Bacterial and Viral Skin Diseases

Dermatol Clin 25 (2007) 663–676

Bacterial and Viral Skin Diseases Eleonora Ruocco, MD, PhDa, Giovanna Donnarumma, MDb, Adone Baroni, MD, PhDa, Maria Antonietta Tufano, MDb,* a

Department of Dermatology, Second University of Naples, Via Pansini 5, 80131 Naples, Italy b Department of Experimental Medicine, Microbiology and Clinical Microbiology Section, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy

Unimpaired skin protects the underlying tissue and is an excellent frontline defense against the invasion of pathogenous microorganisms thanks also to the presence of the skin microbiota. Throughout the life of an individual the skin is colonized by a number of microorganisms that can vary from a few hundred per cm2 on the dry surfaces of the forearm and back, where the prevalent bacterium is Staphylococcus epidermidis, to 10,000 per cm2 on the damp areas, such as the armpits and groin, where propionibacteria predominate, but where corynebacteria and negative coagulase staphylococci can also be observed. What is surprising is that the skin microbiota is made up of microorganisms belonging to a very limited number of species and that the microbial load of the healthy skin is kept consistent, considering the large variety and number of potential colonizers to which the skin is prey. It is not surprising, however, that the skin, the barrier between the body and the environment, is the site of frequent infections [1]. The integrity of this barrier is influenced by the degree of scaling but also by several factors whose alterations upset the environmental balance of the resident flora and predispose the subject to infection [2]. Moreover, the skin displays microbicidal activity even when its physical integrity is impaired [3]. It contains the bioactive molecules, among which antimicrobial peptides such as defensins and cathelicidins are of critical importance to the host defense against microbial invasion [4]. * Corresponding author. E-mail address: [email protected] (M.A. Tufano).

At least two different populations of microorganisms can be found in the skin microbiota: a permanent or resident flora, which is always present, and a temporary or transient flora, which settles on the human skin only for a certain period of time. The permanent flora is a stable population of microorganisms that is more or less regularly present on the skin in considerable numbers and does not usually comprise pathogenous microorganisms. The permanent flora is consistently present and if removed reforms within 24 to 72 hours. It is made up of aerobic or microaerophil microorganisms. The main bacterium resident on free skin (ie, nonfollicular) is S epidermidis; in the area of the follicular ostium, with a reduced oxygen supply, are mainly present Propionibacterium acnes, Propionibacterium granulosum, and Propionibacterium avidum. Species of Peptococcus, which are anaerobic staphylococci, are present in 20% of humans, especially on the forehead and in the elbow crease. Gram-positive liophil bacteria belonging to the genus Corynebacterium settle in sebum-rich areas, whereas bacteria belonging to the genus Brevibacterium are present in particularly humid areas. Gram-negative bacteria are not normal components of the skin flora. The microorganisms that make up the transient flora settle only temporarily on the skin from the external environment or from the adjacent mucosal areas. Unlike in the resident flora, the bacterial species present are numerous, since most microorganisms can at least temporarily survive on the skin. They cannot, however, multiply and, therefore, colonize the skin. In some subjects, Staphylococcus aureus is present in the nose and peri-anal area and can spread to other areas of the skin. Gram-negative

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bacteria can also be isolated, particularly those belonging to the Enterobacteriaceae and Pseudomonaceae families. The former are part of the normal intestinal flora, the latter are found in the environment, most readily in damp places [5]. It is therefore evident that possible colonization and invasion by pathogenous microorganisms is counteracted both by the host defenses and by the resident flora, which contrast colonization by other microorganisms competing for nutrients or producing peptides with antimicrobial activity [2]. Most skin infections are therefore self-limiting in healthy subjects. Infections arising in a healthy skin are defined as primary infections. They are usually caused by a single microbial species; the entry point of the germ is often unknown, although a slight trauma is probably implicated. Instead, infections defined as secondary develop on preexisting skin lesions, which, therefore, facilitate the entry of the microorganisms. Atopic dermatitis, psoriatic lesions and other eczematous disorders are the most common examples, but also prone to this complication are surgical or injury wounds, burns, insect bites or stings, ulcers, and areas of maceration [6,7]. Secondary infections, usually polymicrobial, are generally caused by microorganisms that in themselves have little pathogenic power. When the humoral and cell immune defenses are low, secondary infections arise more readily and develop more rapidly [8]. Once the skin barrier has been penetrated, the microorganisms belonging to the resident flora, mainly coagulase negative anaerobic staphylococci, can cause infections, especially skin abscesses. However, also responsible for skin infections are microorganisms that, acquired from the environment, are temporarily part of the skin flora, for example S aureus and Streptococcus pyogenes. In general, a skin infection can follow three different events (Fig. 1):  a lesion of the skin that favors infection from the outside;  skin manifestations of systemic infections, which can spread through the blood from the site of infection to the skin or by direct invasion/penetration;  skin damage caused by toxins.

