Viruses utilize host subcellular machinery for replication. All viruses have a basic structure of a genome as well as a protein capsid. Broadly, they can be divided into DNA- or RNA-based genomes as well as enveloped or nonenveloped structures based on the presence or absence of a membrane surrounding the protein capsid. Enveloped viruses are less resistant to environmental changes and disinfectants.
Viral classification and associations (for dermatology-relevant viruses) are summarized in Table 3.1.
The skin’s strongest protection against infectious diseases is the mechanical barrier. This is well demonstrated by the propensity for patients with AD, Hailey-Hailey disease, and Darier disease to develop secondary herpetic infections (Kaposi varicelliform eruption). Acquired immunodeficiency may result from viral infections (eg, HIV), other medical disorders (eg, Kwashiorkor, Cushing disease/Cushing syndrome, diabetes mellitus, nephrotic syndrome, cancer), aging (immunosenescence), pregnancy, and medications.
HIV may present as a congenital infection.
Hereditary immunodeficiency syndromes are summarized in Table 3.3.
 HERPES SIMPLEX → Diagnosis Group 1 |
Table 3.1. VIRAL CLASSIFICATION AND ASSOCIATIONS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Table 3.2. MUCOCUTANEOUS SIGNS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||
Table 3.3. HEREDITARY IMMUNODEFICIENCY SYNDROMES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Herpes simplex is an infection caused by HSV-1 (HHV-1) and HSV-2 (HHV-2). ˜50% and ˜15% of the US population have been infected with HSV-1 and HSV-2, respectively, though the minority manifest clinical disease. HSV-1 is the major cause of orolabial herpes, while HSV-2 is the major cause of genital herpes. However, HSV-1 is a more common cause of genital herpes than HSV-2 in young adults.
HSV can be transmitted by subclinical shedding at mucous membranes in addition to overt clinical lesions. Risk factors for genital herpes include increased number of sexual partners, homosexuality, and lower socioeconomic status and education. Genital herpes increases risk of HIV infection (and vice versa).
Herpes simplex is the leading association with EM (80% of cases).
HSV may present as a congenital infection (15%) due to transplacental transmission or a neonatal infection (85%) due to perinatal transmission. The majority of women with active HSV infection at the time of delivery are asymptomatic. The nature of maternal infection, primary vs recurrent, is the most important risk factor. Risk increases with vaginal delivery (8%) vs C-section (1%).
Recall congenital infections with the TORCH acronym: Toxoplasmosis, Other, Rubella, CMV infection, Herpes simplex. The “other” category includes varicella, parvovirus B19 infection, mumps, zika, HIV infection, and syphilis.
In children, HSV infection is primarily due to HSV-1.
Primary HSV can be preceded by 3 to 7 days of fever, malaise, and lymphadenopathy, with eventual tingling, burning, and mucocutaneous lesion formation. Characteristic HSV lesions are grouped vesicles on an erythematous base. After primary infection, HSV establishes residency in sensory ganglia and reactivation leads to recurrent local infection. Recurrent HSV is frequently asymptomatic but can feature a sensory prodrome (˜24 hours) prior to vesicle formation. Systemic symptoms are not generally observed and severity is typically less than primary infection.
Herpes simplex variants in adults are summarized in Table 3.4.
Congenital HSV infection lesions range from vesicles to scars. Systemic manifestations include limb abnormalities, microcephaly, seizures, and chorioretinitis.
Neonatal HSV infection is divided into three types: (1) localized skin, eye, and mouth (SEM) disease; (2) CNS ± localized SEM disease; and (3) disseminated disease with multiorgan involvement.
Primary herpetic gingivostomatitis is the most common herpes simplex variant in children.
The differential diagnosis of orolabial herpes includes EM, SJS/TEN, recurrent aphthous stomatitis, Behçet disease, viral pharyngitis, and oropharyngeal candidiasis.
Table 3.4. HERPES SIMPLEX VARIANTS IN ADULTS
Varianta
Classic description
Notes
Primary
Primary herpetic gingivostomatitis
Gingivitis, stomatitis.
Primary genital herpes
Most common site is the glans and shaft of the penis in men and the vulva and vagina in women.
Recurrent
Recurrent herpes labialis (cold sore, fever blister)
Less severe than primary infection. Most common sites are the vermillion border, buccal mucosa, and gingiva.
Triggers include stress, immunosuppression, sun exposure or phototherapy (especially nbUVB), chemical peels, and laser.
Recurrent genital herpes
Less severe than primary infection.
Frequency of HSV shedding decreases in the first year after initial infection but persists at high rate.
Miscellaneous variants
Chronic ulcerative HSV
Polycyclic well-defined ulcerations with friable tissue and a scalloped border. Most common sites are the perianal area and buttocks.
Seen in HIV-infected and other immunocompromised patients.
Eczema herpeticum
See below.
Herpes encephalitis
Fever, confusion, focal neurologic deficits, and seizures.
Dormant HSV in trigeminal ganglion, travels retrograde to the brain, targets temporal region. Association with natalizumab.
Herpes folliculitis (herpes sycosis)
Erythematous papules and plaques ± vesicopustules.
VZV > HSV.
Herpes gladiatorum
Grouped vesicles and erosions on exposed sites (eg, face, neck, arms).
Wrestlers.
Herpetic whitlow
Acute paronychia.
Primarily HSV-1 in children and HSV-2 in adults.
Keratoconjunctivitis
Eyelid edema, chemosis, and photophobia.
Dendritic corneal ulcerations are visible with fluorescein staining.
a Illustrative examples provided.
AD, atopic dermatitis; HIV, human immunodeficiency virus; HSV, herpes simplex virus; nbUVB, narrowband ultraviolet B; VZV, varicella zoster virus.
The differential diagnosis of genital herpes includes Behçet disease, chancroid, gonococcal urethritis/cervicitis, granuloma inguinale, lymphogranuloma venereum (LGV), and primary syphilis.
Diagnostic tests for herpes simplex include:
Tzanck smear: reveals multinucleated keratinocytes with nuclear molding and margination of basophilic chromatin to the periphery.
Tzanck smear reveals the “3 Ms”: multinucleation, molding, and margination (“eggshell” chromatin). It can NOT distinguish between HSV and varicella zoster virus (VZV).
Skin biopsy: helpful in unclear cases.
Viral culture: viral culture can help identify treatment resistance.
Serologies: IgG can identify previous infection; IgM not recommended as not type specific and can be positive in primary or recurrent infection.
Direct fluorescent antibody (DFA): rapid but poor sensitivity compared to reverse transcriptase (RT) polymerase chain reaction (PCR) and not type specific.
RT-PCR: most sensitive and specific; type-specific.
Ophthalmological evaluation is indicated if there is concern for eye involvement.
