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Emerging fungal among children: A review on its clinical manifestations, diagnosis, and prevention

Akansha Jain, Shubham Jain, Swati Rawat1

SAFE Institute of ABSTRACT Pharmacy, Gram The incidence of fungal infections is increasing at an alarming rate, presenting an enormous challenge to Kanadiya, Indore, 1Shri healthcare professionals. This increase is directly related to the growing population of immunocompromised Bhagwan College of Pharmacy, Aurangabad, individuals especially children resulting from changes in medical practice such as the use of intensive India chemotherapy and immunosuppressive drugs. Although healthy children have strong natural immunity against fungal infections, then also fungal among children are increasing very fast. Virtually not all fungi are Address for correspondence: pathogenic and their infection is opportunistic. Fungi can occur in the form of , mould, and dimorph. In Dr. Akansha Jain, children fungi can cause superficial infection, i.e., on skin, nails, and like oral thrush, candida diaper rash, E-mail: akanshajain_2711@ yahoo.com tinea infections, etc., are various types of superficial fungal infections, subcutaneous fungal infection in tissues under the skin and lastly it causes systemic infection in deeper tissues. Most superficial and subcutaneous fungal infections are easily diagnosed and readily amenable to treatment. Opportunistic fungal infections are those that cause diseases exclusively in immunocompromised individuals, e.g., , , etc. Systemic infections can be life-threatening and are associated with high morbidity and mortality. Because diagnosis is difficult and the causative agent is often confirmed only at autopsy, the exact incidence of systemic infections is difficult to determine. The most frequently encountered pathogens are and Received : 16-05-10 spp. But other fungi such as non-albicans Candida spp. are increasingly important. Review completed : 16-07-10 Accepted : 07-08-10 DOI: 10.4103/0975-7406.72131 KEY WORDS: Candida diaper rash, , opportunistic,

majority of children, at one time or other suffers some or Fungi come in many forms but only three are of our interest as A the other form of fungal infection. For instance, if a child they may cause disease in human being: develops a rash on the buttocks or white patches in the mouth, 1. – round/oval, unicellular, and reproduce via budding it is as a result of fungal or yeast infection.[1,2] Fungal infections 2. – long, floppy, fluffy colonies that microscopically which were quite rare at the beginning of this century are now can be seen as long tubular structures called hyphae and increasingly growing at a rapid rate. This is probably due to reproduce by forming spore-forming structures at the end the result of the increase in number of immunocompromised of hyphae called conidia. children.[3] Normally children have strong natural immunity to 3. Dimorphs – most medically important, can change from fungi. Only a couple of fungi out of thousands are pathogenic. yeast to and back, and grow in environment as molds Fungi are very good at taking advantage of some abnormality and in humans as yeast. Fungi can produce toxins but this in the human host and, thus, virtually every fungal infection is not relevant to human infections. Fungi can produce is opportunistic.[3-5] human disease because of their sheer size (50–100 times larger than bacteria) and by eliciting an immune response Fungi are eukaryotic, nonmotile, and usually aerobic. They as a result of themselves or their by-products.[8-9] can exist as parasites or free living organisms and need organic sources of nourishment. They have a dense rigid cell wall made Types of Fungal Infections of glucan and chitin (found in crab shells). Their cell membrane contains sterols (ergosterol), making them similar enough to Fungal infections in children are broadly classified into three types: human cell membranes to have negative implications for the I. Superficial/cutaneous – present on skin, hair, nails membrane destroying properties of drugs.[6,7] II. Subcutaneous – infection in tissues under the skin

How to cite this article: Jain A, Jain S, Rawat S. Emerging fungal infections among children: A review on its clinical manifestations, diagnosis, and prevention. J Pharm Bioall Sci 2010;4:314-20

 314 Journal of Pharmacy and Bioallied Sciences October-December 2010 Vol 2 Issue 4 Jain, et al.: Emerging fungal infections among children 

