KANDIDIASIS MULUT

Overview
Background
Candidiasis describes a group of fungal infections involving the skin and mucous membranes.
Infection is caused by Candida species, primarily Candida albicans. [1] C albicans is a dimorphic
fungus that can asymptomatically colonize the oral or genital mucosae in healthy individuals. [2]
Oral colonization is estimated in 50% of healthy adults, [3] while genital colonization is seen in 21%
of women. [4] When the local ecology is disturbed, or where there is an immune defect, Candida
overgrowth may lead to an opportunistic infection. The mucosal surfaces primarily affected by
candidiasis are the oral cavity, esophagus, angles of the mouth, and genitals (causing
vulvovaginitis in females, balanitis in males).

Oral candidiasis may present as either white or erythematous lesions and either an acute or
chronic infection. [5] Thus, the presentations can be divided into the following four subtypes:

 Acute pseudomembranous candidiasis (thrush): The classic multiple white-flecks on the

tongue, buccal mucosa, and palate
 Chronic hyperplastic candidiasis: Thick white plaques on the buccal mucosa and labial
commissures
 Acute atrophic (erythematous) candidiasis: Erythematous patches on the palate
 Chronic atrophic candidiasis (denture stomatitis): A form of erythematous candidiasis,
resulting from poorly fitted dentures causing a burning, sore mouth

There are also conditions that may predispose individuals to chronic, multifocal infections from
Candida. This can lead to syndromes such as chronic mucocutaneous candidiasis (CMC).

Pathophysiology
C albicans is a dimorphic fungus that asymptomatically inhabits the mouths of almost 50% of
the population. Overgrowth of Candida is protected against by local T cells and interleukin (IL)–
17. [6] Thus, when immunity is compromised, growth proceeds unchecked and leads to
opportunistic infections.

Candidiasis is seen in people with altered ecology, which in oral cases can be attributed to dental
appliances, xerostomia, antimicrobials, nasopharyngeal steroids, or oral cancer. Impaired
systemic immunity is another major cause of infection, notably in patients who are on
immunosuppressive therapy, infected by HIV, or have diabetes. [7, 8]

C albicans is the predominant causal organism of most candidiasis. Other species, such as
Candidatropicalis and Candidastellatoidea, more often appear in persons who are severely
immunocompromised.
Secreted aspartyl proteinases (SAPs) are proteins secreted by Candida that contribute to
virulence by facilitating invasion and inflammation. The prevacuolar protein sorting gene, VPS4,
is required for extracellular secretion of SAPs, and it is a key component of the virulence of
Candida. [9] Additionally, studies have shown that women with vulvovaginal candidiasis have
higher levels of SAPs in their vaginal fluid. [10]

In those with dental devices, Candida, upon attachment, can form a small subcolony of persister
cells. These cells have been shown to be highly resistant to antimicrobials, and they provide a
mechanism for the recurrent formation of biofilms. [11]

Chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis (CMC) describes a group of rare syndromes, in which

persistent mucocutaneous candidiasis responds poorly to topical treatment. It is associated with
immune defects, particularly in T-cell, dendritic cell, and T-helper 17 (Th17) cell function.
Studies have demonstrated specific signals that when compromised, cause defects in the
response to candidal antigens. Identified defects include overproduction of IL-6, underproduction
of IL-23, and deficiency of IL-17.

Epidemiology
Risk factors

There are many risk factors that increase the incidence of candidiasis. Immunosuppression is the
most significant of these, and it can be due to diabetes, antibiotics, immunosuppression, systemic
steroid use, and HIV infection, among others.

 Immunocompromise: Increased carriage rates are seen in several conditions, including

HIV infection, diabetes, systemic steroid use, aerosolized steroid use,
immunosuppression, and malignancy
 Hyposalivation: Increases carriage of Candida and can be due to drug effects
(antipsychotics), Sjögren syndrome, radiotherapy, or chemotherapy
 Poor oral hygiene: Candida counts increase during sleep but are reduced by eating and
brushing the teeth
 Dentures: Removal and reinsertion of dentures cause increases in salivary candidal
counts, suggesting that plaque on the dentures harbors C albicans
 Missing teeth: Being edentulous increases the overlap of skin at the corners of the mouth,
increasing the risk for angular cheilitis formation
 Smoking: Increases Candida carriage by 30-70%
 Antibiotic use: Increases carriage of Candida
 Vitamin deficiencies: Higher association of candidiasis with vitamin B-12 and iron
deficiency

Prognosis
The prognosis is good for most infections in the immunocompetent host, but in patients who are
immunocompromised, antifungal resistance is commonplace. Oral candidiasis may predispose
individuals to esophageal spread. Systemic spread is rare, but can occur in the severely
immunocompromised.

Physical Examination
Acute pseudomembranous candidiasis (thrush)

White patches on the surface of the oral mucosa, tongue, or other parts of the body characterize
thrush. Lesions develop into confluent plaques that resemble milk curds that when removed,
reveal a raw, erythematous, and sometimes bleeding base.

Pseudomembranous candidiasis.

Chronic hyperplastic candidiasis

This is characterized by thick, white plaques on the buccal mucosa or the tongue that are hard or
rough to the touch. Unlike the lesions of acute pseudomembranous candidiasis (thrush), the
lesions of chronic hyperplastic candidiasis are more adherent and difficult to scrape off. [5]

Homogeneous or speckled areas, which do not rub off (nodular lesions), can be seen. Speckled
leukoplakia accounts for 3-50% of candidal leukoplakias. [12]

Acute atrophic (erythematous) candidiasis

Erythematous areas on the dorsum of the tongue, palate, or buccal mucosa are characteristic.
Lesions on the dorsum of the tongue present as depapillated areas. Angular stomatitis may also
be present. In those taking antimicrobials, a sore red mouth, especially of the tongue, may be
present.

Chronic atrophic candidiasis (denture stomatitis)

Chronic erythema and edema of the mucosa that contact the fitting surface of the denture are
characteristic, causing soreness and burning. The mucosa below the lower denture rarely is
involved. It may co-present with angular cheilitis.

Denture-related stomatitis; a common

form of oral candidiasis.

Denture-related stomatitis is classified into three clinical types as follows:

 Localized inflammation or a pinpoint hyperemia

 Generalized erythema involving a part of, or the entirety of, denture-covered mucosa
 Granular type (inflammatory papillary hyperplasia) commonly involving the central part
of the hard palate and the alveolar ridge: Hyperplasia of oral mucosa can be seen

Angular stomatitis (perlèche, angular cheilitis)

This is a subset of erythematous candidiasis. Lesions affect the angles of the mouth, causing
soreness, erythema, and fissuring. Both yeasts (candidal) and bacteria (especially Staphylococcus
aureus) may be involved.
 Angular cheilitis; a common form of
oral candidiasis, typically seen in patients with denture-related stomatitis, especially those in
whom the denture needs adjustment. In others, it may be a sign of diabetes, nutritional deficiency,
or immune defect.

Angular cheilitis is not specific for mucosal candidiasis. It can also be seen with vitamin B-12 or
iron deficiency, Down syndrome, orofacial granulomatosis, Crohn disease, HIV infection, or
diabetes.

Median rhomboid glossitis (glossal central papillary atrophy)

This is also a subset of erythematous candidiasis. Median rhomboid glossitis is an erythematous,

atrophic lesion on the dorsum of posterior tongue. It is most frequently seen in those who smoke
or have HIV infection.

Differential Diagnoses
 Aphthous Stomatitis
 Chemical Burns
 Denture Stomatitis
 Dermatologic Manifestations of Oral Leukoplakia
 Fordyce Spots
 Graft Versus Host Disease
 Leukoplakia and Erythroplakia - Premalignant Squamous Lesions of the Oral Cavity
 Lichen Planus
 Pernicious Anemia

Approach Considerations
Diagnosis begins with a thorough history and physical examination.
Patients should be asked about immunosuppressive agents (local and systemic), antibiotics, other
opportunistic infections, risky sexual contact, and dental procedures. Patients should be asked
about difficulty or pain with swallowing, which can be an indication of esophageal spread.
During the physical examination, directly visualize the lesions by examining all areas of the
mouth or genitals.

Depending on the severity of the infection, potassium hydroxide (KOH) preparation, culture, and
antimicrobial sensitivities should be done to confirm the diagnosis.

Laboratory Studies
The initial test for Candida infection is usually cytologic examination by scraping a lesion and
placing the sample on a slide. Application of 10% KOH and applying gentle heat lyses host cells
and allows for visualization of the organism. Candida presents with pseudohyphae and budding
yeasts. In patients with chronic or recalcitrant disease, culture may be performed to confirm the
diagnosis and identify resistant organisms. Susceptibility to antifungals can also be obtained and
may be useful in the cases of treatment-resistant, recurrent, or immunosuppressed-associated
infections. [13]

As tests of humoral immunity, the Candida agglutinin test, Candida complement-fixation test,
Candida precipitin test, immunofluorescence, and enzyme-linked immunoassay (ELISA) are
available options. Immunity in superficial candidiasis and in oral candidiasis is predominantly
cell mediated. Delayed skin hypersensitivity to antigens and in vitro tests of cellular immunity
can demonstrate cell-mediated immunity to candidal antigens.

In suspected cases of chronic mucocutaneous candidiasis (CMC), testing for HIV disease,
diabetes, folate, vitamin B-12, ferritin, hemoglobin, and blood cell counts should be performed.
Tests of thyroid or adrenocortical function are warranted in selected individuals, since endocrine
disorders can be associated with oral candidiasis or CMC.

Medical Care
Medical therapies

Medications used to treat candidiasis can be topical or systemic agents, and, in most cases,
therapy is initiated with topical medications. However, severe disease, esophageal involvement,
or inadequate response to topical medications may warrant systemic therapy. The following
treatment recommendations are adapted from the Clinical Practice Guideline for the
Management of Candidiasis from the Infectious Diseases Society of America (IDSA). [14]

Oropharyngeal treatment is as follows:

 Mild: Nystatin suspension four times a day for 1-2 weeks, or 10 mg clotrimazole troche
five times a day for 1-2 weeks
 Moderate to severe: 100-200 mg oral daily fluconazole for 1-2 weeks
  Refractory to fluconazole: 200 mg itraconazole solution once a day for up to 4 weeks
 HIV patients: Antiretroviral therapy strongly recommended
 Dentures: Disinfect dentures along with antifungal therapy
 Chlorhexidine oral rinses may be of some benefit in the control of oral candidiasis, as
may some essential oils [15]

Esophageal treatment is as follows:

 Requires systemic therapy; empiric treatment is acceptable prior to endoscopy

 Initial therapy: 200-400 mg oral daily fluconazole for 2-3 weeks
 Unable to tolerate oral medication: 400 mg daily intravenous fluconazole, or an
echinocandin (eg, 150 mg daily intravenous micafungin), then deescalate when tolerable
to 200-400 mg oral daily fluconazole
 Refractory to fluconazole: 200 mg itraconazole solution once a day, or 200 mg oral or
intravenous voriconazole twice a day for 2-3 weeks
 Recurrent: Long-term therapy with 100-200 mg oral fluconazole three times per week

Vulvovaginitis treatment is as follows:

 Uncomplicated: Any topical azole or a single dose of 150 mg oral fluconazole

 Severe or immunosuppressed: 2-3 doses of 150 mg oral fluconazole every 72 hours
 Candida glabrata infection, unresponsive to azoles: 600 mg intravaginal boric acid
capsule nightly for 10-14 days, [16] or intravaginal nystatin [17]
 Recurrent: Induction therapy with 2 weeks of a topical agent or oral fluconazole,
followed by weekly 150 mg oral fluconazole for 6 months

Balanitis treatment is as follows:

 Mild: Topical imidazole twice a day for 1-2 weeks

 Severe or recurrent: 50-100 mg oral fluconazole once a day for 2 weeks

Chronic mucocutaneous candidiasis treatment is as follows:

 Patients with associated endocrine abnormalities, such as those involving the parathyroid,
should have electrolytes monitored and corrected as necessary
 Initial: 400-800 mg oral fluconazole once a day for 4-6 months
 Maintenance: 200 mg oral fluconazole once a day

Resistance of fungi to azoles is rare, but some Candida species, such as C glabrata and C krusei,
are innately less susceptible to azoles. C albicans can acquire azole resistance. [18]

Boric acid

This can be compounded by a pharmacist or purchased online. Patients may also make their own
capsules using boric acid powder and gelatin capsules. They should fill the narrow half of the
capsule, and then cap it with the wider half. To prevent recurrence, boric acid can be used twice
a week. The mechanism by which topical boric acid is effective in vulvovaginitis due to Candida
is not well understood, but one theory is that it may inhibit oxidative metabolism or impair
virulence. Adverse effects can be mild, such as local irritation. Systemic adverse effects can also
occur and can include fever, vomiting, and seizures. Patients should be warned that boric acid
capsules can be fatal if swallowed, and they should not be used during pregnancy.

Treating underlying causes

Attention to the underlying cause helps avoid prolonged or repeated courses of treatment. If
antibiotics or corticosteroids (oral or inhaled) are the underlying cause, reducing the dose or
changing the treatment may help. Intermittent or prolonged topical antifungal treatment may be
necessary when the underlying cause is unavoidable or incurable.

