The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Wendy C. Matsuno. This current third edition chapter is a revision and update of the original author’s work.
A 15-year-old male presents to the office with itching to his head for two weeks and has noticed that some hair has fallen out. He also has some itching to his arms. He otherwise is healthy and participates in athletics including wrestling at his school.
Exam: VS T 37.0, P 68, R 22, BP 115/78. Height and weight are in the 60th percentile. His scalp is noted to have areas of scale and alopecia. Black dot hairs are seen close to the scalp. Suboccipital lymphadenopathy of 1 cm is palpated. He also is noted to have erythematous circular plaques with scale and central clearing to his arms.
Due to his clinical findings, the patient is started on griseofulvin by mouth as well as topical ketoconazole. A fungal culture is obtained which returns positive for Trychophyton tonsurans. Upon follow up in one month, he is no longer itchy and is starting to have some hair growth in the areas of alopecia. The lesions to his skin have almost completely resolved.
Superficial Fungal Infections
Cutaneous mycoses are fungal infections of the skin, hair, and nails. These infections are common in children and adolescents and are widespread throughout the world though seen more frequently in tropical climates (1,2). The most common fungi that cause these infections include dermatophytes, Candida species, and Malassezia species. The causative fungi seen depends to some degree on geographic location (2). Other fungi can cause infection, especially in patients who are immunocompromised, which will be discussed later in this chapter.
Worldwide, dermatophytes cause the most common mycotic cutaneous diseases. They belong to the genera Microsporum, Trichophyton, and Epidermophyton and can be classified based on the source of infection. Accordingly, they can be anthropophilic (acquired from humans), zoophilic (acquired from animals), or geophilic (acquired from the soil). Trichophyton rubrum is the most common anthropophilic dermatophyte worldwide. These infections easily spread from person to person (1). Zoophilic dermatophytes do not commonly cause infections in humans though, occasionally, can cause a severe, suppurative, inflammatory response. The most common zoophilic dermatophyte is Microsporum canis. These infections typically do not spread amongst people (2). These organisms spread through direct contact or through a fomite intermediary and invade the epidermis by adhering to the surface keratinocytes (2). A dermatophytic or "id" reaction may be seen due to a hypersensitivity reaction that presents as diffuse, pruritic, vesicular, papular, or eczematous lesions that start in areas distant from the fungal infection (3). The diagnosis is usually made by history and examination. More elaborate, technically laborious measures include examination under a microscope with 10% to 20% potassium hydroxide, fungal cultures of scrapings from the lesion on Sabouraud’s agar, or examination with Wood’s lamp (1). Candida and fungal infections are extensive and briefly tabulated in table 1.
Table 1 – Abbreviated characteristics of candida and fungal infections
| Common site(s) of initial infection | Organisms | First line treatment(s) | |
| Superficial fungal infections | |||
|---|---|---|---|
| Tinea capitis | scalp | T. tonsurans, M. canis, M. audouinii | oral griseofulvin |
| Tinea corporis | body | T. tonsurans, M. canis, T. mentagrophtes, T. rubrum, E. floccosum | topical miconazole, clotrimazole, or tolnaftate |
| Tinea cruris | groin, thigh, pubic, perianal | T. mentagrophytes, T. rubrum, E. floccosum | topical miconazole, clotrimazole, or tolnaftate |
| Tinea unguium, onychomycosis | nails (usually toenails) | T. mentagrophytes, E. floccosum | oral terbinafine, traconazole, fluconazole, or griseofulvin |
| Pityriasis versicolor | upper trunk and neck | Malassezia furfur | topical miconazole, clotrimazole, or selenium sulfide lotion |
| Oral thrush | oral mucosa | Candida species | oral nystatin |
| Candidal diaper rash | diaper region | Candida species | topical miconazole, clotrimazole, or nystatin |
| Candidal vulvovaginitis | vulva, vagina | Candida species | intravaginal topical clotrimazole or miconazole |
| Endemic fungal infections | |||
| Blastomycosis | lungs | Blastomyces species | amphotericin |
| Coccidiodomycosis | lungs, skin, brain | Coccidiodes species | fluconazole |
| Cryptococcosis | lungs, skin, brain | Cryptococcus species | fluconazole, amphotericin |
| Histoplasmosis | lungs, systemic, brain | Histoplasma capsulatum | itraconazole, amphotericin |
| Paracoccidioidomycosis | lungs, skin, systemic | P. brasiliensis, P. lutzii | itraconazole, amphotericin |
| Sporotricosis | skin, joints, lungs | S. schenckii | itraconazole |
| Invasive fungal infections - mostly in immunocompromised patients | |||
| Invasive candidiasis (IC) | systemic | C. albicans, other candida species | echinocandins |
| Aspergillosis | lungs, systemic | Aspergilla species | voriconazole |
| Mucormycosis | lungs, brain, GI, skin | Rhizopus arrhizus and Mucorales species | amphotericin |
Tinea capitis is a dermatophytic infection of the scalp, typically seen in childhood and more commonly seen in African-American children (1). In the United States, it is most commonly caused by Trichophyton tonsurans, Microsporum canis, and Microsporum audouinii, with T. tonsurans causing up to 95% of infections (3,4). There are three patterns of infection, namely alopecia, seborrheic, and inflammatory. In alopecia, there are one or more oval or round patches with partial to complete alopecia and scaling. Black dot hairs can be seen with T. tonsurans infections, which are hairs that break at the scalp level. Microsporum species cause an incomplete alopecia as hairs break further from the scalp so no black dot hairs are seen. Seborrheic infections have patchy or diffuse gray to white scale. Inflammatory infections have papules, pustules, and crusting, and some patients can also have a tender, boggy mass known as a kerion. Suboccipital and/or posterior cervical lymphadenopathy can be present. It can also occur with tinea corporis so older children that participate in contact sports, especially wrestling, should have a full body examination as well (3). The presence of pruritus, scale, alopecia, and posterior cervical lymphadenopathy is highly suggestive of tinea capitis. The diagnosis can be confirmed with a fungal culture or microscopic evaluation of a potassium hydroxide wet mount. If spores are seen on the inside of the hair follicle, this is consistent with T. tonsurans while spores coating the hair shaft is consistent with M. canis infection. If a Wood’s lamp is used, it will only be helpful if the infection is by a fungus from the Microsporum genus, in which case it would glow blue-green. The differential diagnosis includes alopecia areata, atopic dermatitis, seborrheic dermatitis, trichotillomania, bacterial folliculitis, psoriasis, bacterial abscess, traction alopecia, and seborrheic dermatitis (3,4).