III. Systemic – they are of two types: “true pathogens” (term is spp. and the commensal microbial flora is perhaps the next becoming obsolete) – which have the ability to cause disease critical mechanism modulating oral Candidal colonization. in healthy hosts and opportunists – which cause disease The commensal flora regulates yeast numbers by inhibiting exclusively in immunocompromised individuals.[10,11] the adherence of yeasts to oral surfaces by competing for sites of adherence as well as for the available nutrients. The above three infections are discussed in detail below. Candida diaper rash Superficial fungal infections It is sometimes called napkin dermatitis, a rash which occurs in These infections are common all over the world (but specifically the buttocks. Nappy rash will occur when the skin is sensitive based on geographic distribution) and are caused by fungi called and there is a presence of a trigger factor which includes [21-23] , which produce keratinase. This allows them prolonged exposure to urine and being unwell or thrush. It to metabolize and live on human , i.e., on skin, nails, tends to be in the deepest part of the creases in the groin and and hair. They cause superficially but cannot buttocks. The rash is usually red with a clearly defined border invade deeper into the dermis. The common superficial fungal and consists of small red spots close to the large patches. In infections caused by Tinea worm are body ring worm by Tinea general, any diaper rash that lasts for 3 days or longer may be [24-26] corporis, athlete’s foot by Tinea pedis, etc.[4,5,8,10] Such infections . A Candida skin infection can come from the are red, itchy, and scaly. The diagnosis and confirmation upper gastrointestinal tract, the lower gastrointestinal tract, or should be based on clinical observations. The procedure exposure from a care provider. A Candida diaper rash can be which is followed is to scrape the lesion and observed under accompanied by Candida infection of the mouth (thrush). A breastfeeding infant with a thrush infection may inadvertently the microscope, and in case of Wood’s lamp (UV) colonies infect the mother’s nipple/areola area. If such an infection is will fluoresce. suspected, simple topical medications may be prescribed by her doctor.[27,28] Another important superficial infection is cause by the yeast furfur.[12] It does not even get into the keratin – more Tinea infection (ringworm) superficial than the dermatophytes. It digests the top layer of lipids and affects adolescents and adults to cause the superficial It is a skin infection caused by fungi. It is called “ringworm” infection called – round, hypo-, and sometimes because the infection may produce ring-shaped patches on hyperpigmented patches. It never penetrates into the skin but the skin that have red, wavy, worm-like borders. Some of the can, especially nosocomially, infect the blood by contaminating ways of catching Tinea is by direct skin-to-skin contact with an lipid IV solutions. infected person, by sharing items with an infected person, or by touching a contaminated surface (such as floors in shower Some of the types of superficial fungal infections that occur and locker rooms).[4] frequently in children are discussed below. Some of the more common types of Tinea infections that Oral thrush occur in children are discussed next. results in a diffuse, itchy, scaling of the scalp that resembles dandruff. It is an infection of the yeast , Candida albicans, which It can cause patches of hair loss on the scalp. It is especially occurs on the surface of the tongue and inside the mucus of common among children aged 3–9, particularly children who the cheeks. It appears as white patches known as “plaques” live in crowded conditions in urban areas. Scalp ringworm [13-15] which resemble milk curds. One way to distinguish candida spreads via contaminated combs, brushes, hats, and pillows.[8,9] plaques from milk curds is that if the surface of the plaque is means “ringworm of the body”; it involves the scraped away, a sore and reddened area will be seen underneath, nonhairy skin of the face, trunk, arms, or legs. This would which may sometimes bleed. It occurs most commonly produce the classic ring-shaped patches with worm-like borders in babies, particularly in the first few weeks of life.[16-18] which may occur singly or in groups of threes and fours. It can Outbreaks of thrush in older children may also be the result of occur in persons of all ages.[8] an increased use of and steroids, which disturbs the balance of microbes in the mouth. This causes an overgrowth Tinea pedis (athlete’s foot) produces area of redness, scaling, or of Candida, which results in thrush.[19,20] cracked skin on the feet, especially between the toes. The affected skin may or burn, and the feet may have a strong odor. It The stratified squamous epithelium of the oral mucosa forms is often acquired by walking barefoot on contaminated floors.[5] a continuous surface that protects the underlying tissues and functions as an impervious, mechanical barrier. The protection Tinea versicolor or more commonly known as “white spots” is so provided is dependent on the degree of keratinization and caused by a fungus known as . This fungus is the continuous desquamation or shedding of epithelial cells. present on the skin of most of the people but will only cause Indeed, the latter mechanism is considered to play a pivotal role infection in some of them. This infection is common round the in maintaining a healthy oral mucosa and in limiting Candidal year in hot and humid climate. It occurs more often in older colonization and infection. The interaction between Candida children and young adults.[10]

