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A 74-year-old white woman presents to an emergency department in Flint, Michigan, after suffering with low-grade fever, dry cough, and shortness of breath for the previous 2 days.

Her medical history for the week before includes elective surgery at an­other hospital for total replacement of the right knee. She notes that she was healthy on admission and at discharge. She stayed in a private room, and had no contact with individuals who were ill or who had traveled recently. She states that since the surgery, though, she has had pain, redness, and swelling in her right knee.

Her past medical history was pertinent for essential hypertension, obesity, myasthenia gravis in remission, and osteoarthritis.

Physical examination shows:

• Body temperature: 37.3°C

• Blood pressure: 121/82

• Pulse: 87 beats per minute

• Respiratory rate: 16 breaths per minute

• Oxygen saturation: 87% in ambient air

Lung auscultation reveals bilateral rhonchi with rales, and chest radiography shows patchy air space opacity in the right upper lobe suspicious for pneumonia; other findings are unremarkable.

Clinicians order a rapid nucleic acid amplification test for influenza A and B, which is negative. Concerns about community transmission of COVID-19 prompt a nasopharyngeal swab, which is sent to the state laboratory for detection of SARS-CoV-2. The patient is admitted to the airborne-isolation unit, maintaining compliance to the CDC recommendations for contact, droplet, and airborne precautions.

After drawing blood and sputum cultures and giving supportive care with two liters of supplemental oxygen, clinicians start the patient on broad-spectrum antibiotics, cefepime and levofloxacin, in consideration of the risks associated with her recent hospitalization for knee surgery.

On the third day, the patient develops mild diarrhea, generalized weakness, and fatigue. After evaluation by neurologists, she is started on 1 g/kg intravenous immunoglobulin for 4 days due to a mild exacerbation of her myasthenia gravis and an impending related crisis. She reports progressively worsening shortness of breath since her admission, and oxygen requirements have increased up to 10 L high-flow nasal cannula.

Results of the nasopharyngeal swab are positive for SARS-CoV-2 by reverse-transcriptase polymerase chain reaction (RT-PCR). Clinicians start treatment with oral hydroxychloroquine 400 mg once and then 200 mg twice a day, along with intravenous azithromycin 500 mg once a day, zinc sulfate 220 mg three times a day, and oral vitamin C 1 g twice a day.

When blood and sputum cultures are negative for any organisms, broad-spectrum antibiotics are discontinued.

The patient's dyspnea rapidly worsens, and oxygen requirements increase to 15 liters. She is drowsy, in moderate distress, and her airways remain unprotected.

Blood pressure is 78/56 mm Hg; heart rate is 112 beats per minute, temperature is 38°C, and respiratory rate is 28 breaths per minute.

Changes in arterial blood gases (ABGs), complete blood count, and basic metabolic profile studies during hospitalization (days 1-6) include mild absolute lymphopenia and anemia. ABGs reveal a pH of 7.46, partial pressure of carbon dioxide (pCO2) of 44.6 mm Hg, partial pressure of oxygen (pO2) of 94.7 mm Hg, and bicarbonate of 31.4 mmol/L.

By day 6, creatinine kinase and lactic acid are normal, and there are elevations in lactate dehydrogenase (312 units/L), ferritin (767 ng/mL), and interleukin-6 (52 pg/mL).

Bilateral alveolar infiltrates are evident on chest x-ray, due to pneumonia and interstitial edema, consistent with acute respiratory distress syndrome (ARDS).

Given her rapid deterioration, the patient is intubated on an emergent basis and started on pressure-regulated volume-controlled mechanical ventilation.

Clinicians also initiate treatment with norepinephrine 0.02 mcg/kg/min for septic shock, and titrate the dose to maintain a mean arterial pressure over 65 mm Hg, along with colchicine 0.6 mg twice a day to address the cytokine storm ­given the elevated interleukin-6 levels.

On day 7, the second day of mechanical ventilation, at the request of the family when the patient develops ARDS, she is started on a continuous intravenous infusion of high-dose vita­min C (11 g /24 hours). Two days later, her clinical condition gradually begins to improve, and the clinicians discontinue supportive treatment with norepinephrine.

On day 10, the fifth day of mechanical ventilation, another chest x-ray shows that both the pneumonia and interstitial edema have improved considerably. The patient responds well to a spontaneous breathing trial with continuous positive airway pressure/pressure support, with the settings of positive end-expiratory pressure (PEEP) of 7 mm Hg, pressure support above PEEP of 10 mm Hg, and a fraction of inspired oxygen of 40%.

