**3.1 Colonisation and infection**

112 Atopic Dermatitis – Disease Etiology and Clinical Management

coagulase-negative *Staphylococcus*, a major member of normal microbiota, and *S. aureus*, a harmful enemy from the environment that irritates the skin. In the skin of AD patients, the

Coagulase-negative *Staphylococcus* provides a protective function to the skin by producing antimicrobial peptides against *S. aureus* (Cogen et al., 2010). Therefore, the growth of *S. aureus* leads to their production of exotoxins which exaggerate AD while the coagulasenegative *Staphylococcus* tries to eliminate them by they produce. The skin of AD patients is a

Furthermore, *Stenotrophomonas maltophilia*, a previously unidentified bacterium on the skin and occasionally causes opportunistic sepsis in immunodeficient patients, was detected on the skin of patients with AD at a high frequency (Dekio et al., 2007). This species is closely related to *Pseudomonas* species and is considered to have high pathogenicity. This bacterial

In addition to bacteria, fungal species also contribute to the pathogenesis of AD. Although there is no convincing report that the *Malassezia* species in patients with AD differs from the *Malassezia* species of healthy humans, Sugita et al. (2004) reported that the genome sequence of the intergenic spacer (IGS) of *M. restricta*, one of the major members of the microbiota, differs between AD patients and healthy humans. Possessing a certain group of strains of *M.* 

Moreover, 10-20% of patients with AD have specific IgE against *Malassezia* species in the serum and show a positive result to the prick test of the fungus. Such AD patients tend to present a diffuse erythema on the face and neck (Darabi et al., 2008). This condition is often observed in adult humans and is improved by frequent washing, unlike most

A complete picture of the skin microbiota has not yet been attained. Therefore, its distinction in AD patients is also underinvestigated. However, biochemical and genomic techniques focused on specific molecules should lead to a total understanding in the near future.

The skin of patients with AD often causes a variety of secondary infections. This may be due to dryness, impairment of natural immunity, scratching behaviour, and application of topical drugs. The dryness attracts pathogens because the rough surface yields a high point of scaling that easily captures environmental pathogens and deep crevices that make the pathogens accessible to deeper tissues. The presence of *S. aureus* in high numbers irritates the skin and results in aggravation of dryness. The decrease of antimicrobial peptides in the sweat exaggerates the possibility of the pathogen growing at the site. Extensive scratching by the patient enlarges the area of infection and also helps the pathogen to degrade the skin and invade it further. Topical drugs commonly used for treatment of AD, such as steroids and pimecrolimus/tacrolimus, suppress the immune function of the host and allows infectious microorganisms to grow at the site. In such cases, the diagnosis becomes difficult because it is

not easy to ascertain that the lesion is caused by a secondary infection or by AD itself.

former is higher than usual while the latter also increases.

battlefield of outnumbered 'the good' and growing 'the evil'.

species may thus plays a specific role in development of AD.

*restricta* may be a worsening factor of AD.

**3. Infections in atopic dermatitis** 

**2.3.2 Fungus in AD** 

symptoms of AD.

**2.3.3 Conclusion** 

Colonisation is a condition wherein parasitic organisms become attached to the skin and multiply without an apparent reaction of the host. Colonization is clinically invisible but may be detected in a culture test. When a microorganism colonises a host, there is a possibility that the microorganism will only harm the host incrementally. It may therefore become a hidden pathogen.

On the other hand, infection accompanies apparent host reaction in addition to colonisation. A host reaction is a kind of defence mechanism, and at the skin it is expressed as inflammation or oozing. Inflammation is a cytokine-mediated complex mechanism. Oozing is also a defensive reaction, because serum prevents microorganisms from multiplying. Therefore, when human skin is infected, a mixed reaction of inflammation and oozing occur. The clinical expression of this is redness, oozing, itching, and pain.

