By Carol A. Kemper, MD, FACP
Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases, Santa Clara Valley Medical Center
Dr. Kemper reports no financial relationships relevant to this field of study.
IL-6 Inhibition and Liver Failure
SOURCE: Busani S, Bedini A, Biagioni E, et al. Two fatal cases of acute liver failure due to HSV-1 infection in COVID-19 patients following immunomodulatory therapies. Clin Infect Dis 2020; Aug. 25. doi:10.1093/cid/ciaa1246. [Online ahead of print].
Anti-IL-6 receptor monoclonal antibodies, such as tocilizumab and sarilumab, and anti-IL-6 monoclonal antibodies, such as siltuximab, have been proposed as a possible means to down-regulate the cytokine storm observed in some patients with COVID-19. Tocilizumab is currently Food and Drug Administration (FDA)-approved for use in the United States in adults with severe rheumatoid arthritis who have failed to respond to methotrexate or other agents, adults with giant cell arthritis, and children with systemic or polyarticular juvenile idiopathic arthritis. The immunosuppression seen with such agents may, however, last for months, and serious opportunistic infections have been reported.
These authors in Modena, Italy, report on the deaths of two patients with severe COVID-19 pneumonia treated with tocilizumab who died from complicating herpes simplex virus-1 (HSV-1)-associated liver failure. While modest elevations in hepatic transaminases may occur commonly in COVID-19 infection, frank hepatic failure has not been observed.
The first patient was a 66-year-old man who presented with COVID-19 pneumonia, treated with hydroxychloroquine for seven days and azithromycin for five days. He received tocilizumab on day 2 of hospitalization (162 mg subcutaneously in two sites). Because of persistently elevated inflammatory markers, methylprednisolone 80 mg was administered, with tapering doses over the next four days. The patient’s respiratory status began to improve, but his mental status deteriorated. Severe elevation in hepatic enzymes (> 2,000 U/L) was observed by day 12 of hospitalization, although initial bilirubin levels were normal. Serologic studies for hepatitis viruses, Epstein-Barr virus, and cytomegalovirus were negative, and there was no hepatic vein thromboembolic disease on imaging. On day 15, polymerase chain reaction (PCR) testing detected extreme elevations in cell-free plasma levels of HSV-1 (> 14,375,000 copies/mL). Despite the addition of acyclovir, the patient continued to deteriorate and succumbed to frank hepatic failure on day 17 of hospitalization.
The second patient was a 49-year-old man who was overweight and who presented with COVID-19 pneumonia, and was also treated with hydroxychloroquine and azithromycin, as described earlier. He continued to develop progressive hypoxic respiratory failure requiring mechanical ventilation. On day 13 of hospitalization, he received two parenterally administered doses of tocilizumab 800 mg 12 hours apart. On day 25 of hospitalization, he developed agitation and panic attacks requiring sedation and antipsychotics. By day 29, while providers were attempting to wean him from mechanical ventilation, progressive elevations in hepatic enzymes > 6,000 were observed, although, again, initial bilirubin levels were normal. Viral serologies and imaging were unremarkable. On day 33 of hospitalization, real-time PCR detected > 14,375,000 copies/mL of HSV-1 in cell-free plasma and no SARS-CoV-2 virus. Cerebrospinal fluid also was HSV-1 PCR-positive (> 800,000 copies/mL). Despite the addition of acyclovir, the patient died from progressive hepatic necrosis.
Neither patient had a known history of HSV-1 infection. Post-mortem examination showed hemorrhagic necrosis of both livers, and HSV immunoassays showed positive staining of hepatic nuclei. It is likely the second patient also had central nervous system (CNS) infection.
Researchers in Bologna and Modena, Italy, were among the first to investigate the use of tocilizumab in severe COVID-19 illness.1 In a retrospective cohort study of 544 adults with severe pneumonia from SARS-CoV-2 infection, the administration of tocilizumab to a non-random subset of patients was associated with a possible reduction in mechanical ventilation and mortality. All patients received the standard of care treatment, including hydroxychloroquine for seven days, azithromycin for five days, and low molecular-weight heparin. In addition, 179 patients received tocilizumab either as two infusions (8 mg/kg, up to a maximum of 800 mg) or as two subcutaneous injections (each 162 mg) when the IV formulation was not available.