Antiviral therapy decreases lesion duration, viral shedding, and pain. Oral antivirals include acyclovir, famciclovir, and valacyclovir. Acyclovir and penciclovir are available in topical formulations. IV acyclovir is indicated in HIV-infected and other immunocompromised patients with severe disease.
Figure 3.1. CLINICOPATHOLOGICAL CORRELATION: HERPES SIMPLEX. Herpes simplex is characterized by an intraepidermal vesicle with acantholysis and ballooning and reticular degeneration of keratinocytes. Mild CSVV may be present. IHC can detect HSV. Keratinocytes (balloon cells) are multinucleated with nuclear molding and margination of basophilic chromatin to the periphery. While most keratinocytes exhibit homogenous pale chromatin, some exhibit Cowdry A bodies: eosinophilic intranuclear inclusion bodies surrounded by a halo. A, Low-power view. B, Medium-power view. C, High-power view. Solid arrow: eosinophilic intranuclear inclusion body (Cowdry A body) surrounded by a halo within a “balloon cell.” CMV, cytomegalovirus; CSVV, cutaneous small vessel vasculitis; HSV, herpes simplex virus; IHC, immunohistochemistry; VZV, varicella zoster virus.
(Histology images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
For episodic therapy, regimens of acyclovir, famciclovir, and valacyclovir appear equally efficacious. More than 10 outbreaks per year may require suppressive therapy.
Foscarnet may be used in case of acyclovir resistance.
Skin biopsy with IHC, viral culture, and RT-PCR are tests that can differentiate between HSV and VZV.
Valacyclovir 2 g twice daily or famciclovir 1 g single dose can be very effective at aborting orolabial HSV recurrence when administered in the prodrome period.
HSV prophylaxis should be administered for moderate/deep chemical peels and laser resurfacing.
 ECZEMA HERPETICUM Synonym: Kaposi varicelliform eruption → Diagnosis Group 1 |
Eczema herpeticum refers to dissemination of HSV due to disrupted skin barrier in AD. Secondary herpetic infections can be seen in other disorders of skin barrier function. The most common cause is HSV-1.
Eczema herpeticum is associated with filaggrin deficiency and younger age (<5 years).
Eczema herpeticum most often presents on the head and neck but can progress to widespread involvement of monomorphic umbilicated vesiculopustules and punched out erosions with crusting. Fevers, malaise, and lymphadenopathy can be observed and can be life threatening.
Staphylococcal and streptococcal superinfections are common.
Eczema herpeticum shares the histopathological features of herpes simplex.
The differential diagnosis of eczema herpeticum includes AGEP, varicella, disseminated herpes zoster, eczema vaccinatum, eczema coxsackium, and GAS infection.
Tzanck smear and RT-PCR are commonly employed to detect HSV, along with superficial wound culture to evaluate for bacterial superinfection.
IV acyclovir is first line in severe cases.
Addition of a penicillinase-resistant antibiotic is reasonable given the propensity for staphylococcal superinfection (>70%).
Ophthalmological evaluation is indicated if there is periocular involvement.
An acute, widespread flare in patients with severe AD should prompt consideration of eczema herpeticum, molluscum contagiosum, eczema coxsackium, and Staphylococcus aureus.
GAS infection closely mimics eczema herpeticum due to erosions and crusting; however, the lesions are not as uniform in size.
 VARICELLA Synonym: chickenpox → Diagnosis Group 1 |
Varicella is an infection caused by VZV (HHV-3). Varicella refers to primary VZV infection, whereas herpes zoster refers to latent VZV reactivation.
98% of the worldwide population is seropositive for VZV. Varicella incidence has declined dramatically since introduction of the vaccine in 1995.
Airborne respiratory droplets are the most common route of transmission. The incubation period after exposure is up to 3 weeks. Varicella is extremely contagious (>90% attack rate in susceptible hosts). Individuals are infectious from 1 to 2 days before skin lesions occur until all are crusted over.
Varicella may present as a congenital infection. The highest risk of complications occurs with primary infection in the first 20 weeks of pregnancy.
Neonatal varicella is seen 5 days before to 2 days after delivery. It is associated with high mortality (30%) due to lack of maternal antibody protection.
A prodrome of fever and malaise can precede the varicella rash. Pruritic macules and papules progress in a cephalocaudal distribution and rapidly evolve into vesicles and vesiculopustules followed by erosions in ˜12 hours. Lesions in all stages of development are seen simultaneously. Keratoconjunctivitis and mucosal ulcers may occur (the enanthem may precede the exanthem by 1-3 days).
Vesicles on a red base are classically described as “dew drops on a rose petal.”
Complications include hepatitis, meningoencephalitis, and pneumonitis. Thrombocytopenia and idiopathic thrombo-cytopenic purpura (ITP) can occur acutely and postinfection; anti-platelet antibodies have been observed.
Varicella is more severe in adolescents and adults, and adults have an increased risk of complications. Elderly or immunocompromised patients may manifest confusion, fatigue, headache, loss of appetite, and seizures due to syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Congenitalvaricellaischaracterizedbystellatecicatriciallesions at birth. Complications include limb abnormalities (hypoplasia, paresis), CNS involvement (hydrocephalus, intellectual disability), and ocular involvement (cataracts, chorioretinitis).
Neonatal varicella is characterized by generalized varicella at birth.
The differential diagnosis of varicella includes PLEVA, AGEP, disseminated herpes simplex, disseminated herpes zoster, hand-foot-mouth disease (HFMD), and scabies.
Diagnostic evaluation includes the same battery of tests as for HSV.
Ophthalmological evaluation is indicated if there is concern for eye involvement. In complicated disease, consider additional evaluation for hepatitis, meningoencephalitis, and pneumonitis.
Healthy children with uncomplicated varicella do not require therapy. IV acyclovir is indicated in HIV-infected and other immunocompromised patients with severe or complicated disease.
Even for uncomplicated varicella, adults should receive oral antivirals given the increased risk of complications.
The live attenuated varicella vaccine confers protection to patients whose antibody levels are undetectable. Post-exposure vaccination is indicated within 3 to 5 days if > 12 months of age, not pregnant, and not immunocompromised (these populations should receive VZV-Ig).
A common sequela of pediatric varicella is scarring as a result of scratching given the degree of pruritus associated with the exanthem. Soothing baths with colloidal oatmeal and antipruritic drugs (eg, antihistamines, camphor, menthol, pramoxine [>2 years of age]) can be helpful.
 HERPES ZOSTER Synonym: shingles → Diagnosis Group 1 |
Herpes zoster refers to latent VZV reactivation in sensory ganglia.
Varicella vaccination in childhood appears to confer less risk for development of herpes zoster than natural infection with varicella, although the risk is still present with the vaccine VZV strain.
Associations include older age and immunosuppression. The risk of herpes zoster is 3%/y in HIV-infected patients and 70% in the first year in leukemia or bone marrow transplant patients.
There is no risk to the fetus in maternal herpes zoster.