Bacterial infections Bacterial infections can be classified on the basis of the site involved, although some skin

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infections with a bacterial etiology can involve more than one part of the body. Thus, infections with a bacterial etiology associated with an inflammatory process limited to the hair follicle are classified as folliculitis. They are characterized clinically by the presence of abscesses and the formation of typical papules or pustules. Impetigo, erysipelas, and cellulitis are widespread infections. Impetigo is an infection limited to the epidermis and characterized by a bullous rash that evolves in crusts and pustules. Erysipelas is an acute erythematous infection that spreads rapidly and is usually associated with systemic symptoms. If the lesion is located in the subcutaneous fat and mainly involves the derma, it is called cellulitis. Both infections are associated with an intense inflammatory process. Infections characterized by rapidly progressive cellulitis that causes extensive damage to the tissue below the derma, in particular to the muscular tissue, and impairs the blood flow are known as necrotizing infections, subsequent to which necrotizing fasciitis and gas gangrene (infections not considered of dermatological competence) arise. The microorganisms most commonly involved in skin infections of a bacterial etiology are listed in Table 1. Gram-positive cocci are responsible for most skin infections and often the same microorganism can cause different infections according to the different layers of skin that it is able to colonize. Staphylococci are generally aerobic, grampositive cocci catalase-positive, which appear in irregular, so-called grapelike clusters under the microscope, although single and paired cells are the most common in a fluid culture. The dominant species of staphylococcus on the skin is S epidermidis on the face and chest, with a lesser but still substantial role for Staphylococcus hominis. In recent years there has been a much greater appreciation of the role of the normal skin flora in infection. Because of the normal colonization of skin by coagulase-negative staphylococci it is difficult to be sure that small, localized lesions such as folliculitis are really caused by these organisms [9]. There are a number of miscellaneous infections attributed to coagulase-negative staphylococci. S epidermidis and S hominis, coagulase-negative staphylococci, are now well-established pathogens in certain areas of the skin, while S aureus, a species of coagulase-positive staphylococci, remains a potent pathogen able to exhibit new antibiotic resistance patterns and to

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toxin or immuno-complex

microorganism

microorganism

blood vessel Systemic infection

Toxin-mediated infection

Epithelial cells invasion

Dermis cells invasion PAPILLOMA

leukocytes

MACULA

PAPULE

BLISTER

ULCER

Fig. 1. Mucocutaneous lesion pathogenesis.

continue to infect both the immunocompetentand incompetent-host [10]. S aureus permanently colonizes the moist squamous epithelium of the anterior nostrils of 20% of the population, and is transiently associated with another 60% [11]. Occasionally, the organism can cause superficial skin infections. Primary staphylococcal infections of the skin are chiefly boils, foruncles and other localized pustular lesions, and impetigo plus its more severe manifestation, scalded skin syndrome [12]. S aureus expresses a wide range of secreted and cell-surface–associated virulence factors, including surface proteins that promote adhesion to damaged tissue and to the surface of the host cells [13], which bind proteins in the blood to help evade immune responses and promote iron uptake [14]. Most strains express a polysaccharide capsule [15]. Moreover, S aureus has been regarded as a noninvasive pathogen but it is now evident that the bacterium can invade many types of

host cells by a mechanism involving the formation of a fibronectin bridge between the bacterial fibronectin-binding proteins and host a5b1 integrin molecules, which triggers internalization [16,17]. The ability of S aureus to cause infection seems to depend on the ability of the organism to produce a cocktail of enzymes or toxins that contribute to the appearance of disease. The microorganism can secrete a range of extracellular enzymes such as proteases, a hyaluronidase, a lipase, and a nuclease that facilitate tissue destruction and the spread of membrane-damaging toxins, which cause cytolytic effects on the host cells and tissue damage, and superantigens, which contribute to the symptoms of septic shock [18]. Toxic shock syndrome (TSS) is characterized by fever, headache, and confusion, with an erythematous rash resembling scarlet fever and desquamation in the later stages. The symptoms are also usually accompanied by diarrhea, vomiting, and hypotensive shock. TSS is caused by

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Table 1 Main bacteria that involve the skin Microorganisms

Diseases

Staphylococcus aureus

Toxic shock syndrome Pyoderma Impetigo Furuncle Scarlet fever Streptococcal toxic shock syndrome Pyoderma Erysipelas Necrotizing fasciitis Erythrasma

Streptococcus pyogenes

Corynebacterium minutissimum Corynebacterium diphteriae Pseudomonas aeruginosa Propionibacterium acnes Proteus Mycobacterium ulcerans

Cutaneous diphtheria Septicemia Ulcer Acne Folliculitis Folliculitis Buruli ulcer

exotoxins, the most common of which is toxic shock syndrome toxin 1 (TSST-1), produced mainly by strains of phage-group I S aureus. This toxin acts as a superantigen, stimulating the production of T cells and the release of cytokines [19]. Scalded skin syndrome or Ritter disease is also caused by a strain of toxigenous S aureus [20]. The toxin implicated in this syndrome is known as exfoliating toxin or scalded skin toxin. Initially the skin lesions may be mild, but the toxin causes the destruction of the desmosomes and the detachment of the superficial layer of the epidermis. It is generally regarded as a sporadic disease with most cases in children aged 0.5 to 2 years. Few adult patients are reported, chiefly in the immunosuppressed, although cases in immunocompetent adults are known [21]. Impetigo is characterized by golden, stuck-on crusts or blisters (bullae); the blisters are most probably caused by small amounts of epidermolytic toxin or by the toxin in an otherwise resistant host [22]. About three quarters of the cases are in patients younger than 20, with about 35% in those younger than 10. In Europe it is chiefly a staphylococcal disease, though one third of lesions have both S aureus and S pyogenes. American experience would suggest a predominantly streptococcal background, although there are signs that this may be changing. In AIDS patients an extensive atypical intertriginous form of