Mechanical ventilation was required in 57 of 365 (16%) patients receiving standard of care alone vs. 33 of 179 (18%) patients receiving standard of care plus tocilizumab (including 16/88 [18%] receiving parenteral therapy and 17/91 [19%] receiving subcutaneous treatment, respectively). Death occurred in 20% of the standard care group vs. 7% of those receiving tocilizumab (P < 0.0001). After adjustment for age, sex, duration of symptoms, and Sequential Organ Failure Assessment (SOFA) score, a statistically significant reduction in the risk of invasive mechanical ventilation and death was observed in patients treated with tocilizumab. However, 13% of patients treated with anti-IL-6 therapy developed complicating infections vs. 4% of those receiving standard of care alone (P < 0.0001).
As of Aug. 27, 2020, the U.S. National Institutes of Health COVID-19 Treatment Guidelines Panel does not recommend the use of IL-6 receptor agonists or anti-IL-6 monoclonal antibodies, except in the context of a clinical trial. Additional preliminary clinical trial data have not supported the use of tocilizumab or sarilumab in the treatment of patients with COVID-19, and there are little data using siltuximab.
- Guaraldi G, Meschiari M, Cozzi-Lepri A, et al. Tocilizumab in patients with severe COVID-19: A retrospective cohort study. Lancet Rheumatol 2020;2:e474-e484.
Can Chopsticks Make You Sick?
SOURCE: Lui G, Lai CKC, Chen Z, et al. SARS-CoV-2 RNA detection on disposable wooden chopsticks, Hong Kong. Emerg Infect Dis 2020;26. doi: 10.3201/eid2609.202135.
Although some people may feel threatened by the possible presence of SARS-CoV-2 virus on their cereal box, these authors added a twist to the tale of surface contamination. Using real time polymerase chain reaction (RT-PCR), they examined the risk of viral contamination of chopsticks used by patients with COVID-19 infection.
Five patients hospitalized for COVID-19 infection were recruited for this study, including one patient who remained asymptomatic, two patients whose symptoms had resolved, and two patients with active infection with moderate to severe COVID pneumonia. Patients were given a set of plain, unvarnished wooden chopsticks in a sealed plastic bag for meals. The chopsticks were collected, dipped in a buffered solution, and shaken for 30 seconds. SARS-CoV-2 ribonucleic acid (RNA) was detected using RT-PCR and compared with the results of serial sputum samples and nasopharyngeal (NP) and throat swabs.
Chopsticks from all five patients were positive at various time points, similar to the results of sputum and NP/throat swabs, including those from the asymptomatic patient. This patient had been exposed to a known infected patient and, although she remained asymptomatic, she was hospitalized for isolation. On day 2 of her hospitalization — 12 days after exposure — her throat and sputum samples tested positive for SARS-CoV-2, and a pair of chopsticks also tested positive. Although she was described as asymptomatic, a high-resolution chest computed tomography showed patchy bilateral ground glass infiltrates and small areas of consolidation.
Chopsticks from two other patients were positive for up to two to three days post-resolution of symptoms, although viral RNA could be detected in sputum specimens for up to eight days. And multiple sets of chopsticks were positive during the acute phase of illness in the remaining two patients (at days 5-7 in one patient with pneumonia and respiratory failure and at days 7-8 in the final patient with fever and pneumonia).
This small study suggests that salivary contamination of utensils with SARS-CoV-2 virus can occur — and sharing food and utensils, or having communal food bowls, which is common throughout Asia, is probably not a good idea if you are trying to avoid COVID-19. The Chinese government had been pushing to change the age-old practice of sharing morsels of food with children and partners using your own chopsticks — as a demonstration of love and respect — or even of intimacy. A number of restaurants have changed their practices by adding “serving chopsticks” to communal food bowls — but the practice still is limited, and many families have been resistant to this change.1
- Qin A. Coronavirus threatens China’s devotion to chopsticks and sharing food. The New York Times. May 25, 2020.