key: cord-0803942-qxttxvxe
authors: Hosoba, Rika; Makita, Shinichi; Shiotsuka, Mika; Kobayashi, Osamu; Nakano, Kiyoko; Muroya, Mimiko; Okada, Naoko; Suzuki, Makiko; Ida, Hanae; Fukuhara, Suguru; Munakata, Wataru; Suzuki, Tatsuya; Maruyama, Dai; Maeshima, Akiko Miyagi; Matsushita, Hiromichi; Yamamoto, Noboru; Ohe, Yuichiro; Iwata, Satoshi; Izutsu, Koji
title: COVID-19 pneumonia in a patient with adult T-cell leukemia-lymphoma
date: 2020-09-03
journal: J Clin Exp Hematop
DOI: 10.3960/jslrt.20030
sha: 86aa36b303e17b5328d57223462f17f8ab9eae7e
doc_id: 803942
cord_uid: qxttxvxe

Although some patients with COVID-19 develop only mild symptoms, fatal complications have been observed among those with comorbidities. As patients with cancer are immunocompromised, they are thought to have a high risk of severe illness associated with COVID-19. We report a COVID-19 patient with adult T-cell leukemia-lymphoma (ATL) who was treated using favipiravir. A 69-year-old woman with lymphoma-type ATL was treated using cyclophosphamide, doxorubicin, vincristine, prednisolone and mogamulizumab (M-CHOP) with substantial efficacy. However, in cycle 4 of M-CHOP therapy, she developed fever with mild cough. The patient was admitted to the hospital and CT revealed bilateral ground-glass opacities. SARS-CoV-2 was detected by RT-PCR and the patient was diagnosed with COVID-19. Considering severe immunosuppression caused by ATL, we initiated favipiravir therapy. Subsequently, the fever improved without antipyretics and her C-reactive protein level decreased rapidly. SARS-CoV-2 PCR tests were negative on days 17 and 18 of favipiravir therapy, and the patient was discharged without residual disease on the final CT. This is the first documented case of COVID-19 in a patient with ATL. Although severe immunosuppression caused by ATL was present, severe COVID-19 pneumonia did not develop. The immunosuppressed condition caused by hematological malignancy may not always be a risk factor for severe illness associated with COVID-19. Further accumulation of data regarding COVID-19 in patients with hematological malignancies is warranted to clarify the risk factors for severe illness, the best-in-class antiviral agent, and the optimal treatment strategy in this population.

malignancies, including ATL, and no past history. She was started on cyclophosphamide, doxorubicin, vincristine, and prednisolone in combination with mogamulizumab (M-CHOP) with substantial efficacy. However, on day 15 of M-CHOP cycle 4, she developed fever of up to 38.0˚C with mild cough and sore throat. Levofloxacin at 500 mg once daily was administered as empiric therapy for febrile neutropenia, but fever persisted. On day 20 of cycle 4, the patient visited our hospital. Although she had mild cough and sore throat, her oxygen saturation was 98% in room air. Her peripheral white blood cell count was 2,700/μL (neutrophils, 84%; lymphocytes, 4%), hemoglobin was 11.2 g/dL, and platelet count was 27.1×10 4 /μL. Her CD4-positive T-cell count was low (23/μL) and her C-reactive protein (CRP) level increased to 4.11 mg/dL. Other laboratory findings, including biochemical analysis and coagulation assays, were normal (Table 1) . Whole-body computed tomography (CT) revealed bilateral and subpleural ground-glass opacities typical of COVID-19 (Fig. 1A) . However, lymphadenopathy was not observed and her ATL was in complete remission. The patient was admitted to the hospital and empiric therapy for bacterial (piperacillin/tazobactam) and fungal infection (voriconazole) was started. Her performance status was 1 on admission. The next day, SARS-CoV-2 was detected by real-time reverse transcription polymerase chain reaction (RT-PCR) from a nasopharyngeal swab and the patient was diagnosed with COVID-19. With no standard-of-care for COVID-19, she received only supportive care such as acetaminophen. Five days after admission, RT-PCR for SARS-CoV-2 remained positive even though her fever was self-limited with supportive care. Considering the severe immunosuppression caused by ATL, we initiated favipiravir therapy at 1,600 mg twice daily (BID) on day 5 after admission, followed by 800 mg BID. The patient provided written informed consent and emergency approval for off-label use was obtained from the Director of National Cancer Center Hospital, followed by institutional review committee approval.