ABGs reveal a pH of 7.49 mm Hg, pCO2 of 40.2 mm Hg, pO2 of 77.1 mm Hg, and bicarbonate of 30.2 mmol/L.

The clinicians note the patient's "remarkable improvement clinically and on chest x-ray," and extubate her to 4 L of oxygen with a nasal cannula.

Her breathing status continues to improve over days 11-15. On day 16, she shows significant recovery, with oxygen saturation of 92% while breathing ambient air, and chest radiography reveals almost complete resolution of the infiltrates.

During her hospitalization, the patient received a total of 5 days of treatment with hydroxychloroquine and azithromycin along with 4 days of colchicine. Treatment with high-dose vitamin C infusion and oral zinc sulfate were continued for a total of 10 days.

The patient received inpatient physical and occupational rehabilitation after being transferred from the critical care unit to an isolation room. On day 16 of her illness, she still tests positive and is in stable condition with an additional 14 days of quarantine.

Discussion

Clinicians reporting this of an older woman treated with high doses of intravenous vitamin C for COVID-19, septic shock, and ARDS note that she was the first patient at their hospital who was able to discontinue mechanical ventilation early and recover from the disease.

The case report authors note that the mortality rate associated with ARDS is up to 45%, which is almost equal to the 50% case fatality rate reported in patients with severe COVID-19 disease requiring critical care management. Numerous studies have shown that high-dose intravenous vita­min C reduces systemic inflammation in a variety of ways, including by attenuating the cytokine surge, and vitamin C has also been shown to prevent lung injury in patients with severe sepsis and ARDS.

Vitamin C in­fusion is not approved as a standard treatment for SARS-CoV-2 and thus was not part of the hospital's COVID-19 treatment regimen. Nevertheless, the case authors point out that for decades, vitamin C has been recognized as an essential component of immune cell function with a critical role in numerous immune system mechanisms. Severe vitamin C deficiency is also known to increase the risk for fatal scurvy, as well as for pneumonia and other infections.

Vitamin C enhances neutrophil motility, phagocytosis, microbial killing by activating reactive oxygen species, and apoptosis, and prevents oxidative damage by its antioxidant properties. It also promotes the proliferation of B and T lymphocytes and antibody production. More recent research suggests that vitamin C also prevents the production of pro-inflammatory cytokines, including interleukin-6, a component of the cytokine release syndrome associated with severe COVID-19 that results in lung injury and leads to ARDS.

When this immune response is diminished by microorganisms, the resulting severe inflammatory state and tissue necrosis can lead to multiorgan failure and ARDS that necessitate mechanical ventilation -- up to 75% of patients who are critically ill with COVID-19 require invasive mechanical ventilation in the intensive care unit (ICU).

Although the data on vitamin C are mixed, a recent meta-analysis suggests that in patients with severe sepsis and ARDS, vitamin C lessens both the duration of mechanical ventilation and the length of ICU stay. In a recent randomized of 167 patients with sepsis and ARDS, treatment with high-dose intravenous vitamin C up to 15 g per day was associated with a significant reduction in 28-day mortality and a shortened duration of ICU stay.

These data may have contributed to the recent increase in use of vitamin C in the treatment of COVID-19 disease, the case authors note. For instance, a phase II trial has been initiated at Wuhan University in China to study the efficacy of vitamin C infusion in the treatment of ARDS associated with SARS-CoV-2.

The case authors also pointed to a study of COVID-19 in critically ill patients in the Seattle region that found a median ICU stay of 14 days and duration of mechanical ventilation of 10 days, whereas the patient in the case report had a 6-day ICU stay and 5 days of mechanical ventilation.

According to a 2017 of vitamin C and immune function, epidemiological studies have indicated that hypovitaminosis C (i.e., plasma vitamin C less than 23 mmol/L) is relatively common in Western populations, and vitamin C deficiency (less than 11 mmol/L) is the fourth leading nutrient deficiency in the U.S.

The 2007-2010 U.S. National Health and Nutrition Examination Survey of approximately 16,000 children and adults found that almost 40% had low levels of vitamin C, while 88% of the U.S. population did not meet the daily requirement for vitamin E (noted to enhance the effects of vitamin C).

Conclusions

The case authors conclude that their report highlights the potential benefits of high-dose intravenous vitamin C in critically ill COVID-19 patients in terms of rapid recovery and shortened length of mechanical ventilation and ICU stay, and urge further research.

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