Treatment of tinea capitis always requires systemic medication. Topical agents are ineffective since the infection is usually within the hair follicle and topical medications do not penetrate the tissue sufficiently (4). Griseofulvin is the first-line therapy used in children 2 years and older for at least 6 weeks. Terbinafine granules can be given to children 4 years and older and can potentially be used for a shorter duration than griseofulvin (3). Infections with T. tonsurans are better treated with terbinafine, while M. canis infections are better treated with griseofulvin (1,5). Fluconazole and itraconazole can also be used, though neither are FDA-approved for tinea capitis (4). Topical treatments such as shampoos with selenium sulfide, ketoconazole, or ciclopirox may be used as an adjunct (4). Patients with kerion can be treated concurrently with prednisone (5). All patients should be seen in 1 month to assess response (1,4). With treatment, the areas of alopecia should resolve; however, if a large kerion was present, permanent alopecia may occur (3).
Tinea corporis (or ringworm of the body) is a superficial infection of the skin and can involve the face, trunk, or limbs (4). It is another common fungal infection caused by the dermatophytes Trichophyton tonsurans, Microsporum canis, Trichophyton mentagrophytes, Trichophyton rubrum, and Epidermophyton floccosum (3,4). It is transmitted by direct contact with infected humans, animals, soil, or fomites (4). Small lesions start as erythematous, scaling papules or plaques, and as they enlarge, become annular with a raised border and an area of central clearing. The border can be studded with vesicles and papules. Lesions can be pruritic (1-4). Patients who were previously treated with topical corticosteroids can have lesions called tinea incognito. These lesions have decreased erythema and scale and may no longer be annular. Majocchi granuloma can occur when organisms penetrate hair follicles to the level of the dermis resulting in pustules or nodules (1). Tinea corporis is diagnosed clinically and through microscopic examination of a potassium hydroxide wet mount of skin scrapings or a fungal culture. If a Wood’s lamp is used, Microsporum will appear blue-green (4). The differential diagnoses include pityriasis rosea, granuloma annulare, candidiasis, psoriasis, nummular eczema, and erythema migrans (1,3,4). Topical antifungal agents such as an imidazole (e.g., ketoconazole, miconazole, clotrimazole), allylamine (e.g., terbinafine, naftifine), or tolnaftate can be used to treat tinea corporis (3). Therapy is recommended for 4 to 6 weeks, and should be applied on the lesion and 1 to 2 cm beyond the lesion (1,4). If no improvement is noted after 2 weeks, topical therapy should be switched. If the infection is extensive or unresponsive to topical therapy, griseofulvin, fluconazole, itraconazole, or terbinafine could be used for 4 to 6 weeks (4,5). Topical corticosteroids should not be used due to the risk of Majocchi granuloma and a greater probability of relapse. If a Majocchi granuloma is present, oral antifungal therapy should be used. Athletes can return to matches 72 hours after topical therapy is started and when the affected area can be covered (4).
Tinea cruris, also known as jock itch, is a common superficial fungal infection of the groin as well as the upper thigh and pubic/perianal regions, typically sparing the scrotum. It is seen more commonly in adolescent and adult males and outbreaks can occur in athletic teams. It is uncommon in prepubertal children. It is most commonly caused by Trichophyton mentagrophytes, Trichophyton rubrum, or Epidermophyton floccosum and is seen more commonly in warm, humid environments (3,4). It is acquired through skin-to-skin or indirect contact with desquamated epithelium or hair. Moist conditions including wearing wet clothing or excessive sweating, close-fitting clothing, friction, obesity, and noncotton undergarments are predisposing factors and recurrences are common (1,4). Tinea cruris typically presents with ring-shaped or circular, well-demarcated, erythematous lesions with a raised scaly, pustular, or vesicular border. There is often an area of central clearing. The lesions can be intensely pruritic and scratching can cause lichenification (3,4). Treatment with corticosteroids can cause an altered appearance known as tinea incognito and these patients can also develop Majocchi granuloma which was discussed earlier (4). Like tinea corporis, the diagnosis is made clinically and can be confirmed with potassium hydroxide preparation by scraping the scale on the border of the lesion. Differential diagnosis includes candidiasis, intertrigo, psoriasis, and erythrasma (1,3,4). Treatment of tinea cruris is similar to the treatment of tinea corporis with topical antifungal, and avoidance of predisposing factors. Patients can also use antifungal powders which reduce the risk of recurrence. Oral therapy is typically not needed (3,4).
Tinea pedis, also known as athlete’s foot, is a dermatophyte infection of the feet typically caused by Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum (3). It is seen commonly in adolescents and less commonly in prepubertal children (1,3). It is also more common in males (1). It is caused by contact with infected skin or organisms that live in damp areas. It can easily spread in households (4). Predisposing conditions include wearing occlusive footwear, foot sweating, and exposure to communal areas. About one-third of patients with tinea pedis also have a tinea unguium (onychomycosis) infection (1). Tinea pedis usually starts in the lateral interdigital spaces, then spreads medially, and is most commonly seen in the third and fourth interdigital spaces (1,4). Interdigital infections are most commonly caused by T. rubrum or E. floccosum. Pruritus, erythema, fissures, scaling, peeling, and maceration is seen (1-4). A vesicular infection, caused by T. mentagrophytes, can be seen on the instep of the foot and presents with vesicles, bullae, and erosions (3). "Moccasin foot" is caused by T. rubrum or E. floccosum and presents to the plantar surface and sides of the feet with erythema, scaling, and hyperkeratosis (1,3). The diagnosis is made clinically. If in doubt, it can be confirmed with a potassium hydroxide preparation or fungal culture (3). The differential diagnosis includes contact dermatitis, dyshidrotic eczema, juvenile plantar dermatosis, psoriasis, or pitted keratolysis (1,3). Similar to tinea corporis and tinea cruris, topical antifungals are used to treat tinea pedis. Severe or widespread infections can be treated with oral therapy, including griseofulvin or other antifungal agents such as fluconazole, itraconazole, or terbinafine (5). Predisposing factors should be avoided. The feet should be kept clean and dry and well-ventilated footwear should be worn; topical absorbent antifungal powder can also be used (3,4).
