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Drugs for COVID-19

The media have reported extensively about drugs that might be effectively used for the treatment of patients with COVID-19. At present, however, no drugs are available in the Netherlands that have been authorised for COVID-19. Now that some more studies have been published, Ge-Bu takes stock of the current situation: what drugs could be effective, what hypotheses have been proposed about their modes of action, and what are the efficacy and the risks of these drugs? Although the hypotheses about modes of action of the drugs at present might seem promising, none of these agents have been sufficiently proven to be effective to justify prescribing them to patients with COVID-19 (at least outside the context of research studies).

  • There is no evidence for the efficacy of chloroquine or hydroxychloroquine, azithromycin or zinc for the treatment of COVID-19. 
  • There is possibly an increased risk of mortality for patients treated with chloroquine or hydroxychloroquine, and the risk appears to be further increased by combining them with macrolides like azithromycin. 
  • The evidence for the efficacy and safety of remdesivir is still limited, while evidence for other antiviral therapies (lopinavir and ritonavir) is lacking.
  • There is as yet no evidence for the efficacy and safety of tocilizumab, anakinra, icatibant, lanadelumab, C1-esterase inhibitor or valsartan. Studies into these drugs are being started or have just begun. 
  • It is not a rational approach to prescribe any of the above drugs, except in the context of research studies.
This article refers as much as possible to the current situation concerning the use of drugs for COVID-19, and has been updated until just before publication. Studies and reports published after 18 June 2020 could not, however, be reviewed here.

The SWAB website is continually trying to keep up with the current state of affairs regarding the evidence for COVID-19 treatments (

Figure 1 shows the three stages of COVID-19 (Coronavirus Disease 2019) and the various steps in the disease process which might be targeted by drugs, based on their theoretical mode of action. The early stage is mostly characterised by virus replication, which might be targeted by hydroxychloroquine, chloroquine, azithromycin, zinc and antiviral drugs like remdesivir. During the later stages of inflammation and hyperinflammation, other drugs might be effective: tocilizumab, anakinra, icatibant, lanadelumab, and valsartan.

Figure 1. Course of a SARS-CoV-2 infection.

ACE2: angiotensin-converting enzyme 2, Ang: angiotensin, AT1-receptor: angiotensin 1 receptor, B1/B2: bradykinin 1- and 2 receptors, IL: interleukin.

Stage 1, viral response:
1. The virus penetrates the cell via ACE2.
2. Endocytolysis, releasing the viral components into the cell, which activates the macrophages (A).
3. RNA replication of the virus components in the Golgi apparatus.
4. Viruses are broken down and removed from the cell by lysosomes, or leave the cell intact to infect other cells or other hosts.

Stage 2/3, inflammatory / hyperinflammatory response: increase in the number of bradykinin receptors and downregulation of the amount of ACE2 in the membranes.
5. Secretion of inflammatory mediators by macrophages, increased vascular permeability (B).
6. Secreted IL-1 and IL-6 activate neutrophils, T-cells and B-cells; the inflammatory response proceeds further.
7. Vascular injury activates Factor XII (C); release of interleukins activates the bradykinin pathway (F); bradykinin from plasma activates the B2 receptor and the amount of bradykinin in the lung increases. 
8. Activation of Factor XII (C) converts kallikrein into plasma bradykinin, increasing the amounts of bradykinin in the lungs via B2 receptors; activation of the B1 receptors results in angioedema. 
9. Conversion of angiotensin II into angiotensin 1-7 is reduced by downregulation of ACE2 (E). Angiotensin II is a pro-inflammatory compound which causes vasoconstriction and increased permeability of the vascular walls.

The first stage

Stage 1 of the infection is characterised by the replication of the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). In the early infection stage, patients have mild respiratory and systemic symptoms. The virus has a specific affinity for the lungs, as it can penetrate into the pulmonary tissue via the angiotensin-converting enzyme 2 (ACE2) on the surface of pneumocytes . The literature sometimes mentions the ACE2 receptor, but this refers to the ACE2 enzyme, which is located in the cell membrane and acts as a receptor for SARS-CoV-2. 

The second and third stages

Some patients proceed to stage 2, in which local inflammation of the lung occurs.1 The virus causes downregulation of ACE2, resulting in increased permeability of the blood vessel walls. In addition, various mechanisms contribute to the upregulation of bradykinin receptors (B1 and B2), which can eventually lead to local angioedema (Figure 1). These patients develop viral pneumonia. A number of these patients proceed to stage 3, which involves a clinical picture resembling that of the ‘acute respiratory distress syndrome’ (ARDS). This is probably caused by systemic hyperinflammation. This hyperinflammation most closely resembles a cytokine storm , such as that which sometimes occurs in response to CAR-T cell therapy  or in patients with haemophagocytory lymphohistiocytosis (HLH).1,2,3,4

A proportion of the patients also develop serious complications due to thrombosis. It is not yet known exactly how this increased tendency towards thrombosis arises. It is probably caused by a combination of cell injury, blood stasis due to immobilisation and an increased tendency to coagulate caused partly by increased viscosity (‘thickness’) of the blood. It is as yet unknown why it is particularly patients with COVID-19 who develop this increased coagulation. The clinical picture is not identical to that of ‘diffuse intravascular coagulation’ (DIC), as patients with this disorder actually often have haemorrhagic instead of thrombotic complications.5 

Key role for macrophages in hyperinflammation

Macrophages play an important part in the response to SARS-CoV-2. Macrophages in the lung are probably already activated in stage 1 by damaged cells and components of the virus (Figure 1, A). Macrophages then secrete cytokines, including the interleukins IL-1 and IL-6, with which they attract T-cells and neutrophils to clear the virus (Figure 1, B).3 These inflammatory mediators cause increased permeability of the vascular walls. Greatly increased activity of these inflammatory mediators can lead to cell death and damage to pulmonary tissue. This macrophage-driven hyperinflammation causes the ARDS-like clinical picture that characterises the later stages of the SARS-CoV-2 infection. In addition, stimulation of the bradykinin cascade may also play a major role in the development of angioedema in the lung (Figure 1, C and D).6
At the time of publication of this Ge-Bu article, a randomised controlled trial into the effects of various drugs for COVID-19 has entered its final phase (, NCT04381936).7,8 The primary outcome measure of this trial is all-cause mortality, assessed during 28 days after randomisation.