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The infection causes a rash which may appear on the back, neck, schenkii, which is characterized by the development on the skin, upper chest, shoulders, armpits, and upper arms. The skin rash in subcutaneous tissue and in lymph nodes, of nodules which consists of peeling, oval patches with sharply defined borders, soften and break down to form indolent ulcers. The fungus is a and pimple-like bumps. The patches appear white or black on saprophyte found widely on plants, thorns, and timber. Infection dark-skinned people and are usually pink or tan on the more is acquired through thorn pricks or other minor injuries. Rare fair-skinned. More often than not, it does not cause itching instances of transmission from patients and infected horses unless the person is hot or sweaty. The patches may be more and rats have been recorded. It needs a splinter or a thorn to prominent after the skin has been exposed to the sun, because introduce it into human tissue – it can only live inside the the patches do not tan [Figure 1].[11] body. It travels along lymphatics and causes a combination of pyogenic and granulomatous reaction. It manifests itself as a Subcutaneous fungal infections set of ulcerating nodules along a hard cord as it slowly grows up the lymphatics. It moves from distal to proximal and can lead to If get a chance to introduce through the , these bone and joint destruction. It can become disseminated almost fungi have the biological ability to grow in subcutaneous tissue exclusively in immunocompromised individuals. The classic and sometimes can cause significant human disease. They can clinical presentation of this is with individuals with outdoor grow up lymphatic and into bones or joints if in the way. These encounters: gardeners, golfers, hunters, etc. The culture mount infections are far more common in the developed world. There of this fungus show fine branching hyphae and pear-shaped are a variety of species that cause them: in India, Africa, and conidia borne in rosette like clusters at tips at lateral branches the Far East, generally speaking, they cause mycetoma (Madura and singly along sides of hyphae.[31,32] foot). Individuals walking barefoot may get a splinter or injury to the foot and be inoculated, and slowly the bones of the foot and the ankle joint can be destroyed.[30] This infection is caused by soil-inhabiting fungi of family Different types of subcutaneous fungal infection are discussed Dematiaceae family. They enter the skin by traumatic next. implantation. The lesion develops slowly around the site of implantation. The most common fungi responsible are the Sporotrichosis Fonsecaea spp. – F. pedrosoi, F. compactum, F. dermatitidis, Phialophora spp – P. verrucosa and Clostridium spp. – C. This infection is caused by the Sporothriz carrionii. Infections caused by F. pedrosoi and P. verrucosa have

a b c

d e f Figure 1: Clinical presentations of some frequently observed fungal infections: (a) Tinea capitis due to tonsurans; (b) due to ; (c) chronic ; (d) chromoblastomycosis; (e) histopathological appearance of an . (f) Cutaneous lesions in a patient with disseminate candidiasis.[8] (Reproduced with permission from Richardson et al.)[29