Herpes zoster classically follows a sensory prodrome of pruritus, tingling, and burning with the development of grouped vesicles on an erythematous base in a dermatomal distribution. Individual lesions evolve rapidly over 1 to 2 days. Classic herpes zoster can involve adjacent dermatomes
and can rarely cross the midline. The most common location is the trunk; however, the single most common nerve is the trigeminal nerve. Keratoconjunctivitis and mucosal ulcers may occur.
Neuropathic complications are dependent on location. For example, lumbar involvement can lead to motor neuropathy of the leg, while sacral involvement can lead to obstructive urinary symptoms.
Hutchinson sign (herpes zoster involving the nasal tip) may indicate ocular involvement since the external nasal branch of the anterior ethmoidal nerve and the ciliary nerve are both branches of the nasociliary nerve. Uveitis > keratitis can lead to visual loss.
Do NOT confuse Hutchinson sign of herpes zoster with Hutchinson sign of nail unit melanoma or Hutchinson teeth in Hutchinson triad of late congenital syphilis.
Bell palsy is due to herpes zoster of the facial nerve with ipsilateral paralysis/paresis.
Ramsey-Hunt syndrome is due to herpes zoster of the facial nerve affecting the geniculate ganglion with ipsilateral paralysis/paresis, hearing loss/vestibular dysfunction, and loss of taste from the anterior two-thirds of the tongue.
Disseminated herpes zoster (> 20 vesicles outside the dermatome) is typically seen in HIV-infected and other immunocompromised patients with hepatitis, meningoencephalitis, and pneumonitis.
The most common complication of herpes zoster is postherpetic neuralgia (PHN). This manifests in up to 20% of cases, with an increased incidence and severity with age.
Pruritus and localized GA may occur in herpes zoster scars.
Herpes zoster shares the histopathological features of varicella.
The differential diagnosis of herpes zoster includes contact dermatitis, herpes simplex, and bullous impetigo.
Tzanck smear and RT-PCR are commonly employed to detect VZV. A fourfold increase in IgG serology titers over baseline is also diagnostic.
Ophthalmological evaluation is indicated if there is concern for eye involvement. In disseminated disease, consider additional evaluation for hepatitis, meningoencephalitis, and pneumonitis.
For herpes zoster prevention, Zostavax (live attenuated vaccine, approved ≥50 years of age, 50% decrease in disease, 67% decrease in PHN) has been superseded by Shingrix (recombinant vaccine, approved ≥50 years of age, >90% effective at prevention of zoster and PHN). Shingrix is a subunit vaccine (HZ/su) containing recombinant VZV glycoprotein E and the AS01B adjuvant system.
Antiviral therapy decreases the severity and duration of skin lesions and pain, as well as the frequency and duration of PHN. Oral antivirals include acyclovir, famciclovir, and valacyclovir. IV acyclovir is indicated in disseminated herpes zoster.
Gabapentin, pregabalin, or TCAs are first line for PHN.
Antivirals are most effective if initiated within 48 to 72 hours.
Concomitant systemic corticosteroids have no effect on the frequency or duration of PHN but may decrease acute pain.
INFECTIOUS MONONUCLEOSIS Synonym: glandular fever
Reprinted with permission from Salimpour RR, Salimpour P, Salimpour P. Photographic Atlas of Pediatric Disorders and Diagnosis. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013.
Infectious mononucleosis is caused by EBV (HHV-4). By early adulthood, 95% of individuals have been infected with EBV. While the virus is most commonly transmitted through saliva, it can be transmitted through blood and other body fluids as well as organ transplants. The incubation period is 3 to 7 weeks. EBV infects mucosal epithelial cells and B-cells (mediated by CD21 binding). After acute infection, EBV can establish latent infection in B-cells (mediated by Epstein-Barr nuclear antigen 1 [EBNA1] and lateral membrane protein 2 [LMP2]). Immunocompetent hosts generally prevent cellular transformation from EBV; however, in susceptible hosts, latent infection in B-cells can lead to EBV-positive lymphoproliferative disorders (LPDs) and lymphomas.
Though EBV infection is commonly asymptomatic in children, ˜50% of adolescents and young adults develop infectious mononucleosis (fever, fatigue, lymphadenopathy, pharyngitis). An exanthem (morbilliform, urticarial, or purpuric eruption 4-6 days after symptom onset) is seen in 70% of hospitalized patients and 10% of patients overall. An enanthem of palatal petechiae (Forchheimer spots) may occur. Dermatologic signs of EBV infection are summarized in Table 3.5.
EBV reactivation has been implicated in DRESS syndrome, HLH, hydroa vacciniforme (HV), extranodal NK/T-cell lymphoma, nasal type (includes
HV-like CTCL), posttransplant lymphoproliferative disorder (PTLD), lymphomatoid granulomatosis, Hodgkin lymphoma, endemic Burkitt lymphoma, and nasopharyngeal carcinoma.
Table 3.5. DERMATOLOGIC SIGNS OF EPSTEIN-BARR VIRUS INFECTION
Diagnosisa
Classic description
Notes
Gianotti-Crosti syndrome (papular acrodermatitis of childhood)
Asymptomatic skin-colored or pink-red edematous papules favoring the cheeks, buttocks, and extensor extremities and monomorphic, flat-topped acral papules. Systemic features include diarrhea, low-grade fever, and lymphadenopathy.
Onset between 3 months and 15 years of age.
Viral associations include HBV (most common in Europe), EBV (most common in the United States), CMV, and enterovirus. Vaccination associations include HBV.
Self-limited over 2-3 weeks (do not treat with oral corticosteroids).
Infectious mononucleosis
See above.
Lipschutz ulcer
Acute anogenital ulcer.
Nonvenereal.
Oral hairy leukoplakia
White patch favoring the lateral tongue.
Oral hairy leukoplakia is often described as having a “corrugated” surface.
Papular purpuric gloves and socks syndrome
Lacy eruption associated with burning, pruritus, edema of the hands and feet.
Viral associations include parvovirus B19 infection > EBV infection.
a Illustrative examples provided.
CMV, cytomegalovirus; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HIV, human immunodeficiency virus; US, United States.
Infectious mononucleosis has nonspecific histopathology.
Infectious mononucleosis-like syndromes include acute retroviral syndrome and CMV infection. Transaminitis and lymphocytosis are common. Diagnostic tests include the heterophile antibody test (Monospot), EBV-specific serologies, and PCR.
Treatment of infectious mononucleosis is supportive. Morbilliform eruption may occur with amoxicillin/ampicillin administration. Patients are recommended to avoid contact sports for 4 weeks given the risk of splenic rupture.
CYTOMEGALOVIRUS INFECTION
Congenital cytomegalovirus infection reprinted with permission from Sweet RL, Gibbs RS. Atlas of Infectious Diseases of the Female Genital Tract. Lippincott Williams & Wilkins; 2004.