The trial has so far included over 11 500 patients and randomised them into 6 groups, each of which received a different drug in addition to usual care. A seventh group was only given usual care. The 6 drugs are:
- lopinavir/ritonavir
- low-dose dexamethasone 
- hydroxychloroquine
- azithromycin
- tocilizumab
- blood plasma with antibodies against SARS-CoV-2 obtained from recovered patients.

Preliminary results of two arms of the trial have been published. The results for low-dose dexamethasone for patients on a ventilator appear to be favourable, but no definitive conclusion on its efficacy and safety can be drawn until the results have been officially published and have gone through peer review.

Preliminary results for dexamethasone
The dexamethasone arm was terminated when enough patients had been included.7 A total of 2014 patients were given 6 mg dexamethasone for 10 days, intravenous or as tablets; these were compared with a control group of 4321 patients who did not receive adjunctive drug treatment.

Among the patients who were on a ventilator, the control group had a mortality rate of 41%, while the rate in the dexamethasone group was one third lower (rate ratio 0.65, 95% CI 0.48 to 0.88). Among the patients who were receiving oxygen support but who had not been intubated, there was a significant, but lower reduction in mortality (rate ratio 0.80, 95% CI 0.67 to 0.96). Among patients who needed no breathing support there was no significant effect (rate ratio 1.22, 95% CI 0.86 to 1.75).7

Preliminary results for hydroxychloroquine

The hydroxychloroquine arm was terminated in June 2020 as preliminary results showed that the treatment with hydroxychloroquine did not offer any added value.8 A total of 1542 patients who were given hydroxychloroquine were compared with 3132 patients without any adjunctive treatment. The primary outcome measure, mortality within 28 days, was achieved by 25.7% of the patients given hydroxychloroquine, compared to 23.5% of the patients without any adjunctive treatment (hazard ratio 1.11, 95% CI 0.98 to 1.26).8

Chloroquine and hydroxychloroquine

There is no evidence from randomised studies for the efficacy of chloroquine or hydroxychloroquine in the treatment of COVID-19. In vitro studies have confirmed the hypothetical modes of action, but clinical studies did not find any clinically relevant effect. 

What is chloroquine/hydroxychloroquine? 

Chloroquine is a chemical derivative of quinine. Quinine is obtained from the bark of the cinchona tree, and has long been known as an antipyretic. Chloroquine was often prescribed for the prophylaxis of malaria, but is used less and less these days due to increasing resistance. Like chloroquine, the chemically related hydroxychloroquine is authorised for the treatment of systemic lupus erythematosus (SLE) and rheumatoid arthritis, but has proved less toxic than chloroquine in animal tests.9

Hypothetical mode of action of chloroquine/hydroxychloroquine in COVID-19

There are various hypotheses concerning the mode of action of chloroquine/hydroxychloroquine in viral infections, which are all based on in vitro studies of individual cells or animal models. The assumption is that chloroquine and hydroxychloroquine have roughly the same mode of action.

Figure 1.1. Targets for drugs for SARS-CoV-2 infection, part 1.

ACE2: angiotensin-converting enzyme 2, B1/B2: bradykinin 1 and 2 receptors.

Stage 1, viral response:
1. The virus penetrates the cell via ACE2.
2. Endocytolysis, releasing the viral components into the cell, which activates the macrophages (A).

One hypothesis is based on indications that chloroquine/hydroxychloroquine reduces the affinity of ACE2 to the previous coronavirus SARS-CoV (Figure 1.1, No. 1). In vitro studies found that this hampered the infection of human cells by SARS-CoV.10

A second hypothesis is based on the fact that chloroquine/hydroxychloroquine is a weak base, and hence increases the pH within a cell. This happens, for instance, in lysosomes, which use an acidic environment to break down cell products. The presence of chloroquine/hydroxychloroquine theoretically results in reduced decomposition of the endosomes that arise as the virus penetrates the cell (Figure 1.2, No. 2).11 In addition, the virus replication in the Golgi apparatus in the cell also involves various pH-dependent steps, which can theoretically also be influenced by chloroquine/ hydroxychloroquine (Figure 1.2, No. 3).11,12

Figure 1.2. Targets for drugs for SARS-CoV-2 infection, part 2.

ACE2: angiotensin-converting enzyme 2, B2: bradykinin 2 receptors.
Stage 1, viral response:
2. Endocytolysis, releasing the viral components into the cell, which activates the macrophages.
3. RNA replication of virus components in the Golgi apparatus.
4. Viruses are broken down and removed from the cell by lysosomes, or leave the cell intact to infect other cells or other hosts

The virus replication can be followed by ‘xenophagy’. Autophagy is a decomposition process which is started in cells in response to, for instance, malnourishment, the aim being to recycle cellular products. If instead of ‘self’ cell components, the process decomposes foreign items such as viruses, this is called xenophagy. This decomposition process also utilises the acidic environment in lysosomes, and the basic properties of chloroquine/hydroxychloroquine might reduce the effectiveness of this process (Figure 1.3, No. 4).13

Figure 1.3. Targets for drugs for SARS-CoV-2 infection, part 3.