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bullous impetigo has been reported as part of AIDS-related pruritis [23]. Besides infections such as boils or impetigo, S aureus also colonizes and aggravates lesions such as those of atopic dermatitis. Some studies indicate that when the density of S aureus exceeds a certain level, such as 106/cm2, an exudative or impetiginized form of lesion occurs. The reason for the overgrowth of S aureus in atopic dermatitis and not in diseases such as psoriasis is not known [24,25]. Protein A elicits a much less vigorous response in atopics than in normal skin or psoriatics, but this may be the result rather than a cause of colonization. Attention has recently focused on the skin lipids and there is some evidence that fatty acids, which may control staphylococcal colonization, are deficient in atopics [4,26]. The therapy of choice for staphylococcal infections is usually a penicillase-resistant penicillin. The administration of erythromycin is frequent, although an increase in the frequency of erythromycin-resistant strains has been reported. Meticillin-resistant S aureus (MRSA) is a problem particularly for hospitals; vancomycin is the only drug available but strains resistant to it are also emerging (vancomycin intensive S aureus [VISA]) [27,28]. Skin infection with streptococci covers a range from simple colonization to primary and secondary infections; the skin provides an important portal of entry for systemic infection by these organisms. Streptococci are gram-positive, spherical, aerobic, and facultatively anaerobic bacteria, arranged in chains or pairs. They are nonsporing, catalase negative, oxidase negative, and mainly nonmotile. Hemolysis on blood-agar culture provides a useful division of streptococci into those that are hemolytic (beta hemolytic, showing a zone of complete hemolysis, and alpha hemolytic or viridans streptococci, showing a zone of incomplete hemolysis) and nonhemolytic (those with no effect on red blood cells). Hemolytic streptococci are further divided according to the carriage of polysaccharide or teichoic acid or Lancefield group antigens. Direct streptococcal infection of the skin may take on a number of forms [29,30]. S pyogenes (group A hemolytic streptococcus) remains the major streptococcal pathogen in these infections but non–group A streptococci also play a part and have become more commonly recognized with the widespread use of modern, rapid laboratory test kits. S pyogenes is the etiological agent of streptococcal impetigo and erysipelas, skin pathologies also

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caused by S aureus. Infection generally arises from contact with infected skin lesions in other individuals. Once S pyogenes has colonized the skin, it invades the epithelium through small wounds, with consequent development of the lesion. A complex interaction of bacterial and host defense factors underlies the initiation, development, and clinical manifestations of streptococcal infection [31]. The M-protein molecule is known to be a major virulence factor of streptococci. It is present as a double-stranded coiled-coil structure projecting from the cell surface. The functional properties of M-protein include binding of fibrinogen, fibronectin, and b2-microglobulin; adherence to host cells; interference with complement deposition; and the conferring of resistance to phagocytosis [32]. The quantity of M protein expressed on the cell surface appears to be an important factor in the pathogenesis: freshly isolated strains of group A, C, and G streptococci, particularly those from invasive infections, are often rich in this substance [33], and serotypes of S pyogenes such as M1, which express large quantities, are commonly associated with an invasive disease [34]. Enhancement of M-protein expression may be a factor underlying the increased virulence observed when streptococci are rapidly passed from host to host. The binding of fibrinogen and fibronectin by streptococcal surface structures may play an important part in the attachment of microorganisms to wounds and clots in the first stages of colonization and infection [35]. Other projecting cell-surface molecules with similarities to M protein, such as F-protein, in their cell-wall attachment structure show further functions including the inactivation of complement C5a, a major signal substance for the chemotactic attraction of leukocytes, and binding to the Fc portion of immunoglobulin (Ig) G and IgA antibodies. Teichoic acids also contribute to the virulence of S pyogenes by helping the microorganism bind to the epithelial cells [36]. A streptococcal skin infection develops 24 to 48 hours from the penetration of the skin and stimulates a marked inflammatory response. S pyogenes elaborates a series of toxic products and enzymes, like hyaluronidase, that helps the microorganism to spread in the tissues. Lymphatic system involvement is common, which causes lymphadenitis and lymphangitis. Skin infection by S pyogenes may be complicated by nonsuppurative sequelae such as nephritis and scarlet fever; conversely, streptococcal infection at other sites in the body may lead to skin