CMV (HHV-5) may be transmitted via body fluids, transplanted tissues, and fomites. The seroprevalence increases with age, averaging 60% in adults and over 90% in patients >80 years of age. Infection rate is inversely proportional to socioeconomic status (increased in low-income countries). The pathogenesis involves an incubation period of 4 to 8 weeks followed by viremia and multiorgan dissemination. Recurrent infection may occur due to reactivation of latent CMV (eg, immunosuppression) or reinfection with a different antigenic type.
CMV is the leading cause of congenital infection. The highest risk of complications occurs with primary infection in the first trimester.
>90% of CMV infections are subclinical or asymptomatic. In immunocompetent patients, CMV infection may present as an infectious mononucleosis-like syndrome. In immunosuppressed patients, CMV has protean manifestations including cutaneous vasculitis, morbilliform eruption, and chronic perineal ulcers (eg, HIV-infected patients with CD4 < 50 cells/mm3). Sequelae of multiorgan involvement include esophagitis, colitis, chorioretinitis, and pneumonitis. CMV reactivation has been implicated in DRESS syndrome.
The perineal location of CMV ulcers is easy to recall based on proximity to colitis.
Figure 3.2. CLINICOPATHOLOGICAL CORRELATION: CYTOMEGALOVIRUS INFECTION. CMV infection is characterized by a superficial perivascular lymphocytic infiltrate in the dermis with prominent vessels. Endothelial cells are large and irregularly shaped with Cowdry B bodies: homogenous amphophilic glassy intranuclear inclusion bodies surrounded by a halo. IHC can detect CMV. A,Low-power view. B, High-power view. Solid arrow: crystalline intranuclear inclusion bodies surrounded by a clear halo (“owl’s eyes”). CMV, cytomegalovirus; HSV, herpes simplex virus; IHC, immunohistochemistry; VZV, varicella zoster virus.
(Histology images courtesy of Anjela Galan, MD.)
Congenital CMV infection classically presents with petechiae, purpura, and vesicles along with extramedullary hematopoiesis (purpuric papules and nodules due to bone marrow dysfunction). It is the leading infectious cause of deafness and intellectual disability in the United States, which may be delayed.
Congenital CMV is in the differential diagnosis of “blueberry muffin” lesions.
Viral culture is the diagnostic gold standard, but more rapid tests include skin biopsy, CMV-specific serologies, assays to detect CMV antigens within leukocytes, and PCR. Diagnosis of cutaneous CMV should prompt ophthalmologic evaluation for chorioretinitis.
Treatment of CMV mononucleosis-like syndrome is supportive. Organs and hematopoietic stem cells from seronegative donors are preferentially transplanted into seronegative recipients. For prophylaxis or treatment of CMV in immunosuppressed patients, IV ganciclovir or oral valganciclovir is first line. Alternatives include cidofovir and foscarnet.
RUBEOLA, RUBELLA, AND ROSEOLA
Rubeola synonyms: 1st disease, 14-day measles, measles
Rubella synonyms: 3rd disease, 3-day measles, German measles
Roseola synonyms: 6th disease, 3-day fever, baby measles, exanthem subitum, roseola infantum
Rubeola reprinted with permission from Lugo-Somolinos A, McKinley-Grant L, Goldsmith LA, et al. VisualDx: Essential Dermatology in Pigmented Skin. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011.
Table 3.6. RUBEOLA, RUBELLA, AND ROSEOLA
Diagnosis
Classic description
Rubeola
Exanthem: cephalocaudal spread of erythematous macules and papules coalescing into patches and plaques.
Enanthem: gray papules on buccal mucosa (Koplik spots) precede the exanthem.
Systemic features: myocarditis, fever, lymphopenia, encephalitis ± subacute sclerosing panencephalitis, conjunctivitis, coryza, cough.
The “3 Cs” of rubeola are conjunctivitis, coryza, and cough.
Rubella
Exanthem: morbilliform eruption.
Enanthem: palatal petechiae (Forchheimer spots).
Systemic features: mild prodrome. tender lymphadenopathy (occipital, postauricular, cervical).
Roseola
Exanthem: circular to elliptical red macules or papules ± white halo favoring the trunk > extremities.
Enanthem: red papules on the soft palate and uvula (Nagayama spots).
Systemic features: sudden-onset high fever ± seizures (exanthem begins as fever subsides).
The exanthem of roseola is “rose red.”
Rubeola is due to morbillivirus; rubella is due to rubella virus; and roseola is due to HHV-6 and HHV-7. Rubella may present as a congenital infection. The highest risk of complications occurs with primary infection in the first trimester.
Rubeola, rubella, and roseola are summarized in Table 3.6. Congenital rubella classically presents with petechiae, purpura, and vesicles along with extramedullary hematopoiesis. Complications include cardiac defects, hepatosplenomegaly, cataracts, and deafness.
Congenital rubella is in the differential diagnosis of “blueberry muffin” lesions.
Rubella has been associated with granulomatous eruptions in immunocompromised patients. HHV-6 and HHV-7 infection has been associated with PR and reactivation has been implicated in DRESS syndrome.
Rubeola, rubella, and roseola exanthems have nonspecific histopathology.
Rubeola, rubella, and roseola can be diagnosed with serologies for IgM/IgG or PCR.
The measles, mumps, rubella (MMR) vaccine is the cornerstone of prevention. Unfortunately, there has been a resurgence of outbreaks with increased vaccine hesitancy. Treatment is supportive, which may involve vitamin A supplementation for acute rubeola.
 WART Synonym: verruca → Diagnosis Group 1 Focal epithelial hyperplasia. |
A wart is an infection caused by HPV. Alpha HPV types are generally involved with clinically evident papillomas (less so with beta and gamma types).
The HPV genome includes E (early) and L (late) genes, encoding respective gene products important for early (replication and growth) and late (capsid) parts of the HPV life cycle. E6 binds to and promotes the degradation of P53, thereby abrogating its tumor suppressor function. E7 binds to RB, leading to de-repression of E2F family transcription factors and cell division. The affinity of E7 for Rb may explain the increased oncogenic behavior in higher risk (16, 18) vs lower risk (6, 11) HPV types.
Table 3.7. WART VARIANTS
Varianta
HPV typesa
Classic description
Notes
Common wart (verruca vulgaris)
1, 2, 4
Verrucous papule favoring the hands and fingers, including periungual.
Flat wart (verruca plana)
3, 10
Flat topped skin colored papules, often in linear array, favoring the face and dorsal hands.
Triggered by sun exposure.
Focal epithelial hyperplasia (Heck disease)
13, 32
Oral mucosal flat warts.
Recurrent respiratory papillomatosis
6, 11
Hoarseness, stridor.
Genital wart (condyloma acuminatum)
6, 11
Skin colored or white exophytic papillomas on anogenital skin; may be discrete or coalesce.
Most common STD.
