Case Report: Use of hydroxychloroquine and N-acetylcysteine for treatment of a COVID-19 patient

Background

A novel coronavirus, SARS-CoV-2, isolated in January 2020¹ was implicated as the cause of COVID-19 that resulted in an outbreak of pneumonia in Wuhan, China. Human to human transmission has reached pandemic levels with cases infecting millions of individuals resulting in significant morbidity and mortality. Although multiple therapies have been proposed against SARS-CoV-2 virus, no clear consensus exists on the best approach for treatment^2,3.

The human body requires an efficient innate immune system in the airway mucosa to respond to viral or bacterial antigens and preserve tissue homeostasis. SARS-CoV-2 enters the human airway in a process reminiscent of other viruses^4,5. The virus invades healthy cells, replicates, and leads to cellular necrosis⁶. Neutrophils are essential for a proper innate response to antigens derived from cellular necrosis⁷. We previously demonstrated that restoring the capacity of the innate immune system by modulating neutrophil activity with hydroxychloroquine (HCQ) and N-acetylcysteine (NAC) was sufficient to ameliorate local tissue effects of cellular necrosis and inflammation⁷ HCQ is a well-known therapy for certain inflammatory autoimmune diseases such as rheumatoid arthritis and lupus erythematosus and has significant impact on Toll-like receptor 9 (TLR-9) activity⁸. NAC has been used as an antioxidant, as a modulator of inflammatory responses due to its actions on NF-κβ⁹, as a mucolytic agent, and for the treatment of acetaminophen-induced liver failure¹⁰. In a patient with SARS-CoV-2 infection, we used oral low-dose HCQ in combination with intravenous NAC in an effort to modulate the inflammatory response secondary to COVID-19.

Case report

We describe a 54-year-old Caucasian male patient, with past medical history significant for hypertension, hyperlipidemia, and obesity, who tested positive for SARS-CoV-2 by reverse-transcriptase-polymerase-chain-reaction (RT-PCR) 11 days prior to his admission on mid April, 2020 (Table 1) at Holy Family Hospital in Methuen, Massachusetts. Following transfer from another hospital, he was admitted to the Intensive Care Unit with shortness of breath, body aches, fever, diaphoresis, tachypnea, low oxygen saturation of 92% requiring oxygen supplementation via non-rebreather mask, elevated lactic acid of 7.6 (0.5–2.2 mmol/L), and hyperglycemia with blood glucose of 402 (<100 mg/dL fasting). His vital signs included initial blood pressure of 92/62 mmHg (72 MAP), respiratory rate of 48 bpm, heart rate 120-130 bpm, and temperature of 97°F.

Initial laboratory work-up showed elevations of inflammatory markers common to patients diagnosed with COVID-19^7–9 (Table 2); particularly lymphocytes 900 (850-3900 cells per mm³), high-sensitivity C-reactive protein 149.2 (1.0–3.0mg/L), D-dimer 16.47 (<0.5 μg/ml FEU), lactate dehydrogenase 1579 (102–266 U/L), and serum ferritin 23713 (30–400 ng/L). A noticeable decrease in lactic acid 7.6 to 2.4 (0.5–2.2 mmol/L) was observed in the first 24 hours of treatment. He also showed signs of multi-system end-organ damage, as evidenced by elevations in alanine aminotransferase 1017 (14–63 U/L), aspartate amino transferase 852 (15–41 U/L), and serum creatinine 1.4 (0.6–1.4 mg/dL). At presentation, lung auscultation was remarkable for scattered rales, chest radiograph was unremarkable, and abdominal exam was normal.

In the ICU he received empiric antibiotic therapy that included Azithromycin 500 mg IV (1 dose) and Vancomycin 2750 mg IV (divided doses), while the results of bacterial cultures were obtained. Antibiotic therapy was reassessed and discontinued due to very low probability of bacterial infection (patient afebrile, negative cultures, low procalcitonin levels). Culture data was reported as follows: On April 14, MRSA PCR swab (negative); blood cultures (negative); April 17, sputum with light growth normal respiratory flora; April 20, tracheal aspirate showed heavy growth of Serratia Marcescens, for which he received levofloxacin. No vasopressors were utilized in the medical care of this patient. Other prescribed medications included gastrointestinal prophylaxis (protonix 40 mg/po), propofol and fentanyl during the intubation period, anti-anxiolytics, laxatives and cough medications as needed.