Denture plaque often contains Candida species. To prevent denture-induced stomatitis, denture
cleansing that includes removal of candidal organisms is a necessary and important factor.
Cleansers can be divided into groups according to their primary components: alkaline peroxides,
alkaline hypochlorites, acids, disinfectants, and enzymes. Yeast lytic enzymes and proteolytic
enzymes are the most effective. Denture soak solutions with benzoic acid eradicate C albicans
from the denture surface by being taken up by the acrylic resin and eliminating the organism
from the internal surface of the prosthesis. Oral rinses containing 0.12% chlorhexidine gluconate
eliminate C albicans on the acrylic resin surface of the denture, and they reduce palatal
inflammation. Protease-containing denture soaks (alkalize protease) remove denture plaque,
especially when combined with brushing.

Xerostomia causing candidiasis can benefit from keeping the mouth moist through hydration, ice
chips, or lozenges. If the dry mouth is the anticholinergic adverse effect of another medication,
consider switching to another medication or changing the dosage. Treatment with cholinergic
agents may also be considered.

Prevention
Patients should be counseled about smoking, and they should be warned about the risk of
developing mucosal candidiasis after taking medications that impair salivation, antibiotics,
corticosteroids, and other immunosuppressants.

Medication Summary
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Azoles
Class Summary

Azoles are synthetic antifungals with broad-spectrum fungistatic activity against yeasts and fungi,
including candidal species. By blocking fungal cytochrome P450-dependent enzymes, azoles
disrupt the synthesis of ergosterol, which is the principal sterol in fungal cell membranes. The
two subclasses of azoles are imidazoles (eg, clotrimazole, miconazole, econazole, ketoconazole)
and triazoles (eg, fluconazole, itraconazole).

The most common adverse effect of topical azoles is local skin and mucous membrane irritation.
The most common adverse effects of systemic azoles are gastrointestinal distress, morbilliform
rash, and hepatotoxicity. Most azoles have additional adverse effects specific to each drug, and
these are listed below. Diazoles (eg, ketoconazole, miconazole) have a stronger effect on human
cytochromes than triazoles (eg, fluconazole, itraconazole) and therefore tend to have more severe
adverse effects.

Azoles are effective antifungals, but resistance is occasionally reported. Development of cross-
resistance of C albicans to different azoles during treatment with a single azole derivative has
been described.

Clotrimazole (Lotrimin, Mycelex, Femizole, Gyne-Lotrimin)

Clotrimazole is available as topical therapy. As a 10-mg troche, clotrimazole is effective against

oral candidiasis in some patients who are immunocompromised. It is less effective than other
azoles in patients with HIV infection.

Fluconazole (Diflucan)

Fluconazole is available as systemic therapy. Compared with other azoles, it has lower toxicity
while maintaining a half-life of 30 hours in patients with normal renal function. Fluconazole is
active against most C albicans, although resistance is occasionally seen. It is less active against
other species, such as C glabrata, and it has no activity against C krusei.

Itraconazole (Sporanox)

Itraconazole is available as systemic therapy. Itraconazole is active against all Candida species.
Therefore, it may be advantageous in patients who are immunocompromised and in whom other
antifungals may predispose to selection and overgrowth of resistant species. It may interact with
terfenadine, astemizole, and cisapride to produce dysrhythmias and to increase the activity of
anticoagulants, cyclosporine, midazolam, and sulfonylureas. Adverse effects include
hepatotoxicity, hypokalemia, and peripheral neuropathy.

Voriconazole (Vfend)

Voriconazole is available as systemic therapy. It is effective against organisms that demonstrate

resistance to fluconazole, including C krusei. The associated adverse effects include
phototoxicity, arrhythmia, and visual disturbances.

Polyenes
Class Summary

This class of antifungals includes the drugs amphotericin B and nystatin. Amphotericin B is
available as a systemic therapy, and nystatin is available as topical therapy. Polyenes irreversibly
bind to the cell membrane sterol, ergosterol, causing disruption by increasing cell membrane
permeability. They are fungistatic at low concentrations and become fungicidal at higher
concentrations.

Amphotericin, in particular, is notorious for its adverse effects. It can cause fevers, electrolyte
disturbances, nephrotoxicity, arrhythmias, as well as a number of skin eruptions. Severe
reactions from amphotericin include seizures, agranulocytosis, and hepatotoxicity.

Amphotericin B deoxycholate (Amphotericin B (conventional), Fungizone)

This is one of the oldest antifungals and has been in use for more than 40 years; it is the criterion
standard of antifungal therapy. Lipid formulations have been developed. The total dose must be
adjusted depending on the type of candidal infection being treated. Most patients receive a total
dose of 0.5-1.5 g.

Nystatin (Mycostatin, Nilstat, Nyamyc)

This is a fungicidal and fungistatic antibiotic obtained from Streptomyces noursei. It is effective
against various yeasts and yeastlike fungi. It changes the permeability of the fungal cell
membrane after binding to cell membrane sterols, causing cellular contents to leak. Membrane
channel activity is increased at lower doses, and pores are formed at higher concentrations.
 APTOSA

Practice Essentials
Recurrent aphthous stomatitis (RAS) is a common ulcerative inflammatory condition of the oral
cavity; it typically starts in childhood or adolescence as small recurrent, painful, round or ovoid
ulcers with well-defined erythematous margins, like a halo, and a central yellow or gray floor.

See the images below.

Recurrent aphthous ulcer with well-defined

erythematous halo and central yellowish gray base, on left anterolateral tongue.
View Media Gallery
 Traumatic ulcer on ventrum/lateral
margin of tongue; these must be differentiated from aphthae.
View Media Gallery

A positive family history of RAS is common, and the natural history typically involves
resolution in the third decade of life. Not all recurring ulcers represent RAS, however, so the
clinician must distinguish localized RAS from lesions arising from an underlying systemic
disorder. Proposed causative factors for RAS include nutritional deficiency, immunologic factors,
psychological stress, and dietary allergies, as well as trauma in patients with genetic
susceptibility to RAS. [1] Ulcers with similar clinical features but rarely resolving spontaneously
with age may be associated with systemic conditions such as Behçet syndrome, auto-
inflammatory syndromes, gastrointestinal disease, or immune defects such as HIV/AIDS. [2]

Diagnosis of RAS is based on history and clinical features. Topical corticosteroids (TCs) remain
the mainstays of treatment. If RAS fails to respond to local measures, systemic
immunomodulators may be required. A wide spectrum of agents has been suggested as beneficial,
but few studies have been performed to assess the efficacy of these drugs (or their adverse effects
are significant).

Key points include the following:

 RAS is the most common ulcerative condition of mouth

 The clinician must distinguish localized RAS from ulcers resulting from an underlying
cause
 Topical and systemic therapies are used to manage RAS

Pathophysiology
The etiology of RAS is still unknown; the condition may in fact manifest from a group of
disorders of quite different etiologies rather than from a single entity. [3]
Despite many studies trying to identify a causal microorganism, RAS does not appear to be
infectious, contagious, or sexually transmitted. Immune mechanisms appear to be at play in
persons with a genetic predisposition to oral ulceration.

A genetic basis exists for some RAS. This is shown by a positive family history in about one-
third of patients with RAS; an increased frequency of human leukocyte antigen (HLA) types A2,
A11, B12, and DR2; and susceptibility to RAS, which segregates in families in association with
HLA haplotypes. RAS probably involves cell-mediated mechanisms, but the precise
immunopathogenesis remains unclear. Phagocytic and cytotoxic T cells probably aid in
destruction of oral epithelium that is directed and sustained by local cytokine release.

Patients with active RAS have an increased proportion of gamma-delta T cells compared with
control subjects and patients with inactive RAS. Gamma-delta T cells may be involved in
antibody-dependent cell mediated cytotoxicity (ADCC). Compared with control subjects,
individuals with RAS have raised serum levels of cytokines such as interleukin (IL)–6 and IL-2R,
soluble intercellular adhesion modules (ICAM), vascular cell adhesion modules (VCAM), and E-
selectin; however, some of these do not correlate with disease activity.

Cross-reactivity between a streptococcal 60- to 65-kd heat shock protein (hsp) and the oral
mucosa has been demonstrated, and significantly elevated levels of serum antibodies to hsp are
found in patients with RAS. Lymphocytes of patients with RAS have reactivity to a peptide of
Mycobacterium tuberculosis. Some cross-reactivity exists between the 65-kd hsp and the 60-kd
human mitochondrial hsp. Monoclonal antibodies to part of the 65-kd hsp of M tuberculosis
react with Streptococcus sanguis. RAS thus may be a T cell–mediated response to antigens of S
sanguis, which cross-react with the mitochondrial hsp and induce oral mucosal damage. RAS
patients have an anomalous activity of the toll-like receptor TLR2 pathway that probably
influences the stimulation of an abnormal Th1 immune response.

Predisposing factors may include any of the following:

 Stress - This underlies RAS in some cases; ulcers appear to exacerbate during school or
university examination times.
 Trauma - Biting of the mucosa and wearing of dental appliances may lead to some ulcers;
RAS is uncommon on keratinized mucosae.
 Endocrine factors in some women - RAS is clearly related to the progestogen level fall in
the luteal phase of the menstrual cycle, and ulcers may then temporarily regress in
pregnancy.
 Cessation of smoking - This may precipitate or exacerbate RAS in some cases.
 Allergies to food - Food allergies occasionally underlie RAS; the prevalence of atopy is
high. Patients with aphthae may occasionally have a reaction to cow's milk and may have
been weaned at an early age.

Aphthous-like ulcers may be seen in the following:

 Hematinic deficiency: Up to 20% of patients are deficient of iron, folic acid (folate), or
vitamin B.
  Malabsorption in gastrointestinal disorders: About 3% of patients experience these
disorders, particularly celiac disease (gluten-sensitive enteropathy) but, occasionally,
Crohn disease, pernicious anemia, and dermatitis herpetiformis. HLA DRW10 and
DQW1 may predispose patients with celiac disease to oral ulceration.
 Immune deficiencies: Ulcers (aphthous-like ulcers) may be seen in patients with HIV,
neutropenias, and some other immune defects.
 Drugs, especially NSAIDs, alendronate, and nicorandil [4] : These may produce mouth
ulcers, but the history should distinguish them from RAS.
 Sodium lauryl sulfate (SLS): This is a detergent in some oral healthcare products that
may aggravate or produce oral ulceration.

A study by Gülseren et al suggested that food additives may be involved in the etiology of RAS.
In the study, patch testing was used to test for reactions to 23 food additives in 24 patients with
RAS and 22 controls. The study found that 21 (87.5%) of the patients with RAS demonstrated
positive patch test reactions to one or more allergens, compared with 3 (13.6%) of the controls,
with the additives producing the most positive reactions in the RAS patients being cochineal red
(15 patients; 62.5%), azorubine (11 patients; 45.8%), and amaranth (6 patients; 25%). [5]

A study by Zhang et al indicated that impairment of the enzymatic antioxidant defense system
may be key to the pathogenesis of RAS in patients with the condition who have active lesions.
The investigators found significantly lower serum levels of superoxide dismutase, catalase, and
glutathione peroxidase in active lesion RAS patients than in patients in the remission stage of
RAS or in healthy controls. Serum levels did not significantly differ between the remission
patients and controls. [6]

Epidemiology
Frequency

United States

RAS affects 5-66% of the population. Approximately 1% of children from higher socioeconomic
groups in developed countries have RAS; however, 40% of selected groups of children can have
a history of RAS, with ulceration beginning before age 5 years and with the frequency of
affected patients increasing with age. Multiple factors such as the specific population evaluated,
diagnostic criteria, and environmental factors, affect the prevalence of RAS. [1]

Mortality/Morbidity

Most patients with RAS are otherwise healthy.

Race

RAS has been reported in all races

Sex

A slight female predominance exists.

Age

RAS normally first arises in childhood or adolescence, predominantly between the ages of 10
and 19 years, with the frequency decreasing in subsequent years. The chance of children with
RAS-positive parents presenting with RAS is high, up to 90%, while the chance of presentation
in children with RAS-negative parents is just 20%. It is interesting to note that the prevalence of
presentation has been found to be five times greater in children with high socioeconomic status.
[1]

Prognosis
Minor aphthous ulcers (MiAUs) are usually self-limiting, with the usual duration being about 10-
14 days without any active treatment. Major aphthous ulcers (MjAUs) can last up to about a
month. A third type of RAS, the herpetiform ulcers, are devastating, lasting from 10 days to
about 100 days. Ulcers respond well to topical medications, although sometimes a systemic
medication may be necessary.

Patient Education
Patient education regarding this condition may facilitate early treatment during prodromal phases
to minimize the discomfort. Children with extensive ulcers should receive proper diet and
hydration, as they may avoid food intake as well as hydration. When using palliative measures
such as topical numbing medication, the patient must be cautioned against trauma to anesthetized
areas while eating or sleeping. The patient should avoid precipitating factors, such as allergens,
trauma, and other potential triggers.

History
The 3 main clinical types of recurrent aphthous stomatitis (RAS) are as follows:

 Minor aphthous ulcers (MiAUs, 80% of all RAS)

 Major aphthous ulcers (MjAUs)
 Herpetiform ulcers.

However, any significance of these distinctions is unclear (ie, they could just be 3 distinct
disorders). Diagnosis is based on history and clinical features. (See the image below.)
 Recurrent aphthous stomatitis with
ulcers of varying sizes - large ulcers on the right buccal mucosa and a small ulcer on the anterior
tongue.
View Media Gallery

Characteristics of MiAUs (ie, Mikulicz ulcers) include the following:

 They occur mainly in persons 10-40 years of age.