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manifestations, such as in rheumatic fever and acute guttate psoriasis. These conditions will be discussed later in this article. Streptococcal infections of the mouth; alimentary, respiratory, and genitourinary tracts; or deeper structures will not be discussed here except insofar as they are relevant to the skin [37]. Many streptococcal infections are toxin-mediated. Lysogenic strains of S pyogenes produce one or more types of pyrogenous exotoxins (previously called erythrogenic), like SPE-A, SPE-B, and SPE-C, which act on the blood vessels of the skin and cause a diffuse rash arising in association with streptococcal pharyngitis accompanied by scarlet fever. The exotoxin that causes scarlet fever is generally SPE-A [38]. Clinical manifestations similar to staphylococcal toxic shock syndrome are often supported by streptococcal toxins, particularly the pyrogenous exotoxin A, generally produced by M1, M3, or M5 phagotypes of the S pyogenes strains. Streptococcal toxic shock syndrome (STSS) varies somewhat from staphylococcal or classic forms. In most cases the primary site of infection is the skin, often in surgical wounds. In other cases STSS follows chickenpox or can infect immunodepressed patients. These clinical pictures often contrast with those seen in patients with staphylococcal toxic shock syndrome, in whom the primary infection is often subclinical [39]. Necrotizing fasciitis is an acute or subacute infection that spreads above the fascial planes causing thrombosis of the vessels and necrosis of the dermis and subcutaneous fat. It is usually caused by hemolytic or anaerobic streptococci or S aureus [40]. The disease may follow a trivial or unapparent injury to the skin and presents initially with cellulitis, which quickly develops a dusky discoloration, hemorrhagic bullae, and underlying areas of necrosis. There is risk of septicemia and rapid death. Necrotizing fasciitis is most commonly seen in elderly patients, often in association with serious preexisting medical disorders [41]. The rationale of antimicrobial therapy for streptococcal infections of the skin is to hasten the resolution of the lesion, to reduce the risks of suppurative and nonsuppurative complications, and reduce the chances of transmission of infection to others. Streptococci are still remarkably sensitive to penicillin. Many alternative drugs are available including erythromycin, tetracycline, and cephalosporin [42]. Other gram-positive bacteria belonging to the skin microbiota are coryneform bacteria. They are

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considered responsible for skin odor and can be associated with pathologies of the skin. This heterogeneous group of microorganisms includes both aerobic and anaerobic pleomorphic bacteria that do not form spores. Because of their similarity to the diphtheria bacillus, these microorganisms were formerly referred to as ‘‘diphtheroids.’’ In cutaneous infections, coryneform bacteria are clearly involved both as a primary pathogen and a secondary superinfection of other cutaneous infections such as syphilis and streptococcal pyoderma. There are several cutaneous lesions from which coryneforms can be recovered and in which they are seen as playing important pathophysiological roles. These include trichomycosis axillaris, erythrasma, interdigital toe-web-space infections, acne, and pitted keratolysis [43]. About 20% of the population is colonized by Corynebacterium minutissimum, which causes erythrasma only in some cases [44]. Erythrasma is a superficial cutaneous infection ranging from low-grade scaling to thickly macerated areas of the skin. The preferred sites are the skin folds; predisposing factors are obesity, diabetes, and hyperhydrosis. Most infections show a typical reddish fluorescence with Wood’s light. The fluorescence a result of a production of porphyrins, which fluoresce under long-wave ultraviolet light [45]. Corynebacterium diphtheriae is not an inhabitant of normal skin, although it may be recovered from intact skin under epidemic conditions. This microorganism is more commonly found on mucous membranes [46]. The skin may be the primary portal of entry; the microorganisms can be auto- or hetero-inoculated in an otherwise insignificant wound; there is a high frequency of asymptomatic carriers. Strains of C diphtheriae have been divided into gravis, intermedius, and mitis types on the basis of physiological, morphological, and molecular characteristics. Its pathogenic properties depend on the ability to produce toxins; only the strains infected by the pro-phage b have the toxþ gene and produce the exotoxin. C diphtheriae infections are more common in tropical and subtropical areas but epidemics have been described in temperate climates like North America. Erosive, ulcerative lesions with thick crusts are the most common clinical findings [47]. The key therapy is the administration of the antitoxin, which should be administered early on. Antibiotic therapy can be performed with penicillin G or erythromycin [48].

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Anaerobic coryneforms recovered from human skin belong above all to the genus Propionibacterium, and P acnes is the most numerous species. This bacterium plays an important role in acne but is not considered the cause. P acnes proliferates and generates inflammation-provoking substances, resulting in the disruption of the follicular epithelium and progressive inflammation as the contents of the follicle are injected into the dermis. In addition to its role in acne, P acnes is also a frequent opportunistic pathogen. Some authors [49,50] report the isolation of P acnes from an infected wound and in osteomyelitis and endocarditis. There are several reports of meningitis and botryomycosis due to P acnes. The antibiotics used to treat acne include tetracycline and erythromycin [51]. Gram-negative bacterial skin infections are much less frequent than gram-positive infections, but have considerable clinical importance. Pseudomonas aeruginosa is the cause of some superficial infections with particular characteristics. The microorganism readily colonizes damp environmental pockets and, as such, some areas of the body. In recent years there has been an increase in the cases of folliculitis from P aeruginosa in people attending saunas, Jacuzzis, and swimming pools. The skin rash is itchy papules or pustules characteristically distributed in the areas rich in apocrine and eccrine sweat glands. There may be associated symptoms of the infection in other areas, eg, mastodynia and earache. These disorders tend to have a spontaneous recovery but the use of quinolones may be useful. The genus Pseudomonas is frequently isolated from surgical wounds, varicose ulcers, bedsores, and burns, particularly during and after antibiotic therapy. The presence alone of Pseudomonas in these sites is a sign of infection, but the real danger is that the germ may multiply in depth and cause bacteremia [52]. Other gram-negative microorganisms can cause folliculitis during antibiotic treatment for acne, usually with tetracycline. When in young people receiving therapy for acne there is an increase in the pustular lesions, a gram-negative superinfection of the follicules should be suspected, in particular by Proteus or Pseudomonas. It is often sufficient to suspend tetracycline, but it is often necessary to switch to another antimicrobial according to the sensitivity studies. After surgery or traumas associated with contamination of the wound, serious skin infections by mixed aerobic or anaerobic flora can occur [53]. These

