Version 1
: Received: 30 June 2020 / Approved: 3 July 2020 / Online: 3 July 2020 (08:52:22 CEST)
How to cite:
Scholz, M.; Derwand, R.; Zelenko, V. COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study. Preprints2020, 2020070025 (doi: 10.20944/preprints202007.0025.v1).
Scholz, M.; Derwand, R.; Zelenko, V. COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study. Preprints 2020, 2020070025 (doi: 10.20944/preprints202007.0025.v1).
Cite as:
Scholz, M.; Derwand, R.; Zelenko, V. COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study. Preprints2020, 2020070025 (doi: 10.20944/preprints202007.0025.v1).
Scholz, M.; Derwand, R.; Zelenko, V. COVID-19 Outpatients – Early Risk-Stratified Treatment with Zinc Plus Low Dose Hydroxychloroquine and Azithromycin: A Retrospective Case Series Study. Preprints 2020, 2020070025 (doi: 10.20944/preprints202007.0025.v1).
Abstract
Objective: To describe outcomes of patients with coronavirus disease 2019 (COVID-19) in the outpatient setting after early treatment with zinc, low dose hydroxychloroquine, and azithromycin (the triple therapy) dependent on risk stratification. Design: Retrospective case series study. Setting: General practice. Participants: 141 COVID-19 patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the year 2020. Main Outcome Measures: Risk-stratified treatment decision, rate of hospitalization and all-cause death. Results: Of 335 positively PCR-tested COVID-19 patients, 127 were treated with the triple therapy. 104 of 127 met the defined risk stratification criteria and were included in the analysis. In addition, 37 treated and eligible patients who were confirmed by IgG tests were included in the treatment group (total N=141). 208 of the 335 patients did not meet the risk stratification criteria and were not treated. After 4 days (median, IQR 3-6, available for N=66/141) of onset of symptoms, 141 patients (median age 58 years, IQR 40-60; 73% male) got a prescription for the triple therapy for 5 days. Independent public reference data from 377 confirmed COVID-19 patients of the same community were used as untreated control. 4 of 141 treated patients (2.8%) were hospitalized, which was significantly less (p<0.001) compared with 58 of 377 untreated patients (15.4%) (odds ratio 0.16, 95% CI 0.06-0.5). Therefore, the odds of hospitalization of treated patients were 84% less than in the untreated group. One patient (0.7%) died in the treatment group versus 13 patients (3.5%) in the untreated group (odds ratio 0.2, 95% CI 0.03-1.5; p=0.16). There were no cardiac side effects. Conclusions: Risk stratification-based treatment of COVID-19 outpatients as early as possible after symptom onset with the used triple therapy, including the combination of zinc with low dose hydroxychloroquine, was associated with significantly less hospitalizations and 5 times less all-cause deaths.
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received:
4 July 2020
Commenter: Bob O'Hara
(Click to see Publons profile: )
The commenter has declared there is no conflict of interests.
Comment:
The main problem with this work is that the demographics of the control group are not reported, so we have no idea if they are similar. This them means that we have no idea if the differences in outcomes are because of the treatment, or if they would be expected because of the demographies of the groups.
A subtler point is that the reported age profile of the treatment group is impossible. Group A is aged >60 years, and almost half of the treatment group was in that group. But the IQR was reported as 40-60, so only 25% of the treatment group had an age >60. I hope this was due to excessive rounding, or a similar error that can be corrected.
Received:
6 July 2020
Commenter:
john mecomb
The commenter has declared there is no conflict of interests.
Comment:
The control group would have to be people with symptoms at high risk for progression of disease. Would this not be unethical for this kind of study? I for one would not want to be in such a control group and, as a patient, if informed as such would decline.
As a physician, under the current circumstances, it would violate my hippocratic oath to place people in such a control group.
If this was remdesivir, this study would be on the front page of the NYT.
The "control group" has to be a preponderance of the evidence at this point.
It appears from this study, these medicines do no harm in the first several days of the infection.
Let practicing physicians be free to judge not policicophysicians without patients.
Response 2 to
Comment 1
Received:
6 July 2020
Commenter:
Tom Hogan
The commenter has declared there is no conflict of interests.
Comment:
[I am a random internet personality with a BA (chem) and a MA (physics). I was involved in the internet analysis of the withdrawn Lancet article on hydroxychloroquine.]