 They often cause minimal symptoms.
 They are small round or ovoid ulcers 2-4 mm in diameter. (MiAUs are round or ovoid in
most situations.)
 They have an ulcer floor that is initially yellowish but assumes a gray hue as healing and
epithelialization proceeds.
 They are surrounded by an erythematous halo and some edema.
 They are found mainly on the nonkeratinized mobile mucosa of the lips, cheeks, floor of
the mouth, sulci, or ventrum of the tongue; they are uncommonly seen on the keratinized
mucosa of the palate or dorsum of the tongue.
 They occur in groups of only a few ulcers (ie, 1-6) at a time.
 They heal in 7-10 days.
 They recur at intervals of 1-4 months.
 They leave little or no evidence of scarring.

Characteristics of MjAUs (ie, Sutton ulcers, periadenitis mucosa necrotica recurrens [PMNR])
include the following:

 They are larger, of longer duration, of more frequent recurrence, and often more painful
than MiAUs.
 They are round or ovoid like MiAUs but are larger and associated with surrounding
edema.
 They reach a large size, usually about 1 cm in diameter or even larger.
 They are found on any area of the oral mucosa, including the keratinized dorsum of the
tongue or palate.
  They occur in groups of only a few ulcers (ie, 1-6) at one time.
 They heal slowly over 10-40 days.
 They recur extremely frequently.
 They may heal with scarring.
 They occasionally are found with a raised erythrocyte sedimentation rate or plasma
viscosity.

Characteristics of herpetiform ulceration (HU) include the following:

 They are found in a slightly older age group than the other RAS.
 They are mainly found in females.
 They begins with vesiculation that passes rapidly into multiple, minute, pinhead-sized,
discrete ulcers.
 They involve any oral site, including the keratinized mucosa, increase in size, and
coalesce to leave large round ragged ulcers.
 They heal in 10 days or longer.
 They are often extremely painful.
 They recur so frequently that ulceration may be virtually continuous.

Most patients with RAS appear to be otherwise well, but a minority have etiologic/precipitating
factors that can be identified by the history. These factors may include the following:

 Dentifrices containing sodium lauryl sulfate

 Trauma
 Stress
 Cessation of smoking
 Menstrual cycle association
 Food allergy

Aphthous-like ulcers may appear in the following diseases and states:

 Hematinic deficiency (eg, iron, folate, vitamin B-12)

 Celiac disease
 Crohn disease
 Behçet syndrome, which may include genital, cutaneous, ocular, or other lesions (The
mouth ulcers in Behçet syndrome often mimic major aphthae, with frequent episodes and
long duration to healing.)
 Immunodeficiencies such as human immunodeficiency virus (HIV) infection, and
neutropenia (Ulcers appearing on a regular 3-week cycle may indicate cyclic neutropenia.)
 Auto-inflammatory syndromes, such as periodic fever, aphthous stomatitis, pharyngitis,
and cervical adenitis syndrome (PFAPA) in children
 Malignancy (Ulcers appearing for the first time in an older individual may reflect
underlying systemic disease [eg, colonic carcinoma with chronic hemorrhage].)
 Drug use (eg, cytotoxic drugs, nicorandil, NSAIDs, others)
 Sweet syndrome, a rare immunologically mediated condition that belongs to the group of
neutrophilic dermatoses and must be differentiated, particularly from Behçet disease
 o Sweet syndrome is characterized by red-brown plaques and nodules that are
frequently painful and occur primarily on the head, neck, and upper extremities.
o Patients often also have neutrophilia and fever and may have oral ulceration.

Physical
RAS ulcers, which can occur in otherwise healthy patients, are relatively small recurrent, round
or ovoid ulcers with well-circumscribed erythematous margins presenting like a halo and with a
yellow or gray floor. For 2-48 hours before an ulcer develops, RAS is characterized by a
prodromal burning sensation. [1] Ulcers commonly present on lining oral mucosa, such as buccal
and labial mucosa, and on the tongue, rather than on attached oral mucosa.

A report of oral ulceration on routine physical evaluation or oral ulceration presenting as the
patient's chief complaint should prompt a thorough extraoral and intraoral examination. When an
active ulcer is noted, a recall in 2 weeks will be beneficial to monitor the prognosis. No specific
investigations exist for RAS; however, a linear ulceration in areas of the buccal or labial
vestibule may warrant further workup, since the other causes of recurrent mouth ulceration
should be excluded. Indeed, any ulcer that lasts for more than 3 or 4 weeks requires evaluation to
rule out other, serious disease processes. If a solitary, nonhealing ulcer is reported, a biopsy may
be warranted and the clinician should rule out malignancy.

Causes
Some RAS cases involve a familial and genetic basis; approximately 40% of patients with RAS
have a familial history, but inheritance may be polygenic with penetrance dependent on other
factors.

Most relevant studies have found hematinic (eg, iron, folic acid, vitamin B-12) deficiencies in as
many as 20% of patients with recurrent ulcers. In addition, deficiencies of vitamins B-1, B-2, and
B-6 have been noted in some patient cohorts.

The previously proposed association between recurrent ulcers and celiac disease (gluten-
sensitive enteropathy [GSE]) is tenuous, despite some evidence that the haplotype of HLA-DRW
10 and DQW1 may predispose patients with GSE to RAS.

Hypersensitivity reactions to exogenous antigens other than gluten do not have a significant
etiologic role in RAS, and associations with atopy are inconsistent. Moreover, a consistent
association between aphthous ulceration and psychological illness, zinc deficiency, or sex
hormone levels is unlikely.

Local physical trauma may initiate ulcers in susceptible people, and RAS is uncommon where
mucosal keratinization is present or in patients who smoke tobacco.

Various microorganisms have been examined for a causal association. Latterly, Helicobacter
pylori has been detected in lesional tissue of ill-defined oral ulcers, but the frequency of serum
immunoglobin G (IgG) antibodies to H pylori is not increased in RAS. On the other hand, a
study by Gülseren et al indicated that H pylori may play a role in the etiology of RAS. The rapid
urease test was used to find the bacterium in dental plaque samples from 34 of 38 patients with
RAS (89.5%), compared with 24 of 43 controls (55.8%). [7]

A study by Hijazi et al also suggested that the development of idiopathic RAS is associated with
changes in the mucosal microbiome. The investigators found, for example, that species of the
bacterial family Porphyromonadaceae related to periodontal disease were more abundant in
ulcerated areas in the mucosae of patients with RAS than in the mucosae of healthy controls. In
contrast, species of the bacterial family Streptococcaceae that are associated with oral health
were more abundant in the healthy controls than in the ulcerated areas of RAS patients. [8]

Similarly, a study by Kim et al suggested that dysbiosis contributes to the development of RAS.
In an analysis of the oral mucosa and saliva from RAS patients and controls, the investigators
found that the patients with RAS had reductions in healthy core microbiota and increases in rare
microbial species. These changes included decreases in Streptococcus salivarius and increases in
Acinetobacter johnsonii. [9]

Little evidence suggests an etiologic association between viruses and RAS. Human herpesvirus
(HHV)–6 and HHV-7 DNA has not been demonstrated in RAS, but HHV-8 DNA is present in
HIV-related oral ulcers.

Diagnostic Considerations
Mouth ulcers can arise from local causes, malignancy, drug adverse effects, and systemic
conditions (particularly infections, blood disorders, gastrointestinal disorders, and skin diseases).

Recurrent multiple ulcers are most typical of the following conditions (before making a
diagnosis of recurrent aphthous stomatitis [RAS], potentially overlooked causes of oral ulcers
must be considered):

 Hematinic deficiency (eg, iron, folate, vitamin B-12)

 Celiac disease
 Crohn disease
 Neumann bipolar aphthosis
 Behçet syndrome
 Sweet syndrome
 HIV infection, neutropenia, and other immunodeficiencies
 Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA)
in children

Approach Considerations
It is important to rule out any underlying cause in the case of oral ulcers. A thorough history is
essential, since this and a review of systems can assist the clinician in determining whether ulcers
are related to a systemic inflammatory process or are truly idiopathic. Diseases causing oral
ulcers that should not be mistaken for recurrent aphthous stomatitis (RAS) include Behçet
syndrome, cyclic neutropenia, recurring intraoral herpes infections, human immunodeficiency
virus (HIV)–related oral ulcers, and gastrointestinal diseases such as Crohn disease and
ulcerative colitis. Minor aphthous ulcers (MiAUs) most commonly form on nonkeratinized oral
mucosa, usually on the buccal and labial mucosa; they have a duration of about 10-14 days
without scar formation. [1]

Laboratory Studies
See the list below:

 Systemic disorders should particularly be suspected in the presence of features that may
suggest a systemic background.
 Diagnosis of recurrent aphthous stomatitis (RAS) is based on history and clinical features.
No specific tests are available; however, to exclude systemic disorders discussed above,
the following tests may be helpful:
o Complete blood cell count
o Hemoglobin test
o White blood cell count with differential
o Red blood cell indices
o Iron studies (usually an assay of serum ferritin levels)
o Red blood cell folate assay
o Serum vitamin B-12 measurements
o Serum antiendomysium antibody and transglutaminase assay (positive in celiac
disease)
 Rarely, biopsy may be indicated in cases in which a different diagnosis is suspected.
Occasionally, for example, pemphigus may mimic RAS. Occasional RAS can mimic a
neoplasm, necrotizing sialometaplasia, or TUGSE (traumatic ulcerative granuloma with
stromal eosinophilia).

Histologic Findings
The histology of RAS is nonspecific. The ulcer is depressed well below the surface, and the
inflammation extends deeply. The surface of the ulcer is covered by a fibrinous exudate
infiltrated by polymorphs. Beneath is a layer of granulation tissue with dilated capillaries and
edema. Deeper still is a repair reaction, with fibroblasts in the surrounding connective tissue
laying down fibrous tissue.

Medical Care
Identify and correct predisposing factors for recurrent aphthous stomatitis (RAS). Ensure that
patients brush atraumatically (eg, with a small-headed, soft toothbrush) and avoid eating
particularly hard or sharp foods (eg, toast, potato crisps) and avoid other trauma to the oral
mucosa.
SLS should be avoided if implicated as a predisposing factor. Any iron or vitamin deficiency
should be corrected once the cause of that deficiency has been established. If an obvious
relationship to certain foods is established, these should be excluded from the diet. Patch testing
may be indicated to reveal allergies. The occasional patient who relates ulcers to her menstrual
cycle or to use of an oral contraceptive may benefit from suppression of ovulation with a
progestogen or a change in the oral contraceptive.

In most cases, the natural history of RAS is one of eventual remission. However, for some
patients, remission occurs spontaneously several years later; thus, treatment is indicated in these
patients if discomfort is significant. Relief of pain and reduction of ulcer duration are the main
goals of therapy. There is a huge range of supposed or possible remedies available, but objective
evidence shows the most efficacy from corticosteroids and antimicrobials used topically. [10, 11]

Topical corticosteroids (TCs) remain the mainstays of treatment. A spectrum of different TCs
can be used. At best, TCs reduce painful symptoms but not the rate of ulcer recurrence. The
commonly used preparations are as follows:

 Hydrocortisone hemisuccinate pellets (Corlan), 2.5 mg used 4 times daily

 Triamcinolone acetonide in carboxymethyl cellulose paste (Adcortyl in Orabase
[withdrawn in some countries], Kenalog), administered 4 times daily
 Betamethasone sodium phosphate as a 0.5-mg tablet dissolved in 15 mL of water to make
a mouth rinse, used 4 times daily for 4 minutes each time

Hydrocortisone and triamcinolone preparations are popular because neither causes significant
adrenal suppression; however, ulcers still recur.

Betamethasone, fluocinonide, fluocinolone, fluticasone, and clobetasol are more potent and
effective than hydrocortisone and triamcinolone, but they carry the possibility of some
adrenocortical suppression and a predisposition to candidiasis.

Other topical medications that can reduce discomfort include the nonsteroidal anti-inflammatory
drugs (NSAIDs) diclofenac and amlexanox paste; the latter has been found to shorten the time it
takes minor aphthae to heal. Swishing three or four times daily with so-called “magic
mouthwash” (MMW) can also offer some pain relief. [1] MMW can be obtained in several
formulations, an example being as follows:

 One part viscous lidocaine 2%

 One part Maalox (do not substitute Kaopectate)
 One part diphenhydramine (12.5 mg per 5 mL)

Benzydamine hydrochloride mouthwash, though no more beneficial than a placebo, can produce
transient pain relief. Chlorhexidine gluconate and bioadhesive (Gelclair) mouth rinses reduce the
severity and pain of ulceration but not the frequency.

Topical tetracyclines may reduce the severity of ulceration, but they do not alter the recurrence
rate. A doxycycline capsule of 100 mg in 10 mL of water administered as a mouth rinse for 3
minutes or tetracycline 500 mg plus nicotinamide 500 mg administered 4 times daily may
provide relief and reduce ulcer duration. Avoid tetracyclines in children younger than 12 years
who might ingest them and develop tooth staining.

If RAS fails to respond to local measures, systemic immunomodulators may be required. A wide
spectrum of agents has been suggested as beneficial, but few studies have been performed to
assess the efficacy of these drugs (or their adverse effects are significant). Thalidomide 50-100
mg daily is effective against severe RAS, although ulcers tend to recur within 3 weeks.
Teratogenicity, neuropathy, and other adverse effects dissuade most physicians from its use.