The colonisation may change to infection. This is due to a shift of the host defence mechanism (Table 2) and when it occurs, hidden pathogens increase in number and become infectious to do apparent harm; *Streptococcus* species is such an example in AD to develop impetigo. Therefore, doctors should be aware of this phenomenon and instruct patients to avoid activities that may cause such infections.

#### **Possible triggers converting colonisation to infection**


Table 2. Triggers to potentially causing a decline in the host defence mechanisms in the skin of AD patients

#### **3.2 Impetigo**

Impetigo is a bacterial infection caused by *S. aureus* or *Streptococcus* species. The former causes bullous impetigo and the latter causes non-bullous (or crusted) impetigo. This condition is typically seen in children but adult patients with AD are also affected and sometimes pre-sepsis occurs with high fever. In children without AD, the pathogen is considered to originate from the environment, but in patients with AD, it may also originate from their own colonising microbiota.

As these pathogens often reside on the skin of AD patients as members of the microbiota, they may not originate directly come from the outer environment, as they do for impetigo patients without AD. It is impossible to assess whether the pathogen originates from a patient's own microbiota or the environment, but it is meaningful to evaluate the patient's microbiota by using culture analysis after a successful treatment.

The clinical appearance of impetigo in AD patients includes sudden oozing, crust, and itching (Fig. 3). Culture tests using a scrubbed swab usually show the presence of pathogenic Gram-positive cocci. However, culture results require 2-3 days, so treatment should be administered before identification of the pathogen. Therefore, diagnosis by professional observation is needed. Otherwise, Gram stain may be used to visualise the pathogen at the point of consultation. Treatment should include a combination of oral and topical antibiotics. Usually treatment fails when only topical antibiotics are prescribed. Washing helps improvement of the healing process.

Microorganisms and Atopic Dermatitis 115

The impetigo sites of AD patients are often very itchy and patients tend to scratch too much and exaggerate the infection. Scratching not only worsens the site but also inoculates the pathogen at other sites and other individuals. Doctors should advise the patient not to touch the site. Covering with a gauze or a sticking plaster helps to do this. The site should be kept

In adult patients, it sometimes worsens at the neck (Fig. 4). This is because skin of the site is fragile and easy to scratch. A severe condition at this site causes difficulties in rotating the head because of the pain at the skin. This lowers activities of daily living of the patients.

Tinea corporis is a fungal infection caused by ringworm-forming fungi, such as *Trichophyton rubrum*. The pathogen is not contained in the microbiota and is thus considered to originate

The symptom is an erythema with a margin and slightly raised edge (Fig. 5). The erythema grows daily. In patients without AD, a strong itch is a hallmark, but patients with AD tend to suppress the itchy sensation with the use of ointments. This has the effect of masking this hallmark. Attention is needed to diagnose this infectious condition and careful examination

The filamentous fungus is easily seen in microscopic observation of the scales using the KOH technique (Fig. 6). Usually there is no need to perform a culture test, but it should be done if the patient is involved in close contact sports such as wrestling. This is because *Trichophyton tonsurans*, one of the pathogens transmitted by close contact, is difficult to observe using KOH technique. In most cases, the recommended treatment is a topical antifungal drug combined with discontinuance of topical application of drugs for AD. Oral

from patients with tinea pedis (athlete's foot) or from the outer environment.

dry beneath the covering.

with a microscope is required.

antifungals should be administered in severe cases.

Fig. 5. Ring-like erythema on the back of a patient with AD.

**3.3 Tinea corporis** 

Fig. 3. Mild impetigo in a child with AD exhibiting erythema and crust.

Fig. 4. Severe impetigo in an adult patient with AD. Erythema, oozing, and crust are visible.

The impetigo sites of AD patients are often very itchy and patients tend to scratch too much and exaggerate the infection. Scratching not only worsens the site but also inoculates the pathogen at other sites and other individuals. Doctors should advise the patient not to touch the site. Covering with a gauze or a sticking plaster helps to do this. The site should be kept dry beneath the covering.

