Above: Herpes Simplex. Immunofluorescence staining of viral antigen in infected cells in the left temporal lobe of a patient who died of HSV encephalitis. Below: Varicella-zoster. Immunofluorescence staining of viral antigen in the frontal nerve of a patient with ophthalmic zoster. [Frontispiece HERPES SIMPLEX VARICELLA AND ZOSTER CLINICAL MANIFESTATIONS AND TREATMENT BY B. E. JUEL-JENSEN MA DM Cand Med Consultant in Communicable Diseases, Department of the Regius Professor of Medicine, Radclijfe Infirmary, Oxford AND F. O. MACCALLUM MA MD FRCP FRC Path Consultant Virologist, Radclijfe Infirmary, Oxford WILLIAM HEINEMANN MEDICAL BOOKS LTD LONDON First Published 1972 © 1972 B. E. Juel-Jensen and F. O. MacCallum SBN 0 433 17800 0 Text set in 10/11 pt. Monotype Times, printed by letterpress, and bound in Great Britain at The Pitman Press, Bath PREFACE I am grateful to my colleagues, Drs. Juel-Jensen and MacCallum, for giving me an opportunity to read their manuscript. Based as it is upon years of painstaking clinical observation, in conjunction with com petent virological diagnostic procedures, this body of information must, I think, be the definitive source for some time to come. While the approach is predominantly clinical the discussion of etiologic agents is authoritative and up-to-date. The authors are justified in limiting their attention to these two viruses in view of similarities in tissue tropisms and character of the lesions. Furthermore the disease manifestations that they produce are amenable to chemotherapeutic agents that man can tolerate. Certainly the clinical data presented here leave little room for doubt that the chemotherapy of some virus diseases of man has become a practical reality. Nuffield Department of Medicine, P. B. Beeson Radclijfe Infirmary, Oxford. 1972 INTRODUCTION We have written this book for the clinician. Although the literature on microbiological aspects of herpes simplex virus is considerable, the clinical diseases caused in man by that virus and its close relative, the varicella-zoster virus have not, to our knowledge, been dealt with in any detail before in a single volume. Many of the clinical manifestations of the two viruses which this book is about are trivial, some are serious or even lethal. Until a few years ago they merely gave the doctor an opportunity to exercise his diagnostic powers, he could do very little to alter the clinical course. The situation has changed. The first antiviral agents which have shown promise in man are effective against herpes simplex and varicella- zoster virus. We have attempted not only to outline the various disease patterns but to give some guidance to rational treatment with antiviral agents. We are very grateful to our colleague Dr. Albert Tomlinson for his constant help with our investigations over many years and for his helpful criticism of this book. We are indebted to our neurosurgical colleague, Mr. Joe Pennybacker for his constructive criticism of the chapter on herpes simplex encephalitis, to Professor Peter Wildy for the loan of electron microphotographs of herpes simplex virus, to Mr. Philip Awdry for the loan of photographs of ocular herpes, to Dr. F. W. Wright for the loan of the X-ray of acute varicella pneumonia, to Dr. A. A. Sharp for the photograph of a patient with purpurafulminans, and to Professor Barrie Jones for permission to draw heavily on his work in herpes simplex ocular disease, and not least to Professor Paul Beeson for writing the preface. We must record our gratitude to Mr. Floyd and his staff of the Department of Medical Illustration in the Radcliffe Infirmary for taking the majority of the photographs of our patients which appear in this book, and we are deeply indebted to Miss Deborah Pollard and Miss June Glenister for countless hours of patient deciphering of illegible handwriting and for typing and retyping the manuscript. Oxford B. E. J-J. January, 1972 F.O.M. Chapter 1 THE HISTORICAL BACKGROUND Ερπης, derived from the verb ερπειν, to creep, has been used for at least 2500 years in medicine to describe spreading lesions of the skin, such as cancer, infections like lupus vulgaris, erysipelas and ringworm, and various forms of eczema. Early writers used the word in a much wider sense than we do today, and it is questionable whether the lesions described by early sources such as the Prorrhetics, the Aphorisms and Epidemics of the Hippocratic writings include herpes zoster, though it is conceivable that some of the cases of "ardent fever, phrensy, aphthous