Oral vitamin B-12 may significantly reduce or eliminate RAS recurrences. For example, a
randomized, double-blind, placebo-controlled study by Volkov et al found that in patients taking
1000 μg of sublingual vitamin B-12 daily for 6 months, there was a significant decrease in the
number of ulcers and level of pain, as well as in the duration of outbreaks, at 5 and 6 months no
matter what the patients' initial B-12 blood levels had been. Moreover, during the sixth month of
treatment, 74.1% of the patients taking B-12 achieved "no aphthous ulcers status," compared
with 32.0% of patients in the control group. [12]

Few, if any, of the other medications used for RAS have undergone serious scientific evaluation.
These include aloe vera, biologics, transfer factor, gamma-globulin therapy, sodium
cromoglycate lozenges, dapsone, colchicine, pentoxifylline, levamisole, colchicine, azathioprine,
prednisolone, azelastine, alpha 2-interferon, ciclosporin, deglycerinated liquorice, 5-
aminosalicylic acid (5-ASA), prostaglandin E2 (PGE2), sucralfate, diclofenac, and aspirin.

A randomized, single-blind, placebo-controlled trial by Albrektson et al indicated that low-level

laser therapy can relieve RAS pain. The study, which involved 40 patients with RAS, also found
that patients who received laser treatment found it easier to eat, drink, and brush their teeth than
did the placebo patients. [13]

Consultations
Patients with oral ulcers typically present to a general dentist. These dentists are usually well
versed in primary management of such lesions, but if the presentation is severe or the ulcers are
recalcitrant to topical therapy, a systematic workup and management beyond topical therapies
may be essential, as the condition may compromise diet and hydration and significantly impact
the patient's quality of life. These cases may be beyond the scope of a general dentist, and
referral to a specialist in oral medicine may be necessary. Depending on the etiology of the
ulcers, interdisciplinary care may be needed with, as applicable, a gastroenterologist, an
immunologist/allergologist, a hematologist, a rheumatologist, and a dermatologist.

Diet
The patient should avoid consuming any foods that could lead to RAS.

Medication Summary
TCs remain the mainstay of treatment for recurrent aphthous stomatitis (RAS). TCs reduce the
number of ulcer days compared with controls, but they have no consistent effect on the
frequency of ulceration. TCs may reduce the ulcer duration and pain. Amlexanox oral adhesive
pellicles or oral adhesive tablets appear to reduce ulcer pain and duration.

Chlorhexidine gluconate mouth rinses reduce the severity and pain of ulceration but do not affect
the frequency.

The range of systemic medications available is of variable or unproven efficacy or may have
serious adverse effects; such agents include systemic corticosteroids, colchicine, clofazimine,
and thalidomide (and many others). [14]

Corticosteroids
Class Summary

A spectrum of different TCs can be used. All can reduce symptoms, and neither hydrocortisone
nor triamcinolone preparations cause adrenal suppression. Ulcers still recur.

Hydrocortisone topical (Cortaid, Dermacort, Westcort)

Decreases inflammation by suppressing migration of PMNs and reversing increased capillary

permeability.

Triamcinolone topical (Aristocort, Flutex, Kenalog)

Decreases inflammation by suppressing migration of PMNs and reversing capillary permeability.

Betamethasone topical (Alphatrex, Diprolene, Maxivate)

For inflammatory dermatoses responsive to steroids. Decreases inflammation by suppressing

migration of PMNs and reversing capillary permeability.

Fluocinolone (Synalar, Fluonid)

High-potency topical corticosteroid that inhibits cell proliferation and is immunosuppressive,

antiproliferative, and anti-inflammatory.

Fluocinonide (Fluonex, Lidex)

High-potency topical corticosteroid that inhibits cell proliferation and is immunosuppressive and
anti-inflammatory.

Clobetasol (Temovate)
Class I superpotent topical steroid; suppresses mitosis and increases synthesis of proteins that
decrease inflammation and cause vasoconstriction.

Oral Rinses
Class Summary

Mucoadhesive action reduces pain by adhering to the mucosal surface of the mouth.

Bioadherent oral (Gelclair)

This agent adheres to the mucosal surface of mouth and forms a protective coating that shields
exposed and overstimulated nerve endings. Ingredients include water, maltodextrin, propylene
glycol, polyvinylpyrrolidone (PVP), sodium hyaluronate, potassium sorbate, sodium benzoate,
hydroxy ethylcellulose, polyethylene glycol (PEG)–40, hydrogenated castor oil, disodium
edetate, benzalkonium chloride, flavoring, saccharin sodium, and glycyrrhetinic acid.

Deterrence/Prevention
Avoid precipitants (eg, trauma).

Complications
Scarring can be severe in rare cases.

Prognosis
The natural history of RAS is of amelioration with age.
 HERPES MULUT

Background
Herpes simplex viruses are ubiquitous, host-adapted pathogens that cause a wide variety of
disease states. Two types exist: herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). Both
are closely related but differ in epidemiology. HSV-1 is traditionally associated with orofacial
disease (see the image below), while HSV-2 is traditionally associated with genital disease.
Lesion location, however, is not necessarily indicative of viral type, as HSV-1 is associated with
genital infections more often than HSV-2 in some unique subpopulations.

The term herpes is derived from the Greek word “to creep or crawl” and dates back to early
Greek civilization, approximately 2000 years ago, in reference to the spreading nature of herpetic
skin lesions.

Herpes simplex virus type 1. Primary

herpes can affect the lips, and the ruptured vesicles may appear as bleeding of the lips. Courtesy of A.K.
ElGeneidy, DDS.

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See Herpes Simplex Viruses: Test Your Knowledge, a Critical Images slideshow, for more
information on clinical, histologic, and radiographic imaging findings in HSV-1 and HSV-2.

Also, see the 20 Signs of Sexually Transmitted Infections and Clues in the Oral Cavity: Are You
Missing the Diagnosis? slideshows to help make an accurate diagnosis.

Up to 80% of herpes simplex infections are asymptomatic. Symptomatic infections can be

characterized by significant morbidity and recurrence. In immunocompromised hosts, infections
can cause life-threatening complications.
The prevalence of HSV infection worldwide has increased over the last several decades, making
it a major public health concern. Prompt recognition of herpes simplex infection and early
initiation of therapy are of utmost importance in the management of the disease.

Microbiology
HSV belongs to the alpha herpesvirus group. It is an enveloped virus that is approximately 160
nm in diameter with a linear, double-stranded DNA genome. The overall sequence homology
between HSV-1 and HSV-2 is about 50%. HSV-1 has tropism for oral epithelium, while HSV-2
has tropism for genital epithelium. HSV infection is mediated through attachment via ubiquitous
receptors to cells, including sensory neurons, leading to establishment of latency. [1]

Pathophysiology
HSV-1 and HSV-2 are characterized by the following unique biological properties: [1]

 Neurovirulence (the capacity to invade and replicate in the nervous system)

 Latency (the establishment and maintenance of latent infection in nerve cell ganglia proximal to
the site of infection): In orofacial HSV infections, the trigeminal ganglia are most commonly
involved, while, in genital HSV infection, the sacral nerve root ganglia (S2-S5) are involved.
 Reactivation: The reactivation and replication of latent HSV, always in the area supplied by the
ganglia in which latency was established, can be induced by various stimuli (eg, fever, trauma,
emotional stress, sunlight, menstruation), resulting in overt or covert recurrent infection and
shedding of HSV. In immunocompetent persons who are at an equal risk of acquiring HSV-1 and
HSV-2 both orally and genitally, HSV-1 reactivates more frequently in the oral rather than the
genital region. On the other hand, HSV-2 reactivates 8-10 times more commonly in the genital
region than in the orolabial regions. Reactivation is more common and severe in
immunocompromised individuals. [2]

Cellular immunity is an important defense against herpes simplex. Dissemination of herpes

simplex infection can occur in people with impaired T-cell immunity, such as in organ transplant
recipients and in individuals with AIDS. Herpes simplex infection can also complicate burn
wounds or damaged skin such as in atopic dermatitis or other allergic dermatoses.

HSV is distributed worldwide. Humans are the only natural reservoirs, and no vectors are
involved in transmission. Endemicity is easily maintained in most human communities owing to
latent infection, periodic reactivation, and asymptomatic virus shedding. [3]

HSV is transmitted by close personal contact, and infection occurs via inoculation of virus into
susceptible mucosal surfaces (eg, oropharynx, cervix, conjunctiva) or through small cracks in the
skin. The virus is readily inactivated at room temperature and by drying; hence, aerosol and
fomitic spread are rare.

Epidemiology
Frequency

United States

HSV is the most common cause of genital ulcers in the United States. HSV-1 is usually acquired
in childhood by contact with oral secretions that contain the virus. The presence of HSV-2 can be
used as an indirect measure of sexual activity. Seroprevalence rates do not reflect how many of
these individuals have or will have symptomatic episodes of HSV recurrence, as the presence of
antibodies is poorly correlated with disease protection.

Seroprevalence: Antibodies to HSV-1 increase with age starting in childhood and correlate with
socioeconomic status, race, and cultural group. By age 30 years, 50% of individuals in a high
socioeconomic status and 80% in a lower socioeconomic status are seropositive. Antibodies to
HSV-2 begin to emerge at puberty, correlating with the degree of sexual activity. The lifetime
seroprevalence can be 20%-80%. [4] More than 90% of adults have antibodies to HSV-1 by the
fifth decade of life. [1] A slight crossover of immunity occurs between HSV-1 and HSV-2,
allowing for milder subsequent infection by the partner virus type.

International

HSV is well distributed worldwide, with over 23 million new cases per year. An increase in
seroprevalence of antibodies to HSV-2 has been documented throughout the world (including the
United States) over the last 20 years. [1]

Mortality/Morbidity

Morbidity and mortality rates associated with HSV infections are discussed in Complications.
Overall, the mortality rate associated with herpes simplex infections is related to 3 situations:
perinatal infection, encephalitis, and infection in the immunocompromised host.

Race

A national health survey conducted in the United States revealed a seroprevalence of HSV-2
antibodies in 45% of blacks, 22% of Mexican-Americans, and 17% of whites. [4]

Sex

Seropositivity to HSV-2 is more common in women (25%) than in men (17%). [4]

Age

HSV-1 infections transmitted via saliva are common in children, although primary herpes
gingivostomatitis can be observed at any age. HSV-2 infections are clustered perinatally (from a
maternal episode at delivery) and primarily once sexual activity begins. HSV-2 genital infections
in children can be an indication of sexual abuse. Increased age (after onset of sexual activity) and
total number of sexual partners are independent factors associated with increased seroprevalence
of HSV-2 antibodies. [4]

History
HSV can cause either primary or reactivation (recurrent) infections. Both HSV-1 and HSV-2 are
implicated in genital and orofacial primary infections after contact with infectious secretions that
contain either HSV-1 (usually oral secretions) or HSV-2 (usually genital secretions). The clinical
course depends on the age and immune status of the host, the anatomic site of involvement, and
the antigenic virus type. Primary HSV-1 and HSV-2 infections are accompanied by systemic
signs, longer duration of symptoms, and higher rate of complications. Recurrent infections are
typically milder and shorter. HSV infections in immunocompromised host tend to be more
severe, prolonged, and widespread and are more likely to recur than HSV infections in
immunocompetent individuals.

Acute herpetic gingivostomatitis

This is a manifestation of primary HSV-1 infection that occurs in children aged 6 months to 5
years. Adults may also develop acute gingivostomatitis, but it is less severe and is associated
more often with a posterior pharyngitis. [5]

Infected saliva from an adult or another child is the mode of infection. The incubation period is
3-6 days.

Clinical features include the following:

 Abrupt onset
 High temperature (102-104°F)
 Anorexia and listlessness
 Gingivitis (This is the most striking feature, with markedly swollen, erythematous, friable gums.)
 Vesicular lesions (These develop on the oral mucosa, tongue, and lips and later rupture and
coalesce, leaving ulcerated plaques.)
 Tender regional lymphadenopathy
 Perioral skin involvement due to contamination with infected saliva

Course: Acute herpetic gingivostomatitis lasts 5-7 days, and the symptoms subside in 2 weeks.
Viral shedding from the saliva may continue for 3 weeks or more.

Acute herpetic pharyngotonsillitis

In adults, oropharyngeal HSV-1 infection causes pharyngitis and tonsillitis more often than
gingivostomatitis.

Fever, malaise, headache, and sore throat are presenting features.

The vesicles rupture to form ulcerative lesions with grayish exudates on the tonsils and the
posterior pharynx.

Associated oral and labial lesions occur in fewer than 10% of patients.

HSV-2 infection can cause similar symptoms and can be associated with orogenital contact or
can occur concurrently with genital herpes.

Herpes labialis

This is the most common manifestation of recurrent HSV-1 infection, referred to by many
as ”cold sores.” A prodrome of pain, burning, and tingling often occurs at the affected site,
commonly the face, around the lips, followed by the development of erythematous papules that
rapidly develop into tiny, thin-walled, intraepidermal vesicles that become pustular and ulcerate.
In most patients, fewer than two recurrences manifest each year, but some individuals experience
monthly recurrences. [6]

Maximum viral shedding is in the first 24 hours of the acute illness but may last 5 days.

Herpetic whitlow

HSV infection of the finger, termed herpetic whitlow, can occur following inoculation of the
virus from primary orofacial or genital infections. Inoculation may occur from self or from other
infected persons. Healthcare workers, including dentists, are at risk for herpetic whitlow owing
to oral examinations and other oral care provided with ungloved hands.

Herpes gladiatorum

Herpes gladiatorum is HSV infection of the face, arms, neck and upper trunk, typically seen in
wrestlers and participants in some contact sports such as rugby. Infection is promoted by trauma
to the skin sustained during matches.

