Six patients who visited Hanzomon Clinic for diagnosis and satisfied with the following 3 criteria were included in the present study:

1) COVID-19 patient with pneumonia determined by CT scan, and 2) COVID-19 patient with clinical symptoms & signs, elevated CRP and decreased SpO2, 3) COVID-19 patient who was diagnosed as mild or severe.

In this study severe patients were defined as those who complained of dyspnea, or those who required O₂ inhalation irrespective of assist ventilation. COVID-19 patients free from dyspnea were defined as mild. Critical cases indicate the patients in whom sufficient O₂ saturation could not be obtained despite O₂ administration provided even under assist ventilation. None of the critical cases were enrolled.

Administration of 5-ALA with SFC, favipiravir, chloroquine, ciclesonide, and camostat described in this paper was approved by the ethical committee of Hanzomon Gastrointestinal Clinic, and the informed consent was obtained from the patients or his proxy (Case 1). This research was conducted in accordance with the Helsinki Declaration. CARE guidelines were also followed for this study.

5-ALA and SFC were enclosed in a capsule and administered orally to all patients, except for Case 1, for whom the contents of the capsule were dissolved in water and administered via a nasogastric tube. One capsule contains 25 mg 5-ALA and 28.7 mg SFC. These capsules are available as ALAplus Tou-Down Rich from SBI ALApromo, Tokyo, Japan. When the dose of 5-ALA was altered, the dose of SFC was also changed accordingly in the same proportion. The dose of 5-ALA was determined depending on the clinical severity. When the patient was recognized as severe, the initial dose was set to 1,500 mg/day (500 mg t.i.d., approximately 25 mg/kg of body weight). In mildly affected patients, the initial dose was set to 750 mg/day (approximately 12.5 mg/kg of body weight). Thereafter, the dose was altered according to the clinical symptoms and data.

Patient’s nasal cavity and pharynx samples were obtained with cotton swabs and tested for SARS-CoV-2 using a RT-PCR test according to the national standard. Testing was conducted by local public health laboratories in Tokyo area using the procedure described by National Institute of Infectious Diseases, Japan [26].

To detect antibodies (IgM and IgG) against SARS-CoV-2, we used a rapid immunochromatographic test manufactured by Kurabo Industries Ltd. (Osaka, Japan). The sensitivity of IgM test was 82.58% and the specificity was 100%. The sensitivity of the IgG test was 76.38% and the specificity was 100%.