This article is groundbreaking and important, if not conclusive. I expect it to be published if only to set a starting bar for outpatient studies where hydroxychloroquine / zinc / azithromycin are used to treat covid and for its method of triaging patients for treatment.
It's unfortunate that we know nothing about demographics/comorbidities/disease severity of the control group. The patient numbers aren't large enough to tell us anything about potential mortality reduction for group A. However, the rate of hospitalization looks quite low for group A. This makes this study important for public health policy.
It would also be helpful to break the ages for group A into (<70, 70-79, 80+). The fatality rates go from 3% for 60-69 to 10% for 70-79 to 30% for 80+ in my county and I suspect that there is similar variability everywhere.
Group B seems like a throwaway as it stands. There is no evidence of SOB beyond self-reporting in group B from the reported data. At least pO2 should be reported for Group B for SOB confirmation.
Response 3 to
Comment 1
Received:
6 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment:
Dear Mr O'Hara,
thank you very much for your comment! We went back to the respective data matrix to check the IQR for age of the total treatment group (N=141). Indeed, there is a typo in the current version of the manuscript: the IQR is 40-67 and not 40-60. We will revise this and upload a version 2 as soon as possible. Again thank you very much for informing us.
Best regards,
Martin Scholz
Response 4 to
Comment 1
Received:
6 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment:
Dear all,
thank you very much for all your comments. As you have read this retrospective case series study analysed data from COVID-19 outpatients with 100 % confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a community in New York State, USA. Outcome of patients who were treated with the specific triple therapy zinc, low dose hydroxychloroquine, and azithromycin was compared to public reference data of patients in exactly the same community who were not treated with this therapy. However, for our analysis we unfortunately only had access to the outcome data of the untreated patient group (not treated with the triple therapy zinc, low dose HCQ, and azithromycin) and so we were also not able to do a risk adjustment. However, the patients in the treated group were all positively risk-stratified while the risk of the untreated group was probably lower as this group included high- and low-risk patients. Of course, this issue is mentioned (page 3) and discussed (page 15) in the paper.
Again thank you very much for your feedback and support.
Best regards,
Martin Scholz
Response 5 to
Comment 1
Received:
7 July 2020
Commenter:
Dr. Chirag Shah
The commenter has declared there is no conflict of interests.
Comment:
First of all congratulations for this wonderfully written article and sharing this extremely valuable evidence in these pandemic times. My question is about the rationale behind presence of at least 1 comorbidity in Group C? Would there be any data that may indicate positive evidence in symptomatic patients <60 without any co-morbidities? Thank you.
Response 6 to
Comment 1
Received:
8 July 2020
Commenter:
Nick Divito
The commenter has declared there is no conflict of interests.
Comment:
Curious to hear your thoughts on other potentially repurposed existing drugs such as famotidine and ivermectin that have similar retrospective data but are not in the public arena? Also would like to hear your thoughts on the MATH+ protocol that some are using.
Comment 2
Received:
5 July 2020
Commenter:
Brian Hollingworth
The commenter has declared there is no conflict of interests.
Comment:
The paper is excellent and, as far as I, a mere engineer, am able to judge, it is well-founded, has been rigorously conducted and is clearly presented. The authors should justifiably take credit for a solid usable study, one that goes quite some way to counter the cynical efforts of a large and powerful body of self-interested persons and organisations who, in my humble opinion, have placed their own gain above the misery and tragedy of thousands of Covid-19 victims. Well done.
Received:
6 July 2020
Commenter:
Sbabo David
The commenter has declared there is no conflict of interests.
Comment:
"The paper is excellent and, as far as I, a mere engineer, am able to judge, it is well-founded, has been rigorously conducted and is clearly presented."
I am sorry, but did you check the numbers?
IQR for the 141 patients: 40-60. Then a maximum of 25% of the 141 patients = 35,25 are 61 years old or older.
IQR for group A, 69 patients: 64-69. So a minimum of 75% of the 69 patients = 51,75 are 64 years old or older.
Don't you see the problem?
Response 2 to
Comment 2
Received:
6 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment:
Dear Mr Sbabo,
thank you very much for your comment! We went back to the respective data matrix to check the IQR for age of the total treatment group (N=141). Indeed, there is a typo in the current version of the manuscript: the IQR is 40-67 and not 40-60. We will revise this and upload a version 2 as soon as possible. Again thank you very much for informing us.