 316 Journal of Pharmacy and Bioallied Sciences October-December 2010 Vol 2 Issue 4 Jain, et al.: Emerging fungal infections among children  been reported to disseminate to other areas, especially brain. can then disseminate and cause disease in virtually every organ Its clinical manifestations are raised and crusted lesions of the of the body. To differentiate between TB and histoplasmosis, skin. Histological, the lesions show the presence of the fungus one can use sputum or blood smears, and purified protein as round or irregular, dark brown, yeast-like bodies with septate derivative (PPD).[39] called sclerotic cells, which can be diagnosed in KOH mounts or in sections and by culture on Sabouraud’s agar.[33] Coccioidomycosis. This is an infection caused by fungus Coccidiodes immitis. This fungus is probably the most virulent Chronic mucocutaneous candidiasis and prefers to live in hot dry weather (Arizona, Cali, Mexico, Central, and South America). Infection is acquired by inhalation It is caused by Candida spp. (predominantly C. albicans). of dust containing arthrophores of the fungus. This fungus is Various manifestations include white fissures, lesions, dimorphic, occurring in the tissue as yeast and in culture as hyperkeratotic, granulomatous, and vegetative lesions, the mycelial form. The tissue form a spherule, 15–75 µm in autosomal recessive trait associated with endocrine disorders, diameter, with a thick doubly refractile wall and filled with e.g., hypoparathyroidism.[34,35] endospores. Unlike histoplasmosis, this dimorph turns into a spherule not yeast in the human lung. A spherule is a giant Systemic fungal infections seedpod full of thousands of yeast particles called endosperms; thus, it can infect very efficiently (explains virulence). There is After superficial and subcutaneous comes systemic fungal also a skin test for Cocci called coccidiodin. Like histoplasmosis, infection. These are less common but more serious. They can in this case spores are aerosolized and inhaled. When compared be divided broadly into two types namely (a) endemic infections the sequence of events in TB and histoplasmosis, it was and (b) opportunistic infection. found that they are almost similar. However, unlike TB and histoplasmosis, the primary infection with Cocci can have symptoms because one is getting such a huge load of organisms, (a) Endemic infections infect all types of people, including with the endospores disseminating in the lungs. One gets a those with a normal immune system. Although very much self-limited, flu-like syndrome (sometimes called Bali fever). like TB, they cause disease only in specific circumstances. A However, in some people it does disseminate (more commonly huge number of individuals are infected, but only a few get in pregnant women, immunocompromised, and darker skinned diseased. As these infections have a number of properties in people) and causes skin, bone, and CNS disease.[40] common, we should think of them as a group: histoplasmosis, coccioidomycosis, and blastmycosis.[36] Such infections are . The fungus Blastomyces dermatiditis causes this caused by dimorphs. They grow as molds in soil and reproduce disease. This fungus is a dimorph that lives in a soil as a mold there by sporulation. When they enter in a human, which and becomes yeast in the human being upon inhalation. It likes happens exclusively via the respiratory route, they become organic debris and humidity: woodlands, beaver dams, marshes, yeasts. They also have a restricted geographic distribution and peanut farms (for some unknown reason) and are usually and finally, and most importantly, they all cause disease with found at mid-Atlantic, Carolinas, and Mississippi Valley. It is [37] symptoms almost indistinguishable from TB. picked up from aerosolized spores. In its yeast form, blastomyces is much bigger than histoplasma and has broad-based buds and Various types of endemic fungal infections are elaborated next. a small capsule. The pathogenesis is basically the same as the others. The one big difference is that no one has yet discovered Histoplasmosis. It is an intracellular infection of the a characteristic protein for a skin test. We usually do not have reticuloendothelial system caused by dimorphic fungus any idea how many people have been exposed and how many . This fungus reacts like soils with high to develop disease with blastomyces. We do know that with a nitrogen content so it is found in the Ohio-Mississippi Valley, fraction of people (immuncompromised), the disease can go the Caribbean, and Central and South America. It is particularly on to become disseminated or can stay in the lungs to cause a endemic to chicken coups and caves due to the nitrogen in TB-like disease. It likes cool surfaces so it tends to cause a lot of bird and bat droppings. It is caused by inhaling spores, which skin disease (skin lesions that look and behave like skin cancer), change into yeast in the lungs, phagocytosed by macrophages, bone disease, and urinary tract disease in men.[36,39] and are disseminated hematogenously. After about 6 weeks, one can be tested for histoplasmin antigen derivative (just like (b) Opportunistic systemic fungal infections occur primarily TB), which is useful for diagnosing exposure but worthless for when some aspect of the normal host defense is compromised. diagnosing disease. Clinically, histoplasmosis also mimics TB; Such infections are life-threatening and are associated with almost everyone who is infected with this organism has latent high rates of death. Because of the growing population of disease. Very few people get sick, unless there is something else immunocompromised individuals, the frequency of systemic going on and can cause problems for those with an immature fungal infections is increasing significantly.[40] Patients with immune system or immunocompromised.[38] For people with hematological malignancies, such as myeloid and lymphocytic abnormal lungs, histoplasmosis can cause pneumonia if inhaled leukemias, are at particularly high risk of infectious complications. into nonperfused areas. It can cause a chronic, cavitating nodular Infections can occur when the patient develops neutropenia of infection very similar to TB. Histoplasmosis can remain latent long duration caused by the hematological malignancy itself or and reactivate many years later, for example, with AIDS. This the treatment administered. For example, patients receiving