In adult patients, it sometimes worsens at the neck (Fig. 4). This is because skin of the site is fragile and easy to scratch. A severe condition at this site causes difficulties in rotating the head because of the pain at the skin. This lowers activities of daily living of the patients.

### **3.3 Tinea corporis**

114 Atopic Dermatitis – Disease Etiology and Clinical Management

Fig. 3. Mild impetigo in a child with AD exhibiting erythema and crust.

Fig. 4. Severe impetigo in an adult patient with AD. Erythema, oozing, and crust are visible.

Tinea corporis is a fungal infection caused by ringworm-forming fungi, such as *Trichophyton rubrum*. The pathogen is not contained in the microbiota and is thus considered to originate from patients with tinea pedis (athlete's foot) or from the outer environment.

The symptom is an erythema with a margin and slightly raised edge (Fig. 5). The erythema grows daily. In patients without AD, a strong itch is a hallmark, but patients with AD tend to suppress the itchy sensation with the use of ointments. This has the effect of masking this hallmark. Attention is needed to diagnose this infectious condition and careful examination with a microscope is required.

The filamentous fungus is easily seen in microscopic observation of the scales using the KOH technique (Fig. 6). Usually there is no need to perform a culture test, but it should be done if the patient is involved in close contact sports such as wrestling. This is because *Trichophyton tonsurans*, one of the pathogens transmitted by close contact, is difficult to observe using KOH technique. In most cases, the recommended treatment is a topical antifungal drug combined with discontinuance of topical application of drugs for AD. Oral antifungals should be administered in severe cases.

Fig. 5. Ring-like erythema on the back of a patient with AD.

Microorganisms and Atopic Dermatitis 117

Fig. 7. Kaposi's varicelliform eruption. Crusted lesions around an eye of a patients with AD.

Molluscum contagiosum is an infection caused by molluscum contagiosum virus (MCV). The condition is frequent in healthy children and also in patients (children and adults) with AD. The pathogen is not a member of the microbiota in AD skin so its presence reflects a simple infection from other patients or the environment. Because the clinical picture is far more severe in patients with AD and management strategy is different, it warrants a

The skin lesions are whitish papules with diameters of 1 mm to 4 mm (Fig. 8). Scratching causes breakage of the surface of the papule and releases the viral ingredients. This leads to spreading of the lesions (Koebner phenomenon). In patients without AD, itch is not severe and often insensible, but patients with AD usually feel itch within the area of scattered

In healthy children, the lesions disappear within months, but in patients with AD, the lesions may persist for years. The reason for this may be impairment of skin barrier and the use of topical anti-inflammatory drugs for the treatment. Molluscum contagiosum is not harmful to humans, but to prevent transmission to others, extirpation using tweezers is

lesion and scratching behaviour worsens the disease (Fig. 9).

**3.5 Molluscum contagiosum** 

discussion in this chapter.

highly recommended.

Fig. 6. Observation of a scale of the patient by KOH technique.

#### **3.4 Kaposi's varicelliform eruption**

Kaposi's varicelliform eruption (KVE) is an infection caused by herpes simplex virus (HSV). It rarely occurs in individuals without AD, but occurs often in patients with severe AD. HSV is also a pathogen of herpes simplex, a common latent infection of skin, and has life-long persistence in the ganglia of the sensory nerve. Regarding the aetiology of KVE, both persistent HSV in the ganglia and environmental HSV can be the possible cause of the disease. If the patient has a history of developing herpes simplex near the KVE site, it is natural to consider that the pathogen originated from the ganglia via sensory nerve, but otherwise it is impossible to determine the origin of the virus.

Once HSV begins to multiply on the surface of the skin, a varicella-like pustule with an erythematous surrounding appears. The number of the pustules increases and they become crusted. The formation of a crust usually reflects a secondary bacterial infection. Within a couple of days, the area of the lesion exceeds the size of a hand and a high fever develops (Fig. 7). Treatment must include a systemic antiviral drug for HSV (such as aciclovir or valaciclovir) and an antibacterial drug to treat the secondary bacterial infection with Gram-positive cocci.

