Karolinska gets taught German medical ethics

A most bizarre thing happened. In the aftermath of the scandal around the thoracic surgeon and regenerative medicine enthusiast Paolo Macchiarini, which left many patients dead, his former employer Karolinska Institutet (KI) in Stockholm, Sweden, requested a retraction of one of his papers. It was not about a trachea transplant, but about unethical and painful medical experiments on a dying patient (actually, two of them). KI’s decision to request a retraction of the paper Jungebluth et al, “Autologous peripheral blood mononuclear cells as treatment in refractory acute respiratory distress syndrome”, Respiration, 2015 was based on the investigation commissioned by Swedish Central Ethics Review Board (CEPN). The Swiss-German family-owned medical publisher Karger and its journal Respiration however categorically refused to retract the paper and ordered KI not “to patronize the readers of the journal ‘Respiration’.”

It gets much worse. The German Editor-in-Chief of this journal has a huge conflict of interest. It is better you just read on, because if I try to summarize it here, I might get sued by Macchiarini’s German friends and associates once again, and next time it might even be prison for me. In Germany, doctors have a very special status. Journalists or even patients do not, as I learned in court.

The paper Jungebluth et al, Respiration, 2015 reports the case of a burn victim who was on life support by the extra corporeal membrane oxygenation (ECMO) device. Macchiarini and his team decided to test something experimental: they stuffed blood cell down that patient’s airways, combined with erythropoietin (EPO), a growth factor known for its side effect of causing lethal blood clotting. The doctors then subjected the dying patient to no less than 23 painful procedures of bronchoscopy, which the CEPN investigator Dag Lundberg, Professor emeritus of Anesthesiology and Intensive Care at the Lund University in Sweden, suspected to have been medically unnecessary, and only performed in order to obtain some research data for a nice publication (just as Macchiarini’s team did to their trachea transplant patients, read here). The notion that a terminally ill patient was abused as a research subject was further supported by the fact that the paper has 26 authors, many of whom are not even medical researchers. The case is presented in detail in my earlier article here, the full Lundgren report from February 2017 is here. The KI announcement from 30 January 2018 delivered this decision, at the end of the final report:

“KI therefore finds that Paolo Macchiarini, Philipp Jungebluth, Bernhard Holzgraefe and Håkan Kalzén are the ones to be held responsible for the scientific misconduct that preceded the published paper.
Sanctions and other consequences
Paolo Macchiarini was dismissed by KI’s staff disciplinary board in March 2016. Since Philipp Jungebluth, Bernhard Holzgraefe and Håkan Kalzén no longer work at KI no action in terms of labour law will be taken.

The published paper “Autologous peripheral blood mononuclear cells as treatment in refractory acute respiratory distress syndrome” is based on data produced through scientific misconduct during the basic clinical research process. Even though the published paper as such obtained an ethical permit, the underlying research did not. The paper presents its data in an un-nuanced and overwhelmingly positive manner, which might still entail a risk that other patients will be subjected unnecessarily to similar treatment before adequate preclinical data is available to warrant human studies. The journal Respiration will therefore be urged to withdraw the article forthwith”.

A rather straightforward case for a retraction, one would assume. Yesterday however, KI rector Ole Petter Ottersen published an official blog post, where he tells how the journal Respiration and its publisher Karger reacted to KI’s request. After Ottersen contacted the journal with his retraction request, he received on February 6th this message:

”Dear Professor Ottersen,

We have received a request from the Karolinska Institutet to retract the above article. At the same time, we have been contacted by one of the authors asking us to delay our decision regarding this matter.

The Editors and the publishing house are both of the opinion that it is the journal’s duty  to the scientific community to provide a platform for discussions and a forum for debating. Furthermore, the background of the conflict between the two parties should be transparent to the readers to enable them to form their own opinion.

Therefore, we would like to ask all parties concerned to write a ‘Letter to the Editor’ pertaining to this conflict for simultaneous publication. The maximum length should be 4 manuscript pages with the possibility of supplementary online material. The article in question along with the Letters will be ‘Free Access’ with reciprocal links between the article and the Letters. Deadline for receipt of the Letters is the end of February 2018. Please submit to the Editorial Office as an email attachment.

We sincerely hope that both parties will take advantage of this offer to present their viewpoint.

With best regards,

Linda Haas

Editorial Office ‘Respiration’

Maybe a confused editorial office clerk, who doesn’t knows the difference between an academic debate and a major research institution requesting a retraction of an unethical paper after an external investigation? In fact, not just KI, the state of Sweden requested that, since the investigation was done by a central public authority, CEPN. Yet as a response, the journal Respiration declared that all that original medical record evidence, investigations and even legal hearings collected and performed by CEPN and KI, were in no way superior or more convincing or relevant than what Macchiarini et al have to say on that matter. Rector Ottersen wrote back on 23 February 2018, reminding the journal that it is KI, and not some concerned reader, who requests the retraction.  The KI rector got this reply on 10 March 2018, now from the Karger publication manager Thomas Nold and the journal editor in Chief Felix Herth:

“Dear Professor Ottersen, 

Thank you for your reply. 

