Thursday, April 9, 2020

A new possible treatment for COVID-19: interferon alpha.

Copyright 2020 Robert Clark


 A recent Chinese study testing hydroxychloroquine for the coronavirus has been badly reported on by the media:

EDITORS' PICK|113,401 views|
Hydroxychloroquine Use For COVID-19 Coronavirus Shows No Benefit In First Small—But Limited—Controlled Trial.
Tara Haelle Senior Contributor
Healthcare

 The headline is highly misleading, but this is how most articles on this research is being presented.
 But reading what the article actually says is different than the impression the headline gives. The headline falsely gives the impression the conventional treatment group or control group didn’t get any medicine and all they did was give bed rest and perhaps some inhalers, and that for either testing group or control group there was little improvement. Actually, no.
 ALL patients both in the test group and control got antivirals. Plus, most importantly ALL patients showed no virus after two weeks. They were essentially cured!
 Here's the passage in the article by Ms. Haelle where it is discussed that all patients received antivirals of some type:

Usual care included bed rest, oxygen inhalation, and antiviral or antibiotic drugs as needed or recommended according to the hospital’s treatment plan. All patients in both groups received interferon alpha with a nebulizer, and umifenovir—an antiviral treatment approved in China for influenza—was administered to 67% of the usual care patients and 80% of the patients receiving hydroxychloroquine. Two patients received lopinavir-ritonavir, an anti-viral normally used to treat HIV infections. 

 And here it is discussed in Ms. Haelle's article the results showing all patients tests and controls were free of virus in two weeks:

Here were the main findings:
  • One patient developed severe disease. That patient was in the hydroxychloroquine group and stopped receiving it on the fourth day. The authors state that developing severe disease did not appear related to the medication.
  • One week after hospitalization, 86.7% of patients in the experimental group and 93.3% of patients in the usual care group tested negative. This difference was not statistically significant. 
  • It took 4 days for half the hydroxychloroquine patients to test negative and 2 days for half the control group to test negative. This difference was not statistically significant.
  • Patients’ temperatures returned to normal at approximately the same rate in both groups. 
  • Disease progression in CT images was statistically similar between the groups (33.3% of the hydroxychloroquine group and 46.7% of the usual care group).
  • At two weeks, all patients in both groups tested negative and showed improvement in their symptoms. 
  • Short-term diarrhea and abnormal liver function occurred in 26.7% of the hydroxychloroquine group and 20% of the usual care control group.
  • The rate of adverse events (side effects that may or may not be related to the medication) were similar in both groups. 

 The focus has been so much in the news articles describing this research in disproving hydroxychloroquine, that they completely overlook the fact that hospitalized patients with the disease showed a 100% cure rate after using certain antivirals!
 Ms. Haelle has done an admirable job in summarizing in English the results of the original research report written in Chinese. I advise everyone also to read the original research report. It can be downloaded here:


To see an English translation, uploaded it to translate.google.com under the "Documents" option:


 Ms. Haelle mentions both test and control group patients temperatures returned to normal at same rate, but in fact it took on average only 1 day(!) for their temperatures to return to normal, a key indicator for lessening in the severity of the disease. Also important in regards to the rapidity of response to the medication, in both test and control groups while all patients tested negative in two weeks for the virus, in about 90% of the cases, they tested negative in only one week. Moreover for the control group, it took on average only 2 days for the patients to test negative for the virus.
 A rapid positive response to the medication is extremely important. The longer the disease persists the more damage is done to the lungs. This increases the likelihood the patient will have to be intubated, where a tube is inserted down the throat and a ventilator is used to assist with breathing.
 However, doctors treating COVID-19 patients have noted that only 1/3rd to only 1/5th of intubated COVID-19 patients survive. This may be because at that point the damage to the lungs is too severe, or it may be the intubation itself is too damaging. In any case, it is extremely important to stop the progression of the disease before intubation becomes necessary.
 In the Chinese study different drugs were given to different patients. But there was a common denominator for all the patients. The common denominator was that interferon alpha, a potent antiviral, was given to ALL patients. An internet search reveals that interferon of all three types, alpha, beta, and gamma, has previously shown success against other corona-type viruses such as MERS and SARS in all of test tube, animal, and human studies.

