Abstract
No specific therapy is available for COVID-19. We report the effectiveness and adverse effects of triple therapy with hydroxychloroquine, azithromycin, and ciclesonide in patients with COVID-19 pneumonia. The clinical condition of the patients improved within 5 days in response to the therapy.
Keywords: COVID-19, SARS-CoV-2, Pneumonia, Hydroxychloroquine, Azithromycin, Ciclesonide, Therapy, Reverse transcription-PCR
Introduction
Coronavirus disease 2019 (COVID-19), first being reported in Wuhan, Hubei, China in December 2019, has been declared a pandemic.1 Although several investigational approaches are being explored for the treatment for COVID-19 pneumonia, there are no proven or approved treatments. Hydroxychloroquine is commonly used to treat systemic lupus erythematosus, rheumatoid arthritis, and malaria. A representative study reported that patients with COVID-19 who were administered hydroxychloroquine had greater severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance and a shorter time to fever normalization than those in the control group.2 However, an observational study showed hydroxychloroquine administration was not associated with the lower the risk of intubation or death.3 Hydroxychloroquine in combination with azithromycin has been found to be associated with faster virologic clearance than hydroxychloroquine monotherapy.4 Early, not yet peer-reviewed data, suggest ciclesonide, an inhaled corticosteroid used to treat asthma, inhibits the replication of the SARS-CoV-2 in vitro 5. However, the clinical effectiveness of combination therapy with these three agents for COVID-19 pneumonia is not known.
Herein, we report the effectiveness and safety of triple therapy with hydroxychloroquine, azithromycin, and ciclesonide in adult patients with COVID-19 pneumonia.
Materials and methods
This case-series study was conducted at the National Hospital Organization Tokyo Medical Center located in Tokyo, Japan, from March to April 2020.
Patients aged 18 years or older were eligible if the reverse transcriptase-polymerase chain reaction (RT-PCR) test for SARS-CoV-2 in their nasopharyngeal swab specimens was positive and they had pneumonia confirmed by chest imaging. The following data were collected from the medical charts for all patients: age, sex, underlying diseases, smoking history, symptoms, use of angiotensin converting-enzyme inhibitor or angiotensin II receptor blocker medication, body temperature, oxygen saturation in the ambient air on admission, duration of triple therapy from symptom onset, time to fever and respiratory symptom normalization, adverse events, and outcome.
Results
Five patients with COVID-2019 pneumonia were administered triple therapy during the study period. The basic and clinical patient characteristics of the patients are shown in Table 1 . Their median age was 60 years (range: 49–71 years), and three of them were men. Three patients had underlying diseases, including cancer, hypertension, and diabetes mellitus, and four patients were current or former smokers. All patients had flu-like symptoms and, two patients had hypogeusia. Four patients required low-flow nasal cannula oxygenation at admission.
Table 1.
Basic and clinical patient characteristics, treatment, and outcome.
| Patient No. | Age (years) | Sex | Underlying diseases | Smoking history | ACE-I or ARB medication | Principal symptoms | Maximum body temperature (°C) | Arterial oxygen saturation on admission (ambient air) | Oxygen support |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 68 | M | CKD, HT, bladder cancer, renal pelvic cancer | Past | No | fever, headache, fatigue, diarrhea, vomiting, cough, dyspnea, myalgia, arthralgia, hypogeusia | 38.3 | 91% | Low-flow nasal cannula |
| 2 | 71 | F | DM, HL, HT | Current | Yes | Loss of appetite, loss of consciousness, dyspnea | 38.1 | 93% | Low-flow nasal cannula |
| 3 | 49 | F | HT | Current | Yes | fever, headache, arthralgia, dyspnea | 39.6 | 85% | Low-flow nasal cannula |
| 4 | 60 | M | None | Past | No | fever, cough, fatigue | 39.8 | 85% | Low-flow nasal cannula |
| 5 | 51 | M | None | Unknown | No | fever, dyspnea, rhinorrhea, fatigue, headache, myalgia, hypogeusia | 40 | 96% | None |
| Day of starting triple therapy from symptom onset | Daily dose and duration of hydroxychloroquine | Daily dose and duration of azithromycin | Daily dose and duration of ciclesonide | Other antibiotic treatment | Additional treatment | Time to fever and respiratory symptoms normalization | Adverse event | Time from administering triplet therapy to development of adverse events | Outcome |
|---|---|---|---|---|---|---|---|---|---|
| 14 | 400 mg for 10 days | 500 mg IV for 3 days | 2 × 200 mcg puffs tds for 14 days | CTRX | None | 4 days | None | – | Cure |
| 6 | 200 mg for 10 days | 500 mg IV for 3 days | 2 × 200 mcg puffs tds for 10 days | CTRX | None | 7 days | None | – | Cure |
| 8 | 200 mg for 8 days | 500 mg po for 3 days | 2 × 200 mcg puffs tds for 16 days | CTRX | DMX | 11 days | QTc prolongation | 8 days | Cure |
| 13 | 200 mg for 10 days | 2 g po for 1 days | 2 × 200 mcg puffs tds for 5 days | CTRX, TAZ/PIPC | Favipiravir | – | None | – | Intubation |
| 14 | 400 mg for 5 days | 500 mg po for 3 days | 2 × 200 mcg puffs bd for 12 days | CTRX | None | 3 days | Liver dysfunction | 5 days | Cure |
Abbreviations: ACE-I, angiotensin converting-enzyme inhibitor; ARB, angiotensin II receptor blocker; CKD, chronic kidney disease; HL, hyperlipidemia; HT, hypertension; bd, twice a day; CTRX, ceftriaxone; DMX, dexamethasone; IV, intravenously; po, per os (oral); TAZ/PIPC, tazobactam and piperacillin; tds, 3 times a day.