Flat genital wart (condyloma plana)
2, 4
Subtle skin colored sessile papillomas on anogenital skin.
Butcher wart
2, 7
Verrucous papules favoring the hands and fingers.
Palmoplantar wart (verrucae palmares et plantares)
1, 2, 27, 57
Thick endophytic papules and plaques on the palms and soles.
a Illustrative examples provided.
HPV, human papillomavirus; STD, sexually transmitted disease.
Transmission of nongenital HPV types occurs via skin-skin contact and indirect contact with fomites. Sexual transmission of genital warts may occur.
In infants, the most common mode of HPV transmission is vertical.
As HPV is primarily controlled by cell-mediated immunity, extensive warts may be observed in HIV-infected and other immunocompromised patients. For example, anal HPV is present in >90% of HIV-infected men who have sex with men (MSM), and there is a 30- to 50-fold higher risk of anal cancer.
Warts are associated with hereditary immunodeficiency syndromes including epidermodysplasia verruciformis (EDV); hyper-IgM syndrome; warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM); and warts, immunodeficiency, lymphedema, dysplasia (WILD).
Wart variants are summarized in Table 3.7.
Focal epithelial hyperplasia is more common in children than in adults.
Warts can pseudo-koebnerize, which describes local spread at sites of cutaneous trauma.
There is a risk of malignant degeneration into verrucous carcinoma and SCC/cervical cancer/vulvar cancer/vaginal cancer/penile cancer/anal cancer. The risk is governed by HPV type (see Chapter 5: Epidermal Neoplasms) and depth of dysplasia.
 Figure 3.3. CLINICOPATHOLOGICAL CORRELATION: WART. A and B, Common wart. C and D, Flat wart. E and F, Genital wart. G and H, Palmoplantar wart. (G, Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015. H, Histology images courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.) • Common wart: compact hyperkeratosis, parakeratosis on peaks alternating with hypergranulosis in valleys, acanthosis, and papillomatosis (exophytic). Koilocytes (vacuolated cells with hyperchromatic nuclei) are pathognomonic for wart but variably present. • Flat wart: hyperkeratosis, hypergranulosis, acanthosis, and vacuolated keratinocytes. • Focal epithelial hyperplasia: hyperkeratosis, parakeratosis, and epithelial pallor. • Genital wart: hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, papillomatosis, and vacuolated keratinocytes (exophytic). • Palmoplantar wart: compact hyperkeratosis, eosinophilic cytoplasmic inclusion bodies, and eosinophilic nuclear inclusion bodies (endophytic). Flat wart differs from common wart due to the “basket weave” stratum corneum and absence of parakeratosis and papillomatosis. Palmoplantar wart is called “myrmecia” based on its resemblance to an “ant hill.” |
The differential diagnosis of wart includes calluses and corns, molluscum contagiosum, seborrheic keratosis (SK), actinic keratosis (AK), SCCis, and SCC. Condyloma lata may mimic genital warts.
Detection of subtle genital HPV infection can be performed with 5% acetic acid treatment, which leads to whitening of lesions (though not specific).
Skin biopsy may be helpful in unclear cases.
Destructive therapies are the most commonly utilized. Homebased therapies include salicylic acid (typically first line) along with podophyllotoxin, retinoids, and sinecatechins. Officebased therapies include cryotherapy (typically first line) along with cantharidin, podophyllin, intralesional 5-FU or bleomycin, electrosurgery, shave removal, high-concentration TCA, and PDL and CO2 lasers. Immunotherapies include imiquimod (typically first line) and intralesional candida antigen.
Spontaneous clearance of common warts is seen in 70% to 75% of children within 2 years.
Vaccines targeting L1 capsid protein are incredibly effective at preventing the neoplastic sequela of HPV infection. There are three FDA-approved vaccines: Cervarix vaccine (HPV 16, 18); Gardasil 4-valent vaccine (HPV 6, 11, 16, 18); and Gardasil 9-valent vaccine (HPV 6, 11, 16, 18, 31, 33, 45, 52, 68). The Gardasil 9-valent vaccine is approved for males and females ages 9 to 45 years. Vaccines can be administered regardless of history of abnormal Papanicolaou (PAP) smear.
Calluses emphasize dermatoglyphs, whereas warts and corns interrupt them. Paring of a wart will reveal thrombosed capillaries, whereas paring of a callus will reveal layers of yellow keratin and paring of a corn will reveal a yellow core.
SPOTLIGHT ON EPIDERMODYSPLASIA VERRUCIFORMIS
EDV is an AR hereditary disorder due to EVER1 and EVER2 mutations. Evidence suggests that EVER1- and EVER2-encoded proteins function as keratinocyte-specific restriction factors antagonizing HPV replication. The predominant oncogenic HPV subtypes are HPV 5 and 8.
EDV can be acquired in the setting of HIV infection.
EDV is characterized by flat topped, scaly white or red/brown papules and plaques with variable verrucous change. EDV warts typically favor sun-exposed areas but often generalize. 30% to 50% of patients develop skin cancers (typically SCC).
Skin biopsy may be helpful to establish the diagnosis.
Patients should be counseled regarding sun protection. Treatment options for EDV warts are analogous to other warts; however, the widespread distribution presents a challenge.
 MOLLUSCUM CONTAGIOSUM → Diagnosis Group 1 |
 Figure 3.4. CLINICOPATHOLOGICAL CORRELATION: EPIDERMODYSPLASIA VERRUCIFORMIS. Flat warts in EDV are characterized by hyperkeratosis, hypergranulosis, acanthosis, and vacuolated keratinocytes with swollen abundant bluegray cytoplasm. A, Low-power view. B, High-power view. EDV, epidermodysplasia verruciformis. |
Molluscum contagiosum is a common self-limited infection due to molluscipox. Poxviruses use the IL-18-binding protein to suppress the Th1 response.
Transmission of molluscum contagiosum primarily occurs via skin-skin contact and indirect contact with fomites. Sexual transmission may occur.
Molluscum contagiosum is frequently observed in children with AD and other disorders of skin barrier function; however, it is also observed in HIV-infected and other immunocompromised patients. While molluscum contagiosum virus 1 (MCV-1) is the most common subtype overall, MCV-2 is the most common subtype in HIV-infected patients.
Molluscum contagiosum classically presents with shiny skincolored umbilicated papules. Lesions may occur anywhere on body but have a predilection for skin folds. Extensive facial/genital involvement and giant mollusca are observed in HIV-infected and other immunocompromised patients. A Gianotti-Crosti syndrome-like reaction has been reported.
Molluscum contagiosum can pseudo-koebnerize.
Molluscum dermatitis refers to lesional attack by the host immune response, which causes papules to become inflamed and acquire a pustular component with surrounding dermatitis.
Molluscum contagiosum has also been associated with conjunctivitis.
Poxvirus infections are summarized in Table 3.8.
