis to persistent COVID-19. Intravenous immunoglobulin was administered for 3 days, with a 5-day course of nirmatrelvir/ritonavir. The patient was discharged on day 58, as his fever and fatigue had improved, dyspnea had resolved (oxygen saturation improved from the high 80% range at admission to the low 90% range), and all inpatient treatments deemed necessary had been completed. On day 64, when he visited the outpatient clinic, he remained afebrile and no longer experienced fatigue, indicating sustained clinical stability (Figure 2E). However, the SARS-CoV-2 PCR Ct value remained high at 27.6. In Japan, long-term nirmatrelvir/ritonavir prescriptions are not covered by national health insurance, making immediate prescriptions difficult. Given that the patient remained afebrile and no longer experienced fatigue on his outpatient visit, he was considered clinically stable. Therefore, he was treated solely with Mao-to, a “Kampo” medicine typically used for febrile conditions with “yang” presentation. A commercially available extract granule formulation (Tsumura Mao-to Extract Granules, 2.5 g per dose, administered 3 times daily) was prescribed. Mao-to (Ma-huang-tang) is composed of Ephedra Herb (Ephedra sinica, 32.3%), Apricot Kernel (Prunus armeniaca var. ansu, 32.3%), Cinnamon Bark (Cinnamomum cassia, 25.8%), and Glycyrrhiza (Glycyrrhiza uralensis, 9.6%). On day 78, the SARS-CoV-2 PCR Ct value had improved to 41.0, indicating viral clearance. Additionally, the patient’s symptoms and imaging findings had improved further compared with day 64 (Figure 2F), suggesting successful viral elimination.

Discussion

Persistent COVID-19 has been frequently reported in immunocompromised patients and is often refractory to treatment in patients with resistance to standard recommended treatments [6]. Some reports suggest combining 2 antiviral treatments or extending the treatment duration. Notably, the only treatment with some consensus is an extended course of nirmatrelvir/ritonavir, which has been approved by the US Food and Drug Administration [1]. However, cost considerations and ethical concerns regarding exceeding the approved dosage limit make extended treatments difficult to use clinically.

The traditional Japanese herbal medicine, Kampo, is effective against influenza. The addition of Mao-to (Ma-huang-tang), which is a form of Kampo, to standard anti-influenza therapies shortens fever duration [7] and may have antiviral effects and suppress various inflammatory changes [8]. Furthermore, Kampo may be beneficial for COVID-19. While direct evidence for the use of Mao-to alone in COVID-19 remains limited, Shin Takayama et al reported that “Kampo” may contribute to the prevention of and recovery from COVID-19 [9]. In addition, Satoru Chiba et al suggested a potential therapeutic role of “Kampo” in COVID-19 through modulation of the gut microbiota [10]. These findings support the clinical rationale for considering “Kampo” formulations, including Mao-to, in the management of persistent COVID-19, particularly in immunocompromised patients. Compared with Western medicine alone, the combination of Western medicine and Kampo has been associated with improved imaging findings, accelerated PCR negativity, and reductions in the numbers of severe cases [11]. In Japan, Nabeshima et al [12] reported that the use of Mao-to to treat COVID-19 resulted in a reduction in viral load and improved clinical symptoms, as in our case. The mechanism of Mao-to efficacy in COVID-19 remains unclear. However, ephedrine might contribute to reduced plasma branched-chain amino acid levels [13], and Mao-to contains methylephedrine. Notably, amygdalin and glycyrrhizic acid, also components of Mao-to, might play a role in the efficacy of Mao-to in COVID-19 by potentially enhancing immune activation. Based on the patient’s clinical presentation, such as fever, cough, and general preservation of energy, we selected Mao-to, a “Kampo” formula typically indicated for upper respiratory symptoms in patients with a “yang” pattern. While “Kampo” selection is often guided by clinical pattern recognition rather than pathogen-specific targeting, Mao-to was chosen in this case due to its compatibility with the patient’s overall symptom constellation and constitutional characteristics. This dosage of Mao-to follows the standard adult prescription guideline provided by the manufacturer and is appropriate for an adult weighing approximately 70 kg. The patient was initially scheduled for outpatient follow-up 5 days after discharge. Based on the clinical symptoms and PCR results at that visit, the subsequent follow-up was arranged for 2 weeks later. In immunocompromised patients, SARS-CoV-2 RNA can persist for extended periods despite resolution of clinical symptoms. According to the U.S. Centers for Disease Control and Prevention (CDC), outpatient management is appropriate in such cases, provided that the patient is clinically stable and closely monitored [14]. The frequency of outpatient visits was determined by ongoing evaluation of symptom progression and viral clearance.

In terms of cost-effectiveness, the herbal medicine used in this case was considerably less expensive than conventional antiviral therapy. For example, a 20-day course of nirmatrelvir/ritonavir would cost approximately JPY 400 000 (USD $2700, calculated at an exchange rate of approximately $1 USD=150 JPY), whereas the standard dose of Mao-to costs approximately JPY 85 (USD $0.60) per day. Even if administered for 20 days, the total cost would be only around JPY 1700 (USD $11.5). In this case, the patient received Mao-to for 14 days, resulting in a total cost of approximately JPY 1200 (USD $8). Considering the observed clinical improvement, this is a highly cost-effective intervention.

An important advantage of Mao-to is the minimal drug interactions, allowing for add-on use with other treatments. Moreover, there are fewer restrictions regarding cost and duration of usage for Mao-to compared with pharmaceuticals. While pseudoaldosteronism associated with glycyrrhizin is a potential major adverse effect, this occurs primarily with long-term use and can be recognized early by monitoring blood test results. The present case shows the potential role of adding and continuing Mao-to in immunocompromised patients with persistent COVID-19 to facilitate viral clearance. This approach warrants further investigation.

Conclusions

In this case of persistent COVID-19 in an immunocompromised patient, the addition of the traditional Japanese herbal medicine Mao-to resulted in improvement in symptoms and an increase in SARS-CoV-2 PCR Ct value, suggesting viral clearance. Mao-to, traditionally used for febrile upper respiratory conditions, may serve as an adjunctive treatment option in select refractory cases. Given its favorable safety profile, low cost, and minimal drug interactions, it may be a viable therapeutic option in select cases of refractory COVID-19. Further investigation through controlled studies is warranted to elucidate its efficacy, underlying mechanisms, and optimal clinical application.