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are generally cellulitis with diffuse necrosis of the skin and subcutaneous layers, at times extending to the muscles. These infections are extremely difficult to classify because of overlapping of the sites involved, of the germs responsible, and of the clinical manifestations. Many of these infections are severe, rapidly progressive, and associated with high mortality. The flora is composed of clostridia, other anaerobes, enterobacteria, streptococci, and staphylococci. The therapy for these syndromes is surgery with intense antibiotic support. Because the infections are caused by mixed aerobic anaerobic flora, broad-spectrum therapy is indicated, such as aminoglycosides plus clindamycin. Metronidazole, clindamycin, piperacillin, and cefoxitin are useful against anaerobes, and imipenem, ceftazidime, ciprofloxacin, and combinations containing beta lactamase inhibitors and the association of piperacillin and tazobactam are effective against aerobes and facultative bacteria [54]. Warty skin lesions may fallow the inoculation of opportunist mycobacteria into superficial abrasions. These atypical mycobacterial infections of skin are caused by a group of nontuberculous mycobacterial microorganisms [55]. Mycobacterium marinum is the most common and causes cutaneous infection in immunocompetent individuals. This microorganism is found in fresh or salt water, or fish, thus fishermen and those who keep fish are at higher risk [56]. Other pathogens include Mycobacterium avium-intracellular, Mycobacterium ulcerans, Mycobacterium chelonae, and Mycobacterium fortuitum. The infection is mainly via inoculation or trauma. M chelonae and M fortuitum are associated with injection and occur more often in immunocompromised individuals. Immunosuppression is associated with disseminated disease [57]. M ulcerans disease (Buruli ulcer) is an important health problem in several West African countries. It is prevalent in scattered foci around the world, predominantly in riverine areas with a humid, hot climate. M ulcerans infection leads to necrosis of subdermal tissue and secondary skin ulceration [58]. The choice of therapy will depend on the site and nature of the infection, the species of causative organism and the presence of any underlying predisposing condition. Moreover, the in vitro susceptibility to antimicrobial drugs varies considerably both between and within the species of mycobacteria. In general, however, drug sensitivity tests have not proved helpful; the combinations of drugs to which the bacilli are resistant

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in vitro often prove effective in vivo. Therapy is therefore usually empirical and often based on anecdotal evidence or retrospective surveys [59]. Viral infections Viruses cannot be considered a component of the normal flora of the skin but the skin is a frequent site of manifestations of viral infection. The lesions may be limited or widespread as part of a systemic infection. Many common systemic virus infections are clinically apparent, mainly as a generalized maculopapular skin rash. For these virus infections, after an initial replication phase in or close to the site of infection, generally the oropharynx, there is systemic viremia with seeding of the skin. It is probable that the rash is immunemediated. In other cases, the skin lesion caused by the virus is a vesicular lesion. In these cases the skin lesions are the sites of viral replication and are infectious [60]. The microorganisms most commonly involved in skin infections of a viral etiology are listed in Table 2. During the past decade, increasing attention has been paid to papillomaviruses and the conditions they cause. This interest is largely because of advances that have been made in the detection and characterization of nucleic acids, as papillomavirus cannot be isolated in any routine cultures, and because of its association with cervical carcinoma. Human papillomaviruses (HPV) contain double-stranded DNA and are classified into types on the basis of their nucleotide sequences. There are now at least 90 human HPV types, sequentially numbered from 1, with some further divided into subtypes alphabetically if distinctive endonuclease restriction patterns are seen [61]. The types of HPV are associated with the particular consequences of infection. Infection is primarily of the squamous epithelium, and although there are many manifestations, the common wart (verruca vulgaris) and plantar warts are the usual presentations. The principal sites are on the hands and feet, and they are a major cause of dermatological consultation. Plantar warts are most commonly caused by HPV-1, -2, -4, -31, and -32. The virus enters through skin abrasions and infects the cells of the basal layers of the skin. There is no diffusion to the deep tissues. Viral replication is slow and is closely dependent on the differentiation of the host cells. Viral DNA is present in the basal cells, but the viral antigens and the infecting virus are produced only when the cells start to become squamous and

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Table 2 Main viruses that involve the skin Virus family

Virus genus

Virus and disease

Herpetoviridae

Herpesvirus

Poxviridae Papovaviridae Picornaviridae

Molluscipoxvirus Papillomavirus Enterovirus

Paramyxoviridae Togaviridae Parvoviridae

Morbillivirus Rubivirus Parvovirus

Herpes simplex Varicella-zoster Herpesvirus type 6 Molluscum contagiosum Papillomavirus Coxsackievirus A, B Echovirus Measles Rubella Parvovirus B19

