COVID-19 update: 26th March, 2020

We are entering an extremely crucial phase of the COVID-19 pandemic, with many countries, including India, closing their borders and enforcing complete lockdown. Clinicians are passing through a learning curve with increasing real-world experience. New information regarding the causative virus, transmission control, and innovative modalities of treatment are being addressed. This review attempts to summarize recent developments that may help clinicians who may have to care for COVID-19 infected patients. 

Mode of transmission

Does airborne spread occur? 

The virus that causes COVID-19 disease, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is transmitted primarily through droplets and fomites. Does it spread through aerosols? It has significant implications for healthcare workers, as a much higher level of protection is necessary to combat aerosol spread. The stability of SARS-CoV-2 in aerosols and different types of surfaces was evaluated by van Doremalen et al. (1). Aerosols of particle size less than 5 microns containing the virus were generated. The viability of the virus was tested in the aerosol and on plastic, steel, copper, and cardboard surfaces. The SARS-CoV-2 virus remained viable in aerosols during the 3-h duration of the experiment, with a reduction in the infectious titer over time. The virus was more stable on plastic and steel surfaces and could be detected for up to 72 h, although at a largely reduced titer. 

The findings of this experimental study suggest the plausibility of aerosol transmission of the SARS-CoV-2 virus and reassert the importance of the use of personal protective equipment (PPE) that offers aerosol protection.  

Specific treatment modalities 

Hydroxychloroquine (HCQ) 

Discovered in 1934, and extensively used in the treatment of malaria for decades, chloroquine may exhibit anti-viral activity through several mechanisms. It may inhibit pH-dependent steps involved in viral replication, besides inhibition of the generation and release of TNF-alpha and IL-6 (2). It may suppress cellular autophagy, leading to the inhibition of viral replication (3). 

In a pilot study, patients with confirmed COVID-19 disease were randomized to receive HCQ 400 mg/d for 5 days compared to standard care. Clearance of viral nucleic acid from pharyngeal swabs occurred in 13/15 (86.7%) patients in the HCQ group and 14/15 (93.3%) patients in the control group. There was no difference between the HCQ-treated and control groups regarding the time to defervescence or progression of changes on CT imaging (4). 

In a French study, 20 patients with confirmed COVID-19 disease received HCQ 600 mg/d; azithromycin was added based on the clinical situation. Sixteen patients from another center acted as controls. By day 3, 50% of HCQ-treated patients tested negative for the virus by RT-PCR compared to 6.3% in the control group; by day 6, 70% among the treated group tested negative compared to 12.5% in the control group. The addition of azithromycin seemed to augment viral clearance (5).  

However, the outcomes of six patients from the treatment group were not reported in this study. Clinical worsening occurred in three patients requiring ICU admission and one patient died, while treatment was discontinued in two other patients. There was no mortality or requirement for ICU admission in the control group. Hence, apart from early viral clearance, this study does not demonstrate any clinical benefit associated with the use of HCQ. 

The use of hydroxychloroquine is currently being evaluated in several clinical trials as pre- or post-exposure prophylaxis for COVID-19 infection. No data are currently available to guide the dose or duration of prophylactic HCQ. 

Lopinavir-ritonavir combination 

Does specific anti-viral therapy help in COVID-19 disease? 

In a recently published randomized controlled trial, Cao et al. evaluated the efficacy of the lopinavir-ritonavir combination among patients with an oxygen saturation of less than 94% while breathing room air or P/F ratio of less than 300 mm Hg. The primary endpoint was the time interval from randomization to improvement by two points on a seven-category scale or hospital discharge, whichever occurred earlier. There was no difference between the anti-viral combination and standard care in the primary outcome. No significant difference was observed in the 28-d mortality between groups. Besides, there was no difference in the number of patients with detectable viral RNA at different points of time during the course of treatment (6). This study suggests that the lopinavir-ritonavir combination may not improve clinical outcomes or reduce viral shedding in patients with COVID-19 disease. 

A post-hoc analysis of patients who received treatment within 12 days of disease onset revealed reduced mortality among patients who received the lopinavir– ritonavir combination. Whether earlier treatment would favorably influence clinical outcomes needs further rigorous research.

High-flow nasal cannula (HFNC) and non-invasive ventilation (NIV)

In resource-limited situations, high-flow nasal oxygen may be initiated as early supportive therapy in mild hypoxemic respiratory failure. However, there is concern regarding a high level of aerosolization and disease transmission with this modality of treatment. It may be advisable to use relatively low flows (20–30 l/min) to prevent excessive aerosolization. In a simulator-based study, exhaled air dispersion with HFNC therapy was limited with an adequate cannula fit (7). The patient may don a surgical mask over the nasal cannula to reduce the risk of excessive dissemination of aerosol. Close monitoring must be carried out during HFNC therapy, and early intubation should be considered in case of deterioration. 

Anecdotal reports suggest a slightly unusual clinical picture among patients with COVID-19-related acute respiratory distress syndrome (ARDS). This is characterized by a relative lack of subjective discomfort in the presence of hypoxemia, preserved lung compliance, and a favorable response to prone ventilation, suggesting progressively large areas of alveolar collapse. The use of NIV, particularly continuous positive airway pressure (CPAP) may have positive effects in this situation by maintaining high mean airway pressures. NIV may be particularly considered in patients with associated chronic obstructive pulmonary disease. An appropriate expiratory port filter may be attached to single-limb non-invasive ventilation devices to reduce the risk of aerosol transmission (8). Both HFNC and NIV are ideally used in negative pressure areas to reduce the risk of transmission. 