Best regards,
Martin Scholz
Comment 3
Received:
5 July 2020
Commenter:
EDIGEZIR B GOMES
The commenter has declared there is no conflict of interests.
Comment:
O presente artigo reforça a síntese de que a HCQ tem ação na redução da replicação viral, Seu uso no tratamento das artrites, a princípio era entendido como potencial amplificador dos efeito anti-inflamatórios dos corticoides no corpo humano. Alguns endocrinologistas, mais recentemente demonstravam conhecimento de que a droga sozinha sem associação com corticoide, agia efetivamente na redução dos efeitos inflamatórios de algumas artrites. E só mais recentemente como a pandemia do Covid-19, é que seu uso como antivirótico foi introduzido. Essa sequencia clínica, fora espelhada pelo Dr. Siddiqui, que tornou fácil o entendimento clinico das fases da doença em curso, levando de imediato a conclusão de que o tratamento das fases iniciais com HCQ, Zinc , Azitromicina e corticoides reduziam drasticamente a evolução da doença para fases mais tardias onde praticamento o sistema imunológico perderia para a tempestade citotóxica. Por outro lado, com a replicação viral reduzida pelo efeito comprovado da HCQ, problemas menores ocorreriam na troca gasosa alveolar, reduzindo a necessidade de entubação e mesmo se assim o fossem, haveria suficiente troca gasosa nos pulmões.
Desta forma quero deixa aqui meus elogios ao Ilustres colegas Scholz, M.; Derwand, R.; Zelenko, V, que tanto lutaram nessa guerra política que pela primeira vez, graças as Mídias Sociais , a Industria Farmacêutica perde sua hegemonia em impor medicações caras , e muitas vezes sem devido seguimento dos efeitos colaterais. Uma coisa nós sabemos, a HCQ tem 0 anos de uso no mundo sem nenhum relato de danos ao usuário necessitado.
Received:
6 July 2020
Commenter:
Del McReynolds
The commenter has declared there is no conflict of interests.
Comment:
Dr Zelenko is one of hundreds and probably more like thousands of doctors who use this protocol with their patients and themselves. You doubters and your reasons for not trusting anything that could save the world from people like you wanting to put your trust in a vaccine called "WARP SPEED" is strange. The drug has been safe to use for other issues for the past 65 years which already proves is it safe and is still being used by MILLIONS today. Now it is being used off label for covid 19 with world saving success, so to use something that will probably save your life and inexpensive is a no brainer. It sure won't kill you to at least try it.
Received:
6 July 2020
Commenter:
Brian K
The commenter has declared there is no conflict of interests.
Comment:
I have been closely following Dr. Zelenko and researching this combination protocol since March 2020. Congratulation to Dr. Zelenko et al for the hard work and courage in conducting this study. With politically tainted bias subtracted it is becoming easier to distinguish sincere HCQ studies from tainted HCQ studies that have been creatively constructed to discredit HCQ. Many HCQ studies didn't administer the treatment early, omitted zinc, administered unsafe dosing and/or included patients with comorbidities at a higher rate in the treatment group. This study should open the door for further HCQ and zinc studies, perhaps a HCQ and zinc prophylaxis study.
Received:
7 July 2020
The commenter has declared there is no conflict of interests.
Comment:
I am concerned with a number of biases in the data that seem to stack the deck in favor of the treatment group:
1) The inclusion of 37 cases substantiated by an antibody test is highly problematic, as in order to receive the antibody rest, each of these patients needed to survive covid. Any additional patients that died prior to otherwise receiving an antibody test are excluded. This stacks the deck in favor of the treatment group, and absent any intervention at all, we would still expect them to fare better than the control.
2) Separate from the study itself, I feel compelled to observe that the data described in the report seems to contradict public statements by one of the authors, Dr. Zev Zelenko. The author has publicly claimed to have treated more than 1500 patients with this treatment, but only provides data on 377.
The study states that the control group is based on laboratory results of patients in the same community - how big a population were these drawn from? If these are Dr. Zelenko’s patients, where are the rest of them? Why are we presented with no results from the other patients treated with this cocktail? If these are not Dr. Zelenko’s patients, who are they?
This is an interesting read, but in the public interest, the authors should publish results from the entirety of the patient population treated by Dr. Zelenko.
Received:
7 July 2020
Commenter:
Baruch Wilks
The commenter has declared there is no conflict of interests.
