key: cord-1016380-pnaa8hoj
authors: Murai, Yushi; Kawasuji, Hitoshi; Takegoshi, Yusuke; Kaneda, Makito; Kimoto, Kou; Ueno, Akitoshi; Miyajima, Yuki; Kawago, Koyomi; Fukui, Yasutaka; Ogami, Chika; Sakamaki, Ippei; Tsuji, Yasuhiro; Morinaga, Yoshitomo; Yamamoto, Yoshihiro
title: A case of COVID-19 diagnosed with favipiravir induced drug fever based on positive drug-induced lymphocyte stimulation test
date: 2021-03-18
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.03.048
sha: 15290f4a18da73629db264f65e519c53dac1a249
doc_id: 1016380
cord_uid: pnaa8hoj

As of October 2020, there is still no specific drug to treat COVID-19 as it rages around the world. Favipiravir, indicated for the treatment of new and re-emerging influenza infections, has been suggested to be effective against SARS-CoV-2, although this has not yet been fully validated. We administered favipiravir to a 64-year-old female patient with COVID-19. Her symptoms resolved quickly after the start of treatment, with reduction of SARS-CoV-2 viral load, but she developed a fever again on day 12. Since the fever was relieved by discontinuation of favipiravir, and based on positive results with a drug-induced lymphocyte stimulation test, we diagnosed her with favipiravir-induced drug fever. Decrease in the serum concentration of favipiravir was observed along with resolution of the fever. The present case suggests that drug fever should be considered in the differential diagnosis of relapsing fever episodes in COVID-19 patients receiving favipiravir.

Coronavirus disease 2019 (COVID-19) has been spreading around the world since 2019, and Japan is no exception. COVID-19 is characterized by a wide variety of clinical presentations, with some cases remaining asymptomatic and others progressing J o u r n a l P r e -p r o o f to fatal pneumonia [1] .

As of October 2020, the only drugs approved for COVID-19 in Japan are remdesivir and dexamethasone, both of which have been reported to be effective [2, 3] .

On the other hand, favipiravir, which was developed in Japan and is indicated for the treatment of new and re-emerging influenza infections, is undergoing clinical trial and has been suggested its efficacy for COVID-19.

The common side effects of favipiravir include hyperuricemia, diarrhea and neutropenia, along with a few reports of drug fever. We experienced a case of COVID-19 who had a fever during administration of favipiravir and was diagnosed with favipiravir-induced drug fever based on positive result of drug-induced lymphocyte stimulation test.

J o u r n a l P r e -p r o o f

The patient was a 64-year-old woman who presented with fatigue, joint pain, and loss of appetite. She was admitted to the hospital for treatment of COVID-19 after testing positive on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antigen test. When she came to the hospital, she reported having had a persistent fever for approximately one week.

Vital signs on admission were as follows: blood pressure, 121/89 mmHg; heart rate, 84 beats/min; body temperature, 36.9 ˚C; respiratory rate, 18 breaths/min; and SpO2, 94% (room air). Blood tests showed normal total white blood cell count and absolute lymphocyte count, elevated C-reactive protein levels, and high lactate dehydrogenase (LD) levels (white blood cell count: 5,200/μL [Neut 69.7%, Lympho 24.0%; 1248/μL], CRP: 3.30 mg/dL, and LD: 280 U/L). Her chest computed tomography (CT) showed extensive ground glass opacity in both lungs.

After admission, favipiravir (3,600 mg per day on the first day and 1,600 mg per day thereafter) was started on day 1 (Figure 1 ). SARS-CoV-2 quantitative reverse transcription-polymerase chain reaction (RT-qPCR) of nasopharyngeal swabs just before the administration of favipiravir indicated a SARS-CoV-2 RNA viral load of 2.64×10 5 copies/μL [4, 5] . She had a fever of 38°C on day 2 and oxygen was started on J o u r n a l P r e -p r o o f day 3; by day 6, she had improvement in the fever and other symptoms. Therefore, we considered that COVID-19 was in remission.

However, on day 12, she again developed a fever of 38°C, which was thought to be caused by bacterial pneumonia or drug fever related to favipiravir. Her respiratory condition was good and supplemental oxygen was discontinued on day 12. There were no findings of lung crackles, abdominal irritation, skin phlebitis/cellulitis and sinusitis in the physical examination. Blood tests showed no evidence suggestive of bacterial pneumonia, and severe anemia and elevated bilirubin were not observed. The uric acid level was high at 10.6 mg/dL, but suspected clinical symptoms of gout, such as swelling of the joints, were not observed. Chest radiographs were taken besides blood tests, but there were no signs of pneumonia, and blood cultures were negative. Urine culture was not performed because there were no complaints including bladder irritation sign suggesting bacterial urinary tract infection. Favipiravir was discontinued on day 13

because there were few subjective symptoms other than fever, and decreased viral load of nasopharyngeal swab collected on day 9 was revealed on day 12 with the strong suspicion of drug fever caused by favipiravir. There was, however, no new skin rash that was suspicious of a drug eruption.