ACE2: angiotensin-converting enzyme 2, Ang: Angiotensin.
Stage 1, viral response:
4. Viruses are broken down and removed from the cell by lysosomes, or leave the cell intact to infect other cells of other hosts.

Chloroquine/Hydroxychloroquine can also inhibit the release of IL-1, which hampers the immune response. This third hypothesis is based on studies of the effect of chloroquine/hydroxychloroquine on infections with adenoviruses. Infections with these viruses can produce a form of ARDS similar to that in COVID-19 (Figure 1.4, No. 5).11

Figure 1.4. Targets for drugs for SARS-CoV-2 infection, part 4.

ACE2: angiotensin-converting enzyme 2, IL: interleukin.
Stage 2/3, inflammatory/hyperinflammatory response: increase in numbers of bradykinin receptors and downregulation of the amount of ACE2 in the membranes.
5. Release of inflammatory mediators by macrophages, increased vascular permeability (B).
6. Released IL-1 and IL-6 activate neutrophils, T-cells and B-cells, the inflammatory reaction proceeds further.

No evidence for efficacy of chloroquine/hydroxychloroquine

There have been no studies that proved a clinically relevant effect of treatment with chloroquine/hydroxychloroquine. So far, 6 studies have been published that compared the effect of chloroquine/hydroxychloroquine for COVID-19 with treatment without chloroquine/hydroxychloroquine. 

The first randomised, non-blinded, study, among Chinese hospitalised patients  compared treatment with hydroxychloroquine (n=75) with no adjunctive treatment (n=75). The primary outcome measure was negative virus conversion (the virus being no longer detected by tests).14 Of the participating patients, 148 had a mild to moderate form of COVID-19, while 2 patients were severely ill. The patients were given a loading dose of 1200 mg hydroxychloroquine daily for 3 days, after which the dosage was 800 mg daily. In the hydroxychloroquine group, 85.4% of the patients were free of virus, versus 81.3% in the untreated group. This difference is not statistically significant (4.1% [95% CI -10.3 to 18.5%]). However, the authors point out that too few patients had been included to be able to establish a difference. The researchers did find a favourable effect of hydroxychloroquine on the reduction of CRP (C-reactive protein), a compound whose plasma concentration is greatly increased during an inflammation. The clinical relevance of this effect of hydroxychloroquine is unclear, and the authors did not publish any results regarding clinical improvement.14 

The second Chinese randomised, non-blinded, study found a shorter recovery time in the group treated with hydroxychloroquine.15 However, the publication of this study has not (yet) passed through a peer-review process. The primary outcome measure was ‘time to clinical recovery’, defined as the time that elapsed until a normal body temperature and a mild to absent cough for at least 72 hours. Sixty-two patients with moderate to severe COVID-19 with pneumonia were randomised to hydroxychloroquine (200 mg 2 times daily for 5 days) or no treatment. The authors reported that both the cough and the body temperature returned to normal faster (1 day faster and ‘significantly reduced’, respectively). The authors did not report a confidence interval, and failed to offer a detailed description of the statistical procedures.15

A third, observational, study including a total of 42 patients compared hydroxychloroquine (600 mg/daily) with no adjunctive treatment.16 Six of the patients had azithromycin added to their treatment. The combination of hydroxychloroquine and azithromycin led to a reduction of the viral load on day 6. The hydroxychloroquine group had a considerable loss-to-follow-up (6 of the 26 patients in the hydroxychloroquine group). A more extensive description of this study and its results is provided below, in the section on azithromycin.16

The fourth, retrospective observational study compared 84 patients who had received hydroxychloroquine (600 mg daily) during hospital admission with 97 patients without adjunctive treatment.17 The patients had been hospitalised with pneumonia, and were all given oxygen support. The composite endpoint was admission to the intensive care unit (ICU) or death within 7 days. In the hydroxychloroquine group, 20.2% of the patients were admitted to the ICU or died, versus 22.1% of the patients without adjunctive treatment (relative risk 0.91; 95% CI 0.47 to 1.80). Eight patients in the hydroxychloroquine group had ECG changes.17

The fifth, prospective observational study, including 1376 patients, found no difference in the composite endpoint of intubation or mortality. A total of 811 patients were treated with hydroxychloroquine (1200 mg on day 1, followed by 400 mg daily), while 565 patients received no adjunctive treatment. The hazard ratio for intubation or death was 1.04 (95% CI 0.82 to 1.32) for the hydroxychloroquine group relative to the group without adjunctive treatment.18 

The sixth, observational, study among 368 veterans actually found increased mortality in the hydroxychloroquine group. Since this study also investigated azithromycin, it is discussed more fully below, in the section on azithromycin.19

Lancet retracts publication by Mehra et al.

