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Coronavirus: Learning to live with the enemy

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Recent studies suggest that male patients are more Recent studies suggest that male patients are more likely to test positive for coronavirus

W

e will probably need to learn to live alongside COVID-19. Many experts believe that SARS-CoV-2 will cause several disease peaks until the long-awaited herd immunity emerges.1 Meanwhile, our growing understanding of the biology of SARS-CoV-2 and studies of potential COVID-19 treatments strengthen our ability to tackle the pandemic.

We now know, for instance, that certain people are particularly likely to test positive. According to one study, 15.4% of 3802 SARS-CoV-2 tests collected routinely in the UK community were positive. After adjusting for confounders, the proportion that tested positive was about five times higher in people aged 40 to 64 years (odds ratio [OR] 5.36), of black ethnicity (OR 4.75) and living in urban areas (OR 4.59) compared with children, whites and those from rural areas respectively. People from the most deprived areas were twice as likely to be positive (OR 2.03) than those living in the most affluent communities.2

Men were 55% more likely than women to test positive in the UK study,2 adding to evidence that males are more likely to contract SARS-CoV-2, experience severe symptoms and die from the infection. To understand why, researchers measured concentrations of angiotensin converting enzyme 2 (ACE2) in plasma from European heart failure patients. Spike proteins anchor SARS-CoV-2 to ACE2 in the lower respiratory tract. Mean ACE2 plasma concentration was significantly higher in men than women. Indeed, being male most strongly predicted elevated ACE2 concentrations of several factors assessed. The study did not, however, measure ACE2 concentrations in lung and other tissues and the patients were not infected with SARS-CoV-2.3

Another recent study suggests that men clear SARS-CoV-2 more slowly. The study – which, at the time of writing, has yet to be peer reviewed – enrolled 48 males and 20 females aged between 3 and 75 years admitted to a hospital in Mumbai with COVID-19. Based on nasal swabs, females cleared SARS-CoV-2 in a median of 4 days (range 1-10 days) compared with 6 days (range 1-15 days) in males. In all three households in which men and women tested positive, females cleared SARS-CoV-2 more rapidly than males. An analysis of molecular biological databases showed that testes, lungs and kidneys have particularly high ACE2 levels. In contrast, ACE2 expression is very low in ovaries. The authors suggest that ‘testicular viral reservoirs’ may contribute to viral persistence and called for larger clinical studies to test their hypothesis.4

Age-related differences in ACE2 levels may help explain why children account for less than 2% of COVID-19 cases. Based on nasal swabs, US researchers reported an age-related increase in expression of the ACE2 gene. For example, expression of the ACE2 gene rose by 29% comparing children younger than 10 years to adults aged 25 years and older.5

Comorbidities influence outcomes

Comorbidities can also influence the likelihood of testing positive for SARS-CoV-2 and the severity of COVID-19. In the UK study, active smoking reduced the likelihood of a positive test result by 51%.2 In a press release, the authors note that this ‘does not indicate that smoking protects against infection’. Smoking may, for instance, reduce the test’s sensitivity. Smokers are also likely to cough and, therefore, be tested. The authors add, however, that smoking seems to ‘increase the severity of COVID-19’.2

In the UK study, patients with chronic kidney disease and obese people were 91% and 41% more likely to test positive as those without renal conditions and of a healthy body mass index respectively. No significant association emerged with other chronic conditions.2 Several other studies suggest, however, that diabetes increases COVID-19 severity.6 Moreover, patients with ‘metabolic associated fatty liver disease’ (MAFLD), which affects about a quarter of people worldwide, seem prone to severe COVID-19.6

A recent consensus group suggested replacing the ‘outdated’ terms non-alcoholic fatty liver disease and non-alcoholic steatohepatitis with the term MAFLD to ‘more accurately [reflect] current knowledge of fatty liver diseases associated with metabolic dysfunction’.7 The study from China enrolled 65 people with COVID-19 and MAFLD. The same number of matched controls had COVID-19 with but no liver disease. None of those enrolled had diabetes. People with MAFLD were, after adjusting for confounders, 4.07 times more likely to have severe COVID-19. Those with one MAFLD criterion (overweight/ obese or metabolic dysregulation) were 2.60 times more likely to have severe COVID-19 compared with controls. People who were overweight or obese and showed metabolic dysregulation were 5.25 times more likely to have severe COVID-19.6