Onychomycosis is a fungal infection of the fingernails or toenails. Tinea unguium refers to an infection specifically caused by the dermatophytes Trichophyton rubrum, Trichophyton mentagrophytes, or Epidermophyton floccosum. It is seen more commonly in adolescents with the incidence increasing with age. While less common, it can also be seen in children (1,3). It has been proposed that children are less affected due to faster nail growth, smaller nail size, and lower incidence of tinea pedis. When children have tinea unguium, it is usually due to close contact with a relative with tinea unguium or tinea pedis (1). Tinea unguium and tinea pedis are commonly seen together. Toenails are more commonly affected (compared to the nails of the hands) and infections are more commonly seen in the deeper nail plate and hyperkeratotic nail bed (1). Subungual onychomycosis, the most common form, presents as thickening of the nail with yellow discoloration. Superficial white onychomycosis presents as white discoloration of the nail with a fine, powdery scale that can also be seen in children (3,4). Thickening of the nail occurs due to accumulation of subungual debris and the nail can become soft (1,4). Infections are typically asymptomatic, though itching can occur (1). The diagnosis is made clinically and can be confirmed with fungal culture, potassium hydroxide preparation, or fungal stain of nail clippings (3,4). The differential diagnosis includes trauma, psoriasis, and so-called twenty-nail dystrophy (4). Oral therapy is typically needed for treatment of subungual onychomycosis of the toenails. Options include terbinafine, itraconazole, fluconazole, and griseofulvin (1,3,5). Milder cases can be treated with topical therapy such as ciclopirox lacquer. Mechanical and chemical debridement of the nail with urea ointment can also be used (4).
Pityriasis versicolor (PV) (previously known as Tinea versicolor) is a common fungal infection of the skin, especially of the upper trunk and neck. It is caused by Malassezia furfur species invading the stratum corneum (3). Malassezia can exist as yeast and mycelia, the latter being the pathogenic form (2). Moisture, heat, and lipid-containing sebaceous secretions cause overgrowth of hyphae which is why infection is more common in hot, humid environments (4). It is primarily seen in adolescents and adults and is rarely seen in children. It is more common in females (1-3). Risk factors for infection include warm temperatures with high humidity, excessive sweating, oily skin, and immunosuppression (1). PV typically presents with small, hypo- or hyperpigmented, round or oval, scaly macules with well-defined borders. Lesions can coalesce into large patches (3). The size and color of the lesions can vary in the same patient. The lesions do not tan in the summer and are darker than the surrounding skin in the winter. Lesions are usually asymptomatic though pruritus can occur (4). The diagnosis can be made clinically. The evoked-scale sign is elicited by stretching the skin, resulting in a visible white patch of scale over the affected area which remains after the skin is released. A Wood’s lamp is also helpful as the lesions will fluoresce yellow-green. Potassium hydroxide preparation shows the classic "spaghetti and meatballs'' appearance with short hyphae and clusters of yeast forms (4). The differential diagnosis includes vitiligo, pityriasis alba, and pityriasis rosea (3). Treatment of PV includes topical azoles, terbinafine cream, or selenium sulfide lotion or shampoo (1,3,5). Repigmentation can take months despite successful treatment (4). Recurrence is common and oral therapy including fluconazole or itraconazole can be used for recurrent or extensive lesions (5).
Candida is the most common cause of mucocutaneous fungal infections in humans in the world (1,2). Candida reproduces through budding and can form long chains called pseudo hyphae. The infective form is called a blastoconidia. There are at least 15 Candida species, the most common being Candida albicans which causes about 50% of Candida infections and is normally found on the mouth, skin, intestinal tract, and vagina (1). Other species that can cause infection include C. tropicalis, C. parapsilosis, C. glabrata, C. krusei, C. guilliermondii, C. lusitaniae, C. dubliniensis, and C. auris (4). Candida infections can be very serious especially in immunocompromised patients and extremely preterm neonates where it can cause a disseminated infection affecting almost all organs (1). Malnutrition, prolonged antibiotic use, indwelling central venous catheter, and endocrine dysfunction can also predispose to Candida infections (2,4). Chronic mucocutaneous candidiasis can be seen in patients with dysfunction of T lymphocytes since that is the primary defense mechanism against Candida infections. It can also be seen in patients with other immunologic disorders, primary immunodeficiency, and HIV (1,4).
Oral candidiasis, or oral thrush, is most commonly seen in newborns and 20% to 40% of healthy children will develop thrush in the first year of life (1). It can be acquired in utero or from passage through the vaginal canal. It is more common in bottle-fed babies (as opposed to breast-fed), in patients with asthma on daily inhaled corticosteroids, and in patients with prolonged antibiotic use (1,3). Patients are often asymptomatic but can also present with fussiness, pain, or poor feeding. Older children may also be asymptomatic or could complain of loss of taste or cotton-like dry mouth. Oral candidiasis is diagnosed clinically by visualizing white adherent plaques that look like curdled milk on the tongue, soft palate, uvula, and/or buccal mucosa. Scraping of the plaques can cause bleeding or erythema at the base of the plaque (1). Further work-up could be done with potassium hydroxide suspension to confirm the diagnosis. Treatment is with oral nystatin suspension. Oral fluconazole could also be used for more severe cases. Nystatin and clotrimazole lozenges, clotrimazole troches, or miconazole mucoadhesive buccal tablets can be used in older children (1,4).