CT imaging

Patients with COVID-19 disease have shown characteristic features on CT imaging that may help with early diagnosis and evaluation of disease progression. Peripheral and subpleural ground-glass opacities (GGO) are one of the common features. The GGO may be unilateral or bilateral (9). Thickening of interlobular septa and intralobular lines against a background of GGO may result in a typical “crazy paving” pattern. Patchy consolidation, air bronchograms, pleural thickening, and sub-pleural curvilinear lines are other CT features among patients with COVID-19 pneumonia (Fig. 1) (10).

Chest CT imaging may allow early, reliable diagnosis in patients presenting with COVID-19 pneumonia compared to RT-PCR. Ai et al. studied 1014 patients who underwent CT imaging and RT-PCR testing during a 1-month period in Wuhan, China. Among patients suspected of COVID-19 disease, RT-PCR was positive in 601/1014 (59%), while CT imaging was diagnostic in 888/1014 (88%) patients. When RT-PCR was used as the reference, chest CT revealed a sensitivity of 97%. Among 308 patients with negative RT-PCR and a diagnostic CT scan, 147 (48%) were considered to be highly likely, and 103 (33%) patients were considered to have probable COVID-19 disease (11). When serial RT-PCR and CT scans were analyzed, 60–93% of patients had an initial diagnostic CT, prior to positive RT–PCR test results. 

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in COVID-19

Do ACE inhibitors and ARBs help or harm? 

It has been shown that COVID-19 uses the ACE2 receptor to gain access into cells (12). This has led to the hypothesis ACE inhibitors and ARBs may upregulate ACE2 expression, leading to increased predisposition to COVID-19 infection. However, according to Perico et al., the entry of the virus into the cell is a complex, tightly regulated process involving several steps. Besides, ARBs and angiotensin II compete for the same receptor; this may result in an increase in the release of angiotensin. An increase in angiotensin II levels leads to enhanced binding to the catalytic site of ACE2 receptors. An increase in binding may lead to a structural change in the ACE2 receptor that may inhibit the binding of the virus to the receptor and prevent cellular entry (13). This has led to the suggestion that ARBs may, in fact, reduce the extent of lung damage in patients with COVID-19 disease. Considering the conflicting theories and lack of clinical data, most guidelines, including those of the American College of Cardiology recommend the continued administration of ARBs and ACE inhibitors among patients who are currently on treatment (14). 

Summary

1. The primary mode of COVID-19 spread is through droplets and fomites; however, it is plausible that aerosol transmission may also occur. Hence, healthcare workers need to take appropriate precautions with the use of appropriate personal protective equipment.
2. There is an ongoing debate regarding the efficacy of hydroxychloroquine in the treatment of COVID-19 disease; based on the limited data available, no definitive conclusions can be drawn.
3. There may be a role for the use of HFNC and NIV (especially CPAP), albeit with a marginally increased risk of aerosolization and disease transmission.  
4. CT imaging appears to be a sensitive diagnostic modality, especially during the early stage of the disease. Early diagnosis may enable transmission control measures. 
5. There are conflicting hypotheses regarding the impact of ACE inhibitors and ARBs on viral entry into cells and disease causation. Patients who are already on these drugs are advised to continue treatment. 
6. There is ongoing research on several treatment modalities, which may help guide treatment in the near future. 

References

1.         van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020 Mar 17;NEJMc2004973. 

2.         Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005 Aug 22;2:69. 

3.         Golden EB, Cho H-Y, Hofman FM, Louie SG, Schönthal AH, Chen TC. Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors. Neurosurg Focus. 2015 Mar;38(3):E12. 

4.         43f8625d4dc74e42bbcf24795de1c77c.pdf [Internet]. [cited 2020 Mar 26]. Available from: http://subject.med.wanfangdata.com.cn/UpLoad/Files/202003/43f8625d4dc74e42bbcf24795de1c77c.pdf

5.         Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar;105949. 

6.         Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 Mar 18;NEJMoa2001282. 

7.         Hui DS, Chow BK, Lo T, Tsang OTY, Ko FW, Ng SS, et al. Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different masks. Eur Respir J. 2019 Apr;53(4):1802339. 

8.         COVID-19: How to safely optimize NIV therapy [Internet]. Philips. [cited 2020 Mar 26]. Available from: https://www.philips.com/a-w/about/news/archive/blogs/innovation-matters/2020/20200325-covid-19-how-to-safely-optimize-niv-therapy.html

9.         Chung M, Bernheim A, Mei X, Zhang N, Huang M, Zeng X, et al. CT Imaging Features of 2019 Novel Coronavirus (2019-nCoV). Radiology. 2020;295(1):202–7. 

10.       Ye Z, Zhang Y, Wang Y, Huang Z, Song B. Chest CT manifestations of new coronavirus disease 2019 (COVID-19): a pictorial review. Eur Radiol [Internet]. 2020 Mar 19 [cited 2020 Mar 26]; Available from: http://link.springer.com/10.1007/s00330-020-06801-0

11.       Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020 Feb 26;200642. 

12.       Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020 Mar;579(7798):270–3. 

13.       Perico L, Benigni A, Remuzzi G. Should COVID-19 Concern Nephrologists? Why and to What Extent? The Emerging Impasse of Angiotensin Blockade. Nephron. 2020 Mar 23;1–9.

14.       HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19 [Internet]. American College of Cardiology. [cited 2020 Mar 26]. Available from: http%3a%2f%2fwww.acc.org%2flatest-in-cardiology%2farticles%2f2020%2f03%2f17%2f08%2f59%2fhfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19