Journal of Pharmacy and Bioallied Sciences October-December 2010 Vol 2 Issue 4 317   Jain, et al.: Emerging fungal infections among children bone marrow transplants are given immunosuppressive drugs of immunosuppression in the patient group, fungal infections (e.g., corticosteroids or cyclosporine) to prevent or treat can be unusually virulent and persistent. Between 60% and 90% rejection. Intensive myelosuppressive chemotherapy also causes of individuals with progressive HIV disease develop at least one neutropenia in patients. fungal infection during the course of the disease.[48] Among the most frequently occurring fungal infections in this group are Approximately 20–50% of patients who die from hematological candidiasis, , and less frequently aspergillosis,[49] malignancies have evidence of invasive fungal infections at although, in specific geographical regions, endemic mycoses autopsy. The death rate is even higher in patients with mixed are important (e.g., , penicilliosis with Aspergillus and Candida tissue infections. Solid organ transplant Penicillium marneffei, and histoplasmosis).[50] Individuals recipients who receive immunosuppressive medications to with chronic granulomatous disease (CGD), an inherited limit the risk of rejection also have an increased susceptibility abnormality of the neutrophils that serve as an important to systemic fungal infections. Fungal infections occur in defense against fungi, are also predisposed to infection. Various 5–45% of all solid organ transplant patients and are a primary types of opportunistic systemic fungal infections are described cause of morbidity and mortality.[41,42] Burnt patients are next. another population at high risk; the wound site is susceptible to colonization by opportunistic fungi such as Candida, but /candidaemia. It is caused by C. albicans and nowadays this is generally well managed and Candidiasis in other nonalbicans Candida spp. Its clinical manifestations are burnt patients may originate in the gastrointestinal tract or prolonged -resistant fever, often associated with weight from intravenous catheters.[43] Changes in medical procedures loss, abdominal , and hepatic and/or spleen enlargement. CT have contributed to the increased incidence of systemic fungal scan may reveal small radiolucent lesions in liver or spleen in patients infections. The skin and mucosal surfaces normally prevent with chronic invasive candidiasis (hepatosplenic candidiasis).[55,56] micro-organisms entering the body, but, if these barriers are compromised, for example, during surgery or when in Invasive aspergillosis. It is caused by Aspergillus spp. The dwelling catheters are used, fungal cells are able to invade. commonest human disease caused by aspergilli is . Its Myelosuppressive chemotherapy may also cause mucosal clinical manifestations are prolonged antibiotic-resistant fever, lesions, allowing the invasion of fungi. Allogeneic bone marrow histopathological appearance of nonpigmented, septate hyphae transplant recipients face the additional risk of developing graft- with dichotomous branching. CT scan shows characteristic halo versus-host disease, which can damage the mucosal surfaces and and/or air crescent signs. In this, the fungus actively invades normally requires an increase in immunosuppressive therapy. the lung tissue. Disseminated aspergillosis involving the brain, kidney, and other organs in fatal complication sometimes seen In lung transplant recipients, the donor organ can also in debilitated patients on prolonged treatment with antibiotic, be a reservoir for pathogenic fungi, which may have been steroids, and cytotoxic drugs. dormant or harmless in the donor but can be a source of post- transplantation infection in the immunosuppressed recipient. Diagnosis may be made by microscopic examination and by Previous fungal infection may predispose high-risk patients culture. The fungus grows rapidly on culture media. Identification to subsequent systemic infections because fungi can remain of Aspergillus is easy based on growth characteristics and dormant for some time and become reactivated when the morphology. Aspergillus has septate hyphae. Asexual conidia are patient is immunosuppressed.[44,45] High-risk patients with arranged in chains, carried on elongated cells called “sterigmata,” damaged mucosal surfaces caused by bacterial or viral infections borne on expanded ends (vesicles) of conidiophores.[51] Meningitis may be at a higher risk of infection by Candida spp. A high level is the most common clinical manifestation. Hematogenous spread of colonization by Candida in the gastrointestinal tract and may also occur, giving rise to widespread cutaneous lesions.[52] oral cavity may also increase the threat of systemic Candidal infection in patients at high risk. An additional contributory Zygomycosis. It is caused by Rhizopus spp., Absidia spp., and Mucor factor is the use of antibiotics, which disrupt the microbial flora, spp. It may manifest as rhinocerebral, pulmonary, gastrointestinal, allowing colonization by fungi. Antibiotic therapy also leads or cutaneous . Disseminated mucormycosis can to increased survival of patients who are predisposed to fungal follow, spreading most frequently to the brain, with possible infection. Immunocompromised patients readily acquire fungal metastatic lesions in the spleen, heart, and other organs. infections from their environment if standard safety procedures are not followed. For example, Aspergillus spp. is airborne fungi Other invasive infections. It is caused by Malassezia spp. and may be propagated through ventilation systems. The risk Its manifestations are characterized by catheter-associated of infection can be greatly reduced by the use of high-efficiency sepsis related to hyperalimentation with lipid emulsions particulate air (HEPA) filtration.[46] Transmission of Candida and pneumonia. spp. can cause infrequent from the hands of medical professionals is also an important disseminated disease which occurs in granulocytopenic patients, cause of nosocomial infections. Hand washing is therefore with fatal outcome. Bloodstream infections manifest as skin vital, but unfortunately the rigorous compliance necessary to and lung lesions and give false positives in cryptococcal antigen reduce infection is not always present.[47] Other patients at tests. Infections due to spp. can cause mycetoma, risk include those with medical conditions that compromise endophthalmitis, facial granuloma, osteomyelitis, and brain the immune system, the most notable being advanced HIV . Disseminated disease in neutropenic patients has immune dysfunction or AIDS. Because of the extreme degree positive blood cultures and skin lesions.[52]