After the discontinuation of favipiravir, her body temperature gradually decreased, 

Discussion Favipiravir (AVIGAN®) prevents viral replication by selectively inhibiting RNA polymerase, which is used for gene replication in RNA virus cells [6] . It is effective against all human A, B and C influenza viruses, including neuraminidase inhibitorresistant viruses. Favipiravir shows moderate antiviral activity in vitro against SARS-CoV-2, a type of RNA virus, and is expected to be a therapeutic agent for COVID-19 [7] .

The dosing protocol for favipiravir in COVID-19 is 1800 mg twice a day on day 1 and 800 mg twice a day on day 2 and thereafter for 10 days (maximum 14 days).

Although favipiravir has been shown to be safe in various studies, the risks of teratogenicity, QT prolongation, and hyperuricemia need to be considered [8] . Elevated blood uric acid levels are a particularly frequent side effect of favipiravir. However, blood uric acid levels normalize quickly after discontinuation of favipiravir, and few symptoms due to hyperuricemia were observed in most studies [9] . Case reports of drug fever with favipiravir, as experienced in the present case, are still few.

Drug fever is the febrile response to a drug without cutaneous manifestations [10] .

Although the mechanisms of drug fever are diverse, the positive DLST in our patient revealed that the drug fever in this case was caused by type IV hypersensitivity. DLST J o u r n a l P r e -p r o o f is the most commonly used in vitro test to detect the causative agent of drug allergy, and assesses the proliferation of lymphocytes sensitized by the antigenic stimulus of a drug [11] . However, DLST does not have high sensitivity and specificity, and it is not used as a definitive diagnostic test of drug fever, but is instead used as a reference value. Also, the SI that should be considered as indicative of sensitization is rather controversial, because the SI depends on various factors. In general, we use an SI of >2 to classify the test as positive, based on negative values in exposed but not allergic individuals [12] .

Drug-induced immune hemolytic anemia (DIIHA) due to an autoimmune mechanism may occur in cases of drug-induced fever without skin symptoms and has been reported for antimalarial agents such as artesunate [13, 14] . Although a direct antiglobulin test was not performed in this case, severe anemia and elevated bilirubin were not observed around the time when fever has recurred, and the patient was considered unlikely to have had DIIHA.

Although in vitro studies such as DLST might be helpful, in many cases, fever is relieved by discontinuation of the causative drug and is a clue to the diagnosis of drug fever. The fever is usually relieved within 72-96 hours after discontinuation of the causative drug [15] . The most effective way to make a definitive diagnosis of drug fever is a challenge test, but this was not possible in our case from an ethical standpoint. In J o u r n a l P r e -p r o o f our patient, mild eosinophilia was accompanied by an increase in leukocytosis and a slightly delayed increase in CRP, the favipiravir-induced DLST was positive, and fever was relieved about 72 hours after the discontinuation of favipiravir. Based on these factors, a diagnosis of drug fever with favipiravir was definitively established.

Favipiravir treatment for from ten days to two weeks is currently suggested for the treatment of COVID-19. However, as in our case, drug fever after 10 days of favipiravir was described in a case report by Takoi and his colleagues [16] . Also, Kurita et al. reported that the favipiravir-induced drug fever occurred about a week after administration [17] .

We measured blood levels of favipiravir administered for the treatment of COVID-19 in serum from our patient ( Figure 2) . Her blood concentration of favipiravir was maintained at about 60-70 mg/L up to day 13 of treatment with favipiravir, decreasing to 0.15 mg/L at day 15 after discontinuation of favipiravir. After discontinuation of oral favipiravir, it was promptly cleared from the blood in association with rapid resolution of fever. The drug fever in this case was thought to be an allergic reaction and not dose-dependent, and no previous data has been found on the correlation between favipiravir blood levels and its side effects. However, in this case, favipiravir was taken for more than one week even after the clinical findings improved and the J o u r n a l P r e -p r o o f 

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Dexamethasone in Hospitalized patients with Covid-19

Remdesivir for the Treatment of Covid-19 -Final Report

Monitoring of viral load by RT-PCR caused decision making to continue ECMO therapy for a patient with COVID-19

Transmissibility of COVID-19 depends on the viral load around onset in adult and symptomatic patients

Favipiravir strikes the SARS-CoV-2 at its Achilles heel, the RNA polymerase

Tolerability of Favipiravir therapy in critically-ill patients with COVID-19: a report of 4 cases

A review of the safety of favipiravir -a potential treatment in the COVID-19 pandemic

Uric Acid Elevation by Favipiravir, an

Drug fever

Comparative study of the usefulness of the drug-induced lymphocyte stimulation test and the leukocyte migration test in drug allergies

The lymphocyte transformation test in the diagnosis of drug hypersensitivity

Severe delayed autoimmune haemolytic anaemia following artesunate administration in severe malaria: a case report

Positive direct antiglobulin test in post-artesunate delayed haemolysis: more than a coincidence?

Favipiravirinduced fever in coronavirus disease 2019: A report of two cases

A Favipiravirinduced Fever in a Patient with COVID-19

The authors have no conflicts of interest to declare.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.J o u r n a l P r e -p r o o f