Candidal diaper dermatitis and intertrigo are the most common forms of candidiasis seen in children. Intertrigo is an inflammatory condition of two opposing skin surfaces such as the axillae, inguinal and intergluteal folds, neck folds, and scrotum. Diaper dermatitis is common in diapered infants and almost 50% are caused by candida. The peak incidence is between 3 to 4 months of age (1). The rash often starts at the perianal area and then moves forward to the perineum and inguinal creases and appears as confluent, beefy red patches or plaques with scalloped borders and satellite lesions (1,3). Maceration can be seen with intertrigo. The rash is sometimes itchy and can have ulcerations which may be painful. The diagnosis is made clinically, especially in the presence of satellite lesions. Treatment includes topical nystatin or azoles such as clotrimazole. Patients with severe rash can be treated with oral fluconazole or itraconazole. Barrier diaper creams can also be used and the skin should be kept clean and dry. Diapers should be changed frequently and infants should try to be diaper-free at times, if possible (1).
Vulvovaginitis occurs in 75% of women and Candida vaginitis can be seen in sexually active adolescents. It is uncommon in prepubescent girls, though it can be seen in this population if there is poor or excessive hygiene or chemical irritants. Symptoms include vaginal itching, soreness, burning, irritation, and dyspareunia. Patients have a creamy curd-like vaginal discharge that is often odorless. Vulvar erythema and swelling may be seen on examination (1). Treatment includes intravaginal topical clotrimazole or miconazole which are both more effective than nystatin. Recurrent or refractory cases can be treated with oral fluconazole, itraconazole, or ketoconazole (1,4).
Endemic Fungal Infections
Amphotericin B deoxycholate is a parenteral antifungal agent. It has significant renal and other systemic toxicity. Lipid associated amphotericin B products have been developed to reduce systemic toxicity. These include amphotericin B lipid complex and liposomal amphotericin B. Comparing these three agents is beyond the scope of this chapter. There is ongoing research comparing their efficacy and adverse event rates in the many clinical conditions for which amphotericin B is used. Amphotericin will be mentioned generically to refer to any or all of these products for the remainder of this chapter.
Blastomycosis is caused by Blastomyces species which are thermally dimorphic fungi, existing in a mycelial form at room temperature and a yeast form in infected tissues (4). Infection is acquired from the environment through inhalation of conidia produced from the hyphae of the mycelial form. Outbreaks in the United States are typically seen in the central states and most cases occur in the Ohio and Mississippi river valleys, states bordering the Great Lakes, and southeastern states (1,4). It is found in bird and animal excrement. Activities that disrupt the environment, such as construction, and activities such as fishing and boating are associated with a higher risk of infection (4). Only about 10% of cases occur in children (1). Infections are asymptomatic in up to 50% of cases. The most common symptom in children is cough, along with pulmonary disease. Patients can also have fever, chest pain, and nonspecific symptoms such as myalgia and fatigue. Acute respiratory distress syndrome is rare (4). Disseminated blastomycosis is more common in children, occurring in up to 25% of symptomatic cases, and most often involves the skin and osteoarticular structures. On chest radiographs, consolidation, a mass-like infiltrate, nodules, or patchy pneumonitis can be seen (1,4). Definitive diagnosis is by microscopic identification of thick-walled, broad-based, single budding yeast cells from histopathologic specimens or culture at 37 degrees C. A bronchoalveolar lavage may be needed for children with pneumonia who are unable to produce sputum. There are also chemiluminescent DNA probes that can identify B. dermatitidis, though rare false-positive results occur. An enzyme immunoassay for Blastomyces antigen in urine is also useful and is superior to testing from other sites including serum and bronchoalveolar lavage fluid (4). It is recommended that all children with blastomycosis be treated due to the high rate of dissemination. Initial therapy for severe pulmonary disease consists of amphotericin for 1 to 2 weeks, then transitioning to oral itraconazole for 6 to 12 months. For mild to moderate infection, oral itraconazole alone can be used. The prognosis is worse for older patients, those with cancer or chronic obstructive pulmonary disease, and African-American patients (4).
Coccidioidomycosis, also known as San Joaquin Fever or Valley Fever, is an infection caused by dimorphic Coccidioides species. There are primarily two species of Coccidioides, Coccidioides immitis which is found in California, and Coccidioides posadasii, which is found in the rest of the southwestern United States, northern Mexico, and areas of Central and South America. Coccidioides species are found in the soil and clusters of cases can occur following dust-generating events such as storms. It exists in soil in the mycelial phase as mold that grows into branching, septate hyphae. The hyphae produce infectious arthroconidia, or spores, that become airborne, and infect people through inhalation. In tissue, the arthroconidia enlarge to form spherules which release thousands of endospores that develop into new spherules (4). People with impairment of T-lymphocyte-mediated immunity or receiving immune-modulating medications are at significant risk for severe disease. Others that are at high risk include people of African-American and Filipino ethnicities, women in the third trimester of pregnancy or postpartum, and children under 1 year of age (1,4). Infection is seen less commonly in children, aside from the neonatal period (1). Primary pulmonary infection is asymptomatic or self-limiting in 60% to 65% of cases. In symptomatic cases, weight loss and extreme fatigue are common and can persist for months. Other symptoms include fever, malaise, myalgia, arthralgia, cough, headache, and chest pain. Pleural effusion, empyema, and mediastinal involvement are more commonly seen in children (4). Acute infections can also present solely as cutaneous manifestations such as an erythematous maculopapular rash, erythema multiforme, erythema nodosum, or a verrucous granuloma often found on the nasolabial fold (1,4). Disseminated infection occurs in less than 0.5% of cases. In these instances, the infection can affect the skin, central nervous system, joints, and bones. If untreated, meningitis is fatal (4). The diagnosis is established by serologic, histopathologic, or culture methods. An ELISA test and immunodiffusion can be done, as well as complement fixation to detect IgM and IgG. Spherules can also be seen under 100x to 400x magnification from infected body fluid or tissue and the presence of a mature spherule with endospores is diagnostic. Coccidioides species may also be isolated in culture (1,4). Uncomplicated, asymptomatic patients do not need any treatment. For patients with severe disease or at risk of severe disease, fluconazole is used as primary treatment for 3 to 6 months. For diffuse pneumonia, treatment with amphotericin or high-dose fluconazole is recommended. For disseminated infection that is not in the central nervous system, treatment is with oral fluconazole or itraconazole. For severe or refractory central nervous system infections, intrathecal amphotericin can be used along with an azole. Lifelong treatment is required for coccidioidal meningitis. Hydrocephalus is commonly seen with meningitis and almost always requires a ventricular shunt for decompression (4).