Comment:
I agree that it would have been nice to have the full data set to look at but this is standard practice in a lot of studies. Unfortunately there is no way to know what the numbers would have been like if they added more data points. That is why reputation is so important and why it is very hard to extrapolate from studies. You can only look at what you are given and make conclusions based on that data set. I also would have liked a bigger patient population with more subsections but they decided to use this one. Since this is really only an introductory study into the use of zinc and hydroxycloroquine and not conclusive enough to say it is a good treatment I feel that it is fine though.
Response 2 to
Comment 7
Received:
7 July 2020
Commenter:
Grant Klappstein
The commenter has declared there is no conflict of interests.
Comment:
"As of today, my team has tested approximately 200 people from this community for Covid-19, and 65 per cent of the results have been positive. If extrapolated to the entire community, that means more than 20,000 people are infected at the present time. Of this group, I estimate that there are 1500 patients who are in the high-risk category (i.e. >60, immunocompromised, comorbidities, etc)."
Read more at: https://www.vanguardngr.com/2020/03/coronavirus-new-york-doctor-successfully-treats-patients-with-drug-cocktail/
So that is a quote from Zelenko's published letter of late March 2020. Depending how you interpret the word "patients" in the context of his sentence it is possible, although unlikely, that the 1500 refers to patients treated but not confirmed for Covid. Or, more likely, that they were potential patients based on the rate of infection in the general population. In either case I am sure you would not argue Zelenko should include untested patients and/or non patients.
If my memory is right, Zelenko started with claims of 5 or 600 treated patients but later revealed that many of the original treated cohort had not been confirmed for Covid infections, they were putative based on symptoms. He then indicated he was going to get some help from researchers to refine the claims according to general research protocols. This paper appears to be the result of that, I expect the 377 was what was left over when "putative+actual" covid infections were trimmed to "actual".
For a summary of covid 19 trials I found the site clinicaltrials.gov which is from the US National Library of Medicine. I did a search of trials using the following terms, "hydroxychloroquine" and "covid-19" considering "active", "recruiting" or "not yet recruiting". This search yielded 189 studies from around the world, and provides, if perhaps not full accounting, at least a valid sample of ongoing research. When I added "zinc" to the search there were 9 results. In one of those 9 the zinc was mentioned only in the title of the trial, in the other 8 zinc was mentioned in the "interventions' column which lists the drugs and dietary supplements. This result suggests that 9 of 189 are testing HCQ plus zinc and the remainder omit zinc.
Of course if the details of these trials were examined one by one, more using zinc might surface, not listed in interventions nor the title. However it probably gives some sort of reasonable estimate of the ratio of zinc+HCQ trials vs HCQ without zinc, ie about 5%. Since many of these trials are in response to the early anecdotal findings that zinc plus HCQ was a valid treatment, worthy of further testing, it is disappointing that so many of the trials do not include zinc. I am not sure what to make of this exactly but I do share a certain uneasiness about motivations as expressed by comment 6, above.
Response 3 to
Comment 7
Received:
7 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment:
Dear anonymous,
Thank you very much for your comments and questions. Please find enclosed our responses:
Question number 1:
This retrospective case series study analyzed data only from COVID-19 outpatients with a laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a community in New York State, USA. During the peak of the pandemic the responsible primary care physician diagnosed many patients often first clinically during the early course of the disease and initiated treatment with the described triple therapy zinc, low dose hydroxychloroquine, and azithromycin as soon as possible. Most of these patients were already tested for SARS-CoV-2 but did not have a final test result yet. Some others were not able to get a PCR test and the infection was confirmed by IgG tests later. However, in accordance with the study protocol all patients with a positive test result were included in the retrospective analysis at a defined point of time. This included also one deceased patient. The SARS-CoV-2 infection of this patient was also finally confirmed after initiation of treatment and after hospitalization. All patients with a laboratory confirmed COVID-19 diagnosis, who were positively risk stratified, and who were treated with the triple therapy were included in the detailed analysis.
For the analysis of the untreated patient group of the public reference (not of the respective practice and not treated with the triple therapy zinc, low dose HCQ, and azithromycin) unfortunately only the outcome data was available and so also a risk adjustment was not possible. However, the patients in the treated group were all positively risk-stratified while the risk of the untreated group was probably lower as this group included high- and low-risk patients. Of course, this issue is mentioned (page 3) and discussed (page 15) in the paper.
