23 Invasive Fungal Inf

Invasive fungal infections in
children
Blok 24
April 2019
Introduction
• Invasive fungal infections
– important causes of morbidity and mortality in
immunocompromised children
– difficult to diagnose
– outcome depends critically on the prompt initiation
of appropriate antifungal chemotherapy and
restoration of host defenses.
Classification of fungi associated with human infection
(mycoses)
Definition
of fungal
infection
Cutaneous Superficial Fungal Infection
• Very common.
• The majority are caused by three groups of fungi:
– mold dermatophytes such as Microsporium spp. and Trichophyton spp.,
– Candida albicans, and
– Malassezia spp.
• Keratin-containing structures such as hair shafts, nails, and skin
are affected.
• Dermatophyte skin infection (sometimes called ringworm) is
commonly named after the area affected
– E.g. tinea capitis (head) or tinea corporis (body).
Systemic Fungal Infection
• The systemic fungi: Coccidioides immitis, Paracoccidioides
braziliensis, and Histoplasma capsulatum.
– Thermally dimorphic fungi (have both yeast-like and filamentous
forms).
– Environmental organisms, which enter the body usually via
inhalation.
– Infection is geographically circumscribed and often clinically mild.
– Severe disseminated disease can occur, however, particularly in
immunocompromised patients.
Systemic Fungal Infection
• The main fungi that cause disease in immunocompromised
– the yeasts C. albicans, and
– related species such as Candida krusei.
• Aspergillus species
– important environmental filamentous fungi,
– may cause pulmonary or disseminated infection.
• The yeast-like fungi Cryptococcus neoformans

– can cause chronic meningitis in HIV
Pediatric populations at risk for invasive
infections
Defined by specific predisposing defects in host defenses and
several additional, non-immunological factors.
– deficiencies in the number or function of phagocytic cells are associated
with invasive infections by opportunistic fungi, such as Candida spp.,
Aspergillus spp., zygomyces spp. and a large variety of other, less
frequently encountered yeasts and molds.
– deficiencies or imbalances of T lymphocyte function are linked to
mucocutaneous candidiasis and invasive infections by Cryptococcus
neoformans and the dimorphic moulds (Fig. 1).
– Non-immunological factors include the necessary exposure to the
organism, preexisting tissue damage, and, limited to Candida spp., the
presence of indwelling vascular catheters, colonization of mucous
membranes, the use of broad-spectrum antibiotics, parenteral nutrition, and
complicated intra-abdominal surgery
Pediatric populations at risk for invasive infections
Risk factors for invasive Candida infection
Risk factors for invasive Aspergilus infection
• hematologic malignancies, either primary or relapse,

• allogeneic bone marrow transplantation
• granulocytopenia,
• corticosteroids for malignancy
• autoimmune disease,
• immunosuppressive therapies,
• immunodeficiencies, such as chronic granulomatous disease, severe
combined immunodeficiency
• organ transplantation, such as heart-lung transplantation
• Cushing syndrome because of its endogenous high secretion of cortisol
can favor development of IA.
Risk factors for invasive Aspergilus infection
Epidemiology and presentation of invasive fungal
infections in pediatric patients
• The neonate
– Candida spp. colonize the vaginal tract of approximately
30% of pregnant women; very rarely, they can become the
cause of chorioamnionitis and intrauterine infection.
Candida rapidly colonizes the mucocutaneous surfaces]; in
healthy infants, this colonization may result in thrush and
diaper dermatitis].
– In hospitalized, ill neonates, however, Candida has evolved
as important cause of life-threatening invasive infections,
particularly in very low birth weight infants. Candida spp.
now account for 9–13% of all bloodstream isolates in
NICUs
– Invasive candidiasis in preterm infants is most commonly

due to C. Albicans and C. parapsilosis and associated with
prior mucocutaneous colonization, vascular catheters, the
use of broad- spectrum antibiotics and corticosteroids, and
parenteral hyperalimentation.
– Most neonates with systemic candidiasis are symptomatic
at the onset of their disease and present with signs and
symptoms that are virtually identical to those of non-fungal
etiological agents.
– Malassezia spp. are lipophilic commensal yeasts that