In a recent publication in The Lancet the authors claimed to have data from an international observational study including 96 032 patients. They compared the efficacy of chloroquine (n=1868), chloroquine plus a macrolide (n=3783), hydroxychloroquine (n=3016), hydroxychloroquine plus a macrolide (n=6221) and a control group which received no adjunctive treatment (n=81 144).20,21 After major concerns about this study were expressed regarding the reliability of the data used, the study was retracted.22

Hydroxychloroquine not effective as a post-exposure prophylaxis

Hydroxychloroquine does not prevent a symptomatic infection, as shown by a study recently published in the New England Journal of Medicine. This study evaluated the efficacy of hydroxychloroquine as a post-exposure prophylaxis after exposure to COVID-19.23

The randomised, double-blind, placebo-controlled study included a total of 821 asymptomatic participants, and 87.6% reported a high-risk exposure. High-risk exposure was defined as exposure within 1.83 metres (6 feet) for 10 minutes or more to someone who had tested positive for SARS-CoV-2 infection, without face mask or face shield. If a face mask had been worn, the exposure was classified as average risk. The participants received a placebo or 800 mg hydroxychloroquine on day 1 and another 600 mg after 6 to 8 hours, followed by 600 mg daily for 4 days. The primary outcome measure in this study was a symptomatic SARS-CoV-2 infection confirmed by PCR, if a test was available. The study also included unconfirmed SARS-CoV-2 infections, due to a lack of available tests. COVID-19-related symptoms were assessed on the basis of criteria established by the U.S. Council for State and Territorial Epidemiologists. The severity of the infection was not assessed.

The study was terminated after the third planned interim analysis, due to a lack of effect. The incidence of COVID-19 (whether confirmed by PCR or based on symptoms consistent with the disease) did not differ between participants who had received hydroxychloroquine (49/414; 11.8 %) and those receiving a placebo (58/407; 14.3%). The absolute difference was -2.4% (95% CI -7.0 to 2.2). Only a minority of the infections were PCR-confirmed, due to lack of sufficient tests. The hydroxychloroquine group had more adverse effects (40.1% vs. 16.8%). Common adverse effects were nausea, diarrhoea, vomiting and vertigo. Serious adverse effects like arrhythmia and death were not reported.23

Risks of treatment with chloroquine/hydroxy)chloroquine

The main risk of treatment with chloroquine/hydroxychloroquine is a prolonged QT-interval, which may cause cardiac arrhythmias. The EMA has issued a formal warning for this adverse effect.24 Hydroxychloroquine and chloroquine have a long half-life, 50 and 14 days, respectively, so adverse effects may persist long after cessation of treatment. 

A randomised study of patients with COVID-19 using two different dosage regimes for chloroquine found a higher mortality among the patients who had received the higher dosage of chloroquine.25 The authors of a second study concluded that the use of hydroxychloroquine did not result in an elevate risk, but that the combination with azithromycin did result in an increased incidence of heart failure and cardiovascular mortality. This retrospective observational study did not include patients with COVID-19, but concentrated on patients with, for instance, rheumatoid arthritis, who were prescribed this combination.26 

Worldwide, a number of randomised placebo-controlled studies were started which should eventually establish the efficacy and safety of chloroquine/hydroxychloroquine for COVID-19. One study undertaken in Dutch hospitals was the cluster-randomised ARCHAIC study (NCT04362332). Virtually all of these studies have been terminated (permanently or temporarily) until more is known about the safety of chloroquine/hydroxychloroquine for the treatment of COVID-19.


There is no evidence for the efficacy of azithromycin for COVID-19 either, as no randomised studies have been done. Other studies have been of moderate or poor quality.

Azithromycin is a macrolide antibiotic. In addition to its antibacterial effect it may also have antiviral and immunomodulatory properties. It is unknown whether these properties are an effect of the whole group of macrolides or only of azithromycin.

Antiviral and immunomodulatory effects of azithromycin

In vitro studies have shown that azithromycin is effective against the Zika and Ebola viruses.27,28 The efficacy of azithromycin in adult patients with a Zika or Ebola infection has not been investigated. A study among children with viral infections of the lower airways found that azithromycin resulted in a less severe course of the infections, provided it was given at an early stage of the disease.29 Apart from preventing bacterial superinfections, azithromycin may also have an immunomodulatory effect. In vitro studies have found that azithromycin reduces the replication of rhinovirus and increases the production of interferon. It also reduces interleukin-8 in infections with the respiratory syncytial virus (RSV). In theory, this could have a favourable effect on the severity of the course of a SARS-CoV-2 infection.

Small and unreliable study of azithromycin

A small French study used azithromycin for patients with SARS-CoV-2 as an adjunctive treatment with hydroxychloroquine.16 This study has been published in pre-print form and has not yet undergone peer review. The primary outcome measure in this study was SARS-CoV-2 eradication, as assessed with a PCR test on day 6. No sample size calculation was done, and the severity of the infection was not taken into account. The study included patients being treated with hydroxychloroquine. Depending on the clinical presentation (as assessed by the patient’s doctor) azithromycin was additionally started (500 mg on day 1, followed by 250 mg for 4 days). In all, 6 of the 20 patients were given hydroxychloroquine plus azithromycin. Sixteen patients from another centre, who were not given adjunctive drug treatment,  were used as a control group. 

Among the subgroup of 6/6 patients (100%) using hydroxychloroquine plus azithromycin, eradication of SARS-CoV-2 was achieved, compared with 8/14 patients (57%) on hydroxychloroquine monotherapy and 2/16 patients (13%) in the control group. The study protocol does not refer to the analysis of the effect of a combination of azithromycin and hydroxychloroquine, so this was an unplanned subgroup analysis. In addition, a small study also entails a higher risk of sampling error (i.e. the sample not being representative). Another conspicuous aspect of this study is the high dropout rate: 6 patients in the intervention group who were given hydroxychloroquine were not included in the analysis, for instance because they were admitted to an ICU.16 In view of the above methodological limitations, no reliable conclusions can be drawn from the results of this study.

Hydroxychloroquine and azithromycin: no effect and increased risks

A recent retrospective cohort study investigated the effect of hydroxychloroquine and hydroxychloroquine plus azithromycin, compared with ‘best supportive care’ in a group of veterans.19 This retrospective study found no effect of hydroxychloroquine, whether or not combined with azithromycin, on the primary outcome measure: the need for ventilation. The risk of mortality, another primary outcome measure, was greater among the patients given hydroxychloroquine. The study has been published in pre-print form, and has not yet been subjected to peer review.