affections of the mouth ..." might have been due to primary herpetic gingivo-stomatitis. Beswick (1962) in his admirable account of the history of the word herpes points out that the kind of herpes described in the Coon Prognosti­ cations, which affected the groin and spread towards the flank and pubis possibly could have been shingles, which nowhere else is described recognizably in the Hippocratic Corpus. In a passage in Epidemics VI ulceration of the lips in intermittent fevers is described; the lesion was probably what we now call herpes simplex. Pliny (1601 version) thought like many later authors that shingles which he calls zoster and of which he gives a recognizable account was a kind of erysipelas. Celsus's "ignis sacer" (1516 ed.) has been thought to refer to zoster, but even if it included shingles it covered a variety of other lesions. However, it is quite probable that his account of aphthous ulcers of the mouth, which he considered especially dangerous in children, included at least some cases of herpetic gingivo-stomatitis. Galen was confused. In his Definitiones he defines "herpes" as an ulcer in one place, elsewhere as "not always an ulcer". Jean Fernel (1593) probably comes close to a description of what we now under­ stand by herpes: "His proxima est papula. Est autem ardor artem serpentibus minimis pustulis exasperans ac rodens. Graecis herpes apellatur. Ea quidem duplex, una simplex quae herpes est miliaris, altera fera, quae herpes exedens nuncupatur. Papula fera ruptis pustulis veram cutem exulcerat, rodit atque depascit, serpit in latum atque in altum, ex eaque ulcuscula manent arida."—He distinguishes between herpes and erysipelas and claims that the former is the milder condition. Among other later l 2 Herpes Simplex Varicella and Zoster writers, Nicolaus Tulp (1641), immortalized by Rembrandt in his Anatomy Lesson, described what almost certainly is zoster which he maintains is similar to Pliny's "ignis sacer". The earliest good account in English we have been able to find of herpes of the skin of the face is that given by the comparatively obscure Warwick practitioner James Cooke in his Mellificium Chirurgiae (1676): "In herpes there's little Pustles like to millet-seeds, Heat Itching, after rubbing a moistness and little ulcers." This beyond a doubt describes cold sores as we know them today. Of the seventeenth century descriptions perhaps the most interesting is that of Richard Morton in his Exercitatio De Febris Inflammationis Universalibus, 1694. His account seems to correspond very closely to what we today understand by herpes. The observation of the association with febrile conditions is of particular interest: "Quod ad Herpetem attinet, venenum istius morbi author, cutim veram simul ac cuticulam sicut in Erysipelate petit, & utramque inflammat, inibique tuberculos Semini Milii referentes hinc inde con glomerates, & ad exulcerandum aptos efficit, ardore & pruritu potius quam lancinante & spasmodico dolore molestos; utat non procul a' partibus Herpete affectis, ante & post emptionem, dolor erodens a spasmodica Fibrarum constrictione ortus fere semper sentiatur, donee veneno morbisco deleto spiritus non amplius lacessantur, & a spas modico statu liberati ultro quiescant. Hoc facto Dolor, una cum Ardore, Pruritu caeterisque Inflammationis prasentis indiciis evanescit. Febris hanc Inflammationis concomitans est prater omnes alias quot- quot sunt, mitis & benigna, atque ex Urina, Pubis, Lingua vel temperie aegre admodum perceptibilis, unde de ea apud Authores altum est silentilem, rareissime praeterea funesta est. Tempore viro Deubitus exacerbari solet, & Vigiliis, Jactatione inquieta, Calore aucto & Siti, sere aliquatinus prodere. In singulis hisce Exacerbationibus Inflam- matio sensim in partes vicinas serpit, vel alias distantes occupare incipit, indeque nomen Herpetis fortita est." Daniel Turner in 1711 undoubtedly describes both herpes simplex and zoster: "The herpes is a choleric pustule breaking forth of the skin diversely, and accordingly receiving a diverse denomination. If they appear single, as they do often in the face, they arise with a sharp top and inflamed base: and having discharged a drop of matter they contain, the redness and pain go off and they dry away of themselves. "There is another species of this disease, appearing in larger heaps of small pustules upon several parts of the body as the neck, breast, loyns, hips and thighs; these are usually attended with a light fever and inflam mation round about them, and rising up with