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Diagnosis of systemic fungal infections infections are mild but may spread to other areas of the body or, occasionally, to other individuals. More seriously, but less Diagnosis of systemic fungal infections is problematical and frequently, they may develop into invasive forms. Although many infections are confirmed only at autopsy. The clinical not life-threatening, conditions such as onychomycosis can symptoms are nonspecific and similar to those of bacterial have a severe impact on a patient’s quality of life and self- and viral infections. In addition, the isolation of fungi from image. It is therefore desirable to treat local fungal infections clinical samples is unreliable and may be complicated by the to prevent the risk of spread. Systemic fungal infections in presence of a colonizing commensal organism, or ubiquitous immunocompromised patients, such as bone marrow and solid fungi in the environment, causing false-positive results. organ transplant recipients, are associated with high rates of Furthermore, the collection of clinical samples often requires mortality. C. albicans and Aspergillus spp. are the most prevalent an invasive procedure, which may not be advisable in critically pathogens in systemic infections, but a recent shift in the burden ill patients. Direct microscopic examination of clinical samples of disease has seen the emergence of a number of important may provide a tentative diagnosis, but this is often difficult non-albicans Candida spp. in addition to rare infectious agents to confirm by culture because of the presence of atypical such as M. furfur. Although the incidence of fungal infections fungal elements or sparse fungal populations. Serological tests can be reduced by minimizing risk factors in hospitals, such that detect antibodies are low in sensitivity and specificity as poor hygiene practice, our inability to reliably prevent such because many patients with systemic fungal infections are infections highlights the need for effective treatments. immunocompromised and, therefore, have an impaired antibody response. However, even in immunocompetent References individuals, the delay between the onset of infection and the development of the antibody response reduces the practical 1. Groll AH, Shah PM, Mentzel C. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J value of these tests. Improvements in the diagnosis of invasive Infect 1996;33:23-32. pulmonary aspergillosis include the greater use of routine high- 2. Denning DW, Evans EG, Kibbler CC. 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