A total of 368 patients were included (hydroxychloroquine, n=97; hydroxychloroquine plus azithromycin, n=113; and supportive care n=158). The percentages of patients who died in the group treated with hydroxychloroquine, hydroxychloroquine plus azithromycin and best supportive care were 27.8%, 22.1% and 11.4%, respectively. The endpoint of need for ventilation was reached by 13.3%, 6.9% and 14.1% of the patients. The risk of death was greater in the hydroxychloroquine group than in the supportive care group (adjusted hazard ratio, 2.61; 95% CI 1.10 to 6.17). The group with hydroxychloroquine plus azithromycin showed no difference with the best supportive care group (adjusted hazard ratio, 1.14, 95% CI 0.56 to 2.32). As regards the endpoint of need for ventilation, there was no significant difference between the group treated with hydroxychloroquine and the control group (adjusted hazard ratio, 1.43, 95% CI 0.53 to 3.79). The same was found in the group treated with hydroxychloroquine and azithromycin (adjusted hazard ratio, 0.43, 95% CI 0.16 to 1.12).19

A second retrospective study found no difference in mortality among patients treated with hydroxychloroquine, whether or not combined with azithromycin, compared with no drug treatment.30 This study did show that cardiac arrest (unspecified) was about twice as common in the group of patients treated with azithromycin and hydroxychloroquine. 

This retrospective study included a total of 1438 patients from 25 hospitals in New York City. A random sample of patients admitted to hospitals around New York City who had tested positive for COVID-19 between 15 and 28 March 2020 were recruited for this study. After selection, the patient file was requested from the patient’s hospital and was analysed further. The primary outcome measure was in-hospital death and the need for ventilation, while secondary measures included cardiac arrest and an anomalous ECG (arrhythmia and prolonged QTc-interval). Patients were given various dosages of hydroxychloroquine and azithromycin. 

No significant differences were found between the various groups on the primary outcome measure of in-hospital death. The number of patients who died in the group treated with hydroxychloroquine plus azithromycin was 189/735, while the number in the group with hydroxychloroquine monotherapy was 54/271, the number in the group with azithromycin monotherapy was 21/211, and the number in the best  supportive care group was 28/221. The hazard ratio for mortality with hydroxychloroquine plus azithromycin compared with no drug treatment was 1.35 (95% CI 0.76 to 2.40). The other hazard ratios did not differ significantly from those for no drug treatment either.

Anomalous ECGs were more common in the group of patients treated with the combination of azithromycin and hydroxychloroquine (27.1% in the group with azithromycin plus hydroxychloroquine, versus 14% in the non-treated group). After adjustment for confounders, these differences proved nonsignificant. The odds ratio was 1.55 (95% CI 0.89 to 2.67).

In addition, cardiac arrest occurred in a larger proportion of the patients treated with hydroxychloroquine plus azithromycin (114 patients [15.5%] versus 15 patients [6.8%] in the non-treated group) after adjustment for confounders. The odds ratio was 2.13 (95% CI 1.12 to 4.5), a statistically significant difference.30

The studies discussed above were all retrospective, and they probably suffered from selection bias. There is a considerable risk that patients in poorer clinical condition were more likely to be treated with hydroxychloroquine plus azithromycin. The control group may have had less severe disease, which meant that no drug treatment was started. As regards the last mentioned study it remains unclear whether the more frequent occurrence of cardiac arrest was due to the drugs or to the severity of the illness. 

Risks of treatment with azithromycin

Azithromycin has a moderate potential for causing prolonged QT-interval.31 This means that the QTc-interval can be prolonged by 10–60 ms. When patients use multiple QT-prolonging drugs, such as chloroquine/hydroxychloroquine, they require intensified ECG monitoring. In addition, azithromycin can considerably raise the levels of digoxin and ciclosporin.


The lay media have also reported on the element of zinc as a treatment for COVID-19. In vitro research has shown that zinc can inhibit virus replication. The theory is that hydroxychloroquine increases the uptake of zinc by the cell, resulting in increased antiviral activity.

Currently, no scientific literature is available in which this intended effect has been proven in humans. Zinc can, however, reduce the absorption of certain antibiotics, like quinolones and tetracyclines.31

Antiviral drugs: remdesivir

There is growing worldwide interest in the use of the antiviral drug remdesivir. This drug has not yet been authorised in Europe. The first results of studies into its efficacy for COVID-19 have been positive, but these research findings are limited and derive from a non-randomised study involving a small number of patients and from incomplete results of a randomised study. In addition, there is a considerable risk of adverse effects of remdesivir. 

Mode of action of remdesivir

Remdesivir is a viral RNA-polymerase inhibitor, a drug that interferes in the production of viral genetic material, thus inhibiting viral replication (Figure 1.2, No. 3). In vitro research has shown that remdesivir has an antiviral effect in SARS-CoV-2. It is administered intravenously.32 

Authorisation by FDA and EMA 

In the United States, remdesivir was authorised by the FDA in an accelerated procedure in early May 2020, for adults and children who have tested positive for SARS-CoV-2 infection and have a low oxygen saturation or need ventilation. There are ongoing discussions between the FDA and the manufacturer Gilead about making remdesivir actually available to patients.32 In the Netherlands, remdesivir is available through a ‘compassionate use’ programme.33 At EMA, an accelerated procedure is underway to review the drug for authorisation.34

Compassionate use study: reducing oxygen demand

In a ‘compassionate use’ study sponsored by the manufacturer Gilead, 61 hospitalised patients with COVID-19 were treated with remdesivir.35 The patients were given remdesivir for 10 days, 200 mg on day 1 followed by 100 mg on days 2 to 10. The inclusion criteria were having tested positive for SARS-CoV-2 infection and an oxygen saturation <94% with noninvasive ventilation with ambient air or oxygen support. No specific endpoints were defined for this compassionate use study, but so-called ‘key clinical events’ were quantified. These included oxygen demand, mechanical ventilation, extracorporeal membrane oxygenation (ECMO), hospital discharge, serious adverse effects and death. 