Cryptococcosis is caused by only two of the more than 30 species of Cryptococcus, Cryptococcus neoformans and Cryptococcus gattii. Cryptococcus neoformans is typically found in soil contaminated with bird droppings and cause the majority of infections in humans, especially those in immunocompromised individuals. Crypotococcus gattii is seen in certain trees and the surrounding soil, primarily found in British Columbia, Canada, and the Pacific Northwest United States, as well as in the Aboriginal people in Australia and Papua New Guinea. Infection primarily occurs from inhalation of aerosolized propagules found in contaminated soil or organic material (4). Cryptococcosis infections are typically asymptomatic or mild. Symptomatic pulmonary disease presents with cough, chest pain, and constitutional symptoms though it can also present as acute respiratory distress syndrome and mimic Pneumocystis jirovecii pneumonia. Chest radiographs show solitary or multiple masses, patchy, segmental, or lobar consolidation, or nodular or reticulonodular pattern with interstitial changes. Disseminated disease can be found in the skin, bones, and central nervous system. Disseminated infection is rare in children and when it does occur, it happens in children with T-lymphocyte-mediated immune deficiency such as those with leukemia or lymphoma, underwent a solid organ transplant, taking corticosteroids, congenital immunodeficiencies, and those with acquired immunodeficiency syndrome. Patients with meningitis often have increased intracranial pressure (4). The diagnosis is made by detection of cryptococcal antigen by latex agglutination test, lateral flow immunoassay, enzyme immunoassay, or from a culture. In patients with meningitis, crytococcal antigen is detected in more than 95% of patients. Encapsulated yeast cells can be seen using India Ink stain but this has limited sensitivity and is therefore rarely useful (4). Patients with less severe cryptococcal disease can be treated with oral fluconazole or itraconazole. First-line therapy for patients with serious infections and/or meningitis is amphotericin, or amphotericin B lipid complex in combination with oral flucytosine for at least two weeks until cultures are negative, then switch to oral fluconazole. Patients with meningitis who have elevated intracranial pressure should undergo frequent lumbar punctures (4). Patients with immunosuppression may need prolonged prophylaxis.
Histoplasmosis is the most common endemic fungal infection in humans and is seen in most parts of the world including Africa, Americas, Asia, and Europe. It is highly endemic to the central and eastern portions of the United States, especially in the Mississippi, Ohio, and Missouri River valleys, as well as Argentina, Central America, and the northernmost part of South America (1,4). It is caused by Histoplasma capsulatum which is also a dimorphic fungus, growing as a spore-bearing mold in the environment and converting to the yeast phase at body temperature. Infection is acquired by inhalation of conidia that are aerosolized when soil is disturbed. Histoplasma is known to be present in bat guano and bird droppings so infections can also occur after playing in hollow trees or caving (4). Less than 5% of people infected with Histoplasma capsulatum have symptoms (1,4). Most symptomatic patients present with acute pulmonary histoplasmosis, a self-limited illness with fever, chills, malaise, and a nonproductive cough. Radiographic findings may include hilar or mediastinal adenopathy or diffuse reticulonodular or interstitial pulmonary infiltrates. Most patients recover in 2 to 3 weeks. Severe pulmonary infection can occur after exposure to a large inoculum of conidia and symptoms include high fever, hypoxemia, acute respiratory distress syndrome, and diffuse reticulonodular infiltrates. Rarely, mediastinal lymphadenitis can be seen which can cause airway encroachment in younger children. Inflammatory syndromes such as pericarditis can occur and adolescents and adults can develop erythema nodosum. Progressive disseminated histoplasmosis (PDH) can occur in healthy children under 2 years or in older children with primary or acquired cellular immune dysfunction. It can either develop rapidly or as a chronic, slowly progressive disease. Early symptoms include prolonged fever, failure to thrive, and hepatosplenomegaly. If left untreated, malnutrition, mucosal irritation, diffuse adenopathy, pneumonitis, pancytopenia, disseminated intravascular coagulation, and gastrointestinal bleeding can occur. The central nervous system is involved in 5% to 25% of cases for those with chronic PDH, which more commonly occurs in adults with immune suppression (4). A quantitative enzyme immunoassay to detect H. capsulatum polysaccharide antigen is the preferred testing method. It is most sensitive in progressive disseminated infection. For acute, self-limited pulmonary infections, the test may only be positive briefly at the start of infection so a negative test does not rule out the infection. Antibody detection testing can also be used for patients with subacute or chronic pulmonary disease and central nervous system involvement but antibodies take 4 to 8 weeks to appear. Culture can provide a definitive diagnosis and can be obtained from blood, tissue, bone marrow, and sputum (1,4). Treatment is not required for immunocompetent children with uncomplicated or mild-to-moderate acute pulmonary infection. However, if the patient does not improve after 4 weeks, itraconazole should be used for 6 to 12 weeks. Disseminated histoplasmosis should be treated with a lipid formulation of amphotericin B. Concurrently with an antifungal, methylprednisolone could also be used for the first 1 to 2 weeks for severe respiratory complications or if there is adenopathy causing airway obstruction. After clinical improvement, patients should be switched to itraconazole for the duration of therapy. Infants or children with moderate or severe PDH should also be treated with at least 2 weeks of a lipid formulation of amphotericin B and then switched to oral itraconazole for at least 12 months (4).