keratinized once they reach the surface. The incubation period is usually about 4 to 6 months, with transmission by direct contact or by fomite. The natural history is of regression, with about two thirds resolving within 2 years. Other benign skin lesions include flat warts (HPV-3 and -12) and butchers warts (HPV-7) [62]. Epidermodyslasia verruciformis is a rare condition. It is an HPV-specific disorder of cell-mediated immunity resulting in disseminated warty lesions that persist for life. An autosomal recessive mode of inheritance is probable. Up to 23 types of HPV infect these patients, such as HPV-5, -8, -9, and -12, and most do not cause lesions in healthy subjects [63]. Genital warts have attracted great attention because of their association with genital cancer. The common type of genital wart is the condyloma acuminatum, which is due to infection with HPV-6 or -11. The incubation period is about 1 to 6 months and may occur not only on the external genitalia, but also on the mucosal surfaces of the vagina and urethra. They rarely become malignant and usually spontaneously resolve. Infection may often be asymptomatic, so the possibilities of transmission are enhanced since the infected person does not seek treatment. The malignant potential of papillomaviruses has been recognized for many years, but it is only in the past 15 years that involvement in carcinoma of the cervix has been demonstrated The detection of HPV DNA by hybridization techniques has implicated HPV, particularly HPV-16 and -18, in a range of cervical lesions from carcinoma in situ to invasive cervical carcinoma. In malignant cells, the HPV genoma has been integrated into the cell genome, rather than remaining extrachromosomal. These HPV types also occur commonly

Stomatitis, genital herpes, etc. Chickenpox, Zoster Roseola infantum Warts Hand, foot, and mouth disease

Erythema infectiosum, aplastic crisis

in sexually active women with no cervical lesions, so the role of the detection of HPV-16 and -18 in the management of women with a clinically and cytologically normal cervix remains to be defined [64]. Papillomaviruses have also been implicated in human malignancies of the skin, such as squamous cell carcinoma in patients with epidermodysplasia verruciformis, and a similar carcinoma may occur in immunocompromised renal transplant recipients, who have a high risk of developing warts [65]. Herpes simplex virus (HSV) is probably the most common virus infecting the human skin. HSV is divided into types 1 and 2 according to a number of features including DNA fragment size after endonuclease restriction analysis. As with all herpes viruses, they are large, enveloped virions with an icosahedral nucleocapsid consisting of 162 capsomeres, arranged around a linear, double-stranded DNA core. The DNAs of HSV1 and HSV-2 are largely colinear, and considerable homology exists between the HSV-1 and HSV-2 genomes. These homologous sequences are distributed over the entire genomic map, and most of the polypeptides specified by one viral type are antigenically related to polypeptides of the other viral type. This results in considerable cross-reactivity between the HSV-1 and HSV-2 glycoproteins, although unique antigenic determinants exist for each virus. Viral surface glycoproteins mediate HSV attachment to and penetration into the cells and provoke host immune responses. Eleven glycoproteins of HSV have been identified (gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL, and gM), with a 12th predicted (gN). gD is the most potent inducer of neutralizing

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antibodies and appears to be related to viral entry into a cell; gB is also required for infectivity. Antigenic specificity is provided by gG, with the resulting antibody response, thus allowing the distinction between HSV-1 (gG-1) and HSV-2 (gG-2) [66,67]. HSV-1 is generally associated with oro-labial disease, with most infections occurring during childhood, and HSV-2 with genital disease with infection following sexual debut [68]. However, it is possible for HSV-2 to cause oro-labial herpes and HSV-1 to cause genital herpes [68]. Primary infection with HSV-1 usually occurs in childhood and is often asymptomatic, although it can present as stomatitis, occasionally severe. After primary oral infection, the virus becomes latent in the neurons of the trigeminal ganglia, with reactivation likely later in life. The natural history is of a few hours of nonspecific tingling, followed by the development of vesicles, scabbing, and resolution over a few days. Two biologic properties of HSV that directly influence human disease are latency and neurovirulence. During HSV infection, virions are transported by retrograde flow along axons that connect the point of entry into the body to the nuclei of sensory neurons. Viral multiplication occurs in a small number of sensory neurons, and the viral genome then remains in a latent state lifelong. With periodic reactivation brought on by events such as physical or emotional stress, fever, UV light, and tissue damage, the virus is transported back down the axon to replicate again at or near the original point of entry into the body. Such reactivation can result in clinically apparent disease (lesions) or a clinically inapparent (asymptomatic or subclinical) infection. The mechanisms by which HSV establishes latency are currently under investigation. Neurovirulence refers to the affinity with which HSV is drawn to and propagated in neuronal tissue. This can result in profound disease with severe neurological sequelae, as is the case with neonatal HSV central nervous system (CNS) disease and with herpes simplex encephalitis in older children and adults [69]. Although there is debate about the usefulness of antivirals, such as acyclovir, continuous oral therapy is often recommended for herpetic infections to suppress a recurrence [60]. Molluscum contagiosum is a disease caused by a poxvirus of the Molluscipox virus genus that produces a benign self-limited papular rash of multiple umbilicated cutaneous tumors. This

