The Etiology of Atopic Dermatitis Herbert B. Allen The Etiology of Atopic Dermatitis Herbert B. Allen Drexel University Department of Dermatology Philadelphia Pennsylvania USA ISBN 978-1-4471-6544-6 ISBN 978-1-4471-6545-3 (eBook) DOI 10.1007/978-1-4471-6545-3 Springer London Heidelberg New York Dordrecht Library of Congress Control Number: 2014954441 © Springer-Verlag London 2015 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. 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While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Dr. Samuel Moschella is a clinical dermatologist who has been called a “dean” of dermatology and “the dermatologist’s dermatologist.” He has incredible recall of diseases he has seen (and there are not many he has not seen), and an incredible ability to integrate the skin fi ndings into a patient’s pathobiology. I vividly remember him diagnosing an elderly patient’s ichthyosis and integrating it into her apathetic hyperthyroidism, and another patient who looked like she had scleroderma, but he showed that she had porphyria. Sam is a retired captain in the US Navy Medical Corps and, as such, took special interest in the Navy residents and dermatologists. He made our training in leprosy at the USPHS Hospital at Carville, Louisiana, memorable. Further, any meeting where he is present will be much more informative because of his comments. I had picked up Sam in center city Philadelphia, and we were on our way to a funeral for Captain Bernett L. Johnson, Jr., MC, USN (Ret), when the discussion of my thoughts on eczema occurred. Bernie was my chairman when I was a resident at the Naval Hospital in Philadelphia and Sam was his chairman when he was in training. Regarding eczema, I offered, “I think it may be due to miliaria because of the close association with sweating.” Sam replied, “All the docs at NYU felt the same way.” He mentioned Marion Sulzberger, Rudy Baer, and Al Kopf, all of whom were legendary dermatologists. Sometime after the funeral I was able to link Sulzberger and eczema and found his seminal article and the photograph of the occluded sweat duct. Sulzberger had it right, but he did not have many probes with which to pursue the story. Sixty years later, we did, and this book is the outcome. Once again, thanks, Sam. Fig. 1 The author ( left ) with Dr. Moschella ( right ) on Dr. Moschella’s 90th birthday Pref ace Originally, I considered calling this book Heresy , because all of the concepts con- tained herein are somewhat heretical to the current considerations and understand- ing of the pathogenesis of eczema. “Heresy,” from the Greek αίρεση, originally meant “choice”; however, with transformation through the centuries, the word now implies the opposite. True, “heresy” is predominantly thought to have religious con- notations; but, applied somewhat more loosely, the term can be used to describe opposition to any securely held beliefs or “dogmas,” if you will. It is in such a spirit that the word is utilized in this work. Sulzberger started it all in 1947 [1]. He observed an occluded sweat duct in a patient with eczema (Fig. 6.1 ). This occlusion was present in the outermost portion of the acrosyringium in the area where the sweat is released on the surface of the stratum corneum. By way of review, sweat is generated in the eccrine glands in the deep dermis, travels through the dermis in a straight duct, and traverses the epidermis via a coiled section called the acrosyringium. Sulzberger believed this occlusion in the acrosy- ringium played a signifi cant role in eczema (Fig. 1 ), but he lacked probes with which to pursue the concept further. Sulzberger was studying anhidrosis that arose in the tropics during World War II, a condition often severe enough to cause heat prostration that lasted 6 weeks or longer. The primary cause of this disorder was profound miliaria, but he observed that the sweat ducts were occluded not only in patients with miliaria but also in the patient in Fig. 1 with eczema, and in a second patient with seborrheic eczema. (A photomicrograph of that observation in seborrheic eczema was not present.) Fast forward 25 years to the observations of Hölzle and Kligman [2], who showed occlusion of the acrosyringium in patients with miliaria. The occlusions consisted of periodic acid–Schiff (PAS)-positive material (PAS stains polysaccharide- containing molecules) and bacteria. After creating the disorder with heat and occlu- sion, Hölzle and Kligman convincingly showed sweat-duct occlusion in 80 % of the ducts in miliaria before the rash appeared. Shortly thereafter, Mowad et al. [3], in considering the occlusion of the sweat ducts in miliaria noted by Hölzle and Kligman [2], found that the only easily vii viii Preface Fig. 1 Anatomy of the Spiralled eccrine sweat apparatus with duct eccrine gland (coil) in the deep dermis, the straight portion of the duct in the mid dermis, and the Epidermis acrosyringium in the epidermis Straight dermal duct Coiled Dermis dermal duct Coiled gland culturable skin bacterium capable of causing anhidrosis (and thus capable of occlud- ing ducts) was biofi lm-producing Staphylococcus epidermidis . This biofi lm, or “slime,” as it was (and still is) called, is composed of extracellular polysaccharide substance. This would readily stain positive with PAS, as the authors demonstrated (Fig. 2 ). Thus, without demonstrating it directly, these authors developed a compel- ling thesis for the pathogenesis of miliaria. Heat and sweating allow for the prolif- eration of S. epidermidis and its biofi lm; these occlude the sweat ducts and cause miliaria. Heat and sweating also allow for the production of biofi lms by other staphylococci. Fast forward 25 more years to a discussion I was having with Dr. Samuel Moschella: I told him I was thinking that atopic dermatitis might be related to mili- aria. Both diseases were pruritic and both were worsened by sweating. The “occlu- sion” part of the story was well developed for miliaria but had been more diffi cult to elucidate for eczema. I ruminated that given that the most common form of eczema was “fl exural,” perhaps this apposition of two surfaces rendered enough occlusion to produce clinical disease. Dr. Moschella related that Sulzberger and the great New York University School held this theory 50 years ago, but it had been bypassed over time. Hence, back to Sulzberger (who led that school) I went, armed this time with many new probes, and the hypothesis that subclinical miliaria causes atopic dermatitis. In our studies, we have substantiated this hypothesis with many differ- ent protocols. These protocols have included microbiologic cultures, assays, and direct visual- izations of the S. epidermidis organism and its biofi lm taken from lesional skin in patients with atopy. We have performed these studies with conventional microscopy with resolution to 100× and confocal microscopy with resolution to 600×. We have also found many other staphylococcal species, all of which were capable of produc- ing biofi lms in our cultures of the skin lesions of atopic dermatitis [4]. Pathology from lesions has shown an acrosyringium occluded with PAS-positive material together with the spongiosis that is the hallmark feature of this disease. Gram-positive bacteria are present in the ducts as well [5]. One of the more exciting Preface ix Fig. 2 Mowad’s observations from 1995. Sweat duct in miliaria occluded with PAS-positive material. These were the same pathology fi ndings as noted by Hölzle and Kligman in 1978 [2]. (From Mowad et al. [3]; with permission) fi ndings in this endeavor was in the immunology of the specimens. Unlike the situ- ation in normal skin, where Toll-like 2 receptors are found in the basal zone, these receptors are noted around the ducts in the stratum corneum in the areas of occlu- sion [4]. Toll-like receptors are the fi rst responders in the immune system. Considering the ductal occlusion that Sulzberger, and now we, have observed, Eishi’s observations [6] in sweating and eczema fi t better with Hölzle and Kligman than with Eishi’s theory that there is faulty innervation of sweat glands in eczema.