In the end, 53 patients were included in the analysis, with dropout caused by lack of data on the patient’s condition after treatment (n=7) and a dosage error (n=1). At the time of inclusion, 30 patients (57%) were on mechanical ventilation and four patients (8%) were being treated with ECMO. During the 18-day follow-up, 36 patients (68%) needed less oxygen. Seventeen patients on ventilation were able to be weaned from ventilation after the treatment. In all, 25 patients (47%) of this cohort were discharged from hospital and 7 patients (13%) died.35

This study provides limited and low quality evidence for the efficacy of remdesivir for COVID-19. In addition, there are frequently serious adverse effects. It was a study with a small patient sample, with short follow-up, and with an observational design. 

First results of randomised study: faster recovery with remdesivir 

The first results of a randomised study show that patients with pulmonary symptoms in an advanced stage of COVID-19 (n=1063) who were given remdesivir recovered more rapidly than comparable patients who were given a placebo.32 This study (Adaptive COVID-19 Treatment Trial) is being sponsored by the US National Institutes of Health (NIH). The median time to recovery was 11 days (95% CI 9 to 12 days) with remdesivir and 15 days (13 to 19) with placebo. This difference was statistically significant. Clinical recovery was defined as sufficient recovery for discharge from hospital or return to normal activity level. The number of patients who died was lower in the remdesivir group than in the placebo group, but this difference was not significant.32

Treating with remdesivir for 5 or 10 days?

A randomised study investigated the effects of remdesivir for 5 or 10 days on the course of confirmed SARS-CoV-2-infection.36 This study found no difference in clinical status between 5 days and 10 days of treatment with remdesivir.

This randomised open-label Phase 3 study of remdesivir included patients who had tested positive for SARS-CoV-2 infection and had an oxygen saturation <94% without oxygen support. The patients were treated with remdesivir for 5 or 10 days, receiving 200 mg on day 1 and 100 mg on the subsequent days. The endpoint was the clinical status on day 14, assessed on a 7-point scale:
1: died
2: hospitalised, undergoing invasive mechanical ventilation or ECMO
3: hospitalised, undergoing noninvasive ventilation or high-flow oxygen treatment
4: hospitalised, undergoing low-flow oxygen treatment
5: hospitalised, receiving intensive medical care without oxygen treatment
6: hospitalised, without invasive treatment
7: discharged from hospital

Clinical improvement was defined as an improvement of at least 2 points on this 7-point scale. A secondary outcome measure was the occurrence of adverse effects. This study did not compare with a group of patients without adjunctive treatment.

A total of 200 patients were treated with remdesivir for 5 days, and 197 patients were treated for 10 days. The patients in the 10-day group were significantly more severely ill at inclusion than those in the 5-day group. On day 14, 64% of the patients in the 5-day group had improved by at least 2 points, versus 54% of the patients in the 10-day group. This difference was not statistically significant. After adjusting for the difference in clinical status at inclusion, there was no difference between the two groups. This baseline-adjusted difference was -6.5% (95% CI -15.7 to 2.8).

Common adverse events were nausea (9%), worsening respiratory failure (8%), increased ALT (7%) and constipation (7%).

Contradictory evidence about adverse effects

Patients in the compassionate use study frequently showed adverse effects of remdesivir, whereas the randomised study found no difference in this respect between remdesivir and placebo.32,35 Of the 61 patients in the compassionate use study, 32 had adverse events, 12 of which were classified as serious. The most common adverse effects were elevated liver function values, diarrhoea, skin rashes, functional disorders of the kidney and hypotension. Four patients ended the use of remdesivir prematurely during the treatment due to serious adverse events.35 Since this study was not placebo-controlled, it is impossible to ascertain whether the symptoms can actually be attributed to the remdesivir. Some of the adverse events might be consistent with COVID-19.

Antiviral drugs: combination of lopinavir and ritonavir

Lopinavir  and ritonavir  are drugs used to treat HIV. For these drugs, too, there is as yet insufficient evidence for their efficacy and safety in the treatment of COVID-19.

Mode of action of lopinavir/ritonavir

Lopinavir targets the replication of the virus in the cell. In-vitro studies have yielded indications that it is also effective against new coronaviruses, but it has not been specifically investigated in SARS-CoV-2. Ritonavir inhibits the metabolism of lopinavir and thus ensures that the concentration of lopinavir in the plasma is and remains sufficient.37

No evidence of clinical effect 

A systematic review of the effect of the lopinavir/ritonavir combination in treating SARS found and analysed only retrospective, observational studies. After administration in an early stage of the infection, there was a trend towards lower mortality and less need for intubation. In view of the moderate quality of the studies, no major significance can as yet be attached to these favourable findings.38 There has been one randomised study comparing the effect of lopinavir/ritonavir with usual care among 199 patients with COVID-19.39 This study did not find a difference in terms of patients’ clinical improvement, viral eradication or 28-day mortality.