A 62-year-old man began to feel fatigued on April 3, 2020. He reported that before his symptoms developed, one of his office coworkers had received a positive RT-PCR result for SARS-CoV-2. The patient had a history of type 2 diabetes mellitus (HbA1c = 6.9%) and was being treated with oral hypoglycemic agents. On the day after fatigue symptoms started, he had a fever of 38.7 °C. He called the physician in charge, who prescribed an antipyretic (acetaminophen, 500 mg as needed). His fever temporarily decreased. However, fever (from 37.5 to 39°C) returned. His fever persisted for 8 days and was accompanied by cough, appetite loss, and dyspnea. He checked in to the Japanese Red Cross Musashino Hospital by ambulance on April 14, 2020 (Fig. 1A). On admission, he was transferred to the Intensive Care Unit (ICU) because of severe hypoxia and dyspnea on physical examination. Hypoxia resolved after oxygen inhalation, and his SpO2 was 95% with administration of 10 L/min nasal oxygen. Chest radiography and chest computed tomography (CT) scan revealed pneumonia in the right upper lobe and infiltrative shadow in the left hilum (Figs. 1B & C). C-Reactive Protein (CRP) was 28.43 mg/dL, and White Blood Cell count (WBC) was 11,300 /mm³. RT-PCR for SARS-CoV-2 was positive. He was intubated and ventilated. Favipiravir (3,200 mg/day, 1,600 mg b.i.d.), chloroquine (200 mg/day, s.i.d.), and antibiotics (ceftriaxone sodium hydrate 2 g/day, azithromycin hydrate 500 mg/day) for bacterial infection were started. On April 15, the patient’s SpO2 was 99% with 0.5 inspired oxygen fraction (FiO2). His CRP was 19.99 mg/dL, and WBC was 7600 /mm³. 5-ALA (1500 mg/day, 500 mg t.i.d.) with SFC was administered through a nasogastric tube, and ciclesonide (400 μg/day: 200 μg b.i.d.) was given. The dose of favipiravir was reduced to 1,200 mg/day and that of chloroquine was increased to 400 mg/day. On the next day (April 16), his SpO2 recovered to 97.3% with 0.25 FiO2. His CRP was 21.65 mg/dL, and WBC was 8,700 /mm3. On April 17, his clinical symptoms improved, and favipiravir and chloroquine were completely discontinued due to high AST (49 IU/L) and ALT (61 IU/L) values. However, 5-ALA with SFC and ciclesonide were continued. On April 18, he was disconnected from the ventilator, when his SpO2 reached 93.6% with 1 L/min nasal oxygen. The patient’s CRP was 23.99 mg/dL, and WBC was 8,600 /mm3. On the same day, 5-ALA was reduced to 750 mg/day (250 mg t.i.d.). On April 19, the patient was transferred from the ICU to the general ward. His symptoms further improved, and he was free from nasal oxygen on April 22. His SpO2 was 90% on room air, and his CRP decreased to 1.50 mg/dL. Chest X-P on April 23 showed improvement of pneumonia of the right upper lobe (Fig. 1D). On April 24, the liver enzyme levels in blood such as AST and ALT decreased to normal levels. RT-PCR was carried out on April 24 and 26. The results of both RT-PCRs were negative, and he was discharged. He is now living a normal life with no complications or sequelae. The serum anti-SARC-CoV-2 IgM and IgG antibody levels were too low to be detected by a conventional qualitative assay.

In the beginning of April 2020, a 69-year-old man experienced common cold–like symptoms. On April 5, he visited the clinic because his wife was diagnosed with COVID-19 by RT-PCR. He was suspected to have SARS- CoV-2 infection, and 750 mg/day (250 mg t.i.d.) 5-ALA with SFC was prescribed (Fig. 2A). Chest CT scan on April 7 showed bilateral viral pneumonia shadows with ground-glass opacities extending to the subpleural area (Fig. 2B). His body temperature was 37.1°C, SpO2 was 96% on room air, and CRP was 2.01 mg/dL. The dose of 5-ALA was increased to 1,000 mg/day (250 mg q.i.d.). On April 10, the patient’s body temperature was 37.5°C and his CRP was elevated to 5.52 mg/dL. Camostat mesilate (600 mg/day, 200 mg t.i.d.) was added together with antibiotics (tetracycline hydrochloride 100 mg /day, ampicillin sodium 2 g/day, sulbactam sodium 1g/day) against bacteria. Antibiotics were prescribed for 3 days. On April 11, the patient’s body temperature was 36.9°C. However, his CRP had further increased to 7.21 mg/dL, and the 5-ALA dose was increased to 1,500 mg/day (500 mg t.i.d.). On April 12, his CRP decreased to 6.73 mg/dL. Clinical symptoms were improved on April 14, and his fever had subsided. The patient’s CRP decreased to 2.97 mg/dL as well. Beginning on April 15, the dose of 5-ALA was reduced to 300 mg/day (100 mg t.i.d.). Antibodies against SARS-CoV-2 were examined on April 16. Both IgM and IgG were positive. From April 17, the dose of 5-ALA was further decreased to 100 mg/day (50 mg b.i.d.). A chest CT scan was performed on April 21, which revealed a partial improvement of pneumonia, and the patient’s CRP had achieved a normal level (0.05 mg/dL). Chest CT scan taken on May 7 revealed almost complete remission of pneumonia (Fig. 2C). He is now living a normal life with no complications or sequelae. The last RT-PCR was negative.