Paracoccidioidomycosis, formerly known as South American Blastomycosis, is seen in Latin America, from Mexico to Argentina, with 80% of cases in Brazil. Soil is thought to be the reservoir of infection, though this is not definitively established. It is also thought to spread through inhalation, but the true mode of transmission is also not known. Infection is caused by Paracoccidioides brasiliensis, another thermally dimorphic fungi with yeast and mold phases. Armadillo are known to be a reservoir of P. brasiliensis. A new species, Paracoccidioides lutzii, has also been found to cause paracoccidioidomycosis. 90% to 95% of cases occur in adults and typically affect the lungs (4). Infection in the young host can follow an acute or subacute presentation. The initial pulmonary infection is frequently asymptomatic, then followed by dissemination. Dissemination of the infection results in lymphadenopathy and involvement of the bone marrow, liver, and spleen. Skin lesions are also seen on the face, neck, and trunk. Involvement of the mucus membranes, bones, and joints is less common. The chronic form of illness is typically seen in adults, and can present localized to the lungs or disseminated. Infection can be latent for years before causing illness (4). The diagnosis is confirmed by visualization of fungal elements with round, multiple-budding yeast cells with a pilot’s wheel appearance. These can be detected in sputum, bronchoalveolar lavage specimens, ulcer scrapings, or tissue biopsies. Paracoccidioides can also be grown on culture. Antibody detection with semiquantitative immunodiffusion is a preferred test and widely used in endemic areas (4). For less severe or localized infections, oral itraconazole is the first-line therapy, with oral solution preparations being preferred over capsules. Prolonged treatment for at least 9 to 18 months is necessary. Voriconazole is an alternative, but its use has not been widely studied. Oral trimethoprim-sulfamethoxazole is also an alternative though inferior to itraconazole and voriconazole and it must be given for at least 2 years. Amphotericin B is only used for severe cases; patients can then be transitioned to oral therapy after clinical improvement, usually in 3 to 6 weeks (4).
Sporotrichosis is caused by Sporothrix schenckii, another thermally dimorphic fungus. It is also found as a mold or mycelial form at room temperature and becomes a budding yeast at body temperature. S. schenckii is comprised of at least 6 species and S schenckii sensu stricto causes the majority of infections. Infections are seen worldwide but are most common in tropical and subtropical regions of Central and South America and parts of North America and Asia. S schenckii is found in soil and plant material. Thorny plants such as rose bushes or pine trees are common causes of infection due to pricks from their thorns or needles (4). Sporotrichosis can be divided into cutaneous or extracutaneous presentations. There are three cutaneous patterns seen with sporotrichosis. The first is a classic lymphocutaneous process seen more commonly in adults. It occurs after minor trauma with a resulting painless papule that enlarges and becomes a firm, slightly tender subcutaneous nodule that can ulcerate or have a violaceous color. Other lesions can develop along the lymphatic distribution of the primary lesion. A localized cutaneous form, also called a fixed cutaneous form, is more commonly seen in children. Patients have a solitary crusted papule, or papuloulcerative, or nodular lesion most commonly on the face and extremities. Lymphatic spread is not typically seen. A disseminated cutaneous form of infection is seen in immunocompromised children but is rare. Extracutaneous sporotrichosis occurs in 20% of cases and is seen in immunocompromised patients or due to unusual areas of trauma. Osteoarticular infection can result from local inoculation or hematogenous spread and the wrists, elbows, knees, and ankles are most commonly affected. Pulmonary sporotrichosis, a rare form, occurs from inhalation of aerosolized conidia and resembles tuberculosis. Disseminated infection occurs from hematogenous spread from the skin or lungs and can involve multiple areas including the eyes, central nervous system, pericardium, and genitourinary tract. This is typically seen in immunocompromised patients. Pulmonary and disseminated infections are uncommon in children (4). The diagnosis of sporotrichosis requires a culture of Sporothrix species from tissue, sputum, or wound drainage. If it is cultured from the blood, it is indicative of a disseminated infection. Histopathologic examination is not helpful for diagnosis (4). Sporotrichosis infections always require treatment for resolution. Oral itraconazole is the first-line therapy for children with localized and lymphocutaneous infection and treatment is typically 3 to 6 months long. Amphotericin B is the initial therapy for visceral or disseminated infection in children. After improvement, patients can be switched to oral itraconazole and continued for at least 12 months (4).
Invasive Fungal Infections
Children with hematologic malignancies, solid organ or hematopoietic stem cell transplant (HSCT), primary or secondary immunodeficiency, those receiving immunomodulating therapy for an autoimmune condition, premature neonates, and children in the intensive care unit are at risk for invasive fungal disease (IFD) (6). Candida spp is the leading cause of IFD in pediatric patients and the fourth most common hospital-acquired bloodstream infection in children in the United States and Europe. Aspergillus spp and organisms from the Mucorales family cause the most invasive mold disease (6,7). Though Candida and Aspergillus spp are the most common cause of IFD in children with cancer, other non-Aspergillus molds are being increasingly seen (6). In patients with hematologic malignancies or those undergoing HSCT, IFD should be suspected in severely neutropenic patients with continue fever and negative blood cultures despite receiving broad-spectrum antibiotics. IFD are important as they increase mortality and length of hospital stay as well as healthcare costs. Fatality rate for patients with disseminated IFD, persistent neutropenia, or central nervous system involvement ranges from 10% to 70% (6).
Invasive candidiasis (IC) is seen especially in patients with a compromised immune system and can affect almost any organ including blood, skin, eyes, lungs, liver, and spleen. Patients often present with fever. Candida albicans is the most commonly found Candida species, followed by Candida parapsilosis. Etiologies are shifting towards more non-albicans Candida species, though. In patients receiving chemotherapy for cancer and those undergoing a HSCT, rates of IC range from 2.9% to 13.6% depending on geographic location. Rates of neonatal IC are decreasing, likely due to the extensive use of prophylactic fluconazole (6). Conversely, there is a rise in cases of IC in non-neonatal patients which could be due to an increase in need for use of intensive care, immunosuppressive therapy, or prolonged antibiotic use (7). Blood cultures are only less than 50% sensitive to detect Candida species, so negative blood cultures cannot rule out these infections. Next generation sequencing of the blood can be used to identify some of these infections. Patients can also be tested for (1,3)-beta-D-glucan, a molecule from the fungal cell wall, but this test has limited sensitivity and specificity. In patients with suspect or proven IC, dilated fundoscopic exams should be done as retinal lesions may be seen. For neutropenic patients, eye exams should be done one week after count recovery as choroidal and vitreal infections may not be evident until count recovery occurs (4).