The differential diagnosis of molluscum contagiosum includes JXG, wart, and pyogenic granuloma (PG). In immunocompromised patients, opportunistic fungal infections with molluscum contagiosum-like lesions include coccidioidomycosis, cryptococcosis, histoplasmosis, and penicilliosis.
Dermoscopy reveals central umbilication with polylobular white-yellow amorphous structures surrounded by arborizing vessels.
Diagnostic tests for molluscum contagiosum include:
Tzanck smear or KOH: reveals monomorphic, cuboidal, pathognomonic 30 to 35 µm virally transformed cells.
Skin biopsy: helpful in unclear cases.
Treatment of molluscum contagiosum is similar to wart. While curettage remains the most direct and effective treatment, compliance can be challenging in pediatric patients.
Reversal of skin barrier dysfunction can help prevent autoinoculation and spread of molluscum contagiosum through scratching.
Table 3.8. POXVIRUS INFECTIONS
Diagnosisa
Virus
Classic description
Notes
Molluscipox
Molluscum contagiosum
See above.
Orthopoxvirus
Variola (smallpox)
Variola virus
Papules progress to vesiculopustules (same stage of development) and crust over leaving behind pitted scars. The distribution favors the face, trunk, and extremities including the palms and soles and the mucosa. Systemic features include fever, lymphadenopathy, arthritis, encephalitis, panophthalmitis, and pneumonitis.
Animal reservoir: humans.
Individuals at high risk of exposure include military personnel and health care workers.
Potential bioterrorism agent.
Incubation period 7-17 days. Vaccinia vaccination is the cornerstone of prevention. Antivirals include tecovirimat.
Vaccinia
Vaccinia virus
Resembles variola at the vaccine injection site.
Animal reservoir: humans.
For mucocutaneous adverse events of the vaccine, see Chapter 6: Immunosuppressants and Immunomodulators.
Monkeypox
Monkeypox virus
Resembles variola (multiple stages of development), often involving the face, chest, hands, feet, oral cavity, and anogenital area.
Animal reservoirs: humans, monkeys, rodents. JYNNEOS is a preventative vaccine. Tecovirimat is indicated for severe disease and high-risk patients
Cowpox
Cowpox virus
Resembles variola.
Animal reservoirs: humans, cats, cattle (rare), rodents.
Parapox
Orf (contagious pustular dermatosis, ecthyma contagiosum, infectious pustular dermatosis)
Orf virus
Six clinical stages (maculopapular, targetoid, weeping nodule, regenerative dry stage with black dots, papillomatosis, regression with a dry crust, evolves into a crusted nodule prior to resolution). The distribution favors the hands. Systemic features include fever and lymphadenopathy/lymphangitis.
Animal reservoirs: humans, goat, reindeer, sheep (vaccine in livestock can lead to human transmission).
Lives in soil for 6 months.
Self-limited over 7-10 weeks.
Paravaccinia (milker’s nodule, pseudocowpox)
Paravaccinia virus
Resembles an isolated orf lesion.
Animal reservoirs: cattle, humans.
a Illustrative examples provided.
Figure 3.5. SIDE-BY-SIDE COMPARISON: MOLLUSCUM CONTAGIOSUM AND ORF. Both molluscum contagiosum and orf are characterized by inclusion bodies. Inclusion bodies in molluscum contagiosum (Henderson-Patterson bodies, molluscum bodies) are eosinophilic-to-basophilic and cytoplasmic. Inclusion bodies in orf are eosinophilic and either cytoplasmic or intranuclear. A, Molluscum contagiosum. Solid arrow: eosinophilic cytoplasmic inclusion body. B, Orf. Dashed arrow: eosinophilic cytoplasmic inclusion body.
(A, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.)
Eosinophilic cytoplasmic inclusion bodies (Guarnieri bodies) ± eosinophilic intranuclear inclusion bodies are also present in variola and other poxvirus infections.
ERYTHEMA INFECTIOSUM
Synonyms: 5th disease
Reprinted with permission from Burkhart CN, Morrell DS, Goldsmith LA, et al. VisualDx: Essential Pediatric Dermatology. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009.
Erythema infectiosum is due to parvovirus B19. Transmission primarily occurs via respiratory droplets but also via blood and other secretions. It peaks in children during the winter and spring. Through vertical transmission, parvovirus B19 may also present as a congenital infection (hydrops fetalis), with the highest risk of fetal death in the second trimester.
Erythema infectiosum classically presents with bright red macular erythema over the cheeks followed by a lacy eruption of the extremities (signals conversion of IgM to IgG and an end to the infectious state). The enanthem is characterized by erythema of the tonsils and pharynx. There is a risk for aplastic crisis, especially in patients with hereditary spherocytosis and patients on dapsone. Symmetrical polyarthritis can be observed with or without rash. Hydrops fetalis results in abnormal fluid buildup in fetal compartments and is associated with anemia and high-output CHF.
The colloquial name for erythema infectiosum is “slapped cheek disease.”
Papular purpuric gloves and socks syndrome (see above) is a distinct presentation of parvovirus B19 infection that primarily occurs in adolescents and young adults. Unlike the lacy eruption in erythema infectiosum, patients are infectious.
Erythema infectiosum has nonspecific histopathology.
CBC typically reveals leukopenia and anemia with decreased reticulocyte count due to transient effects of parvovirus B19 on erythroid progenitors. If a pregnant woman is exposed, check IgM and IgG levels.
Treatment of erythema infectiosum is supportive. Aplastic crisis may require blood transfusion.
CORONAVIRUS DISEASE 2019
Coronavirus disease 2019 (COVID-19) is due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since its emergence in 2019, the COVID-19 global pandemic has resulted in the deaths of over 6 million people and counting.
One report found that 20% of hospitalized patients had a skin rash attributed to SARS-CoV-2. Analysis of 171 cases in the international registry from the AAD and International League of Dermatological Societies with laboratory-confirmed COVID-19 revealed the most common morphologies to be morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%). Pernio-like lesions affected patients with mild disease, whereas retiform purpura affected ill, hospitalized patients. The association between pernio-like lesions and COVID-19 remains controversial as only a minority of these patients have laboratory-confirmed COVID-19. Alternate hypotheses include changes in behavior during quarantine (eg, not wearing socks and shoes).
Pernio-like skin lesions may occur in interferonopathies such as familial chilblain lupus, Aicardi-Goutières syndrome, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, and SAVI. Because these lesions are attributed to systemic elevations in type I IFN signaling, COVID-19-associated perniolike lesions have been hypothesized to result from a similar underlying pathophysiology.
Pernio-like lesions related to SARS-CoV-2 share the histopathological features of pernio. However, some studies have identified unique features including tight cuffing of lymphocytes around vessels and Spike glycoprotein detection by IHC.
Lymphopenia is the most common laboratory finding. Diagnosis of COVID-19 requires detection of SARS-CoV-2 RNA or antigen in respiratory specimens.