Question number 2:
At the point of closing the database 372 positively tested patients of the respective practice were included and 377 positively tested but untreated COVID 19 patients (not treated with te triple therapy, public reference, s. figure 1). Of course, after this time the pandemic has been still ongoing and more patients have been obviously treated but these were not included in this analysis and report anymore.
During the pandemic many jurisdictions in the United States, like states, counties and even cities released data about COVID-19 cases including outcomes (even based on respective zip codes). This was also the case for the respective community. As described in the study approval section on page 9 this analysis was conducted with de-identified patient data, according to the USA Health Insurance Portability and Accountability Act (HIPAA), Safe Harbor and so it is not allowed to report exact dates or more detailed information about the respective community etc. in the publication.
All data available at the time of analysis is included in this publication.
We agree that it would be very interesting to do an additional analysis of more available patient data at a later point of time.
Best regards,
Martin Scholz & Roland Derwand
Response 4 to
Comment 7
Received:
9 July 2020
Commenter:
samuel gluck
The commenter has declared there is no conflict of interests.
Comment:
this study report would benefit from some easy to read color coded charts, the institutional bias against trump and anything he supports leads to think publication will not be easy. hope i'm wrong. regarding the number of patients treated dr. zz has stated that he did not prescribe the protocol to all the patients he saw only to those over certain age or with other medical conditions etc. that would make them more vulnerable . the way i read it only 377 were treated . this should be clearer.
Comment 8
Received:
7 July 2020
Commenter:
Jeffrey LeRoux
The commenter has declared there is no conflict of interests.
Comment:
A very
A very interesting study. I would love to see a better designed study. There is not enough details in this prepublication study to reach any other conclusion. I would love to see the details about classification and data about the comparability of the groups. The age difference noted above is a big problem.
More research needed.
Received:
7 July 2020
Commenter: Martin Scholz
The commenter has declared there is no conflict of interests.
Comment:
Dear Mr LeRoux,
Thank you very much for your comments. As explained above there is a typo in version 1 of the manuscript: the IQR of the age of the total treatment group (N = 141) is 40-67 and not 40-60. We currently work on a revised version and will upload it soon.
In this retrospective analysis outcome of patients who were treated with the specific triple therapy zinc, low dose hydroxychloroquine, and azithromycin was compared to public reference data of patients in exactly the same community who were not treated with this therapy. For our analysis we unfortunately only had access to the outcome data of the untreated patient group (not treated with the triple therapy zinc, low dose HCQ, and azithromycin) and so we were also not able to do a risk adjustment. However, the patients in the treated group were all positively risk-stratified while the risk of the untreated group was probably lower as this group included high- and low-risk patients. Of course, this issue is mentioned (page 3) and discussed (page 15) in the paper.
To our knowledge this is still the only COVID-19 outpatient risk stratification and treatment study and so we agree that more research is needed. Responsible experts and stakeholders should ensure a common effort to continue to close this gap by designing studies specifically for primary care setting. Based on the observed magnitude of the reported results associated with the use of the triple therapy zinc, low dose HCQ, and azithromycin and based on other available data, we propose to amend ongoing studies with HCQ to include combination with zinc.
Best regards,
Martin Scholz & Roland Derwand
Comment 9
Received:
7 July 2020
Commenter:
Roger Burrows
The commenter has declared there is no conflict of interests.
Comment:
I am a retired engineer, and I am at a loss as to why the study does not headline every news outlet today. Maybe it plays as old, tired news? My Dad's explanation "It is always about the money. Unless they say it is not about the money, and then it is really all about the money"?
I have questions about the participants in the study. Maybe this is in the depth of the study but not clear to me from the extract.
335 candidates -- COVID-19 patients, not yet hospitalized when the selection for treatment was done.
127 treated with the protocol. How were these selected out of the 335 candidates? Some criteria? Randomly?
104 included in the analysis. Why were 23 treated patients excluded from analysis? That is a lot out of such a small sample size. I think hardly any would be found to have contraindications after the treatment was done. I assume all 23 didn't just die due to unrelated somethings. Maybe they got well and were just not seen on follow-up?
37 patients added to the treatment group with positive serum tests. Were these 37 out of the original 208 unselected candidates? Why were these patients added? It could be humanitarian reasons, I think.
141 treated patients included in the analysis.
Thank you and congratulations of your continued high-value contribution.
Received:
8 July 2020
Commenter:
Dr. Chirag Shah
The commenter has declared there is no conflict of interests.