Infection without symptoms

Recent research suggests that asymptomatic people are an important source of SARS-CoV-2 transmission.8 Researchers from Cambridge University Hospitals NHS Foundation Trust screened 1032 healthcare workers who were asymptomatic at the time of testing for SARS-CoV-2 (median age 34 years; 71% female). Of these, 31 (3%) tested positive. Twelve of the 30 people who tested positive and who were examined in more depth had experienced symptoms more than 7 days before testing. Nine of these self isolated and returned to work. Another 12 reported symptoms within the last 7 days. (The symptoms were not necessarily caused by SARS-CoV-2.) Six people had not experienced symptoms compatible with COVID-19 when tested. One became symptomatic. So, the authors estimate, the asymptomatic carriage rate is about 1 in 200 (0.5%).9

Asymptomatic transmission may be especially important in certain settings. Twenty-three days after the first resident in a skilled nursing facility in Seattle tested positive for SARS-CoV-2, 64% of the 89 residents had contracted the virus. Furthermore, 63% of 76 residents tested once or twice a week apart were positive. Of these, 56% were asymptomatic. However, 89% of asymptomatic people developed symptoms during the following week, in a median of four days, most commonly fever (71%), cough (54%) and malaise (42%). Of 57 residents infected with SARS-CoV-2, 15 died (a mortality rate of 26%) and 11 were hospitalised, of whom 3 needed intensive care.10 An accompanying editorial suggests that asymptomatic persons have ‘a major role in the transmission of SARS-CoV-2’.8

In the Seattle study, 35% of those who tested positive reported typical symptoms (fever, cough or shortness of breath). But 8% showed only atypical symptoms.10 Indeed, SARS-CoV-2 can cause symptoms throughout the body including the skin.11 Dermatologists from Italy reported that 18 (20%) of 88 COVID-19 patients developed cutaneous manifestations. Eight patients showed cutaneous involvement at the onset of COVID-19 and 10 patients during hospitalisation. Of these, 14 developed erythematous rash. Three patients showed widespread urticaria and one developed chickenpox-like vesicles. Skin manifestations tended to emerge on the trunk and generally healed in few days. Itching was mild or absent. Further research needs to better characterise skin involvement. But the authors ‘speculate’ that the skin manifestations associated with COVID-19 ‘are similar to cutaneous involvement occurring during [other] common viral infections’.11 In addition, the hyper-inflammation common in COVID-19 as well as certain drugs, including hydroxychloroquine, can exacerbate psoriasis.12

Clinical study update

In parallel with research into the biology of SARS-CoV-2, numerous clinical studies are searching for a COVID-19 treatment. A study from Hong Kong, for example, treated 127 patients with lopinavir-ritonavir. The 86 people who also received ribavirin and interferon beta-1b (combination group) had a significantly shorter median time from start of treatment to negative nasopharyngeal swab (7 days) than controls (12 days) and negative on all samples (eg including saliva and stool; 8 and 13 days respectively). Symptoms resolved in a median of 4 and 8 days in the combination and control groups respectively. Median hospital stay was 9.0 and 14.5 days respectively. No patients died. The study was open label and did not include critically ill patients. So, the authors suggest performing a placebo-controlled phase 3 trial.13

In this study, combination treatment reduced levels of interleukin-6 (IL-6), supporting suggestions that the cytokine is a potential therapeutic target.13,14 IL-6 is among the cocktail of cytokines (which also includes IL-2, IL-7, IL-10, granulocyte-colony stimulating factor and tumour necrosis factor alpha) that can induce the cytokine storm often found in people admitted to the ICU with COVID-19 and that seems to be an important driver of symptom severity and prognosis.14

Tocilizumab binds to IL-6 receptors, preventing the cytokine from binding. A preliminary study from China enrolled 21 people with COVID-19 aged between 25 and 88 years. The average age was 56.8 years, 18 were males, 17 patients had severe COVID-19 and four were in a critical condition. Eighteen patients received a single dose of tocilizumab. The remainder received a second dose within 12 hours. Within 5 days of receiving tocilizumab, one patient no longer needed oxygen therapy. Another 15 had lowered their oxygen intake. Before treatment, 19 patients showed abnormally elevated C-reactive protein (CRP), a marker of inflammation. Five days after tocilizumab, CRP was normal in 10 patients. No-one died and all patients were discharged, on average, 15.1 days after receiving tocilizumab. The authors conclude that ‘preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality’.14