Vaccination is the cornerstone of prevention. Antivirals include nirmatrelvir with ritonavir, remdesivir, and molnupiravir. Antithrombotic therapy may be indicated in select patients. Clinical trials are ongoing.
DENGUE
Dengue is due to dengue virus, an arbovirus transmitted by Aedes mosquitoes. Dengue is most common in Asia and the Caribbean; however, geographic shifts are occurring due to climate change.
50% of dengue patients develop a morbilliform eruption sparing discrete areas of skin. Asymptomatic and mild cases manifest with a nonspecific viral syndrome. Classical dengue fever leads to arthralgias, myalgias, headaches, and retroorbital pain. Prior infection from a different viral serotype can predispose patients to dengue hemorrhagic fever (shock, hemorrhage, confusion, respiratory distress) mediated by nonneutralizing antibodies against the prior viral serotype.
Skin lesions in dengue may be described as “white islands in a sea of red.”
Dengue has nonspecific histopathology.
Diagnostic tests include serologies or PCR. Other arboviruses that cause morbilliform eruptions include West Nile virus (transmitted by Culex mosquitoes, associated with encephalitis), zika virus (transmitted by Aedes mosquitoes and as a sexually transmitted disease [STD]), and chikungunya virus (transmitted by Aedes mosquitoes, associated with arthritis).
Zika may present as a congenital infection resulting in microcephaly.
Skin application of diethyltoluamide (Deet) is widely used for protection from biting arthropods including mosquitoes. Treatment is supportive.
 HAND-FOOT-MOUTH DISEASE → Diagnosis Group 2 |
The most common enterovirus serotypes to cause hand-footmouth disease (HFMD) are coxsackieviruses A16 and A10 and enterovirus 17. The recent emergence of HFMD caused by highly infective coxsackievirus A6 has led to several large outbreaks in the United States and worldwide.
Initial infection occurs in the oropharynx or gut and subsequently spreads to other organs in a viremic phase of illness. Transmission may occur via the fecal-oral route or respiratory droplets. The incubation period is up to 6 days.
HFMD is more likely to affect children and is primary observed in the summer and early fall. However, HFMD caused by coxsackievirus A6 has also been observed in the winter.
While HFMD caused by coxsackievirus A6 is overall more common in children, it may also affect adults.
HFMD classically presents with oral vesicles or erosions on a red base along with elliptical grayish vesicles or pustules favoring the buttocks, hands, and feet. The rash follows the fever by 1 to 2 days.
The elliptical lesions of HFMD resemble American “footballs.” “Hand-foot-mouth-butt” disease would be a more accurate descriptor.
Complications include eczema coxsackium and onychomadesis (nail shedding) after 1 to 2 months.
HFMD caused by coxsackievirus A6 is characterized by an atypical, more widespread, eruption with vesicular and bullous lesions.
HFMD histopathology demonstrates ballooning and reticular degeneration of keratinocytes.
The differential diagnosis of HFMD includes herpangina. This infection, due to group A and B coxsackieviruses and echovirus, classically presents with painful gray vesicles on the palatal, buccal, and tonsillar mucosa. Other mimickers include autoimmune blistering disorders, EM, herpes simplex, varicella, disseminated herpes zoster, and Gianotti-Crosti syndrome.
Skin biopsy may be helpful in unclear cases.
HFMD self-resolves in 1 to 2 weeks. Treatment is supportive.
Eczema herpeticum and eczema coxsackium can have a similar clinical appearance. Generally, evaluation for both entities is recommended. Eczema coxsackium does not respond to antivirals that target HSV.
 Figure 3.6. ONYCHOMADESIS. Onychomadesis (nail shedding) describes detachment of the nail plate from the proximal nail fold. It occurs most often due to mechanical or friction injury; however, involvement of multiple nails may indicate a systemic insult (eg, antecedent HFMD). HFMD, hand-foot-mouth disease. |
Bacteria are single-celled organisms that have evolved to inhabit nearly all environments on the planet. They can be broadly separated into groups on the basis of staining pattern under the microscope:
Gram-positive (GP) bacteria possess a thick peptidoglycan layered cell wall and lack an outer cell membrane layer. They stain purple on Gram stain.
Gram-negative (GN) bacteria only possess a very thin peptidoglycan layer in addition to an outer membrane. They stain red on Gram stain.
Acid-fast bacilli (AFB) require special stains given the lipid content of their cell wall. Nocardia are partially acidfast GP bacteria not considered AFB.
Though traditionally considered pathogenic, there is a growing appreciation for the essential homeostatic interplay between commensal bacteria of the skin and gut and how the microbiome impacts human health. The normal skin flora is colonized by aerobic cocci, aerobic and anaerobic corynebacteria, GN bacteria, and yeast in homeostatic conditions; however, dysbiosis develops in pathogenic states and has been implicated as a potential cause or cofactor in skin diseases (eg, S. aureus in AD; GAS species in guttate psoriasis and EN).
Bacterial classification (for dermatology-relevant bacteria) is summarized in Table 3.9.
Table 3.9. BACTERIAL CLASSIFICATION | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 IMPETIGO → Diagnosis Group 1 |
Impetigo is the most common skin infection in children. It is primarily due to Staphylococcus > GAS species; however, group B Streptococcus (GBS) is an important cause of impetigo in neonates.
Staphylococcus species are facultative aerobic catalasepositive gram-positive cocci (GPCs). S. aureus, a common pathogen, is divided into methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). Methicillin resistance primarily arises due to staphylococcal chromosome cassette (SCC) mec, specifically the mecA gene encoding the alternative penicillin-binding protein (PBP) 2α. Panton-Valentine leukocidin (PVL) is a MRSA virulence factor.
GAS species are facultative aerobic GPCs. M proteins are GAS virulence factors that can prevent phagocytosis, among other functions.
Impetigo is contagious through both direct and indirect contact. While nasal carriage of S. aureus is the major risk factor, pharyngeal, axillary, and perineal carriage also increases risk. Other risk factors include AD, skin injury, contact sports, warm and humid climates, and poor hygiene.
There are two major types of impetigo:
Nonbullous impetigo: 70% of cases.
Bullous impetigo: due to S. aureus phage II types 55 or 71 that express exfoliative toxin (ET)-A (chromosome) and ET-B (plasmid), which cleave desmoglein 1 in the granular layer causing acantholysis and a subcorneal split.
Do NOT confuse ecthyma with ecthyma gangrenosum.
The classic presentation of impetigo varies based on type:
Nonbullous: erythematous macules that evolve into eroded vesicles or pustules with golden crust.
The Latin word aureus means “golden.” Golden crust in impetigo is alternatively called “honey-colored crust.”
Bullous: small vesicles that evolve into superficial bullae, eventually giving rise to larger flaccid bullae that rupture leaving behind a collarette of scale.