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common viral disease is confined to the skin and mucous membranes. It has an incubation period from 1 week to 6 months. The lesions vary in number from one to many hundreds, and develop from papules to flesh-colored or pearly nodules, which often have an umbilicated center. Systemic symptoms are rare. In adults they usually occur on the trunk, genital area, and thighs, and infection may be sexually transmitted. In children, in whom infection is more common, the lesions are predominantly on the trunk and proximal extremities. The disease usually lasts 6 to 9 months, although individual lesions persist for only about 2 months. The virus has not been cultured and, if necessary, a specific diagnosis can be attained by electron microscopy [70]. Measles, rubella, parvovirus B19, and some enteroviruses produce generalized maculo-papular rashes and it may not be easy to distinguish between them clinically, particularly in infections of the latter three. Transmission is by the respiratory route for measles, rubella, and parvovirus B19, but is fecal-oral for the enteroviruses. Measles virus, a member of the Morbillivirus genus, is an enveloped virus with a nonsegmented negative-strand RNA genome. It has two envelope glycoproteins, the hemoagglutinin (H) and the fusion (F) protein, which are responsible for receptor binding and membrane fusion, respectively. The measles virus causes a common childhood disease with high fever and typical skin rash. Measles has an incubation period of about 10 to 11 days, the rash being preceded by a 2- to 3-day prodrome of fever, coryza, and conjunctivitis, with the appearance of the characteristic elevated white Koplik’s spots on the mucosa of the mouth. The rash usually starts around the head and spreads to the trunk and extremities, with resolution after a few days [71]. Complications are not uncommon, arising in about 3% to 4% of cases, and include bacterial pneumonia and otitis media. Postinfectious encephalitis occurs at a rate of about 1 in 2000 to 5000 cases and carries significant mortality. Subacute sclerosing panencephalitis (SSPE) occurs after an interval of some years in about one in a million cases. It reflects a persistent infection with measles virus. Patients present with intellectual impairment and progress to motor dysfunction, coma, and death. In the immunocompromised child, measles may occur without a rash but lead to encephalitis or giant-cell pneumonia, which have high fatality rates [72].

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The use of live attenuated vaccines given in the second year of life has led to a great decline in incidence of measles in countries with a high uptake. Despite the introduction of measles vaccine in the late 1960s, biannual epidemics were still occurring up to the late 1980s. The introduction of mumps, measles, and rubella (MMR) vaccine in 1988, together with more active vaccination campaigns, have led to an increased uptake of vaccine. This follows the example set by the United States, where measles is now an uncommon disease, although it still presents occasional problems of institutional outbreaks in adolescents who are not immunized or have vaccine failure [73]. Rubella virus is a positive-sense, singlestranded RNA virus belonging to the Togaviridae family of the genus Rubivirus [74]. Infection with rubella virus usually results in a mild disease that only rarely produces significant sequelae. Rubella has a somewhat longer incubation period of 16 to 17 days and, particularly in children, is a mild disease, often asymptomatic. It is transmitted through aerosol and is less contagious than measles, but more than parotitis. The virus initially multiplies in the local lymphoid tissues, then spreads to the spleen and distant lymph nodes. Continuous multiplication in these tissues brings on, a week after infection, a viremic phase and an onset of the virus in the respiratory tract and in the skin and, in some cases in the placenta, joints, and kidneys. The pink macular rash usually starts on the face, spreads centrifugally, and lasts only 2 to 3 days. The major complication of rubella is intrauterine infection and fetal damage if infection occurs during the first 4 months of pregnancy. Persistent infection with rubella virus can lead to immunopathological problems presenting after birth, such as pneumonia. No effective antiviral treatment exists. Live attenuated rubella vaccines have been available since the 1970s to prevent congenital rubella. It is given by parenteral route, generally associated with the vaccine for measles and parotitis [75]. The human parvovirus B19 belongs to the genus Erythrovirus and is the only member of the family Parvoviridae to cause a wide range of human diseases in both children and adults [76]. The virus is nonenveloped, and its genome consists of a linear, single-stranded DNA molecule of approximately 5600 nucleotides with terminal palindromic inverted sequences of 383 nucleotides at both ends. Infection with parvovirus B19 cannot be differentiated clinically from rubella in

et al

the adult. In the child, but not in the adult, the rash, erythema infectiosum (or Fifth disease), is usually accompanied by a malar erythema leading to the alternative name of slapped cheek syndrome. In patients with hemolytic anemia, such as sickle cell disease and hereditary spherocytosis, the transient inhibitory effect of parvovirus B19 on the bone marrow may lead to aplastic crisis. Infection during pregnancy does not lead to fetal damage, although hydrops fetalis, intrauterine death, and stillbirth may occur after infection in the second trimester [77]. No vaccine is available. Human herpes type 6 (HHV-6) is the sixth member of the herpes virus family that includes herpes simplex virus 1 and 2, varicella-zoster virus, cytomegalovirus (CMV), and Epstein-Barr virus. It is a member of the beta-herpes virus subfamily, of the Roseolavirus genus. HHV-6 is an enveloped DNA virus of 160 to 200 nm in diameter and approximately 167 kbp in length. The sequence difference between variant A and B is about 4%, and the two can be differentiated by restriction fragment length polymorphism, monoclonal antibodies, polymerase chain reaction (PCR) and in vitro growth characteristics [78]. The isolation and characterization of HHV-6 was first reported in 1986 using cultures of peripheral blood leukocytes (PBL) from patients with acquired immune deficiency syndrome (AIDS) and lymphoproliferative disease. HHV-6 preferentially infects CD4þ T lymphocytes, but can also infect other cell lines of epithelial, fibroblastic, and neuronal origin with different efficiency. The clinical syndrome of exanthem sabitum (or roseola infantum, sixth disease) was first described in 1913; however, its etiological link to HHV-6 was first identified in 1988. Approximately 50% to 60% of children are infected by HHV-6 by 12 months of age and almost all children are infected by the age of 2 to 3 years. This illness is characterized by a high fever that resolves with the appearance of a pinkish macular rash. Studies have implicated HHV-6 as an etiological agent of meningitis and encephalitis in the immunocompromised [79]. Antiviral agents that have been found to be effective in vitro against HHV-6 include ganciclovir, foscarnet, and cidofovir. In otherwise healthy children HHV-6 infection is usually self-limited and no antiviral treatment is needed [80]. Varicella-zoster virus (VZV) is a highly cellassociated member of the Herpesviridae family and one of the eight herpes viruses to infect