A 66-year-old woman became aware of a slight fever on March 31, 2020. A few days prior, she had dinner with an intimate friend who was later diagnosed with COVID-19. On April 5, the patient experienced a sore throat and visited the clinic. She used to be a smoker (40 cigarettes/day for 38 years) but had stopped smoking for the past 9 years. She was suspected to have SARS-CoV-2 infection, and 750 mg/day (250 mg t.i.d.) 5-ALA with SFC was prescribed (Fig. 3A). On April 7, a chest CT scan was performed, which revealed ground-glass opacity in the right upper lobe (Fig. 3B). Her CRP level was 2.95 mg/dL. Thereafter, her CRP gradually decreased, and it was 0.13 mg/dL. When antibodies against SARS-CoV-2 were examined on April 16, both IgM and IgG were positive. On the same day, the 5-ALA dose was reduced to 100 mg/day (50 mg b.i.d.). Chest CT scan on April 21 revealed almost complete resolution of the initial pneumonia, although a new subtle lesion was detected in the subpleural area of the left lower lobe. Her CRP level was 0.05 mg/dL when she visited the clinic on May 2. CT scan on May 7 revealed almost complete resolution of the pneumonia shadow (Fig. 3C). She has been afebrile with normal SpO2 throughout the clinical course. She is now living a normal life with no complications or sequelae. The last RT-PCR was negative.

A 63-year-old man felt a chill and visited the clinic on April 2, 2020. He had been experiencing common cold–like symptoms for a few days prior to clinic presentation. He had been a smoker until 2 years previously (10 cigarettes/day for 30 years and 5 cigars/day for 5 years) but had stopped smoking for the past 2 years. At the time of his visit, his body temperature was 36.3°C, and his CRP level was 0.70 mg/dL. Antibiotic therapy (tetracycline hydrochloride 100 mg/day, ampicillin sodium 2 g/day, sulbactam sodium 1 g/day for the initial 2 days) and 250 mg/day 5-ALA (125 mg b.i.d.) with SFC were prescribed (Fig. 4A). On the next day (April 3), the patient’s fever increased to 38.5°C and the CRP level was elevated to 5.06 mg/dL. Chest CT scan revealed bilateral multiple nodular shadows with ground-glass opacity lesions (Fig. 4B). That day, the dose of 5-ALA was increased to 2250 mg/day (750 mg before dawn and 500 mg t.i.d. during daytime), and the dose was decreased to 1,500 mg/day (500 mg t.i.d.) on April 4. On April 6, the patient experienced watery diarrhea, and 5-ALA was reduced to 750 mg/day (250 mg t.i.d.). Beginning on April 7, the patient’s body temperature decreased to below 37.0°C, and his CRP gradually decreased. Antibodies against SARS-CoV-2 were examined on April 16. Both IgM and IgG were positive. The dose of 5-ALA was decreased to 300 mg/day (100 mg t.i.d.) on April 15, and it was further decreased to 150 mg/day (50 mg t.i.d.) on April 18. Chest CT scan examined on April 21 did not show a distinct improvement, but his CRP level had decreased to 0.34 mg/dL. However, a chest CT scan performed on May 7 revealed almost complete resolution of the pneumonia shadow (Fig. 4C). He is now living a normal life with no complications or sequelae. The last RT-PCR showed negative.