Comment:
First of all congratulations for this wonderfully written article and sharing this extremely valuable evidence in these pandemic times. My question is about the rationale behind presence of at least 1 comorbidity in Group C? Would there be any data that may indicate positive evidence in symptomatic patients <60 without any co-morbidities? Thank you.
Martin Scholz
Commenter:
The commenter has declared there is no conflict of interests.
A subtler point is that the reported age profile of the treatment group is impossible. Group A is aged >60 years, and almost half of the treatment group was in that group. But the IQR was reported as 40-60, so only 25% of the treatment group had an age >60. I hope this was due to excessive rounding, or a similar error that can be corrected.
Commenter: john mecomb
The commenter has declared there is no conflict of interests.
As a physician, under the current circumstances, it would violate my hippocratic oath to place people in such a control group.
If this was remdesivir, this study would be on the front page of the NYT.
The "control group" has to be a preponderance of the evidence at this point.
It appears from this study, these medicines do no harm in the first several days of the infection.
Let practicing physicians be free to judge not policicophysicians without patients.
Commenter: Tom Hogan
The commenter has declared there is no conflict of interests.
This article is groundbreaking and important, if not conclusive. I expect it to be published if only to set a starting bar for outpatient studies where hydroxychloroquine / zinc / azithromycin are used to treat covid and for its method of triaging patients for treatment.
It's unfortunate that we know nothing about demographics/comorbidities/disease severity of the control group. The patient numbers aren't large enough to tell us anything about potential mortality reduction for group A. However, the rate of hospitalization looks quite low for group A. This makes this study important for public health policy.
It would also be helpful to break the ages for group A into (<70, 70-79, 80+). The fatality rates go from 3% for 60-69 to 10% for 70-79 to 30% for 80+ in my county and I suspect that there is similar variability everywhere.
Group B seems like a throwaway as it stands. There is no evidence of SOB beyond self-reporting in group B from the reported data. At least pO2 should be reported for Group B for SOB confirmation.
Commenter:
The commenter has declared there is no conflict of interests.
thank you very much for your comment! We went back to the respective data matrix to check the IQR for age of the total treatment group (N=141). Indeed, there is a typo in the current version of the manuscript: the IQR is 40-67 and not 40-60. We will revise this and upload a version 2 as soon as possible. Again thank you very much for informing us.
Best regards,
Martin Scholz
Commenter:
The commenter has declared there is no conflict of interests.
thank you very much for all your comments. As you have read this retrospective case series study analysed data from COVID-19 outpatients with 100 % confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a community in New York State, USA. Outcome of patients who were treated with the specific triple therapy zinc, low dose hydroxychloroquine, and azithromycin was compared to public reference data of patients in exactly the same community who were not treated with this therapy. However, for our analysis we unfortunately only had access to the outcome data of the untreated patient group (not treated with the triple therapy zinc, low dose HCQ, and azithromycin) and so we were also not able to do a risk adjustment. However, the patients in the treated group were all positively risk-stratified while the risk of the untreated group was probably lower as this group included high- and low-risk patients. Of course, this issue is mentioned (page 3) and discussed (page 15) in the paper.
Again thank you very much for your feedback and support.
Best regards,
Martin Scholz
Commenter: Dr. Chirag Shah
The commenter has declared there is no conflict of interests.
Commenter: Nick Divito
The commenter has declared there is no conflict of interests.
Commenter: Brian Hollingworth
The commenter has declared there is no conflict of interests.
Commenter: Sbabo David
The commenter has declared there is no conflict of interests.
I am sorry, but did you check the numbers?
IQR for the 141 patients: 40-60. Then a maximum of 25% of the 141 patients = 35,25 are 61 years old or older.
IQR for group A, 69 patients: 64-69. So a minimum of 75% of the 69 patients = 51,75 are 64 years old or older.
Don't you see the problem?
Commenter:
The commenter has declared there is no conflict of interests.
thank you very much for your comment! We went back to the respective data matrix to check the IQR for age of the total treatment group (N=141). Indeed, there is a typo in the current version of the manuscript: the IQR is 40-67 and not 40-60. We will revise this and upload a version 2 as soon as possible. Again thank you very much for informing us.
Best regards,
Martin Scholz
Commenter: EDIGEZIR B GOMES
The commenter has declared there is no conflict of interests.