Despite escalating oxygen requirements, intubation was delayed as the patient was assessed to be stable. The patient was prescribed HCQ 400 mg, given as a single oral dose, and NAC intravenously at 75 mg/kg over 4 hours, then 35 mg/kg over 16 hours, followed by 17 mg/kg over 24 hours on Day 2. Prophylactic anticoagulation was started with subcutaneous heparin 5000 Units q8H. An additional 200 mg dose of HCQ was given on Day 2. No cardiac arrhythmia was noticed with either dose of HCQ, with the highest measured corrected QT interval documented at 0.49 (0.36–0.44 seconds).

This patient initially experienced progressive clinical improvement; however, bilateral pulmonary embolism (PE) and right lower extremity popliteal deep venous thrombosis were diagnosed in the setting of persistently elevated D-dimer. A heparin infusion was started, and PE embolization was complicated by severe hypoxemia requiring mechanical ventilation. After three days of mechanical ventilation and catheter-directed thrombolysis, he was successfully extubated and transferred to a general medicine floor on Day 7. The patient was discharged home on Day 12 with stable vital signs, normalizing laboratory values, and on therapeutic anticoagulation with rivaroxaban. SARS-CoV-2 RT-PCR prior to discharge was negative.

Discussion

SARS-CoV-2 infection is characterized by multisystem organ involvement as illustrated in the present case yet no universally accepted standard therapy is available. It is theorized that SARS-CoV-2 causes the human immune system to overcompensate in response to infection and inflict collateral damage on itself, as evidenced by the abnormalities in inflammatory markers^11–13 COVID-19 also appears to increase the risk of thrombotic events^14,15. In this case the initial presentation with fever, diaphoresis, tachypnea, low oxygen saturation, neutrophilia and borderline lymphopenia would suggest an infectious process. Presumption of bacterial infection was addressed with 3 doses of antibiotics administered empirically (Azithromycin 500 mg IV 1 dose, Vancomycin 2750 mg IV divided doses), until culture results were obtained. Antibiotics were discontinued after culture reports found no bacterial presence and with low PCT levels, the possibility of bacterial infection was minimal. The only positive culture revealed was Serratia Marcescens 6 days after ICU admission and was treated with levofloxacin. The combination of elevated inflammatory markers (CRP, Ferritin, LFT’s) and SARS-CoV-2 positive results suggest a viral source for the clinical manifestations of this patient. After the patient received HCQ/NAC, clinical improvement was seen, and laboratory reports progressively normalized. When considering the fast decline of the severe symptoms that followed HCQ/NAC administration, versus natural progression of this disease; or the impact of a single dose of Azithromycin in the evolution of this patient; we concluded that HCQ/NAC offers the best scientific explanation for the observed improvement. Previous work has shown that HCQ and NAC can modulate the innate immune system^7,8, as well as reduce hypercoagulability and inhibit thrombosis^16,17. We recognize that HCQ has been associated with a higher risk of cardiac abnormalities and fatal heart rhythms¹⁸; however, our low-dose strategy (600 mg total) allowed us to take advantage of its potential benefits and long half-life. HCQ may impact viral activity at multiple levels by blocking viral entry into the cells, interfering with endosomal maturation, and lysosomal transport^19–21.

NAC, modulates the activity of the innate immune system by controlling the overproduction of proinflammatoy cytokines at the NF-κβ level, by mitigating cellular damage working as an antioxidant, and replenishing glutathione stores necessary for cellular protection during acute injury. NAC also has potential direct and indirect antiviral activity^22,23, and has shown synergy if combined with HCQ in the treatment of inflammation related to cellular toxicity⁷. NAC has been shown to be safe at doses up to 980 mg/kg over 48 hours when used for acetaminophen overdose¹⁰.

Because of this, we theorized that the administration of HCQ and NAC would be well tolerated and have favorable effects on patient outcomes.

Conclusions

Although there is controversy on the benefits of HCQ in the treatment of viral infections, results of in vitro studies have shown its activity against viral infections including SARS-CoV-2 infection. The clinical studies available have contradictory results with some in support and others against the benefit of HCQ in SARS-CoV-2 infection, however, they all have in common the use of excessive amounts of the medication, naturally inducing toxicity and thus likely negating the therapeutic benefits. Multimodal antiviral therapies such as the one presented in this case report need to be considered to better treat viral infections. Therapeutic interventions with modulators of the innate immune system such as HCQ (low doses) and NAC, are necessary to mitigate the effects of multisystem organ dysfunction observed in viral infections including SARS-CoV-2. Avoidance of mechanical ventilation may represent a secondary benefit of this therapy. A large randomized clinical trial is warranted to further evaluate the benefits of HCQ/NAC combination during SARS-CoV-2 infection.

Consent

Written informed consent for publication of their clinical details was obtained from the patient.

Data availability