A 67-year-old man visited the clinic on April 10, 2020, because he had a slight fever (about 37.5°C) for 1 week. At the time of visit, his body temperature was 36.1°C, CRP level was 4.92 mg/dL, and SpO2 was 97% on room air (Fig. 5A). Chest CT scan on the same day revealed multiple lesions with ground-glass opacity in the subpleural area (Fig. 5B). A dose of 750 mg/day 5-ALA (250 mg t.i.d.) with SFC and camostat mesilate (600 mg/day, 200 mg t.i.d.) were prescribed. The dose of 5-ALA was increased to 1,500 mg/day (500 mg t.i.d.) and camostat mesilate was terminated on April 12. The patient’s CRP level decreased to 0.93 mg/dl on April 14, and 5-ALA was reduced to 750 mg/day (250 mg t.i.d.) on April 15. On April 16, antibodies against SARS-CoV-2 were examined. IgM was negative, but IgG was positive. The CRP level was 0.27 mg/dL, and 5-ALA was reduced to 100 mg/day (50 mg b.i.d.). Chest CT scan on April 21 revealed considerable improvement of lung lesions, and the patient’s CRP had further decreased to 0.08 mg/dL. Chest CT scan on May 7 revealed almost complete resolution of the pneumonia shadow (Fig. 5C). He returned to normal life without problems. The last RT-PCR was negative.

On June 26, 2020, a 56-year-old man experienced common cold–like symptoms with high fever. His body temperature was 37.5 to 38.5 °C. He took OTC antifebrile pills and got his body temperature down to 36.5 °C. However, he became suspicious about his infection by SARS-CoV-2 because he lost taste and smell, and then he visited the clinic. His CRP was 4.49 mg/dL and RT-PCR test showed positive for SARS-CoV-2. On June 30, his chest CT scan showed bilateral viral pneumonia shadows with ground-glass opacity in the right upper lobe (Fig. 6B). Thus, 1,500 mg/day (500 mg t.i.d.) 5-ALA with SFC was prescribed (Fig. 6A). He was also treated with 600 mg/day camostat mesilate (200 mg t.i.d.) together with antibiotics (tetracycline hydrochloride 100 mg/day, ampicillin sodium 2 g/day, sulbactam sodium 1 g/day for the initial 3 days) against bacterial infection. On July 1, he was given the same treatment and his body temperature was 36.8°C, SpO2 was 97% on room air, and CRP was lowered to 3.28 mg/dL. On July 2, he was hospitalized and given 1,500 mg/day (500 mg t.i.d.) 5-ALA with SFC and 600 mg/day camostat mesilate (200 mg t.i.d.) again.

His CRP level decreased to 1.80 mg/dL. He was given only 1,500 mg/day (500 mg t.i.d.) 5-ALA with SFC for 3 more days without any other medications. During his hospitalization, he had a high fever (38.0°C) only once in the night on June 3 but recovered soon by antipyretics. On July 7, the patient’s body temperature was 36.6°C and his CRP decreased to 0.44 mg/dL, SpO2 was 98% on room air, and then he was dismissed. The dose of 5-ALA was decreased to 750 mg/day (250 mg t.i.d.) on July 6 and the same treatment was given at home until July 12 for total 6 days.

On July 14 he visited the clinic. Both IgM and IgG for SARS-CoV-2 were positive and his chest CT scan revealed almost complete remission of pneumonia (Fig. 6C). He is now living a normal life with no complications or sequelae. The last RT-PCR was negative.

High doses of 5-ALA with SFC did not cause serious side effects except for a few cases as follows. In the cases 2, 4, and 5, the patients experienced abdominal swelling, constipation and had blackish feces when 1,500 mg/day 5-ALA with SFC was administered. In case 2, he had skin irritation by sun light exposure after taking 1,500 mg/day 5-ALA with SFC. A patient who had arrhythmia reported palpitations when he took 1,500 mg/day 5-ALA with SFC. Those side effects were all dissolved by dose reduction to 750 mg/day.

Other minor side effects and complaints were abdominal pain, diarrhea, nausea, glow, malaise, and insomnia. None of them were serious and all of them were resolved after the dose reduction.

During the treatment of COVID-19 patients with 5-ALA with SFC, blood liver enzyme levels such as AST (aspartate aminotransferase, GOT)and ALT (alanine aminotransferase, GPT) were normal in all the cases except for the initial period of Case 1. When Case 1 patient was treated with favipiravir and chloroquine, both AST and ALT exceeded the normal ranges as described above. However, after the termination of dosing of favipiravir and chloroquine, both AST and ALT levels decreased to normal levels.