Desta forma quero deixa aqui meus elogios ao Ilustres colegas Scholz, M.; Derwand, R.; Zelenko, V, que tanto lutaram nessa guerra política que pela primeira vez, graças as Mídias Sociais , a Industria Farmacêutica perde sua hegemonia em impor medicações caras , e muitas vezes sem devido seguimento dos efeitos colaterais. Uma coisa nós sabemos, a HCQ tem 0 anos de uso no mundo sem nenhum relato de danos ao usuário necessitado.
Commenter: Jay Silverman
The commenter has declared there is no conflict of interests.
Commenter: Del McReynolds
The commenter has declared there is no conflict of interests.
Commenter: Brian K
The commenter has declared there is no conflict of interests.
The commenter has declared there is no conflict of interests.
1) The inclusion of 37 cases substantiated by an antibody test is highly problematic, as in order to receive the antibody rest, each of these patients needed to survive covid. Any additional patients that died prior to otherwise receiving an antibody test are excluded. This stacks the deck in favor of the treatment group, and absent any intervention at all, we would still expect them to fare better than the control.
2) Separate from the study itself, I feel compelled to observe that the data described in the report seems to contradict public statements by one of the authors, Dr. Zev Zelenko. The author has publicly claimed to have treated more than 1500 patients with this treatment, but only provides data on 377.
The study states that the control group is based on laboratory results of patients in the same community - how big a population were these drawn from? If these are Dr. Zelenko’s patients, where are the rest of them? Why are we presented with no results from the other patients treated with this cocktail? If these are not Dr. Zelenko’s patients, who are they?
This is an interesting read, but in the public interest, the authors should publish results from the entirety of the patient population treated by Dr. Zelenko.
Commenter: Baruch Wilks
The commenter has declared there is no conflict of interests.
Commenter: Grant Klappstein
The commenter has declared there is no conflict of interests.
Read more at: https://www.vanguardngr.com/2020/03/coronavirus-new-york-doctor-successfully-treats-patients-with-drug-cocktail/
So that is a quote from Zelenko's published letter of late March 2020. Depending how you interpret the word "patients" in the context of his sentence it is possible, although unlikely, that the 1500 refers to patients treated but not confirmed for Covid. Or, more likely, that they were potential patients based on the rate of infection in the general population. In either case I am sure you would not argue Zelenko should include untested patients and/or non patients.
If my memory is right, Zelenko started with claims of 5 or 600 treated patients but later revealed that many of the original treated cohort had not been confirmed for Covid infections, they were putative based on symptoms. He then indicated he was going to get some help from researchers to refine the claims according to general research protocols. This paper appears to be the result of that, I expect the 377 was what was left over when "putative+actual" covid infections were trimmed to "actual".
For a summary of covid 19 trials I found the site clinicaltrials.gov which is from the US National Library of Medicine. I did a search of trials using the following terms, "hydroxychloroquine" and "covid-19" considering "active", "recruiting" or "not yet recruiting". This search yielded 189 studies from around the world, and provides, if perhaps not full accounting, at least a valid sample of ongoing research. When I added "zinc" to the search there were 9 results. In one of those 9 the zinc was mentioned only in the title of the trial, in the other 8 zinc was mentioned in the "interventions' column which lists the drugs and dietary supplements. This result suggests that 9 of 189 are testing HCQ plus zinc and the remainder omit zinc.
Of course if the details of these trials were examined one by one, more using zinc might surface, not listed in interventions nor the title. However it probably gives some sort of reasonable estimate of the ratio of zinc+HCQ trials vs HCQ without zinc, ie about 5%. Since many of these trials are in response to the early anecdotal findings that zinc plus HCQ was a valid treatment, worthy of further testing, it is disappointing that so many of the trials do not include zinc. I am not sure what to make of this exactly but I do share a certain uneasiness about motivations as expressed by comment 6, above.
Commenter:
The commenter has declared there is no conflict of interests.
Thank you very much for your comments and questions. Please find enclosed our responses:
Question number 1:
This retrospective case series study analyzed data only from COVID-19 outpatients with a laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a community in New York State, USA. During the peak of the pandemic the responsible primary care physician diagnosed many patients often first clinically during the early course of the disease and initiated treatment with the described triple therapy zinc, low dose hydroxychloroquine, and azithromycin as soon as possible. Most of these patients were already tested for SARS-CoV-2 but did not have a final test result yet. Some others were not able to get a PCR test and the infection was confirmed by IgG tests later. However, in accordance with the study protocol all patients with a positive test result were included in the retrospective analysis at a defined point of time. This included also one deceased patient. The SARS-CoV-2 infection of this patient was also finally confirmed after initiation of treatment and after hospitalization. All patients with a laboratory confirmed COVID-19 diagnosis, who were positively risk stratified, and who were treated with the triple therapy were included in the detailed analysis.