The median time from symptom onset to the initiation of triple therapy was 13 days (range: 6–14 days) (Table 1). All patients also received other antibiotics. Two patients (Patients 3 and 5) had adverse events, including liver dysfunction and QT prolongation, and discontinued hydroxychloroquine. Three patients (Patients 1, 2, and 5) improved within 5 days and completely recovered from fever and respiratory symptoms within 7 days of triple therapy initiation. However, one patient (Patient 3) showed worsening of their respiratory condition on the day after triple therapy initiation. With the administration of dexamethasone, the patient's condition gradually improved. The forth patient (Patient 4) who experienced progressive respiratory deterioration was additionally administered favipiravir, intubated, and transferred to a high care center.
Discussion
We evaluated the clinical characteristics and outcomes of five patients with COVID-19 pneumonia treated with triple therapy. Most patients started triple therapy over 7 days after the onset. Their clinical condition improved within 5 days of initiating triple therapy.
There are no proven treatments for COVID-19 pneumonia. There are some therapeutic strategies for SARS-CoV-2 infection6: inhibiting SARS-CoV-2 cell entry, endocytosis and membrane fusion; inhibiting RNA synthesis; suppressing inflammation. Hydroxychloroquine blocks viral entry into cells by inhibiting the glycosylation of host receptors, proteolytic processing, endosomal acidification, and attenuation of cytokine production and inhibition of autophagy and lysosomal activity in host cells.6 Although azithromycin belongs to a class of antibiotics used to treat several bacterial infections, its use as potential antiviral has come to light in the recent years through studies on its immunomodulatory and anti-inflammatory effects.7 , 8 Adding azithromycin to the treatment regimen may also be effective to treat underlying potential secondary infections. Ciclesonide has an anti-inflammatory effect on respiratory epithelium.5 Although there is no clear evidence, we expected an additive or synergistic effect of using ciclesonide which has anti-inflammatory effect on respiratory epithelium in COVID-19 pneumonia, in addition to the viral clearance effect of the combination of hydroxychloroquine and azithromycin. In our study, response within 5 days from administering triple therapy lead to favorable outcome. However, the difference in host factors influencing the response to triple therapy is unknown. The Infectious Diseases Society of America COVID-19 guideline warns about the potential for QT prolongation with the combination of hydroxychloroquine and azithromycin.7 Although combination therapies with different mechanisms of action generally have an additive or synergistic effect, it is also necessary to consider the risk of synergistic adverse effects. Therefore, if there is no response to therapy within 5 days, it should be discontinued because of the risk of adverse events. As our study had a small sample size and lacked a control group, it is necessary to evaluate appropriate triple therapy in clinical trials.
In conclusion, our study showed the potential benefits and risks of using the combination of hydroxychloroquine, azithromycin, and ciclesonide for COVID-19 pneumonia.
Funding
All the authors declare that they have no financial, non-financial and personal conflicts of interest.
Ethical approval
This study was approved by the National Hospital Organization Tokyo Medical Center Ethics Committee (R20-048). The need for patient consent was waived owing to the retrospective nature of the study.
Declaration of competing interest
All authors do not have any conflicts of interest to declare.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing.
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