 Then THIS should be the focus of the articles reporting on this research, that there maybe a drug that has a 100% cure rate for hospitalized patients with COVID-19.

  Aside, from the effectiveness of interferon alpha, you really can't make any conclusions on the effectiveness of hydroxychloroquine from this study. The reason is the interferon alpha was 100% effective, and it's pretty hard to improve on 100%!
 Since interferon alpha was given to even the hydroxychloroquine patients, it's hard to disentangle the hydroxychloroquine effectiveness from that of interferon alpha. It could be 0%, it could be 50%, it could be 100%, just like interferon alpha. You can't tell since it was always combined with the interferon alpha.
 Better would be a study that applied hydroxychloroquine and interferon alpha to separate groups of patients. Likely though for this recent study they didn't want to do that since this was for hospitalized patients and it was felt unethical to give patients only an unproven treatment.
 Now that hydroxychloroquine has been reported to have some success against COVID-19, such a study could be undertaken that compared it to interferon alpha in separate groups.
 By the way, if interferon alpha really is 100% effective, can there be any benefit in using instead hydroxychloroquine? Conceivably there could be. If say HCQ, perhaps with its associated side medications of azithromycen and zinc, proves to be 90%+ effective as a protective against COVID-19 likely you would have to be taking it continually while the virus is considered actively spreading. Then since HCQ is so well characterized over decades for millions of people for long term use, you would have more understanding of its side effects than for interferon alpha under a scenario of long-term use.

      Bob Clark


UPDATE, April 10, 2020:

 In this review article the authors also suggest that interferon can be used to treat COVID-19 with the recommendation it should be used in the early stages of the disease, and perhaps it can also act as a prophylactic(protective) agent:

Antiviral Research
Available online 7 April 2020, 104791
In Press, Journal Pre-proof
Short Communication
Type 1 interferons as a potential treatment against COVID-19
Erwan Sallard 1, François-Xavier Lescure 2,3, Yazdan Yazdanpanah 2,3, France Mentre 2, Nathan Peiffer-Smadja 2,3
for the C-20-15 DisCoVeRy French Steering Committee
https://www.sciencedirect.com/science/article/pii/S0166354220302059

 The authors here though argue interferon beta(IFNβ) is a more potent inhibitor of corona virus than interferon alpha(IFNα). Certainly interferon of all three types alpha, beta, and gamma should be tried as treatments.


UPDATE, April 16, 2020:

 This research preprint on a trial of interferon also showed it significantly reduced the length of time of detectable virus and lung inflammation:

Interferon-a2b treatment for COVID-19.

Qiong Zhou, Xiao-Shan Wei, Xuan Xiang, Xu Wang, Zi-Hao Wang, Virginia Chen, Casey P Shannon, Scott J Tebbutt, Tobias R Kollmann, Eleanor N Fish
doi: https://doi.org/10.1101/2020.04.06.20042580
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

Abstract
Summary Background The global pandemic of COVID-19 cases caused by infection with SARS-CoV-2 is ongoing. We describe here the clinical course of COVID-19 in a cohort of confirmed cases in Wuhan, China, treated with the repurposed potential experimental therapeutics IFN-α2b, arbidol or a combination of IFN-α2b plus arbidol. Methods 77 adults with confirmed COVID-19 were treated with either nebulized IFN-α2b (5mU,b.i.d.), arbidol (200mg dispersible tablet, t.i.d.) or a combination of IFN-α2b plus arbidol. Serial SARS-CoV-2 testing along with hematological measurements, including cell counts and blood biochemistry, serum cytokine levels, temperature and blood oxygen saturation levels were recorded for each patient during their hospital stay. Findings Treatment with IFN-α2b with or without arbidol significantly reduced the duration of detectable virus in the upper respiratory tract and in parallel reduced duration of elevated blood levels for the inflammatory markers IL-6 and CRP. Interpretation IFN-α2b should be investigated as therapy in COVID-19 cases.