white mattery heads, there succeeds a small round scab, resembling the millet seed, from which the disease has borrowed the name of herpes milaris, being the same with that our people call shingles." He included ringworm as a species The Historical Background 3 of herpes—a view that was held to the middle of the nineteenth century. The eighteenth and nineteenth centuries saw the rise of nosology. De Sauvages in his Nosologia Methodica Sistens Morborum Classes (1763) has several species of "Herpes", and he includes as "H. Periscelis" zoster, which he tried to differentiate in 1768. Most of the eighteenth century writers contributed little of additional interest; they were involved in their attempts at classifications. Heberden FIG. 1. Zoster as illustrated in T. Bateman's Delineations of Cutaneous Diseases. 1817, plate LI. (1816) used "herpes" and "shingles" synonymously. He recognized postherpetic neuralgia in his account of zoster. Thomas Bateman, the pupil of Robert Willan had acquired the plates and material intended for the second volume of Willan's On Cutaneous Diseases of which the first edition of the first volume had appeared some time before 1799. He used these in his Delineations of Cutaneous Diseases, 1817. He recognized six different species of herpes, none of which he thought were infectious: "H. phlyctaenodes', "H. zoster" (Fig. 1), "H. circinatus", "H. labialis", "H. praeputialis", and "H. iris". His "H. phlyctaenodes" was almost certainly zoster of the face or the limbs judging by plate XLIX; his "H. zoster" was confined to the trunk; an excellent example is shown in his plate L. It is interesting that his distinction between "H. labialis" and "H. praeputialis" (Fig. 2) in the event should have turned out to be justified, since the discovery of 4 Herpes Simplex Varicella and Zoster the difference in type between herpes isolated from the genital tract and herpes from other sites. Bateman's "Herpes circinatus" is certainly ring worm, but his "H. iris"—a macular-vesicular lesion of the hands could be a fungus affection or a variety of erythema multiforme. Pringle (1890) distinguished two types of herpes only and by chance he came close to current views. He distinguishes herpes catarrhalis and herpes zoster. The former he divided into two types, herpes facialis and herpes genitalis. Writers of the later nineteenth century attempted classifications, most of which added further confusion to the understanding of the nature of infections with herpes simplex virus. Towards the end of the FIG. 2. The Lesions in Herpes Genitalis ("Herpes praeputialis") in various Stages of Development as illustrated in T. Bateman's Delineations of Cutaneous Diseases. 1817, plate L. century one particular variety, generalized herpes of the skin, was recognized and good descriptions were given by at least three writers. Hebra (1872a, 1872b) described, first by the term "herpes impetigini- formis", later as "impetigo herpetiformis", cases of this generalized eruption, and four of his five patients died. Duhring (1884) in his article Dermatitis Herpetiformis, under the heading dermatitis herpetiformis (pustulosa), almost certainly included cases of generalized herpes. Hebra's pupil, Moriz Kaposi (1899) describes as a complication of eczema larvale infantum a particularly fulminant form of generalized herpes of the skin, and he was in doubt about a suitable name: "Ich bin in Verlegenheit, wie ich dieses, das gewöhnliche Eczema larvale infantum in so gefährlicher Weise complicirende, varicella- ähnliche Exanthem bezeichnen soll,. . ." The term "Kaposi's varicelli- form eruption" has, however, persisted for this condition. Kaposi speculated that the lesions might have been caused by a fungus, though he had been unable to prove this. "Juliusberg's pustulosis acuta varioliformis" is sometimes used as a synonym for this condition, The Historical Background 5 Herxheimer's pupil, Fritz Juliusberg, in 1898 wrote his paper Ueber Pustulosis acuta varioliformis, an account of the short illness of a child who probably had generalized herpes of the skin. There is no mention of whether the child had eczema, but it appears that the lesions were similar to those described by Kaposi. Because he found Staph. pyogenes in the lesions, Juliusberg thought this organism (which probably was a secondary invader) was the responsible agent. One suspects that some of the cases Fox (1880) included under his heading of Hydroa Herpeti- forme in his diffuse essay on Hydroa were cases of generalized herpes of the skin.