Drugs targeting other inflammatory cytokines also look promising in certain patients. Clinicians in Milan use non-invasive ventilation outside of the ICU, hydroxychloroquine and lopinavir-ritonavir to treat 16 patients with COVID-19 who were experiencing moderate-to-severe acute respiratory distress syndrome and hyper-inflammation. Another 29 patients also received high-dose intravenous anakinra, which blocks interleukin1. At 21 days, survival was 90% in the anakinra group and 56% among controls, a significant difference. Mechanical ventilation-free survival was 72% and 50% respectively, although this was not statistically significant. Bacteraemia occurred in four (14%) patients receiving high-dose anakinra and two (13%) controls. A larger controlled study with longer follow-up is needed.15

While, at the time of writing, mortality from COVID-19 is declining, SARS-CoV-2 still presents a major clinical, societal and economic challenge, especially as lock-down eases. We face unprecedented challenges, politically, personally and professionally. But the latest research is beginning to help us plan a trail out of this infectious quagmire.

Mark Greener is a freelance medical writer

References

1. Guy RK, DiPaola RS, Romanelli F, Dutch RE. (2020) Rapid repurposing of drugs for COVID-19. Science. https://doi.org.10.1126/science.abb9332

2. de Lusignan S, Dorward J, Correa A, et al. (2020) Risk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study. The Lancet Infectious Diseases. https://doi.org.10.1016/S1473-3099(20)30371-6

3. Sama IE, Ravera A, Santema BT, et al. (2020) Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin–angiotensin–aldosterone inhibitors. European Heart Journal. 41(19):1810-7. https://doi.org.10.1093/eurheartj/ehaa373

4. Shastri A, Wheat J, Agrawal S, et al. (2020) Delayed clearance of SARS-CoV2 in male compared to female patients: High ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs. medRxiv.

5. Bunyavanich S, Do A, Vicencio A. (2020) Nasal gene expression of angiotensin-converting enzyme 2 in children and adults. JAMA. https://doi.org.10.1001/jama.2020.8707

6. Gao F, Zheng KI, Wang XB, et al. (2020) Metabolic associated fatty liver disease increases COVID-19 disease severity in non-diabetic patients. Journal of Gastroenterology and Hepatology. https://doi.org.10.1111/jgh.15112

7. Eslam M, Sanyal AJ, George J, et al. (2020) MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology. 158(7):1999-2014.e1. https://doi.org.10.1053/j.gastro.2019.11.312

8. Gandhi M, Yokoe DS, Havlir DV. (2020) Asymptomatic transmission, the Achilles’ heel of current strategies to control COVID-19. New England Journal of Medicine. https://doi.org.10.1056/NEJMe2009758

9. Rivett L, Sridhar S, Sparkes D, et al. (2020) Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission. eLife. 9. https://doi.org.10.7554/eLife.58728

10. Arons MM, Hatfield KM, Reddy SC, et al. (2020) Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility. New England Journal of Medicine. https://doi.org.10.1056/NEJMoa2008457

11. Recalcati S. Cutaneous manifestations in COVID-19: A first perspective. Journal of the European Academy of Dermatology and Venereology. https://doi.org.10.1111/jdv.16387

12. Ozaras R, Berk A, Ucar DH, Duman H, Kaya F, Mutlu H. COVID-19 and exacerbation of psoriasis. Dermatologic Therapy. https://doi.org.10.1111/dth.13632

13. Hung IF-N, Lung K-C, Tso EY-K, et al. (2020) Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: An open-label, randomised, phase 2 trial. The Lancet. https://doi.org.10.1016/S0140-6736(20)31042-4

14. Xu X, Han M, Li T, et al. (2020) Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences. 117(20):10970-5. https://doi.org.10.1073/pnas.2005615117

15. Cavalli G, De Luca G, Campochiaro C, et al. (2020) Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. The Lancet Rheumatology. https://doi.org.10.1016/S2665-9913(20)30127-2

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