Ecthyma: ulcer with a necrotic base and surrounding erythema favoring the lower extremities.
Ecthyma has a “punched out” appearance.
Impetigo favors the face but may also affect the anogenital area. In infants, impetigo is in the differential diagnosis for diaper dermatitis.
Complications of impetigo include poststreptococcal glomerulonephritis (GAS); risk is not altered with antibacterial therapy.
 Figure 3.7. CLINICOPATHOLOGICAL CORRELATION: IMPETIGO. Impetigo is characterized by GPCs within small neutrophilic vesiculopustules in the epidermis and a superficial mixed infiltrate in the dermis. DIF, direct immunofluorescence; GPCs, gram-positive cocci; PF, pemphigus foliaceous; SSSS, staphylococcal scalded skin syndrome. (Reprinted with permission from Husain AN, Stocker JT, Dehner LP. Stocker and Dehner’s Pediatric Pathology. 4th ed. Wolters Kluwer; 2015.) • Bullous impetigo: subcorneal split with acantholysis. • Ecthyma: GPCs within neutrophilic crust overlying an ulcer and a neutrophilic infiltrate in the dermis |
The differential diagnosis of nonbullous impetigo includes eczematous dermatitis, herpes simplex, varicella, tinea, candidiasis, and arthropod bites. The differential diagnosis of bullous impetigo further includes autoimmune bullous disorders (eg, PF) and SSSS.
Diagnostics include Gram stain and bacterial culture.
Topical antibacterial therapy is first line (eg, bacitracin, mupirocin, retapamulin) for most cases.
Polymyxin B is NOT a treatment for impetigo.
Oral antibacterial therapy can be employed for a 7-day course if infection is extensive (eg, dicloxacillin, cephalexin). For MRSA, oral options include TMP-SMX, clindamycin, linezolid, and tetracyclines and IV options include daptomycin and vancomycin.
S. aureus decolonization is indicated for recurrent disease.
Culture-positivity for S. aureus from the bullae distinguishes bullous impetigo from SSSS.
STAPHYLOCOCCAL SCALDED SKIN SYNDROME
Synonym: 4th disease, Ritter disease
SSSS is due to S. aureus phage II types 55 or 71. ET-A and ET-B cleave desmoglein 1 in the granular layer causing acantholysis and a subcorneal split. In SSSS, the clinical features are due to hematogenous spread of the toxins, whereas bullous impetigo is due to local toxin-mediated effects. Infants and young children are at highest risk of SSSS due to lack of toxin-neutralizing antibodies and relatively decreased renal toxin clearance.
At-risk adult populations for SSSS include those with renal disease and immunosuppression.
SSSS classically presents with skin tenderness and a prodrome of constitutional symptoms including fever and either rhinorrhea or conjunctivitis. Erythema first occurs on the head and intertriginous areas before generalizing. Formation of superficial flaccid bullae leads to a wrinkled appearance and a positive Nikolsky sign. Periorificial crusting and radial fissuring is characteristic. There is no mucosal involvement. Re-epithelialization without scarring occurs in 1 to 2 weeks.
In SSSS, an unhappy child with superficial flaccid bullae leading to a wrinkled appearance is sometimes described as having “sad man facies.” Periorificial crusting may resemble a child after dunking their face in a bowl of oatmeal.
A helpful clue to distinguish SSSS from SJS/TEN is absence of mucosal involvement. “Jelly roll” preparation will show an intraepidermal split. Bacterial cultures should be obtained from the conjunctivae, nasopharynx, perianal area, and/or injured skin. Blood cultures are typically negative in children but can be positive in adults.
The mortality rate for SSSS in children is low (<4%). Age < 5 years is the most important prognostic factor. SSSS is treated with a penicillinase-resistant penicillin (eg, dicloxacillin) or cephalexin plus clindamycin (clindamycin is added to target toxin production). In severe cases, IV fluids are used to correct insensible losses. S. aureus decolonization is indicated after acute treatment.
The mortality rate for SSSS in adults is up to 60%.
SCARLET FEVER
Synonym: 2nd disease, scarlatina
Reprinted with permission from Sherman SC, Cico SJ, Nordquist E, et al. Atlas of Clinical Emergency Medicine. Wolters Kluwer; 2016.
Scarlet fever is due to GAS species, typically pharyngitis or tonsillitis, and is mediated by streptococcal pyrogenic exotoxin (SPE)-A, SPE-B, and SPE-C. It most commonly affects children 1 to 10 years old during the fall, winter, and spring months in temperate climates.
Scarlet fever occurs in children learning their “A, B, Cs” (SPE-A, SPE-B, SPE-C).
Table 3.10. REVISED JONES CRITERIA FOR ACUTE RHEUMATIC FEVERa
Major Criteria
Carditis
Polyarthritis
Chorea
Subcutaneous nodules
Erythema marginatum
Minor Criteria
aEvidence of streptococcal infection and two major or one major and two minor criteria are required for diagnosis. CRP, C-reactive protein; ECG, electrocardiogram; ESR, erythrocyte sedimentation rate.
Scarlet fever classically presents with sore throat, malaise, nausea, and fevers 1 to 2 days prior to the skin eruption. The skin eruption is characterized by macular erythema of the neck, chest, and axillae, which generalizes to small papules. Other clinical features include circumoral pallor and Pastia lines (linear petechial streaks in body folds). Palmoplantar and fingertip desquamation may occur ≥1 week after the skin eruption. The enanthem includes Forchheimer spots on the soft palate and a tongue that is initially white with red papilla followed by evolution into a bright red appearance. Complications of scarlet fever include rheumatic fever and poststreptococcal glomerulonephritis. The revised Jones criteria for acute rheumatic fever are presented in Table 3.10.
Colloquial descriptions of scarlet fever include “sandpaper skin” and “strawberry tongue.”
Scarlet fever is characterized by perifollicular dilated capillaries and lymphatics, dermal edema, perivascular neutrophilic infiltrates, and hemorrhagic foci. The desquamative stage is characterized by parakeratosis and spongiosis.
CBC frequently shows leukocytosis with a left shift. Nasal and/or throat bacterial cultures are the gold standard for GAS diagnosis, but antigen and RT-PCR-based approaches are increasingly employed. ASO and anti-DNase B or streptozyme titer can be used for confirmation of recent GAS infection.
Penicillin or amoxicillin for 10 to 14 days is the typical treatment.
TOXIC SHOCK SYNDROME
Reprinted with permission from Engleberg NC, DiRita V, Dermody TS. Schaechter’s Mechanisms of Microbial Disease. 5th ed. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2012.
TSS is due to superantigens that crosslink the Vβ region of TCR on T-cells and MHC II on APCs resulting in nonspecific polyclonal activation of large T-cell populations in affected hosts and significant cytokine elaboration. TSS typically affects young healthy individuals. TSS can be divided into two groups:Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