After the initiation of favipiravir, the fever improved without antipyretics and her CRP level decreased rapidly (Fig. 2) . On day 5 of favipiravir, follow-up CT demonstrated a decrease in the distribution of ground-glass opacities (Fig. 1B) . Grade 3 transient transaminitis was observed on day 3 of favipiravir treatment. However, it may have been associated with the increased trough level of voriconazole (14.23 μg/mL). Grade 1 hyperuricemia, which is associated with favipiravir, was observed from day 7, but it was manageable using oral febuxostat. On day 10, SARS-CoV-2 remained detectable by follow-up PCR. Therefore, we continued favipiravir until the maximum approved treatment duration of 14 days. SARS-CoV-2 PCR tests on days 17 and 18 were negative, and the patient was discharged without residual disease on the final CT on day 18 (Fig. 1C) .

To the best of our knowledge, this is the first documented case of COVID-19 in a patient with ATL.

ATL is a distinct entity of peripheral T-cell lymphoma caused by human T-lymphotropic virus type-I (HTLV-1). As HTLV-1 infects CD4-positive T lymphocytes and results in oncogenesis, patients with ATL have severe immunodeficiency associated with lymphoma itself. 8 In addition, low CD4 counts continue following chemotherapy against ATL. In our patient, the CD4 count at COVID-19 onset was only 23/μL. Therefore, patients with ATL are thought to have a high risk of severe illness associated with COVID-19. However, the patient had mild COVID-19 infection that did not require supplemental oxygen or ICU management despite severe immunosuppression by ATL. This was partly because the patient did not have other risk factors for severe illness associated with COVID-19 such as asthma, diabetes, kidney disease, severe obesity and elderly age. Successful disease control of ATL may also have played a role in the favorable clinical course of COVID-19 in this patient. Therefore, the immunocompromised condition caused by hematological malignancies may not be a sole risk factor for severe illness in COVID-19. Currently, anti-inflammatory agents, such as tocilizumab, ibrutinib and acalabrutinib, have been tested for the treatment of COVID-19. 9-12 Thus, the immunosuppressed condition may play a protective role against severe cytokine storm associated with COVID-19. Further accumulation of data is warranted to clarify the risk factors for severe COVID-19 among patients with hematological malignancies.

Favipiravir is a pyrazine analog that selectively and potently inhibits the RNA-dependent RNA polymerase (RdRp) of RNA viruses. 13 It was approved by the Pharmaceutical and Medical Device Agency (PMDA) for the treatment of patients with novel or re-emerging pandemic influenza virus infection in Japan. 14 As the catalytic domain of RdRp is conserved among different types of RNA viruses, favipiravir is expected to be an effective antiviral agent against SARS-CoV-2. In the present case, we decided to use favipiravir because the patient was immunocompromised, which is considered to increase the risk for severe illness associated with COVID-19, and other antiviral agents were not available in Japan at that time. COVID-19 was treated by favipiravir and it may have prevented the progression of COVID-19 to fatal pneumonia. However, we cannot conclude that favipiravir was effective against COVID-19 in this patient because the fever was self-limited with supportive care before the initiation of favipiravir. To confirm the actual efficacy of favipiravir, further evaluation in a largescale clinical trial is warranted. 15 Currently, several agents other than favipiravir with three main mechanisms of action are being tested or approved for the treatment of COVID-19. These include agents that inhibit fusion of the viral envelope, such as nafamostat and camostat, 16, 17 agents that inhibit viral RNA duplication, such as anti-HIV agents lopinavir/ritonavir 18 and remdesivir, 19 and anti-inflammatory agents, including tocilizumab (an interleukin-6 receptor blocker), 9 ibrutinib and acalabrutinib (Bruton's tyrosine kinase inhibitors). [10] [11] [12] Further careful evaluation is required to determine the bestin-class treatment and the actual role of these drugs in the treatment of COVID-19.

In conclusion, we report a case of COVID-19 in a severely immunocompromised ATL patient. As the patient did not develop severe COVID-19 pneumonia, the immunosuppressed condition caused by hematological malignancy may not always be a risk factor for severe illness associated with COVID-19. Further accumulation of data regarding COVID-19 in patients with hematological malignancies is warranted to clarify the risk factors for severe illness, the best-in-class antiviral agent, and the optimal treatment strategy in this population. Dainippon, and received honoraria from Ono Pharmaceutical,

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We thank all of the health care workers, including nurses in Ward 11B and Ward 18, clinical research coordinator (Ms. Miki Ito) and doctors of the COVID-19 Treatment Team (Drs. Yuka Ahiko, Tsutomu Hayashi, Ken Masuda, Makoto Nishino, Junya Oguma, Yu Okubo, Tatsunori Shimoi and Yuki Shinno) at the National Cancer Center Hospital for managing the patient. We also sincerely thank health care workers at the frontlines in the fight against COVID-19 worldwide.