Eczema herpeticum

Eczema herpeticum is secondary HSV infection superimposed on an underlying damaged or

diseased skin, as seen in uncontrolled atopic dermatitis. Extensive infection can occur and
increases the risk of invasive disease, increased morbidity, and mortality.

Genital herpes

The severity and frequency of the disease and the recurrence rate depend on numerous factors,
including viral type, prior immunity to autologous or heterologous virus, gender, and immune
status of the host. [7, 2]

Primary genital herpes

Primary genital herpes can be caused by both HSV-1 and HSV-2 and can be asymptomatic.
HSV-2 tends to have tropism for genital mucosa and has been traditionally more associated with
genital infections. However, HSV-1 is increasingly associated with genital infection and has
been reported to cause more genital infections than HSV-2, especially in young people and
homosexual males. [8, 9] The clinical features and course of primary genital herpes caused by both
HSV-1 and HSV-2 are indistinguishable, but recurrences are more common with HSV-2.

Primary genital herpes is characterized by severe and prolonged systemic and local symptoms.
Preexisting antibodies to HSV-1 have an ameliorating effect on disease severity caused by HSV-
2. Prior orolabial HSV-1 infection appears to protect against or may lower genital HSV-1
infection risk. Symptoms of primary genital herpes are more severe in women, as are
complications. [10, 11, 12, 13]

Clinical features: The incubation period of primary genital herpes is 3-7 days (range, 1 day to 3
weeks). Constitutional symptoms include fever, headache, malaise, and myalgia (prominent in
the first 3-4 days). Local symptoms include pain, itching, dysuria, vaginal and urethral discharge,
and tender lymphadenopathy.

Clinical features in women: Herpetic vesicles appear on the external genitalia, labia majora, labia
minora, vaginal vestibule, and introitus. In moist areas, the vesicles rupture, leaving exquisitely
tender ulcers. Ulcers are seen more commonly than vesicles at the time of presentation because
of the frailty and thin walls of the vesicles. The vaginal mucosa is inflamed and edematous. The
cervix is involved in 70%-90% of cases and is characterized by ulcerative or necrotic cervical
mucosa. Cervicitis is the sole manifestation in some patients. Dysuria may be very severe and
may cause urinary retention. Dysuria is associated with urethritis, and HSV can be isolated in the
urine. HSV-1 infection causes urethritis more often than does HSV-2 infection.

Clinical features in men: Herpetic vesicles appear in the glans penis, the prepuce, the shaft of the
penis, and sometimes on the scrotum, thighs, and buttocks. In dry areas, the lesions progress to
pustules and then encrust. Herpetic urethritis occurs in 30%-40% of affected men and is
characterized by severe dysuria and mucoid discharge. The perianal area and rectum may be
involved in persons who engage in anal intercourse, resulting in herpetic proctitis.

In men and women, the ulcerative lesions persist from 4-15 days until encrusting and
reepithelialization occur. The median duration of viral shedding is about 12 days.

Recurrent genital herpes

Recurrent infection implies infection by the same HSV type as the antibody in the serum. The
major morbidity of genital herpes is due to its frequent reactivation rate. The duration of
symptoms is usually shorter in recurrent infection than in primary infection.

Recurrent genital herpes is preceded by a prodrome of tenderness, pain, and burning at the site of
eruption that may last from 2 hours to 2 days. In some patients, severe ipsilateral sacral neuralgia
occurs.
In women, the vesicles are found on the labia majora, labia minora, or perineum. The lesions are
often very painful. Fever and constitutional symptoms are uncommon. The lesions heal in 8-10
days, and viral shedding lasts an average 5 days. The symptoms are more severe in women than
men.

In men, recurrent genital herpes presents as 1 or more patches of grouped vesicles on the shaft of
the penis, prepuce, or glans. Urethritis is uncommon. Pain is mild, and lesions heal in 7-10 days.
The frequency and severity of recurrences decrease with time. [2]

Subclinical genital herpes

Most primary genital HSV infections are asymptomatic, with 70%-80% of seropositive
individuals having no history of known genital herpes. HSV-2 seropositivity has been associated
with viral shedding in the genital tract, even among individuals with no reported history or
symptoms of genital herpes. [14] However, upon education regarding the varied clinical
manifestations, many patients recognize the symptoms of genital herpes.

Truly asymptomatic viral shedding may occur in 1%-2% of infected immunocompetent persons
and may be as high as 6% in the first few months after acquisition of the infection. [3, 15] This
feature is important when attempting to prevent transmission sexually or perinatally.

Physical
This section describes physical examination findings of the herpetic lesion as it relates to primary
and recurrent lesions of cutaneous or mucosal HSV infection. This can be related to either oral or
genital infection. [1, 2, 5]

Herpes simplex virus type 1. Recurrent

herpes is most often noted clinically as herpes labialis, with clustered vesicles (often coalescing) on the
lip vermilion and often on the perioral skin. Recurrences generally occur in the same area each time,
although their severity may vary. Courtesy of Sara Gordon, DDS.

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Primary mucocutaneous HSV infections

Some primary infections are asymptomatic.

Primary (first-episode) infections manifest within several days of exposure to secretions

containing viable virus.

Often painful, the lesions quickly progress to vesicles and can continue to erupt over 1-2 weeks.

The lesions are prominent and are often present internally on the mucosal surface of the oral or
genital area, as well as on the surrounding skin.

Constitutional symptoms (fever, malaise, myalgias, and anorexia) are often prominent. Weight
loss is not uncommon and is due either to illness or dysphagia (in primary gingivostomatitis).

Individual vesicles on mucosal surfaces break down rapidly, forming shallow painful ulcers
(usually < 8-10 mm in diameter). They may be covered with a white exudate that can be
confused with mucosal candidiasis. Those on cutaneous surfaces remain as vesicles longer, only
to evolve into crusted ulcers that heal within 5-7 days.

Recurrent mucocutaneous HSV infections

Following the establishment of latency in the corresponding sensory nerve ganglion cells, HSV
can cause recurrent infection that can be subclinical (manifesting as viral excretion without
lesions) or overt (manifesting as mucosal or cutaneous lesions with viral excretion).

Oral recurrences are often triggered by recognizable stimuli such as pyrexia (fever blisters and
cold sores), stress, or sunburn. Genital recurrences are more likely to be linked to stress rather
than to pyrexia. Females may relate a relationship to the menstrual cycle.

Localized burning or paraesthesias may precede recurrent lesions. Unlike primary infection,
constitutional symptoms are minimal in most cases.

Recurrences last 3-7 days and can occur numerous times per year or once or twice in a lifetime.
Overall, the number of yearly recurrences tends to decrease over time. [16]

Although recurrent HSV infections may last much longer (>30 d) in immunocompromised hosts,
such as individuals with AIDS, frequent recurrences are not necessarily a sign of an altered
immune system.
Because recurrences can be clinically unrecognizable, transmission to susceptible individuals can
occur in the absence of overt lesions.

Vesicles occurring in a sacral dermatomal distribution (zosteriform) can occur in recurrent

genital HSV disease and be confused with herpes zoster. A history of similar recurrences should
alert the clinician to this possibility.

Sacral HSV infection recurrences also may present with signs and symptoms of meningeal
inflammation; and, in fact, a picture consistent with aseptic meningitis can be found upon
examination of the cerebrospinal fluid (CSF). [17]

Herpes simplex virus type 1. Recurrent

herpes is occasionally observed intraorally. Inside the oral cavity, recurrent herpes typically affects only
keratinized tissues, such as the gingiva or the hard palate. Vesicles often break quickly, so the clinician
may observe small clustered ulcers. Courtesy of Sheldon Mintz, DDS.

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Causes
HSV is transmitted via close personal contact.

HSV infection occurs via inoculation of virus into susceptible mucosal surfaces (eg, oropharynx,
cervix, conjunctiva) or through small cracks in the skin.
The virus is inactivated readily at room temperature and by drying; hence, aerosol and fomitic
spread are rare.

HSV-1 is transmitted chiefly by contact with infected saliva, whereas HSV-2 is transmitted
sexually or from a mother's genital tract infection to her newborn. However, lesion location does
not always indicate viral type.

Differential Diagnoses
 Behcet Syndrome

Noninfectious vasculitic condition characterized by orogenital aphthous ulcers, skin and

ocular lesions, and other distant organ involvement - CNS, gastrointestinal, and joint

 Candidiasis
 Chancroid
 Hand-Foot-and-Mouth Disease (HFMD)
 Herpes Zoster
 Syphilis

Laboratory Studies
Culture

Herpes simplex virus (HSV) infection is best confirmed by isolation of the virus in tissue culture
(the criterion standard for diagnosis). Tissue culture success is operator-dependent, but this
modality can yield positive results within 48 hours of inoculation.

Characteristic cytopathic effect with ballooning of cells and cell death are observed, and death of
the entire monolayer of cells may be rapid.

Immunofluorescent staining of the tissue culture cells can be used to quickly identify HSV and
can distinguish between types 1 and 2.

Tzank smear

The characteristic cytologic changes induced by HSV can be demonstrated in Tzank smears (see
Procedures); however, this procedure does not distinguish between HSV-1 and HSV-2.

Rapid diagnosis (usually within an hour) is possible based on the histological appearance of the
lesion.

Multinucleated giant cells and epithelial cells containing eosinophilic intranuclear inclusion
bodies distinguish the lesions of herpesviruses.
Punch biopsy provides more reliable material for histological examination, particularly when
lesions are infected with bacteria and fungi.

Polymerase chain reaction

Detection of HSV DNA in clinical specimens is possible with polymerase chain reaction (PCR)
techniques. PCR is more sensitive than culture and is the preferred test for CNS and ocular
infections.

In HSV encephalitis, PCR using CSF provides a rapid, noninvasive diagnostic technique that is
as sensitive as brain biopsy. [18]

PCR has been used to detect HSV-2 as the cause of recurrent meningitis (Mollaret) and has
shown a strong association between HSV-1 and Bell's palsy.

PCR can be used to detect asymptomatic viral shedding.

Direct fluorescent antigen (Immunofluorescence)

Cells scraped from ulcer bases can be stained with a direct fluorescent antibody, used to
distinguish HSV-1 from HSV-2. Additionally, tissue culture cells can also be stained (see above).
This procedure can usually be performed within 2-3 hours. [19]

Antibody testing

Antibody testing can demonstrate a primary seroconversion, particularly with HSV-1 in

childhood. [1] If serology results are negative while viral culture of specimen is positive, one can
assume primary infection.

Because of sero–cross-reactivity, HSV-1 and HSV-2 are not generally distinguishable unless a
glycoprotein G antibody assay is available. Testing for HSV-specific immunoglobulin M (IgM)
antibodies is not available.

Antibody titer increases generally do not occur during recurrences of HSV infection. Therefore,
the test is generally not used for the diagnosis of mucocutaneous HSV relapse.

Antibody testing has been the mainstay of large-scale epidemiologic studies.

Imaging Studies
Brain imaging studies in HSV encephalitis generally demonstrate focal localization in the
temporal area that is associated with edema and contrast enhancement.

Procedures
Tzanck preparation

Tzanck preparation is a time-honored procedure for assisting in the diagnosis of cutaneous

herpesvirus infections. However, it does not easily distinguish HSV-1, HSV-2, and varicella-
zoster virus.

Typically, an intact vesicle is used from which the vesicular fluid is aspirated by puncture with a
sterile tuberculin syringe. This fluid can be used for viral culture or PCR.

Aspiration should facilitate complete collapse of the vesicle because it is not multiloculated as
cutaneous poxvirus infections can be.

After aspiration, the vesicle should be unroofed aseptically.

Using a sterile instrument, the floor of the newly produced ulcer can then be scraped. The
obtained material can be spread on a glass microscope slide and then dried and fixed for staining.

Staining can be performed with a Papanicolaou smear stain or, alternatively, whatever is
available will suffice (eg, Gram, Giemsa, or Wright stain).

A positive result is the finding of multinucleate giant cells.

Direct fluorescent antigen

Using appropriate immunofluorescent antibody reagents, the smear can be used to distinguish
different herpesviruses and nonherpesviruses that may be present (eg, vaccinia, smallpox).

Medical Care
Overall, medical treatment of herpes simplex virus (HSV) infection is centered around specific
antiviral treatment. While the same medications are active against HSV-1 and HSV-2, the
location of the lesions and the chronicity (primary or reactivation) of the infection dictate the
dosage and frequency of medication. It is important to note that life-threatening HSV infections
in immunocompromised patients and HSV encephalitis require high-dose intravenous acyclovir,
often started empirically. [20]

When constitutional effects such as fever occur, symptomatic treatment can be used.

Appropriate wound care is needed, and treatment for secondary bacterial skin infections may be
required.

Acyclovir-resistant HSV infections

Acyclovir-resistant HSV infections are often seen in immunocompromised patients (eg, patients
with HIV infection). The options for treatment include cidofovir and foscarnet, but both are very
nephrotoxic.

Recurrent HSV infections

Options for recurrent HSV infections include no treatment (for infrequent episodes) or episodic
treatment with topical agents or oral antiviral agents. Long-term suppressive therapy, which can
be continued for up to one year, is also an option. A modest benefit with lower recurrences has
been reported using this method. [21, 22]

The best approach is to determine the frequency and severity of recurrent infections and the
patient's preference concerning prophylaxis. Options for long-term suppressive therapy include
acyclovir 400 mg orally twice daily or valacyclovir 500 mg orally twice daily for up to a year,
with reassessment at the end of therapy.