Echinocandins (caspofungin, micafungin and anidulafungin) are the first line treatment for candida infections in severely ill or neutropenic patients since there may be some resistance to amphotericin and azoles such as fluconazole or voriconazole. If the patient is clinically stable and is unlikely to have a resistant organism, fluconazole or voriconazole could be used. Patients could also be started on an echinocandin and then transitioned to fluconazole when stable if the organism is found to be susceptible. If indwelling catheters are present and suspect to be infected, they should be promptly removed; in patients with neutropenia, the possibility of a gastrointestinal source of Candida must be considered. Prophylaxis can be used in certain patient populations at high risk, such as neonates, children that are neutropenic from highly myelosuppresive chemotherapy, or those undergoing an allogenic HSCT (4). Most (50% to 75%) of extremely low birth weight (less than 1,000 g) infants who develop IC experience prolonged hospitalization, neurodevelopmental impairment, or death. Fatality rate in neonatal IC is about 20% though it is as high as 50% in extremely low birth weight infants. Fatality rates in general for patients with IC range from 10% to 25%, but can be as high as 50% for patients requiring stay in an intensive care unit (4,6-7).
Aspergillosis is caused by Aspergillus species that are molds growing in the soil or on decaying vegetation. The majority of patients with invasive aspergillosis (IA) have an underlying malignancy (8). The rates of IA have increased three or four-fold in the past decade, possibly due to improved survival among immunocompromised patients and more aggressive treatments. The most common agent causing of IA is Aspergillus fumigatus, which causes over 75% of infections; the second most common is A. flavus; a less common but highly resistant one is A. terreus. Aspergillus is primarily spread through inhalation of spores from the environment including dust, soil, fruits and vegetables, and water supplies. Plants and flowers should not be in intensive care units or in the rooms (hospital or at home) of immunocompromised patients since they can be a reservoir for Aspergillus and other fungi. Hospital outbreaks have occurred during times of construction at the hospital or nearby sites (4). Aspergillosis can cause five different clinical presentations. Aspergillomas and otomycosis occur in immunocompetent children and are non-allergic colonization by Aspergillus. Aspergillomas, or "fungal balls" grow in bronchogenic cysts or preexisting lung cavities, primarily in patients with chronic pulmonary disease including cystic fibrosis. Children with otomycosis have chronic otitis media. Allergic bronchopulmonary aspergillosis is a hypersensitivity disease seen primarily in immunocompetent children with asthma or cystic fibrosis. Patients have low-grade fever, episodic wheezing, expectoration of brown mucus plugs, transient pulmonary infiltrates, and eosinophilia. Allergic sinusitis occurs in patients with nasal polyps or those that have had previous sinusitis or sinus surgery. It is an allergic reaction to colonization by Aspergillus, with patients presenting with chronic sinusitis and dark plugs on nasal discharge. Lastly, chronic pulmonary aspergillosis is seen in patients with underlying pulmonary disease often on corticosteroids. Patients typically have at least three months of chronic pulmonary symptoms or chronic illness with progressively abnormal radiographs and an elevated Aspergillus immunoglobulin level (4). These patients typically are not immunocompromised.
Invasive aspergillosis (IA) occurs primarily in immunocompromised patients that have impaired phagocyte function, prolonged neutropenia, graft versus host disease (GVHD), or in patients who received T-lymphocyte immunosuppressive therapy. Those at highest risk are children with new-onset acute myelogenous leukemia, relapsed hematologic malignancies, allogeneic hematopoietic stem cell transplantation (HSCT) recipients, certain patients with solid organ transplant, and those with chronic granulomatous disease (CGD). Invasive infections are most commonly found in the lungs but are also typically seen in the sinus, cerebral, or cutaneous sites (4,8). IA causes angioinvasion with subsequent thrombosis, widespread dissemination, or it can erode through the blood vessels causing hemorrhage (4).
Aspergillus species are not typically isolated on blood culture, unless the patient has a catheter-associated infection. Conversely, it can be easily isolated from the lungs, sinus, and skin. On a 10% potassium hydroxide wet preparation, dichotomously branched and septate hyphae are seen (4). An enzyme immunosorbent assay for detection of galactomannan (a molecule seen in the cell wall of all Aspergillus species) has high specificity and sensitivity though it can produce false-positive results in patients with other fungal infections and in patients who eat foods containing galactomannan such as rice and pasta. Galactomannan may be most beneficial in monitoring disease response as opposed to its diagnostic value. To optimize the yield of the test, galactomannan is only recommended for patients with hematologic malignancies or those undergoing HSCT; keeping in mind that sensitivity may be lower in patients who are not neutropenic or those who have been receiving mold-active prophylaxis (4,8). Another fungal biomarker, (1,3)-beta-D-glucan, can be useful but is nonspecific (4). Imaging, specifically computed tomography, can be helpful for the diagnosis (9). Pulmonary nodules surrounded by ground-glass opacities on CT are suggestive of an Aspergillus infection.
Voriconazole is the first line therapy for patients with IA, except in neonates for whom amphotericin B deoxycholate is the drug of choice. Unfortunately, Aspergillus species are becoming more resistant to antifungal therapy; there is increasing azole-resistance among Aspergillus fumigatus, especially in patients on long-term azole therapy. Second line therapy is liposomal amphotericin B; other alternative therapies include posaconazole, isavuconazole (for adults), or other lipid formulations of amphotericin B. Echinocandins should not be used as primary therapy though they can be used in combination therapy (4,8,9). Preventative measures for Aspergillus infection include adequate room ventilation and high-efficiency particulate air filters as well as avoidance of construction areas, gardening and lawn mowing, and stagnant water (9). Overall mortality for children with IA is 18% though it can be as high as 57% in patients with cancer and allogeneic HSCT (6,8).