INFECTIOUS SKIN DISEASES

humans. It is a double-stranded DNA virus and is most closely related to herpes simplex virus types 1 and 2. These viruses rapidly proliferate and invade and destroy the infected cells. The virus is ubiquitous in most populations worldwide and the primary infection causes varicella, more commonly known as chickenpox. VZV is neurotropic and establishes latency in sensory neurons. Reactivation from latency, usually during periods of impaired cellular immunity, causes herpes zoster (shingles). Varicella is a common childhood infection with an incubation period of 14 to 16 days. A shortened incubation period can be encountered especially in immunocompromised patients. The skin lesions progress rapidly through the stages of macules to papules to vesicles that rapidly burst and form a crust. The lesions appear in series; therefore, all stages in their genesis can be seen at any one time. Patients with varicella are generally considered to be infectious 2 days before the appearance of the rash and 7 days after the onset, when the vesicles have crusted. In children with normal cellular immunity, varicella is usually a benign and selflimiting illness. In adults, however, varicella presents a higher risk of complications such as viral pneumonia, encephalitis, and skin sepsis. Varicella in the first 5 months of pregnancy may occasionally cause fetal damage [81]. Herpes zoster mainly affects a single dermatome of the skin. It may occur at any age but the majority of patients are older than 50. The latent virus reactivates in a sensory ganglion and tracks down the sensory nerve to the appropriate segment. The lower cervical, thoracic, and lumbar posterior root ganglia are most commonly involved. The rash is commonly preceded by paresthesia, burning pains, and tenderness of the skin. The trigeminal ganglion is another common site of reactivation and the ophthalmic branch of this nerve is 20 times more likely to be involved than the other 2 branches. Facial palsy associated with vesicles in the external auditory meatus is known as the Ramsay-Hunt syndrome and is thought to be a form of zoster involving the VIIth nerve. The skin lesions are usually accompanied by local pain, which often precedes the lesions, but pain may occur without visible lesions (zoster sine herpete). The most severe complication in healthy individuals is persistent pain at the site of the lesions that may last for several months [82]. Some benefit may be had from early use of acyclovir, but whether this influences postherpetic neuralgia has been debated.

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Zoster in pregnancy presents no hazard to the fetus or neonate [83]. Last, it is known that immunocompromised patients present many additional problems regarding viral skin infections, but it is not known whether this is a consequence of therapy or of underlying problems, such as lymphoma or HIV infection. These infections, such as HSV and VZV with a latent state are more likely to reactivate and disseminate rather than remain as a localized lesion. Varicella and measles may be life threatening. Rubella does not seem to present any particular risk, and parvovirus B19 and enteroviruses only rarely present problems. The dissemination of warts can occur in molluscum contagiosum. In conclusion, the past decade has seen exciting developments in identifying the etiological agents for syndromes manifesting in the skin, but there are still others for which a viral origin seems likely. References [1] Kazmierczak AK, Szewczyk EM. Bacteria forming a resident flora of the skin as a potential source of opportunistic infections. Pol J Microbiol 2004; 53(4):249–55. [2] Hartmann AA. The influence of various factors on the human resident skin flora. Semin Dermatol 1990;9(4):305–8. [3] Zasloff M. Antimicrobial peptides of multicellular organisms. Nature 2002;415:389–95. [4] Baroni A, Orlando M, Donnarumma G, et al. Tolllike receptor 2 (TLR2) mediates intracellular signalling in human keratinocytes in response to Malassezia furfur. Arch Dermatol Res 2005;10:1–9. [5] Elsner P. Antimicrobials and the skin physiological and pathological flora. Curr Probl Dermatol 2006; 33:35–41. [6] Hoffler U, Gloor M, Peters G, et al. Qualitative and quantitative investigations on the resident bacterial skin flora in healthy persons and in the non-affected skin of patients with seborrheic eczema. Arch Dermatol Res 1980;268(3):297–312. [7] Marina SS, Bocheva GS, Kazanjieva JS. Severe bacterial infections of the skin: uncommon presentations. Clin Dermatol 2005;23(6):621–9. [8] Edlich RF, Winters KL, Britt LD, et al. Bacterial diseases of the skin. J Long Term Eff Med Implants 2005;15(5):499–510. [9] Akiyama H, Kanzaki H, Tada J, et al. Coagulasenegative staphylococci isolated from various skin lesions. J Dermatol 1998;25(9):563–8. [10] Noble WC. Skin bacteriology and the role of Staphylococcus aureus in infection. Br J Dermatol 1998; 139(Suppl 53):9–12.

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