We would to emphasise that we have taken your request for the retraction of this article very seriously, however, we found it only fair to all parties concerned to offer the option of publishing a letter on this matter in question. 

We believe, that based on the evidence available to the journal, we are not in a position to make a judgement on whether or not to retract this article. We have, therefore, decided to leave it up to our readers to build their own opinion on the matter and decide for themselves with regard to the validity of the conclusions. We do not want to patronize the readers of the journal ‘Respiration’.

Finally, we would like to ask you to reconsider your decision not to engage in any discussion. If you decision remains unchanged, we would like to ask for your consent to publish your retraction request in the journal ‘Respiration’.

Yours sincerely,

Professor Felix J.F. Herth

Editor-in-Chief

Thomas H. Nold

On behalf of S. Karger Publishers”

Ottersen reiterated his demand for retraction as there was nothing much else he could do, except to blog. Indeed, Karger and Herth are legally in the right here: no journal can be forced to publish or unpublish anything. This is the freedom of scholarly publishing, which of course makes retractions, the only available deterrent against research misconduct, a very blunt and often ineffective tool. Fraudsters only have to be careful with certain journals (like Journal of Biological Chemistry), and will be forever safe should they follow Macchairini’s example and publish where he did, e.g. in: Respiration by Karger, Biomaterials by Elsevier and of course The Lancet, also by Elsevier. It is worth remembering that The Lancet stands by its published decisions that Macchiarini is NOT guilty of misconduct, that trachea transplants work, and so far refused to retract any of his and others’ papers, despite it being long known those clinical studies were either fraudulent or even claimed fake ethics approvals. It is therefore quite possible that also the Editor-in-Chief of Lancet Richard Horton will follow the example of his Respiration colleague Herth and tell KI to shove their retraction request and stop trying to patronise their readers.

Speaking of Herth. Ottersen seemingly overlooked who the Respiration EiC actually is and in particular where he works. Professor Felix Herth is Head of the Department of Internal Medicine, Pulmonology and Critical Care Medicine at the Thoraxklinik of the University of Heidelberg in Germany. This is also the affiliation provided in the paper Jungebluth et al, Respiration, 2015 for two of its authors. One is Macchiarini’s former doctoral student and loyal follower Philipp Jungebluth, the much beloved and respected life-saving angel and genius scientist of German medicine, to whose rescue the Berlin courts arrived twice and last month sentenced me in an appeal hearing over two injunctions, on of them in fact about the nature of Jungebluth’s departure from the Thoracic Clinic Heidelberg in August 2016 (read here, here and here). The other Heidelberg associate is Johannes Haag, another doctoral student of Macchiarini’s from the times at Hannover Medical School in Germany (where Macchiarini incidentally still holds adjunct professorship, more here), and first author of that unpublished manuscript over quoting from which I was just 2 weeks ago berated and sentenced by the Berlin court in harshest terms available in German law. Haag and Macchiarini both provided witness affidavits to help the court sentence me.

While Jungebluth left thoracic surgery and now trains as emergency care surgeon in his home town of Wolfenbüttel in Lower Saxony, Haag still works as resident at the Thoraxklinik Heidelberg. Till one year ago, the Thoraxklinik was led by Hendrik Dienemann, a close colleague of the Respiration EiC Herth, in fact the two even head a lung clinic where I live. Jungebluth used to train under Dienemann, who also gave his trainee an excellent reference letter when Jungebluth decided in August 2016, utterly voluntarily of course, to abandon research and thoracic surgery and try something new with his so far exciting and eventful life of curing terminal diseases with plastic trachea implants and saving children.

Dienemann and Jungebluth even published some interesting conference abstracts, which I described here. In September 2015, it was an abstract from the 25th Anniversary Meeting of the German Society of Thoracic Surgery about plastic trachea transplants in rats, with Jungebluth and Dienemann as lead authors, their Heidelberg affiliation was provided. Thing is, those animal experiments were not registered with the German authorities, as I found out. And in Sweden, KI found on a related case Macchiarini’s and Jungebluth’s rat experiments to have had a “deviation from animal ethics permits”. However, why would anyone at University of Heidelberg care about rats? In the same German federal state of Baden-Württemberg it is perfectly legal to test unproven therapies on patients without any ethics vote at all, as former Macchiarini collaborators Heike and Thorsten Walles did.