Mucormycosis is the third most common invasive fungal infection in children (after IC and IA) and the second most common invasive mold disease. It is caused by fungi in the Mucorales order, the most common organisms being Rhizopus arrhizus and Mucor spp (6,10). Similar to Aspergillus, these fungi are also found in soil and organic debris. The incidence of mucormycosis is increasing. Voriconazole use in immunocompromised patients and antifungal prophylaxis which is not active against mucormycosis, have been attributed to the rise (10). Mucormycosis is not seen as commonly in patients with primary immunodeficiencies though hematologic malignancy, hematopoietic HSCT, and solid organ transplant, are significant risk factors. Other risk factors include diabetes, rheumatologic/autoimmune disorders, iron overload syndromes, renal failure, and prematurity. It can also be seen in non-immunocompromised patients with burns or traumatic wounds (4,10). The most common types of mucormycosis are rhino-orbito-cerebral, pulmonary, gastrointestinal, and cutaneous infections. Disseminated disease occurs in about one-third of cases and over half of the cases are seen in neonates. Rhino-orbito-cerebral disease is most commonly seen in patients with diabetes and presents with progressive sinusitis with fever, headache, and nasal discharge with tissue necrosis that can progress into the nasal mucosa, palate, facial skin, orbit, and brain. Pulmonary disease is typically seen in patients with malignancy and presents with progressive pneumonia with hemoptysis, lung necrosis, and spread to adjacent structures. Gastrointestinal and cutaneous infection is seen more commonly in neonates. Neonatal gastrointestinal infection can cause necrotizing enterocolitis; a necrotic eschar can be seen in cutaneous infections (10). The diagnosis of mucormycosis is most commonly made based on histopathologic characteristics consisting of broad, hyaline, hyposeptated hyphae with angioinvasion and tissue necrosis. Cultures are poorly sensitive because Mucorales hyphae are fragile and often damaged during sample collection. Nucleic acid amplification techniques can also be used (4,10). Treatment includes antifungal therapy and surgical debridement, if possible. First-line therapy is liposomal amphotericin B. Posaconazole can be used for salvage or step-down therapy. Echinocandins could be used in combination with liposomal amphotericin B (4,10). Most patients require extensive surgical debridement. Despite all efforts, fatality rates remain high and range from 47% to 56%, as high as 96% in patients with disseminated disease (10).
Questions
1. True or false- Tinea capitis can be treated with topical shampoos alone.
2. Which of the following most commonly occur together?
a. Tinea cruris and tinea pedis
b. Tinea capitis and tinea corporis
c. Tinea unguium and candidiasis
d. Tinea corporis and pityriasis versicolor
3. Blastomycosis most commonly occurs in which region?
a. Ohio and Mississippi River Valleys
b. California
c. Central and South America
d. Europe
4. An 8-year-old male with B-cell acute lymphoblastic leukemia undergoing chemotherapy presents to the clinic with fever, headache, cough, and malaise. His parents own an egg farm in Washington state. What is the most likely cause of his infection?
a. Blastomycosis
b. Sporotrichosis
c. Histoplasmosis
d. Cryptococcosis
5. A 6-year-old female presents to the clinic with a crusted papule to her arm. Upon further history, it is found that she likes to play in the garden at home. What is the best treatment for this patient?
a. Topical steroids
b. Topical bacitracin
c. Oral itraconazole
d. Oral voriconazole
6. A 15-year-old male with acute myelogenous leukemia undergoing intensive chemotherapy develops persistent fever for 1 week with progressive malaise, cough, and dyspnea. He is already on broad-spectrum antibiotics covering gram-positive and gram-negative bacteria. A galactomannan test is positive and chest computed tomography demonstrates nodules with surrounding ground-glass opacities. What is the most likely diagnosis for this patient?
a. Invasive aspergillosis
b. Bacterial pneumonia
c. Atypical pneumonia
d. Invasive candidiasis
References
1. Alter SJ, McDonald MB, Schloemer J, Simon R, Trevino J. Common Child and Adolescent Cutaneous Infestations and Fungal Infections. Current Probl Pediatr Adolesc Health Care. 2018;48(1):3-25. doi: https://doi.org/10.1016/j.cppeds.2017.11.001.
2. Olufemi Ogunbiyi, J, Wick MR. Chapter 20. Fungal and Algal Cutaneous Infections. In: Gru AA (ed). Pediatric Dermatopathology and Dermatology. 2018. Wolters Kluwer health. pp: 790-825.
3. Mancini, A.J. & Krowchuk, D.P. Pediatric Dermatology: A Quick Reference Guide, 4th edition. 2021. American Academy of Pediatrics, Itasca, IL. pp: 237-289.
4. Kimberlin DW, Barnett ED, Lynfield R, Sawyer M. Red Book: 2021-2024 Report of the Committee on Infectious Diseases, 32nd edition. 2021. American Academy of Pediatrics. Itasca, IL. pp: 211-215, 232-233, 246-252, 277-280, 285-288, 417-421, 552-553, 591-592, 676-677, 755-766.
5. Bradley, J.S., Barnett, E.D., & Cantey, J.B. Nelson’s Pediatric Antimicrobial Therapy, 27th edition. 2021. American Academy of Pediatrics, Itasca, IL. pp: 156-157.
6. Pana ZD, Roilides E, Warris A, Groll AH, et al. Epidemiology of Invasive Fungal Disease in Children. J Pediatr Infect Dis Soc. 2017;6(Suppl 1):S3-S11.
7. Hsu J, Lai M, Lee C, Chu S, et al. Comparison of the incidence, clinical features and outcomes of invasive candidiasis in children and neonates. BMC Infect Dis. 2018;18(1):194. doi: https://doi.org/10.1186/s12879-018-3100-2.
8. Apsemidou A, Petridis N, Vyzantiadis T, Tragiannidis A. Invasive Aspergillosis in Children: Update on Current Guidelines. Mediterr J Hematol Infect Dis. 2018;10(1):e2018048. doi: http://dx.doi.org/10.4084?MGHID.2018.048.
9. Papachristou S, Iosifidis E, Roilides E. Invasive Aspergillosis in Pediatric Leukemia Patients: Prevention and Treatment. J Fungi. 2019;5(1):14. doi: 10.3390/jof5010014
10. Francis JR, Villanueva P, Bryant P, Blyth CC. Mucormycosis in Children: Review and Recommendations for Management. J Pediatr Infect Dis Soc. 2018;7:159-164. doi: 10.1093/jpids/pix107.
Answers to questions
1.False. Systemic medication is always needed for tinea capitis
2. B. Tinea capitis and tinea corporis
3. A. Ohio and Mississippi River Valleys
4. D. Cryptococcosis
5. C. Oral itraconazole
6. A. Invasive aspergillosis