In some rare cases, KVE recurs and it becomes difficult to manage. In such cases, preventive antivirals are efficient. Administration of topical acyclovir once in two days, in addition to the usual topical treatment of AD, is effective in many cases. In cases where this treatment is not effective, oral valaciclovir at a low dosage is reported to be effective (Dekio et al., 2011).

Kaposi's varicelliform eruption (KVE) is an infection caused by herpes simplex virus (HSV). It rarely occurs in individuals without AD, but occurs often in patients with severe AD. HSV is also a pathogen of herpes simplex, a common latent infection of skin, and has life-long persistence in the ganglia of the sensory nerve. Regarding the aetiology of KVE, both persistent HSV in the ganglia and environmental HSV can be the possible cause of the disease. If the patient has a history of developing herpes simplex near the KVE site, it is natural to consider that the pathogen originated from the ganglia via sensory nerve, but

Once HSV begins to multiply on the surface of the skin, a varicella-like pustule with an erythematous surrounding appears. The number of the pustules increases and they become crusted. The formation of a crust usually reflects a secondary bacterial infection. Within a couple of days, the area of the lesion exceeds the size of a hand and a high fever develops (Fig. 7). Treatment must include a systemic antiviral drug for HSV (such as aciclovir or valaciclovir) and an antibacterial drug to treat the secondary bacterial

In some rare cases, KVE recurs and it becomes difficult to manage. In such cases, preventive antivirals are efficient. Administration of topical acyclovir once in two days, in addition to the usual topical treatment of AD, is effective in many cases. In cases where this treatment is not effective, oral valaciclovir at a low dosage is reported to be effective

Fig. 6. Observation of a scale of the patient by KOH technique.

otherwise it is impossible to determine the origin of the virus.

**3.4 Kaposi's varicelliform eruption** 

infection with Gram-positive cocci.

(Dekio et al., 2011).

Fig. 7. Kaposi's varicelliform eruption. Crusted lesions around an eye of a patients with AD.

#### **3.5 Molluscum contagiosum**

Molluscum contagiosum is an infection caused by molluscum contagiosum virus (MCV). The condition is frequent in healthy children and also in patients (children and adults) with AD. The pathogen is not a member of the microbiota in AD skin so its presence reflects a simple infection from other patients or the environment. Because the clinical picture is far more severe in patients with AD and management strategy is different, it warrants a discussion in this chapter.

The skin lesions are whitish papules with diameters of 1 mm to 4 mm (Fig. 8). Scratching causes breakage of the surface of the papule and releases the viral ingredients. This leads to spreading of the lesions (Koebner phenomenon). In patients without AD, itch is not severe and often insensible, but patients with AD usually feel itch within the area of scattered lesion and scratching behaviour worsens the disease (Fig. 9).

In healthy children, the lesions disappear within months, but in patients with AD, the lesions may persist for years. The reason for this may be impairment of skin barrier and the use of topical anti-inflammatory drugs for the treatment. Molluscum contagiosum is not harmful to humans, but to prevent transmission to others, extirpation using tweezers is highly recommended.

Microorganisms and Atopic Dermatitis 119

When the skin of the face and the neck is affected in AD patients, the lesions often become itchy, and scratching releases HPV into the nearby skin. It results in an assembled manner of the lesions (Koebner phenomenon). The itching of the lesions is often ignored because the lesions are not itchy in patients without AD. Patients often apply topical anti-inflammatory drug to the lesion but it should be avoided because it promotes the proliferation of HPV.

The first step of treatment should include cryotherapy using liquid nitrogen. When the lesion successfully drops off as a consequence, it is appropriate to apply topical anti-

Therefore, the treatment for such HPV is often complex and difficult.

Fig. 9. Severe molluscum contagiosum in an infant with AD.

inflammatory ointment immediately.

Fig. 8. Molluscum contagiosum on the chest of a patient with AD.