Interactions and adverse effects 

Important drug interactions have been found with lopinavir/ritonavir, which must be  closely monitored, and adverse effects are also common. The hepatotoxicity of these two drugs can also cause problems particularly in patients with COVID-19, as liver function abnormalities are common during the course of COVID-19.39 

Interleukin inhibition: tocilizumab

Tocilizumab is used to treat patients with rheumatoid arthritis who do not respond to conventional DMARDs (Disease Modifying Anti Rheumatic Drugs) like methotrexate.40 Tocilizumab is also the cornerstone of the treatment of patients with a cytokine-storm syndrome like that seen in CAR-T cell therapy.41 Several studies are in progress to assess its efficacy and safety in COVID-19. 

IL-6 inhibition by tocilizumab 

Tocilizumab is a humanised monoclonal antibody against the human IL-6 receptor. Tocilizumab binds to IL-6 receptors and thus counteracts the effect of IL-6. IL-6 has receptors on T-cells, B-cells and neutrophils and hence stimulates inflammatory reactions (Figure 1.5, No. 6).

Figure 1.5. Targets of drugs for SARS-CoV-2 infection, part 4.

ACE2: angiotensin-converting enzyme 2, IL: interleukin.

Stage 2/3, inflammatory / hyperinflammatory response: increase in number of bradykinin receptors and downregulation of the amount of ACE2 in the membranes.
5. Release of inflammatory mediators by macrophages, increased vascular permeability (B).
6. Released IL-1 and IL-6 activate neutrophils, T-cells and B-cells, the inflammatory reaction proceeds further.

Effect and safety of tocilizumab are being investigated

In view of the very plausible effect of hyperinflammation on the severity of the disease process in SARS-COV-2 infections, tocilizumab has already been used once to treat COVID-19. This was published in a case report.42 There are currently no results available of randomised studies. Two studies of tocilizumab are in progress in China (ChiCTR20000308 and ChiCTR2000029765), and another two are in progress in Europe: the COVACTA study (NCT04320615), which is sponsored by the manufacturer of tocilizumab, and a researcher-initiated study sponsored by the University Medical Centre Groningen. In addition, there is an ongoing Phase 2/3 study of sarilumab, a human antibody against the IL-6 receptor (EudraCT: 2020-001162-12, NCT04315298). The current recommendation is to use off-label treatments targeting IL-6 only in the context of research studies (

Theoretical danger of interleukin inhibition

There are risks attached to selective inhibition of cytokines like IL-1 and IL-6 during sepsis. Inhibition of cytokines reduces the body’s ability to inhibit virus replication, resulting in an increased the risk of bacterial infections. It is as yet unclear whether these risks also apply to SARS-CoV-2 infection.43

Interleukin inhibition: anakinra

Anakinra is an effective treatment against auto-inflammatory disorders such as systemic juvenile idiopathic arthritis and Still’s disease in adults.44,45 Anakinra is also used to treat a cytokine storm in haemophagocytic lymphohistiocytosis (HLH).46 

IL-1 inhibition by anakinra 

Anakinra is a human IL-1 receptor antagonist that neutralises the biological activity of IL-1 by competitive inhibition of its binding to the IL-1 receptor (Figure 1.5, No. 6). IL-1 has receptors all over the body, from T-cells, B-cells and neutrophils to the hypothalamus. IL-1 also plays a part in activating other interleukins.47

Effect and safety of anakinra are being investigated 

Based on local protocols, anakinra is exceptionally being used as an off-label drug in the Netherlands (in case of markedly elevated ferritin concentrations in the blood and in patients with high IL-18 concentrations like those seen in HLH). There is currently a large randomised international multicentre study underway, the so-called platform trial REMAP-CAP, which is studying the effect and safety of anakinra and other agents for very ill ICU patients with COVID-19 ( Anakinra is being compared with no adjunctive treatment among patients hospitalised with COVID-19. The primary outcome measure is the number of days the patients survive outside the ICU (, NCT02735707).

Inhibition of the bradykinin pathway: icatibant

Icatibant is a drug that is prescribed as an episodic therapy in hereditary angioedema (HAE). Nothing is as yet known about the efficacy of icatibant in COVID-19. There are, however, plans to investigate the effect and safety of drugs that target the bradykinin pathway in patients with COVID-19, including icatibant.

Bradykinin-2 receptor inhibition by icatibant 

Icatibant has a structure that resembles that of bradykinin and is an antagonist of the bradykinin-2(B2) receptor. Inhibition of the B2-receptor signalling by icatibant could block part of the cascade that leads to angioedema (Figure 1.6, No. 7).6,48

Figure 1.6. Targets of drugs for SARS-CoV-2 infection, part 5.

ACE2: angiotensin-converting enzyme 2, B1/B2: bradykinin 1 and 2 receptors.

Stage 2/3, inflammatory / hyperinflammatory response: increase in number of bradykinin receptors and downregulation of the amount of ACE2 in the membranes.
5. Release of inflammatory mediators by macrophages, increased vascular permeability (B).
7. Vascular damage activates Factor XII (C), release of interleukins activates the bradykinin pathway (F), bradykinin from plasma activates the B2 receptor and bradykinin accumulates in the lung. 
8. Activation of Factor XII (C) converts kallikrein into plasma bradykinin, bradykinin accumulates in the lung via B2 receptors, activation of the B1 receptors results in angioedema. 

Inhibition of the bradykinin pathway: lanadelumab and C1-esterase inhibitor

Lanadelumab and C1-esterase inhibitor  are prescribed for the prophylaxis of episodes in hereditary angioedema (HAE). 