Consultations
Consultation with a dermatologist may be beneficial in cases of atypical lesions.

In immunocompromised patients with invasive HSV infection, consultation of specialty

associated with the organ system affected should be sought early (eg, pulmonologist for possible
HSV pneumonitis) in order to aid in diagnosis. Infectious diseases consultation is reasonable for
immunocompromised patients with CNS herpes infection.

Medication Summary
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Antivirals
Class Summary

Nucleoside analogs are phosphorylated initially by viral thymidine kinase to eventually form a
nucleoside triphosphate. These molecules inhibit herpes simplex virus (HSV) polymerase with
30-50 times the potency of human alpha-DNA polymerase.

Penciclovir (Denavir)

Inhibitor of DNA polymerase in HSV-1 and HSV-2 strains, inhibiting viral replication. Only
topical preparations available, and they are well suited for herpes labialis (cold sores).

Acyclovir (Zovirax)
Synthetic purine nucleoside analogue with activity against a number of herpes viruses, including
herpes simplex and varicella-zoster. Highly selective for virus-infected cells because of its high
affinity for viral thymidine kinase enzyme. This effect serves to concentrate acyclovir
monophosphate into virus-infected cells. The monophosphate then is metabolized into the
triphosphate active form by cellular kinases.

Double dose is suggested for herpes simplex proctitis or ocular infections. Ocular infections also
can be treated with topical acyclovir. Oral suspension available (40 mg/mL).

Valacyclovir (Valtrex)

Prodrug rapidly converted to the active drug acyclovir by intestinal and hepatic metabolism.
Better absorbed than acyclovir and more expensive but has a more convenient dosing regimen.

Famciclovir (Famvir)

Prodrug that when biotransformed into active metabolite, penciclovir, may inhibit viral DNA
synthesis/replication. Similarly to valacyclovir but has better bioavailability than acyclovir. Used
against herpes simplex and varicella-zoster viruses.

Deterrence/Prevention
Because of the ubiquitous and cosmopolitan nature of herpes simplex virus (HSV), avoiding
contact with individuals who (often asymptomatically) are excreting the virus in saliva or genital
secretions is difficult. Daily antiviral therapy can be given to reduce episodes of asymptomatic
genital shedding and to further reduce the risk of transmission; however, it is unclear how long
this should be administered.

Although not easily applicable to oral-oral contact, barrier protection using latex condoms is
recommended to minimize exposure to genital HSV infections.

Because HSV genital ulcers may occur outside of areas covered by the condom, transmission can
occur in those areas.

Herpetic whitlow can be avoided with latex gloves when health care workers insert their hands
into the oral cavity of patients. Transmission of genital virus to the hand can occur during
unprotected finger-genital contact during sexual activities.

Suppressive antiviral therapy can be used in individuals with frequent and/or particularly
symptomatic relapses, but clinical trials have shown variable results.

Some benefit, especially in terms of shortened duration of episodes, has been attributed to
suppressive antiviral treatment compared with no treatment. However, high-dose antiviral
therapy, as opposed to standard dosing, has shown mixed results. In three randomized open-label
crossover trials, high-dose valacyclovir (1 g tid) significantly improved symptom duration over
standard-dose valacyclovir (500 mg bid), but similar benefits were not observed with high-dose
acyclovir (800 mg tid) versus standard-dose valacyclovir. The study also noted that short bursts
of subclinical genital HSV reactivation were frequent and that transmission can still occur during
standard-dose or high-dose suppressive antiviral therapy. [23]

Prophylactic antiviral agents are typically given to recipients of solid organ transplants and
hematopoietic stem cell transplants during the pre-engraftment phase to minimize risk of
infection.

An investigational HSV vaccine was not effective in preventing HSV-2 disease or infection in a
study population that was representative of the general population of HSV-1– and HSV-2–
seronegative women. The investigational vaccine was effective in preventing HSV-1 genital
disease and infection. [24]

Complications
Bacterial and fungal superinfections

Bacterial and fungal superinfections are not uncommon.

Balanitis can occur in an uncircumcised male as a result of bacterial infection of the herpetic
ulcers.

Candidal vaginitis has been described in as many as 10% of women with primary genital herpes,
particularly in women with diabetes. Care should be taken to confirm the diagnosis of
candidiasis, as ulcerative herpetic disease can have whitish mucosal lesions that can be confused
with yeast infection.

Ocular infections

This complication is not uncommon in children as a result of autoinoculation during acute

herpetic gingivostomatosis or asymptomatic oropharyngeal HSV infection.

Ocular infection is caused primarily by HSV-1, except in neonates, in whom it may be caused by
HSV-2, and manifests as unilateral follicular conjunctivitis or as acute herpetic
keratoconjuctivitis with dendritic corneal ulcers. [25, 26]

Other ocular complications attributable to HSV include keratitis, retinal necrosis, and
chorioretinitis.

Recurrences occur in as many as 25% of patients and can be associated with progressive scarring
of the cornea. HSV has been the leading infectious cause of blindness in the United States.

Skin infections

Various cutaneous complications related to HSV can occur.

Eczema herpeticum: This occurs in individuals with underlying dermatitis and may be localized
(which can be confused with herpes zoster) or disseminated. The process can also occur in
patients with extensive skin breakdown as with burns, pemphigus, or Sézary syndrome.

Herpetic whitlow: HSV infections of the fingers occur at or near the cuticle or at other sites
associated with trauma. When involving the nail area, it has been confused with a bacterial felon
and been subjected, inappropriately, to incision and drainage. Herpetic whitlow is associated
with HSV-1 in health care workers and children related to saliva exposure and with HSV-2
related to digital-genital exposure.

Herpes gladiatorum: Scattered cutaneous HSV-1 lesions have been observed in wrestlers who
have had viral contact through exposure to infectious saliva during a match.

Visceral infections

HSV infection of the visceral organs usually results from viremia, and multiple organ
involvement is common. This may occur during otherwise asymptomatic primary infections and
sometimes in seemingly immunocompetent hosts but more often in immunocompromised hosts.
Visceral infections also tend to be more common in neonates. In fact, neonates have the highest
number of visceral infections than any HSV-infected populations.

In most cases of disseminated herpes, the lesions are confined to the skin; however, fatal visceral
dissemination can occur with or without vesicular skin lesions. Multiple organs are involved, but
fulminant HSV hepatitis is usually clinically prominent. HSV-1 and HSV-2 are both implicated
in fulminant hepatitis.

Disseminated disease is often associated with leukopenia, thrombocytopenia, and disseminated

intravascular coagulation.

Disseminated HSV-1 and HSV-2 infections can also result in herpetic esophagitis, adrenal
necrosis, interstitial HSV pneumonitis, HSV cystitis, HSV arthritis, HSV meningitis, and HSV
encephalitis.

Respiratory tract infections

Herpes infection of the upper airway is fairly common in children and can involve the epiglottitis,
laryngitis, and tracheobronchitis. Symptoms usually last about 2 weeks and are typically self-
limiting. Lower respiratory tract infections, including pneumonias, are rare and could follow
disease extension from an upper airway herpetic infection. Cases have been described in
immunocompromised hosts, including patients with HIV infection, recipients of solid organ and
bone marrow transplants, individuals with malignancies, and patients with burns. [27, 28, 29]

Central nervous system complications

Aseptic meningitis
Aseptic meningitis is an acute, generally benign lymphocytic meningitis. It is recurrent and self-
limiting (also known as benign lymphocytic recurrent meningitis [Mollaret meningitis]) and is
typically more common with HSV-2 infection. Meningeal symptoms usually start 3-12 days after
the onset of genital lesions; they reach a maximum 2-4 days into the illness and recede over 2-4
days. However, a history of clinical genital herpes is not always reported. Typically, there are
more than two recurrences of fever and meningeal signs with spontaneous recovery. Signs and
symptoms of encephalitis are unusual, and neurological sequelae are rare. HSV-2 has been
identified by PCR in the CSF of patients with benign lymphocytic recurrent meningitis,
suggesting that HSV may be the cause of this so-called idiopathic syndrome. [17, 30]

Ganglionitis and myelitis

Genital and anorectal HSV infections may be complicated by urinary retention, sacral neuralgia,
and sacral anesthesia. This is due to associated ganglionitis and radiculitis. The symptoms
usually resolve in 1-2 weeks. Transverse myelitis is rarely reported.

Herpes simplex encephalitis

This is an acute necrotizing viral encephalitis that, beyond the neonatal period, is nearly always
caused by HSV-1. It accounts for 10%-20% of all cases of encephalitis and is the most common
cause of sporadic acute necrotizing encephalitis in the United States. Herpes simplex encephalitis
occurs as a primary infection in about 50% of cases and may be due to recurrent infection or to
reinfection with a different strain of HSV-1 in the remainder.

Clinical features include the following:

 Nonspecific findings common to all forms of encephalitis, which include headache, signs of
meningeal irritation, altered mental status, and generalized seizures
 Changes referable to focal necrosis of the orbitofrontal and temporal cortex and the limbic
system, including anosmia, memory loss, olfactory and gustatory hallucinations, and focal
seizures
 Rapid development of hemiparesis and coma may occur. In some patients, the clinical picture is
protracted, mimicking acute psychosis or delirium tremens.
 The CSF has moderate pleocytosis with mixed mononuclear cells and polymorphonuclear cells,
moderate RBC counts, and mildly elevated protein levels with normal glucose levels.
 Brain imaging options include CT and MRI. MRI is the most sensitive imaging procedure.
 The most sensitive method of diagnosis is the demonstration of HSV DNA by PCR.
 The mortality rate is high (70%) in untreated patients. Even with treatment, a high incidence of
neurological sequelae remains

Other neurologic complications attributable to HSV include transverse myelitis and Bell palsy.

Genital herpes and pregnancy

Recurrent genital herpes is similar in pregnant and nonpregnant women, although an increase in
the number of recurrences in the course of pregnancy may occur.
Recurrent genital herpes accounts for 1%-2% of all cases of neonatal herpes. Cesarean delivery
is recommended in mothers who have active genital lesions during labor. However, presence of
active genital lesions is not a good indicator of HSV viral shedding. [31] Thus, the American
College of Obstetricians and Gynecologists (ACOG) recommends that suppressive antiviral
therapy be given in the last 4 weeks of pregnancy to all women with a history of recurrent genital
HSV. [32]

A large nationwide cohort study in Denmark did not find any association between first trimester
in utero antiviral drug (ie, acyclovir, valacyclovir, famciclovir) exposure and birth congenital
anomalies. In 1804 pregnancies exposed to an antiviral drug during the first trimester, 40 infants
(2.2%) were diagnosed with a major birth defect compared with 19,920 (2.4%) unexposed
pregnancies. [33]

Primary genital infection during pregnancy

First-episode infections have more severe consequences to the mother and infant. Thus,
identification of women at risk for primary infection (seronegative for HSV-2) is paramount.

The prevalence of genital infection varies by age, socioeconomic status, and sexual activity.
HSV-2 still causes most genital infection in pregnancy, but HSV-1 is associated with an
increasing number of cases, especially in young women.

Infection in the third trimester of pregnancy is associated with neonatal HSV infections,
intrauterine growth retardation, and prematurity.

Neonatal HSV disease

Ninety percent of infections are acquired perinatally, 5%-8% are acquired congenitally, and a
few are acquired postnatally.

Neonatal HSV infection is caused by contact with infected genital secretions.

In 70% of mothers, the infection is asymptomatic. The risk of transmission from a mother with
primary infection is about 50%. [34]

Neonates and infants (aged < 6 wk) have a very high frequency of visceral and CNS infections.
Without therapy, the mortality rate is 65%, and a high degree of neurological sequelae exists.

The disease may be confined to the skin, eyes, or mouth, or it may manifest as encephalitis or
disseminated visceral disease involving the lungs, liver, heart, adrenals, and skin.
 This neonate displayed a maculopapular
outbreak on his feet due to congenitally acquired herpes simplex virus infection. Courtesy of the
CDC/Judith Faulk.

Copathogenesis with HIV

HSV and HIV can probably be best described as co-partners in disease, with the presence of one
aiding the establishment of the other. Advanced HIV disease causing loss of cellular immunity
generally predisposes to more severe and possibly widespread HSV disease, while genital ulcers
and chronic genital inflammation due to herpes infection (especially HSV-2) has been shown to
promote the acquisition of HIV. [35] Multiple studies have also shown that the presence of
antibodies to HSV-2 increases the risk of becoming infected with HIV, independent of the
presence of genital ulcers. [36] While early studies in Africa have demonstrated a reduction of
HIV viral load in patients with HIV infection receiving therapy directed toward HSV infection,
the mechanism is unclear. [37, 38] The association between HIV and HSV may change the
epidemiologic approach to sexually transmitted diseases worldwide.
 OMPHALITIS

Background
Omphalitis is an infection of the umbilical stump. [1] It typically presents as a superficial cellulitis
that can spread to involve the entire abdominal wall and may progress to necrotizing fasciitis,
myonecrosis, or systemic disease. Omphalitis is uncommon in industrialized countries outside
the setting of umbilical vessel catherization; however, it remains a common cause of neonatal
mortality in less developed areas. It is predominantly a disease of the neonate, with only a few
cases having been reported in adults. Risk factors for omphalitis included septic delivery,
unplanned home delivery, maternal chorioamnionitis, prolonged rupture of membranes, low birth
weight, and umbilical vessel catheterization.