UPDATE, April 17, 2020:

 This is a bombshell report if confirmed. Over 2,400 medical professions in China were given interferon nasal drops as a possible protective against COVID-19. Of these, over 500 were directly involved with care for COVID-19 patients. After, 28 days none of the medical professionals developed COVID-19. 

 This becomes especially important when you consider the large number of medical professionals in China directly involved with COVID-19 patient care who became infected. From the report:

"The control group was drawn from a literature report in the Chinese Journal of Epidemiology [3] on medical staff diagnosed with COVID-19 pneumonia nationwide and in Wuhan from January 1 through February 11, 2020. Chinese medical staff diagnosed with COVID-19 pneumonia as reported by the China-World Health Organization joint inspection expert group as of February 23 were also included in the control group. The 422 medical institutions providing diagnosis and treatment services for patients with COVID-19 pneumonia reported that among 3387 medical personnel, there were 1716 confirmed cases, 1070 clinically diagnosed cases, and 157 suspected cases, and 3062 cases came from Hubei (Table 2)."
p. 5.

(Note: the original version of my blog post interpreted this passage as saying the 3,387 number was all medical professionals in the hospitals considered and the 1,716 number as those infected. Actually, the 3,387 number is those infected from all the hospitals. So a flaw in this report is it doesn't say what is the percentage of all medical professionals that are infected.)

  Table 2 from the report:

P. 13.


An experimental trial of recombinant human interferon alpha nasal drops to prevent coronavirus disease 2019 in medical staff in an epidemic area.
Zhongji Meng, Tongyu Wang, Chen Li, Xinhe Chen, Longti Li, Xueqin Qin, Hai Li, Jie Luo
doi: https://doi.org/10.1101/2020.04.11.20061473

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

Abstract

Objective To investigate the efficacy and safety of recombinant human interferon alpha1b (rhIFN-α) nasal drops in healthy medical staff to prevent 2019 novel coronavirus disease (COVID-19). Methods A prospective, open-label study was conducted. Starting January 21, 2020, at Taihe Hospital in Shiyan City, Hubei Province, 2944 medical staff members were recruited and allocated into a low-risk group or a high-risk group according to whether they were directly exposed to the coronavirus. Participants in the low-risk group received rhIFN-α nasal drops (2-3 drops/nostril/time, 4 times/day) for 28 days; those in the high-risk group received rhIFN-α nasal drops combined with thymosin-α1 (1.6 mg, hypodermic injection, once a week). The primary outcome was new-onset COVID-19 over 28 days. The secondary outcome was new-onset fever or respiratory symptoms but with negative pulmonary images. The results were compared with the number of new cases in medical staff in the same areas of Hubei Province (including Wuhan) during the same period. Adverse reactions to interferon nasal drops were also observed. Results Among the 2944 subjects in our study, 2415 were included in the low-risk group, including 997 doctors and 1418 nurses with average ages of 37.38 and 33.56 years, respectively; 529 were included in the high-risk group, including 122 doctors and 407 nurses with average ages of 35.24 and 32.16 years, respectively. The 28-day incidence of COVID-19 was zero in both the high- and low-risk groups. The 28-day incidence of new-onset clinical symptoms with negative images for pneumonia was also zero in both the high- and low-risk groups. As controls, a total of 2035 medical personnel with confirmed COVID-19 pneumonia from the same area (Hubei Province) was observed between January 21 to February 23, 2020. There were no serious adverse effects in the 2944 subjects treated during the intervention period. Conclusion In this investigator-initiated open-label study, we observed that rhIFN-α nasal drops can effectively prevent COVID-19 in treated medical personnel. Our results also indicate that rhIFN-α nasal drops have potential promise for protecting susceptible healthy people during the coronavirus pandemic.



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