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Reply to Prof. Lippi (about the malaria of Francesco I)

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Elsevier Editorial System(tm) for The American Journal of Medicine Manuscript Draft

Manuscript Number: 15-695

Title: The malaria of Francesco I de' Medici (1587): a confirmed diagnosis Article Type: Reply to Letter to the Editor

Corresponding Author: Prof. Gino Fornaciari, M.D. Corresponding Author's Institution: University of Pisa First Author: Gino Fornaciari, M.D.

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Gino Fornaciari MD Professor Division of Paleopathology

Department of Translational Research on New Technologies in Medicine and Surgery

University of Pisa

University of Pisa, Medical School, Via Roma 57, 56126 Pisa - Italy phone ++039.050992894; fax ++039.050992706 g.fornaciari@med.unipi.it info@paleopatologia.it www.paleopatologia.it Pisa, April 25, 2015 Joseph S. Alpert, MD Editor-in-Chief

Pamela Powers Hannley, MPH Managing Editor

American Journal of Medicine

3615 N. Prince Village Place, Suite 181 Tucson, Arizona 85719

Re: Still about Francesco de' Medici's poisoning (1587)

Dear Editors,

This is the reply to the Letter to the Editor in response to my article in an issue of the American Journal of Medicine.

Thank you for your kindness. Sincerely,

Gino Fornaciari MD

Professor of History of Medicine and Paleopathology Director, Division of Paleopathology

Department of Translational Research on New Technologies in Medicine and Surgery Via Roma 57 - 56126 Pisa - Italy

Phone +39.050.992894; Fax +39.050.992706 Email: gino.fornaciari@med.unipi.it

Division of Paleopathology: www.paleopatologia.it *Cover Letter

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The malaria of Francesco I de’ Medici (1587): a confirmed diagnosis

Gino Fornaciari, MD

Professor of History of Medicine and Paleopathology Division of Paleopathology

Department of Translational Research on New Technologies in Medicine and Surgery University of Pisa Via Roma, 57 50126 Pisa Tel. +39050992894 Fax +39050992706 Mob +393478225295 E-mail gino.fornaciari@med.unipi.it Web site www.paleopatologia.it

No funding source No conflict of interest

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The finding of a document with a description of the conditions of Francesco I in the last moments of his life is of particular interest, as it allows to further clarify the causes of the Grand Duke’s death.

In this document the symptoms presented by Francesco are petechiae, fever and swollen neck. Prof. Lippi concludes that this account “supports the conclusion of poisoning” of a previous work,1 because “skin eruption (such as petechiae), fever and swelling are symptoms of acute arsenic poisoning”.

In acute arsenic poisoning skin rash is described, but only in the form of flushing erythema or maculopapular eruption.2 These findings are totally different from petechiae, historically associated with infectious diseases such as epidemic typhus, which the 16th century physicians could certainly distinguish. On the contrary, these dermatological

manifestations are described among the symptoms of malaria, and are mainly seen with falciparum species.3 The skin lesions consist in petechiae, which are small (1-2 mm) red or purple spots on the body and are caused by minor haemorrhagies.4 The incidence of malaria manifesting with purpura (diffused petechiae) is reported in the range 1.33% to 25.6%.5

The second symptom mentioned in the document is fever, which is never described in acute arsenic poisoning and is instead typical of malaria.3

With regard to the “swollen neck”, although it is a very generic symptom that is not helpful in the diagnosis, it is well-known that swollen neck lymph nodes are a common sign of many infections, not of intoxication.

Finally, as already discussed in the comments to the original paper,1 there are no

evidences of arsenic poisoning of Francesco I, simply because the toxicological analyses were carried out on very questionable soft tissue remains,6 that most likely cannot be attributed to Francesco.

On the contrary, ancient Plasmodium falciparum proteins were really detected in the skeletal remains of the Grand Duke, demonstrating without any doubt that he was affected by falciparum malaria at the time of his death.7

I am grateful to Prof. Lippi for having found the Vatican document, which further supports the diagnosis of severe, acute malaria as the cause of death of Francesco I de’ Medici.

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1

Mari F, Polettini A, Lippi D, Bertol E. 2006. The mysterious death of Francesco I de' Medici and Bianca Cappello: an arsenic murder? British Med J 333: 1299-1301.

2

Uede K., Furukawa F. 2003. Skin Manifestations in Acute Arsenic Poisoning From the Wakayama Curry-Poisoning Incident. British J Dermat 149: 757-762.

3

White NJ, Breman JG. Harrisons Principles of Internal Medicine, 19th ed, Kasper D, Fauci A, Hauser S, et al (Eds), McGraw Hill, New York 2015.

4 Khan A, Chaudhry AA, Khan U. 2012. Falciparum – The Masquerader. J Pak Med Assoc

62: 62-63.

5

Godse KV, Zawar V. 2012. Malaria presenting urticaria. Indian J Dermat 57: 237-238.

6

Fornaciari G, The mystery of beard hairs, bmj.com 29 Dec 2006; Ottini L, Who is who, that is the question, bmj.com 5 Jan 2007.

7

Fornaciari G, Giuffra V, Ferroglio F, Gino S, Bianucci R. 2010. Plasmodium falciparum immunodetection in bone remains of members of the Renaissance Medici family

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