Aerobic bacteria are present in approximately 85% of infections, predominated by

Staphylococcus aureus, group A Streptococcus, Escherichia coli, Klebsiella pneumoniae, and
Proteus mirabilis. [2, 3, 4, 5] Methicillin-resistant S aureus has also been described in association
with omphalitis. [6] In the past, studies emphasized the importance of gram-positive organisms
(eg, S aureus and group A Streptococcus) in the etiology of omphalitis. This was followed by a
series of reports that highlighted the role of gram-negative organisms in the etiology of
omphalitis. These studies suggested that the change in etiology may have been caused by the
introduction of prophylactic umbilical cord care using antistaphylococcal agents, such as
hexachlorophene and triple dye (a widely adopted practice in the 1960s), with a subsequent
increase in gram-negative colonization of the umbilical stump.

More recent reports implicate both gram-positive and gram-negative bacteria in the etiology of
omphalitis. In some cases, anaerobic bacteria have been found. [7] Many cases are polymicrobial
in origin. In some settings, application of herbal and other poultices, human milk, animal dung,
ash, etc, may lead to contamination with pathogenic bacteria, including Clostridium tetani.

In addition to monitoring trends in incidence, monitoring the microbial etiology of omphalitis is

important, as there have been trends toward returning to dry cord care in most settings, with
application of topical antiseptic agents reserved for infants delivered in nonhygenic
environments and in locales where neonatal mortality is high. This trend has been widely
accepted, including by the World Health Organization (WHO) and the American Academy of
Pediatrics (AAP). [8, 9]

Pathophysiology
The umbilical cord connects the fetus to the mother in utero. Composed of connective tissue and
blood vessels, the cord is cut immediately after birth, leaving the umbilical stump. Normally, the
cord area is colonized with potential bacterial pathogens during or soon after birth. These
bacteria attract polymorphonuclear leukocytes to the umbilical cord. Although the precise
mechanisms of umbilical cord separation are unknown, granulocyte influx and phagocytosis, as
well as desiccation, tissue infarction and necrosis, and the activity of collagenase and other
proteases, all contribute to the process.

The umbilical stump represents a unique, but universally acquired, wound that, as the tissue
undergoes devitalization, provides a medium that supports the growth of bacteria. These bacteria
have the potential to invade the umbilical stump, leading to omphalitis. If this occurs, the
infection may progress beyond the subcutaneous tissues to involve fascial planes (necrotizing
fasciitis), abdominal wall musculature(myonecrosis), and, when the bacteria invade the umbilical
vessels, the umbilical and portal veins (phlebitis). The factors that cause colonization to progress
to infection are not well understood. The image below shows the anatomic relationship between
the umbilicus and its embryologic attachments.

Anatomic relationship between the

umbilicus and its embryologic attachments.

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Etiology
Omphalitis is a polymicrobial infection typically caused by a mixture of aerobic and anaerobic
organisms.

Associated risk factors include the following:

 Low birth weight (<2500 g)

 Prior umbilical catheterization
 Septic delivery (as suggested by premature rupture of membranes, nonsterile delivery, or
maternal infection)
 Prolonged rupture of membranes
Omphalitis occasionally manifests from an underlying immunologic disorder. Leukocyte
adhesion deficiency (LAD) is most prominent among the immunodeficiency syndromes. [10, 11, 12,
13, 14, 15, 16]
Numerous infants with acute or chronic omphalitis have been diagnosed with LAD, a
rare immunologic disorder with an autosomal recessive pattern of inheritance. These infants
typically present with the following:

 Leukocytosis
 Delayed separation of the umbilical cord, with or without omphalitis
 Recurrent infections

Omphalitis may also be the initial manifestation of neutrophil disorders in the neonate, including
neonatal alloimmune neutropenia and congenital neutropenia. [17, 18, 19, 20] Affected infants may
present with other cutaneous infections, pneumonia, sepsis, and meningitis.

Neonatal alloimmune neutropenia is a disease analogous to Rh-hemolytic disease and results

from maternal sensitization to fetal neutrophils bearing antigens that differ from the mother's.
[21]
Maternal immunoglobulin G antibodies cross the placenta and result in an immune-mediated
neutropenia that can be severe and last for several weeks to 6 months.

The congenital neutropenias are a disease group of heterogeneous disorders that range from
intermittent to persistent manifestations of varying severity. [22]

Because omphalitis complicated by sepsis can also be associated with neutropenia, the
underlying immune-mediated neutrophil destruction may not be immediately appreciated in
affected newborns.

Rarely, an anatomic abnormality such as a patent urachus, a patent omphalomesenteric duct, or a

urachal cyst may be present. [23, 24, 25, 26, 27]

Epidemiology
International data

The overall incidence of omphalitis varies from 0.2% to 0.7% in industrialized countries. [28] Its
incidence is higher in hospitalized preterm infants than in full-term infants. Omphalitis is usually
sporadic but, rarely, epidemics occur (eg, due to S aureus or group A Streptococcus). [29, 30, 31]

Sex- and age-related demographics

No sex predilection has been reported, although males may have a worse prognosis than females.

In full-term infants, the mean age at onset is 5-9 days. In preterm infants, the mean age at onset is
3-5 days.

Prognosis
The prognosis for infants with omphalitis varies.

Outcome is usually favorable in infants with uncomplicated omphalitis associated with cellulitis
of the anterior abdominal wall. In a study by Sawin and colleagues, no deaths occurred among 32
infants with omphalitis in the absence of necrotizing fasciitis and myonecrosis. [32] The mortality
rate among all infants with omphalitis, including those who develop complications, is estimated
at 7-15%. The mortality rate is significantly higher (38-87%) after the development of
necrotizing fasciitis or myonecrosis. Suggested risk factors for poor prognosis include male sex,
prematurity or being small for gestational age, and septic delivery (including unplanned home
delivery); however, data are limited and conclusions cannot be drawn regarding the role of these
factors in the mortality rate.

Complications

The sequelae of omphalitis may be associated with significant morbidity and mortality. These
include necrotizing fasciitis; myonecrosis; sepsis; septic embolization; and, particularly,
endocarditis and liver abscess formation, abdominal complications (eg, spontaneous evisceration,
peritonitis, bowel obstruction, abdominal or retroperitoneal abscess, abscess of the falciform
ligament), and death. [33, 34, 35, 36]

Necrotizing fasciitis

This is a florid bacterial infection of the skin, subcutaneous fat, and superficial and deep fascia
that complicates 8-16% of cases of neonatal omphalitis. [37, 38, 39, 40, 41, 42, 43] It is characterized by
rapidly spreading infection and severe systemic toxicity. Necrotizing fasciitis typically involves
the abdominal wall but may also involve the scrotum or penis.

Necrotizing soft-tissue infections are caused by production of factors (by single or multiple
organisms) that lead directly to tissue cell death, enzymatic destruction of supporting connective
tissue, and destruction of host humoral and cellular immune responses to infecting organisms.

Certain organisms are well known to invade tissue and proliferate in necrotic areas. Group
A Streptococcus, S aureus, and Clostridium species may elaborate extracellular enzymes and
toxins that can damage tissue, may facilitate movement of organisms through soft-tissue planes,
and may limit host defenses and penetration of systemic antimicrobial agents. [3]

Myonecrosis

This refers to infectious involvement of muscle.

In infants with omphalitis, development of myonecrosis usually depends on conditions that

facilitate the growth of anaerobic organisms. These conditions include the presence of necrotic
tissue, poor blood supply, foreign material, and established infection by aerobic bacteria such as
staphylococci or streptococci. C perfringens, in particular, does not replicate under conditions of
an oxidation-reduction potential (Eh) greater than -80 mV; the Eh of healthy muscle is 120-160
mV. In infections with mixtures of facultative aerobes and anaerobes, the aerobic organisms use
oxygen available in tissue, thereby further reducing the Eh in tissues inoculated
by Clostridium species or other anaerobic bacteria, often to less than -150 mV, allowing
anaerobic bacterial growth.

The toxins produced in the anaerobic environment of necrotic tissue allow rapid spread of
organisms through tissue planes. Local spread of toxins extends the area of tissue necrosis,
allowing continued growth of organisms and increasing elaboration of toxins. Because of
progressive deep tissue destruction and subsequent systemic spread of toxins, anaerobic
infections may be fatal if not treated promptly. In addition, rapid development of edema, which
constricts the muscle within its fascia, may lead to ischemic myonecrosis.

Sepsis

This is the most common complication of omphalitis. In a study by Mason and colleagues,
bacteremia was a complication in 13% of infants with omphalitis. In these infants, shock,
disseminated intravascular coagulation (DIC), and multiple organ failure may occur. [4]

Septic embolization

If septic embolization arises from infected umbilical vessels, it may lead to metastatic foci in
various organs, including the heart, liver, lungs, pancreas, kidneys, and skin.

Abdominal complications

Abdominal complications include spontaneous evisceration, peritonitis, bowel obstruction, and

abscess of the abdomen, retroperitoneum, liver, or falciform ligament.

Long-term or late complications of omphalitis

These may include nonneoplastic cavernous transformation of the portal vein, portal vein
thrombosis, extrahepatic portal hypertension, and biliary obstruction. [44, 45, 46] When extrahepatic
portal hypertension occurs, gastric or esophageal varices may develop, predisposing to upper
gastrointestinal bleeding.

History
A detailed review of the pregnancy, labor, delivery, and the neonatal course is important when
assessing omphalitis. Note the following:

 A history of poor feeding or feeding intolerance may be an early indication of infection. A history
of change in mental status, such as irritability, lethargy, and somnolence, or a history of a
decreased level of activity may be an important indicator of systemic dissemination of the
infection.
 Anaerobic bacteria are part of the normal flora of the female genital tract and are commonly
involved in ascending infections of the uterus and in septic complications of pregnancy;
therefore, the higher incidence of omphalitis caused by anaerobes (especially B fragilis) in
 infants with adverse perinatal histories, such as premature or prolonged rupture of membranes
and amnionitis, may relate to exposure to maternal infection.
 History of urine or stool discharge from the umbilicus suggests an underlying anatomic
abnormality.

Physical Examination
Local disease

Physical signs of omphalitis vary with the extent of the disease. Signs of localized infection
include the following:

 Purulent or malodorous discharge from the umbilical stump

 Periumbilical erythema (Recently, algorithms that attempt to standardize the clinical diagnosis
of omphalitis have been developed, emphasizing extent of periumbilical erythema and absence
or presence of pus.)
 Edema
 Tenderness

The image below shows a case of omphalitis associated with bullous impetigo due
to Staphylococcus aureus.

A case of omphalitis associated with

bullous impetigo due to Staphylococcus aureus.

View Media Gallery

Extensive local disease, with extension

The following signs indicate more extensive local disease, such as necrotizing fasciitis or
myonecrosis, which are typically found in a periumbilical location but may spread across the
abdominal wall, onto the flanks and back, and into the scrotum. These signs may also suggest
infection by both aerobic and anaerobic organisms and include the following:

 Ecchymoses, violaceous discoloration

 Bullae
 Peau d'orange appearance
 Crepitus
 Petechiae
 Progression of cellulitis despite antimicrobial therapy

The images below demonstrate findings in a case of omphalitis (left) associated with extensive
myonecrosis (right).

A case of omphalitis (left) associated

with extensive myonecrosis (right).

View Media Gallery

Systemic disease

Signs of sepsis or other systemic disease are nonspecific and include disturbances of
thermoregulation or evidence of dysfunction of multiple organ systems. Examples include the
following:

 Disturbances of thermoregulation: Fever (temperature >38°C), hypothermia (temperature

<36°C), or temperature instability
 Cardiovascular disturbances: Tachycardia (pulse >180 beats per minute [bpm]), hypotension
(systolic blood pressure <60 mm Hg in full-term infants), or delayed capillary refill (<2-3 seconds)
 Respiratory disturbances: Apnea, tachypnea (respirations >60/min), grunting, flaring of the alae
nasi, intercostal or subcostal retractions, or hypoxemia
 Gastrointestinal tract disturbances: Rigid or distended abdomen or absent bowel sounds
 Cutaneous abnormalities: Jaundice, petechiae, or cyanosis
 Neurologic abnormalities: Irritability, lethargy, weak sucking, hypotonia, or hypertonia
Diagnostic Considerations Special concerns
The clinical picture of omphalitis is sufficiently characteristic that diagnosis can be made with
fair certainty on clinical grounds. Determining whether associated complications such as
necrotizing fasciitis, myonecrosis, sepsis, septic embolization, or intraabdominal complications
are present is important; failure to recognize necrotizing fasciitis or myonecrosis may result in
delay of appropriate surgical intervention.

In neonates with omphalitis and either delayed separation of the umbilical cord or neutropenia,
the presence of a predisposing anatomic abnormality (eg, patent urachus) or an immunologic
problem (eg, leukocyte adhesion deficiency or a neutrophil disorder) must be considered.

Persistence of a portion of the embryonic tract between the bladder and the umbilicus results in
various urachal anomalies. A patent urachus, a free communication between the bladder and
umbilicus, may result in persistent drainage from the umbilicus, which can be mistaken as a sign
of infection. Incomplete obliteration of the urachal remnant may lead to the formation of an
isolated extraperitoneal cyst, which can present with a secondary bacterial infection mimicking
omphalitis. However, these cysts rarely present with secondary infections in the neonatal period.