For the analysis of the untreated patient group of the public reference (not of the respective practice and not treated with the triple therapy zinc, low dose HCQ, and azithromycin) unfortunately only the outcome data was available and so also a risk adjustment was not possible. However, the patients in the treated group were all positively risk-stratified while the risk of the untreated group was probably lower as this group included high- and low-risk patients. Of course, this issue is mentioned (page 3) and discussed (page 15) in the paper.
Question number 2:
At the point of closing the database 372 positively tested patients of the respective practice were included and 377 positively tested but untreated COVID 19 patients (not treated with te triple therapy, public reference, s. figure 1). Of course, after this time the pandemic has been still ongoing and more patients have been obviously treated but these were not included in this analysis and report anymore.
During the pandemic many jurisdictions in the United States, like states, counties and even cities released data about COVID-19 cases including outcomes (even based on respective zip codes). This was also the case for the respective community. As described in the study approval section on page 9 this analysis was conducted with de-identified patient data, according to the USA Health Insurance Portability and Accountability Act (HIPAA), Safe Harbor and so it is not allowed to report exact dates or more detailed information about the respective community etc. in the publication.
All data available at the time of analysis is included in this publication.
We agree that it would be very interesting to do an additional analysis of more available patient data at a later point of time.
Best regards,
Martin Scholz & Roland Derwand
Commenter: samuel gluck
The commenter has declared there is no conflict of interests.
Commenter: Jeffrey LeRoux
The commenter has declared there is no conflict of interests.
A very interesting study. I would love to see a better designed study. There is not enough details in this prepublication study to reach any other conclusion. I would love to see the details about classification and data about the comparability of the groups. The age difference noted above is a big problem.
More research needed.
Commenter:
The commenter has declared there is no conflict of interests.
Thank you very much for your comments. As explained above there is a typo in version 1 of the manuscript: the IQR of the age of the total treatment group (N = 141) is 40-67 and not 40-60. We currently work on a revised version and will upload it soon.
In this retrospective analysis outcome of patients who were treated with the specific triple therapy zinc, low dose hydroxychloroquine, and azithromycin was compared to public reference data of patients in exactly the same community who were not treated with this therapy. For our analysis we unfortunately only had access to the outcome data of the untreated patient group (not treated with the triple therapy zinc, low dose HCQ, and azithromycin) and so we were also not able to do a risk adjustment. However, the patients in the treated group were all positively risk-stratified while the risk of the untreated group was probably lower as this group included high- and low-risk patients. Of course, this issue is mentioned (page 3) and discussed (page 15) in the paper.
To our knowledge this is still the only COVID-19 outpatient risk stratification and treatment study and so we agree that more research is needed. Responsible experts and stakeholders should ensure a common effort to continue to close this gap by designing studies specifically for primary care setting. Based on the observed magnitude of the reported results associated with the use of the triple therapy zinc, low dose HCQ, and azithromycin and based on other available data, we propose to amend ongoing studies with HCQ to include combination with zinc.
Best regards,
Martin Scholz & Roland Derwand
Commenter: Roger Burrows
The commenter has declared there is no conflict of interests.
I have questions about the participants in the study. Maybe this is in the depth of the study but not clear to me from the extract.
335 candidates -- COVID-19 patients, not yet hospitalized when the selection for treatment was done.
127 treated with the protocol. How were these selected out of the 335 candidates? Some criteria? Randomly?
104 included in the analysis. Why were 23 treated patients excluded from analysis? That is a lot out of such a small sample size. I think hardly any would be found to have contraindications after the treatment was done. I assume all 23 didn't just die due to unrelated somethings. Maybe they got well and were just not seen on follow-up?
37 patients added to the treatment group with positive serum tests. Were these 37 out of the original 208 unselected candidates? Why were these patients added? It could be humanitarian reasons, I think.
141 treated patients included in the analysis.
Thank you and congratulations of your continued high-value contribution.
Commenter: Dr. Chirag Shah
The commenter has declared there is no conflict of interests.