Inhibition of bradykinin formation

Lanadelumab is a human monoclonal IgG1 antibody. Lanadelumab inhibits the action of active plasma kallikrein and thus inhibits the formation of plasma bradykinin (Figure 1.6, No. 8). C1-esterase inhibitor blocks two steps in the bradykinin pathway, viz. the step from factor XII activation to plasma kallikrein and the step from plasma kallikrein to plasma bradykinin (Figure 1.6, No. 8 and Figure 2). There are currently plans to carry out proof-of-principle studies with lanadelumab for COVID-19 in a number of university centres in the Netherlands. 

Hypothesis about the development of angioedema

Hyperinflammation in the third stage of COVID-19 appears to cause the development of a clinical picture resembling ARDS. The ARDS-type picture in COVID-19 differs from conventional ARDS as patients with a severe SARS-CoV-2 infection generally do not suffer from reduced pulmonary compliance (hardening of the lung), whereas they do in conventional ARDS.6

Pathophysiologically speaking, the clinical picture in COVID-19 is more similar to the bradykinin-driven angioedema seen in hereditary angioedema (HAE). This form of angioedema is difficult to treat with adrenalin and corticosteroids. Similarly, the effect of corticosteroids in COVID-19 with ARDS is questionable.49

Knowledge about the activation of the bradykinin pathway has been yielded by research among patients with a C1-esterase inhibitor deficiency (HAE types 1 and 2, Figure 2). In this type of HAE, two steps in the bradykinin pathway are not inhibited, viz. the conversion of prekallikrein to kallikrein by activated factor XII and the conversion of kininogen to bradykinin (Figure 2). As a result, the amount of bradykinin increases, and this eventually leads to vascular leakage and angioedema. Patients with HAE develop oedema of the limbs, face, intestines and larynx, but not usually of the lung. This is probably because patients with HAE do not have a local pulmonary inflammatory response like those with COVID-19.6,48 It remains unclear why C1-esterase inhibitor does not appear to control this dysregulation in COVID-19.

Figure 2. Bradykinin-mediated angioedema by C1-esterase inhibitor.

XIIa: activated Factor XII, HMWK: high molecular weight kininogen

Angioedema in COVID-19

Pulmonary and vascular damage activates coagulation factor XII, giving rise to bradykinins (Figure 1.6, C and D). Bradykinin cannot be inhibited in the lung by ACE2 as SARS-CoV-2 results in downregulation and dysfunction of ACE2 (Figure 1.6, E). Tissue bradykinin binds to bradykinin-1(B1) receptors, causing vascular leakage and angioedema. Cytokines IL-1 and IL-6 downregulate both ACE and ACE2 (Figure 1.6, E), as a result of which not only tissue bradykinin but also plasma bradykinin can cause vascular leakage and angioedema. IL-1 and IL-6 also upregulate the B1 and B2 receptors, making more receptors available for the binding of both tissue and plasma bradykinin (Figure 1, F). On the other hand, bradykinin stimulates macrophages to produce more IL-1, aggravating the dysregulation of the kallikrein-bradykinin system (Figure 1.6, G).6,48


Valsartan is an angiotensin II antagonist, which selectively blocks the binding of angiotensin II to the AT1 receptor in various tissues. In a previous issue, Ge-Bu has discussed the potentially negative influence of drugs on COVID-19.50 The authors concluded that ACE inhibitors and angiotensin II antagonists have no direct negative influence on the course of COVID-19. It has recently even been suggested that valsartan might have a positive effect on COVID-19. There is currently no evidence on the effect and safety of valsartan in COVID-19. 

Mode of action: preventing damage by angiotensin II

The familiar action of valsartan involves blocking the activity of angiotensin II, which prevents  vasoconstriction and thus reduces blood pressure. Angiotensin II causes not only vasoconstriction, but probably also inflammation and increased permeability of the vascular wall. In physiological conditions, angiotensin II is broken down by ACE2 into angiotensin 1-7 (Figure 1.7, H). Since the SARS-CoV-2 virus downregulates ACE2, less angiotensin II is broken down, and the pressure can cause fluid to leak from the blood vessels into the lungs. Blocking angiotensin II by valsartan can thus potentially prevent inflammation and cell destruction.

Figure 1.7. Targets of drugs for SARS-CoV-2 infection, part 6.

ACE2: angiotensin-converting enzyme 2, Ang: angiotensin, AT1-receptor: angiotensin 1 receptor.

Stage 2/3, inflammatory / hyperinflammatory response: increase in number of bradykinin receptors and downregulation of the amount of ACE2 in the membranes.
9. Conversion of angiotensin II into angiotensin 1-7 is reduced by downregulation of ACE2 (E). Angiotensin II causes vasoconstriction and increased permeability of the vascular wall, and has a pro-inflammatory effect.

Current studies into valsartan 

At the moment there are two scientific studies in progress in the Netherlands and Germany which are investigating the effect and safety of valsartan in the treatment of COVID-19 (EudraCT: 2020-001320-34 resp. 2020-001431-27).

Combination therapies and timing

How and at what time the therapies discussed above should be applied in COVID-19 is unknown. It is also still unclear what determines which patients go through stages 2 and 3. Greater understanding of this might also lead to a more targeted therapy. These therapies should be used in the context of research studies. An essential aspect is still the clearance of the virus by the immune system itself, whether or not assisted by antiviral therapy. If the virus is effectively cleared, the virus-induced inflammatory cascade and dysregulation of the bradykinin pathway will not arise. Theoretically, a combination of anti-inflammatory treatment and treatment of angioedema must be started at an early stage. This might prevent patients from progressing to stage 3 with inflammation/hyperinflammation and angioedema, which necessitates ICU admission.6,43

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  • Feikje van Stiphout
  • Lisanne L. Krens, dr, pharmacist
  • Maja Bulatović-Ćalasan
  • Tessa M. Bosch