Umbilical granulomas, when they occur, typically develop after the first week of life. Composed
of excess granulation tissue at the base of the umbilical cord, most granulomas appear after the
umbilical cord has separated, although sometimes they are found with incomplete cord
separation. The granulomas, which range from 3-10 mm in size, are pink or dark pink in color
and have a soft, velvety texture. Because most of these granulomas fail to epithelialize, they are
associated with persistent inflammation accompanied by serous or serosanguinous drainage and
a tendency for easy bleeding with trauma. Treatment options include topical applications of
silver nitrate, excision and application of absorbable hemostatic materials, cryosurgery, and
application of various desiccants.

The relatively high incidence of necrotizing fasciitis following omphalitis in the newborn, with
its attendant morbidity and mortality, requires close observation and early surgical intervention if
any question surrounds the diagnosis.

Laboratory Studies
Routinely obtain specimens from umbilical infection and submit specimens for Gram stain and
culture for aerobic and anaerobic organisms. If myonecrosis is suspected, obtain specimens from
the involved muscle rather than the wound surface.

Obtain blood cultures for aerobic and anaerobic organisms.

Obtain a complete blood cell (CBC) count with manual differential. Neutrophilia or neutropenia
may be present in acute infection. An immature-to-total neutrophil ratio greater than 0.2 may be
a useful indicator of systemic bacterial infection in the first few days of life. Thrombocytopenia
may be present.
Other nonspecific laboratory tests, either alone or in combination with a defined scoring system,
have been evaluated for their usefulness in rapid detection of bacterial infection in neonates,
although none has demonstrated sensitivity or specificity sufficiently high to dictate clinical care.
The tests include the following:

 C-reactive protein levels

 Procalcitonin
 Erythrocyte sedimentation rate
 Neutrophil CD64

The following laboratory studies are suggested in neonates in whom sepsis and disseminated
intravascular coagulation (DIC) are suspected:

 Peripheral blood smear

 Prothrombin time
 Activated partial thromboplastin time
 Fibrinogen
 Fibrinogen split products or D-dimer

Other abnormalities associated with serious systemic infection include the following:

 Hypoglycemia
 Hypocalcemia (often related to saponification with fatty acids released by bacterial lipases in
subcutaneous tissue)
 Metabolic acidosis

Approach Considerations
Transfer

Critically ill infants, including those who may require surgical intervention, may require transfer
to an intensive care unit equipped to treat infants. Transport the patient with advanced life
support technology in place and qualified personnel in attendance. Options for further treatment
or intervention must be immediately available. (See Transport of the Critically Ill Newborn.)

Consultations

The following consultations may be indicated:

 Infectious disease specialist: For appropriate antimicrobial selection, particularly if necrotizing

fasciitis or myonecrosis occurs
 Surgeon: If necrotizing fasciitis or myonecrosis is suspected (consult early in the disease course)

Medical Care
Treatment of omphalitis (periumbilical edema, erythema, and tenderness) in the newborn
includes antimicrobial therapy and supportive care. Examine these patients frequently, and
immediately debride any tissue that shows signs of advancing infection or necrosis.

Antimicrobial therapy

Note the following:

 Include parenteral antimicrobial coverage for gram-positive and gram-negative organisms. A

combination of an antistaphylococcal penicillin vancomycin and an aminoglycoside antibiotic is
recommended.
 Some believe that anaerobic coverage is important in all patients. Omphalitis complicated by
necrotizing fasciitis or myonecrosis requires a more aggressive approach, with antimicrobial
therapy directed at anaerobic organisms as well as gram-positive and gram-negative organisms.
Metronidazole or clindamycin may provide anaerobic coverage.
 Pseudomonas species have been implicated in particularly rapid or invasive disease.
 As with antimicrobial therapy for other infections, consider local antibiotic susceptibility
patterns, particularly patterns of S aureus and enterococcal susceptibility.
 Additional topical therapy with triple dye, bacitracin, and other antimicrobials has been
suggested in addition to parenteral antibiotic therapy, but such treatment is unproven.

Supportive care

In addition to antimicrobial therapy, supportive care is essential to survival. These measures

include the following:

 Provide ventilatory assistance and supplementary oxygen for hypoxemia or apnea unresponsive
to stimulation.
 Administer fluid, vasoactive agents, or both (as indicated) for hypotension.
 Administration of platelets, fresh frozen plasma, or cryoprecipitate for disseminated
intravascular coagulation (DIC) and clinical bleeding is suggested.
 Treat infants at centers capable of supporting cardiopulmonary function.

Diet

When omphalitis is associated with systemic symptomatology, do not feed the infant enterally.
Enteral feedings may be resumed once the acute infection improves and associated septic ileus
resolves. In these infants, parenteral nutrition is required.

Other treatment considerations

Consider the following:

 Monitor patients for progression of disease. Early surgical intervention may be lifesaving.
  In uncomplicated cases, expect erythema of the umbilical stump to improve within 12-24 hours
after the initiation of antimicrobial therapy. Failure to respond may suggest disease progression,
presence of an anatomic defect, or an immunodeficiency state.
 For patients who have undergone surgical intervention, postoperatively, inspect the gross
appearance of the tissue on the perimeter of the debrided area several times a day or more
frequently if the infant has any unresolved signs of systemic infection.
 Monitor aminoglycoside levels, and adjust the dose accordingly.
 Monitor and manage metabolic abnormalities, which are common in any ill neonate.
 The role of hyperbaric oxygen in treatment of patients with anaerobic necrotizing fasciitis and
myonecrosis is controversial because no prospective controlled data are available and pediatric
data are scarce. In the treatment chambers, tissue levels of oxygen are maximized when the
patient breathes 100% oxygen at 2-3 atm. The delivery of high concentrations of oxygen to
marginally perfused tissues may have a detrimental effect on the growth of anaerobic organisms
and improve phagocyte function. However, surgical therapy has the highest priority, and
initiation of hyperbaric oxygen therapy should not delay transport to a facility with staff capable
of performing surgical debridement.

Patient/caregiver education

The American Academy of Pediatrics Committee on Fetus and Newborn guidelines emphasize
the importance of parental/caregiver education regarding signs and symptoms of omphalitis. [9]

Referral for psychosocial counseling may assist the family in coping with a critically ill infant.
For patient education resources, see Children's Health Center, as well as Umbilical Cord Care.

Surgical Care
Management of necrotizing fasciitis and myonecrosis involves early and complete surgical
debridement of the affected tissue and muscle. [42, 48] Consider the following:

 Although the extent of debridement depends on the viability of tissue and muscle, which is
determined at the time of surgery, excision of preperitoneal tissue (including the umbilicus,
umbilical vessels, and urachal remnant) is critically important in the eradication of the infection.
 These tissues can harbor invasive bacteria and provide a route for progressive spread of
infection after less extensive debridement.
 Delay in diagnosis or surgery allows progression and spread of necrosis, leading to extensive
tissue loss and worsening systemic toxicity.
 Several surgical procedures may be required before all nonviable tissue is removed.

Routine postsurgical follow-up care is indicated. Infants developing portal vein thrombosis
require follow-up care for complications associated with portal hypertension.

Prevention
The World Health Organization (WHO) recommends dry cord care after institutional delivery or
after home delivery in locales where neonatal mortality rates are low primarily because there
have not been strong studies supporting routine application of topical antiseptic agents. [8,
49]
These recommendations for dry cord care in developed countries are supported by large,
systematic reviews. [50, 51, 52]

A Cochrane review of 12 trials showed that information regarding the effects of chlorhexidine
applied to the umbilical cords of newborns in hospital settings on neonatal mortality is not clear.
[52]
Two trials had moderate-quality evidence that chlorhexidine cord cleansing reduced the risk
of omphalitis/infections compared with dry cord care. Another two trials had low-quality
evidence that no difference exists for omphalitis/infections between groups receiving
chlorhexidine skin cleansing and dry cord care. However, there was high-quality evidence that
chlorhexidine skin or cord care in the community setting led to a 50% reduction in the incidence
of omphalitis and a 12% reduction in neonatal mortality. [52] No difference was noted for
neonatal mortality or the risk of infections in hospital settings for maternal vaginal chlorhexidine
use compared to usual care.

Dry cord care may not be appropriate in certain populations. Because there is increased risk of
omphalitis and other serious neonatal infections when delivery occurs in a nonhygienic
environment and neonatal mortality is high, application of a topic antiseptic agent to the cord
may be indicated. The WHO recommends topical application of chlorhexidine to the umbilical
cord stump during the first week of life for neonates born at home where hygienic conditions are
poor or neonatal mortality is high (>30 deaths per live births). [8]

Several trials comparing dry cord care to chlorhexidine application have been completed in a
variety of settings. [53, 54, 55] In addition, there have been several meta-analyses and/or Cochrane
reviews analyzing studies of topical cord care. [50, 51, 52, 53, 56, 57, 58, 59] The interpretations of the
results of these trials in aggregate have been controversial, with conclusions on a spectrum from
chlorhexidine should be applied universally to no changes to the WHO guidelines are indicated.
[60, 61, 62]
These various interpretations may be due to a number of factors, including comparisons
of different study groups in locales with varying rates of neonatal sepsis, varying end points for
the studies, and variation in control groups. However, overall, the recommendations for topical
antisepsis cord care in locales where hygienic conditions are poor or neonatal mortality is high
are supported by these systematic reviews, [56, 57] noting this intervention significantly reduced
the incidence of omphalitis as well as overall neonatal mortality. [54, 58, 59] Optimal dosing
strategies for chlorhexidine application are unknown. [56]

In 2016, the American Academy of Pediatrics Committee on Fetus and Newborn guidelines
updated their guidelines for umbilical cord care in the newborn. [9] The conclusions of this report
were essentially the same as those of the WHO. Application of antimicrobial agents to the cord is
appropriate in resource poor settings where the risk of omphalitis and its complications are high,
whereas the benefit in high-resource settings is unclear. These guidelines also emphasize the
importance of parental education regarding signs and symptoms of omphalitis.

Dry cord care leads to earlier separation of the cord after birth. It also leads to reports of wetter,
odoriferous cords (described by some parents as "nasty," "smelly," or "yucky") and higher
colonization rates with S aureus and other bacteria (sometimes dramatically so). Whether this
increased colonization rate is, or will be, associated with higher rates of omphalitis or other
neonatal infection is controversial. Some studies have suggested that higher colonization rates
are associated with increased infection, whereas others have not.

Medication Summary
A combination of parenterally administered antistaphylococcal penicillin and an aminoglycoside
antibiotic is recommended for uncomplicated omphalitis. Intravenous antimicrobial therapy with
clindamycin or metronidazole may be indicated in some cases. Some believe that anaerobic
coverage also should be considered in all infants with omphalitis. Omphalitis complicated by
necrotizing fasciitis or myonecrosis requires a more aggressive approach, and antimicrobial
therapy directed at anaerobic organisms, as well as gram-positive and gram-negative organisms,
is suggested. Metronidazole may be added to the combination of antistaphylococcal penicillin
and aminoglycoside to provide anaerobic coverage, or clindamycin may be substituted for
antistaphylococcal penicillin. As with antimicrobial therapy for other infections, consider local
antibiotic susceptibility patterns and results of blood and biopsy specimen culturing.

Application of antimicrobial agents to the cord is appropriate in resource poor settings where the
risk of omphalitis and its complications are high. In these cases, antimicrobial agents applied to
the umbilicus have been shown to decrease bacterial colonization and to prevent omphalitis and
associated complications.

Several effective umbilical cord care regimens are available, including the following:

 Triple dye applied once daily until cord separation

 Triple dye applied once, then alcohol applied daily until cord separation
 Triple dye applied once, then no further antimicrobial treatment
 Povidone-iodine, silver sulfadiazine, or bacitracin ointment applied daily until cord separation
 Chlorhexidine 4% applied once, with no further antimicrobial treatment
 Chlorhexidine 4% applied daily until cord separation
 Salicylic sugar powder (97% powdered sugar, 3% salicylic acid) applied daily until cord
separation

Topical therapy is also commonly used in attempts to control outbreaks of omphalitis.

Blood products (eg, packed red blood cells, platelets, fresh frozen plasma) and other medications
(eg, inotropic agents, sodium bicarbonate) may be required for supportive care.

Antibiotics
Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in
the context of the clinical setting. [63]

Gentamicin (Garamycin)
Aminoglycoside antibiotic for gram-negative coverage. Used in combination both with an agent
against gram-positive organisms and with an agent that covers anaerobes.

Oxacillin (Bactocill)

Antistaphylococcal penicillin. Bactericidal antibiotic that inhibits cell wall synthesis. Used in the
treatment of infections caused by penicillinase-producing staphylococci. May be used to initiate
therapy when staphylococcal infection is suspected.

Clindamycin (Cleocin)

Used to treat infections caused by anaerobic bacteria. Lincosamide for treatment of serious skin
and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic
streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of
peptidyl tRNA from ribosomes causing RNA-dependent protein synthesis to arrest.

Metronidazole IV (Flagyl)

Anaerobic antibiotic that also has amebicide and antiprotozoal actions.

Ampicillin

Broad-spectrum penicillin. Interferes with bacterial cell wall synthesis during active replication,
causing bactericidal activity against susceptible organisms. Bactericidal for organisms, such as
GBS, Listeria, non-penicillinase-producing staphylococci, some strains of Haemophilus
influenzae, and meningococci.

Vancomycin (Vancocin, Vancoled)

Bacteriocidal agent against most aerobic and anaerobic gram-positive cocci and bacilli.
Especially important in the treatment of MRSA. Recommended therapy when coagulase-
negative staphylococcal sepsis is suspected.