The year before, there was another Congress Abstract, from the 24th Anniversary Meeting of the German Society of Thoracic Surgery in 2014, again with Jungebluth as first and Dienemann as last author: “Generation of a tracheal graft and clinical transfer from bench to bedside and back to bench”. In it, Macchiarini’s trachea transplants were portrayed as “successful”, the 8 plastic and 9 cadaveric trachea patients (full list here) were paraded around as seemingly alive and cured. At the time that conference took place in September 2014, almost all of them were already dead, horribly suffocated by their tracheal grafts, either plastic or even cadaveric ones.

This is not all about the conflict of interest this department head of Thoraxklinik had, when Herth refused to retract the work of his past and present colleagues, Jungebluth and Haag. Are you ready for more of German medical ethics? Here goes another Congress Abstract from the Thoraxklinik, from the same German surgeon conference of 2015 mentioned above. Translation from German:

Intratracheal administration of autologous stem cells in patients with ARDS

P Jungebluth ¹ , B Holzgraefe ² , ML Lim ³ , A Duru ³ , V Lundin ³ , S Sjöqvist ³ , P Jones ³ , M Wood ⁴ , T Luedde ⁵ , A. Teixeira ³ , O Hermanson ³ , O Winqvist ³ , H Kalzén ² , J. Nordin ³ , O Wiklander ³ , S EL Andaloussi ³ , E Alici ³ , H Dienemann ¹

• ¹Thoraxklinik Heidelberg
• ²Karolinska University Hospital
• ³Karolinska Institute
• ⁴University of Oxford
• ⁵ University Hospital Aachen

• Congress Abstract

Objective:

Only unsatisfactory treatment options exist for acute respiratory distress syndrome (ARDS). The effort must go towards developing new therapeutic approaches and exploring them. In this study, the intratracheal administration of autologous stem cells in patients with ARDS is studied.

Method:

An intratracheally administered therapy with autologous stem cells has been used in patients with severe ARDS, based on mathematical models. The patients were previously unsuccessfully treated by means of maximum conventional therapy to lung assist method (Extracorporeal membrane oxygenator; ECMO). The autologous cells (mononuclear cells, PBMCs) were isolated from the peripheral blood of the patients and then administered intratracheally. The authorizations for the use and analysis of the cells have been issued by the regional ethics committee.

Result:

4 +/- 2 days after starting therapy, the lung function of patients significantly improved, so that in the follow-up the support of the ECMO system could be reduced significantly. Both the bronchoscopic examination, as well as the biochemical inflammation markers showed a marked decrease in inflammation. At the same time an up-regulation in the serum concentration of specific miRNAs (miR 449a, b, c and 34a) could be demonstrated. Extracellular vesicles of the applied PBMCs showed a significant anti-inflammatory properties in different in vitro assays ( eg TNF-α mediated NFkB in vitro assays). Despite the improvement of the general state and normalization of respiration parameters, the patients died of multiple organ failure during that period.

Conclusion:

The available data show, despite the demise of patients, the promising anti-inflammatory potential of autologous mononuclear cells. Furthermore, the successful intratracheal administration of cells into patients with severe ARDS could be shown. Further studies are needed to uncover the underlying mechanisms.

You probably noticed that this is exactly the description of the content of the paper Jungebluth et al, Respiration, 2015. You might also have noticed that the last author Macchiarini was removed and replaced by the last author Dienemann, the head of the Thoraxklinik and Jungebluth’s then-boss. Why? This is German university medicine, that’s why.

You might also have noticed that the unretractable Respiration paper, which Dienemann’s Thoraxklinik colleague Herth proudly published as “Editor’s Choice” in Open Access, speaks of only one patient, but here, in the same-year German conference abstract we have plural of patients, and all are declared dead. In fact, there were two ECMO patients treated in same way, as established by KI investigation. The authors of Jungebluth et al Respiration 2015 were all asked by KI:

“In the ethical application from 2012, two patients are listed as treated with this
experimental treatment. Why was only one reported in the article and not both? Are there other patients treated with similar treatment that are not reported?”

Macchiarini, as well as the Thoraxklinik surgery trainees Jungebluth and Haag, replied to KI inquiry in 2016:

“The second patient was not included in the analyses as the available data were incomplete. As the authors only of this case study, we have no knowledge of other patients and we recommend, again, getting in contact with the responsible authorities at the Karolinska University Hospital”.

This statement doesn’t really fit to the congress abstract these people published in same year as their paper. In fact, the paper was accepted by the German EiC Herth in November 2015 (see this testimony), after that German surgeon conference where the plural of dead patients was discussed.

It seems, the venerable University of Heidelberg and their Thoraxklinik hold much more information on those Swedish ECMO patients than KI does. And the Germans seem to be quite convinced that all was done right, and that all Macchiarini treatments were scientifically and ethically sound. The good doctors know exactly that after the court farce their colleague Jungebluth repeatedly imposed over me in Berlin, no German media will ever say a word about the affairs of Macchiarini and his partners in Germany, come what might. The law has spoken.

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