colonize the human skin and may cause pityriasis.
• may gain access to the bloodstream via percutaneous vascular
catheters to cause a potentially fatal systemic infection in
premature infants receiving parenteral nutritional lipid
supplements.
• Similar to Candida, the most probable mode of acquisition is via
the hands of health care workers, but direct contamination through
contaminated intravenous (IV) solutions and catheters has also
been reported.
• Special media containing olive oil are required for isolation
– Infections by Aspergillus species and zygomyces
• very rare in the neonatal setting.
• they tend to have a predilection for the skin, and, in the case of the
zygomycetes, for the gastrointestinal tract, resulting in necrotizing
skin lesions and devastating necrotizing gastroenterocolitis,
respectively.
• Potential sources of the organism are contaminated water,
contaminated ventilation systems and contaminated dressing
materials or infusion boards
• The infant
– Disseminated histoplasmosis is a classical example for the potentially
dismal course of a primary infection by an endemic fungus in
apparently healthy infants that were exposed to the organisms.
• The disease is fatal if not detected and treated.
• Its clinical manifestations include prolonged fevers, failure to thrive,
hepatosplenomegaly, pancytopenia, and ultimately, DIC and multiorgan
failure.
– Not much is known about blastomycosis and cocidioidomycosis in this
age group, but ultimately fatal cases have been reported
– Conceptually, primary infection by endemic fungi during infancy is
reminiscent of the infantile form of pulmonary pneumocystosis, which
is associated with young age, malnutrition, and endemic exposure.
– Candida albicans is a ubiquitous agent of diaper dermatitis,
which may be precipitated by moisture, occlusion, fecal
contact and urinary pH.
• Its classical presentation is that of an erythema bordered by a
collarette of scale with satellite papules and pustules.
• Concomitant dermatophytosis may occasionally be present.
• Treatment consists of the correction of physiological factors and
topical antifungal treatment
• Children with congenital immunodeficiencies
– Inherited immunodeficiencies involving the number or function of T
lymphocytes predispose to mucocutaneous and, occasionally, invasive
candidiasis, and conceptually, to cryptococcosis and histoplasmosis
– The role of Ig in host defenses against fungi is important against
cryptococcosis and possibly mucosal and invasive candidiasis.
Children with inherited deficits of B lymphocytes appear to be not at
increased risk for fungal infection, unless there is a concomitant
disorder of T lymphocytes or phagocytosis.
• This includes individuals with the x-linked hyper-IgM syndrome, and
patients with the hyper-IgE syndrome, which is associated with chronic
mucocutaneous candidiasis, and possibly with cryptococcosis and
aspergillosis.
• Children with acquired immunodeficiencies

• Iatrogenic immunosuppression
– Treatment with glucocorticosteroids rapidly provides a
functional impairment of phagocytosis by mono- and PMN
leukocytes. Such therapy is one of the most important
reasons for the increased susceptibility to invasive mycoses
of children with immunosuppressive therapy for
immunological disorders, solid organ transplantation, and
for graft-vs.-host disease (GVHD) following HSCT.
• Cancer
– Prolonged, profound granulocytopenia is the single most
important risk factor for opportunistic fungal infections in
children and adolescents with cancer.
– Other well-known, but notable risk factors include
chemotherapy-induced mucositis, extended courses of
broad-spectrum antibiotics, the presence of indwelling
central venous lines, and, particularly in children with
acute leukemia, the therapeutic use of glucocorticosteroid.
– Oropharyngeal candidiasis (OPC) may occur in up to 15%
of children undergoing intensive chemotherapy or bone
marrow transplantation despite various forms of topical or
systemic antifungal prophylaxis.
– Esophageal candidiasis is also not uncommon, even in the
absence of conspicuous OPC, and Candida epiglottitis and
laryngeal candidiasis may emerge in neutropenic children
as life- threatening causes of airway obstruction.
– Candida- and Aspergillus spp are the most common causes
of invasive fungal infections in children with cancer
– Invasive candidiasis in neutropenic children may

present as catheter-associated candidemia, acute
disseminated candidiasis, and deep single organ
candidiasis
• Catheter-associated fungemia is most commonly caused
by C. Albicans
• Acute disseminated candidiasis occurs typically in
granulocytopenic children and manifests with persistent
fungemia, hemodynamic instability, multiple cutaneous
and visceral lesions and high mortality despite antifungal
therapy
– Invasive aspergillosis has emerged as important cause for
morbidity and mortality in children with hematological
malignancies or undergoing bone marrow transplantation
• the lungs are the most frequently affected site, and disseminated
disease is found in approximately 30% of cases
• primary cutaneous aspergillosis has been preferentially reported in
association with lacerations by armboards, tape, and electrodes and
at the insertion site of peripheral or central venous catheters
• With combined surgical and medical therapy, primary cutaneous
aspergillosis has a comparatively more favorable prognosis
– Similar to histoplasmosis, cryptococcal meningoencephalitis or
pneumonitis are rare opportunistic infections in children with cancer
• HIV infection
– mucosal as well as invasive fungal infections are major causes of
morbidity and mortality in advanced stages of the disease
– OPC is the most prevalent opportunistic infection in HIV-infected
children
– Esophageal candidiasis in the era prior to HAART occurred
– in approximately 10% of patients and was associated with recurrent
OPC, low CD4+ counts, and use of broad-spectrum antibiotics
– In the absence of significant immunological reconstitution,
oropharyngeal and esophageal candidiasis have an exceedingly high
propensity to recur. The chronic use of fluconazole under these
circumstances has been associated with the emergence of fluconazole-
resistant Candida strains; it has been shown that such resistant strains
can be exchanged among HIVinfected family members.
– HIV-related impairment of phagocytosis by mono- and
polymorphonuclear leukocytes makes a major contribution to the
increased susceptibility of patients with advanced HIV infection to
invasive aspergillosis
– Compared to adults, HIV-infected children have lower rates of
cryptococcal infections, and, with the exception of disseminated
penicilliosis, data on histoplasmosis and other endemic mycoses are
very limited
• Children with severe acute illnesses
– Invasive procedures, indwelling vascular and urinary catheters, use of
broad-spectrum antibiotics and corticosteroids, mechanical ventilation
and parenteral feeding as well as length of stay and severity of the
underlying condition, all contribute to a heightened risk of deeply
invasive Candida infections in critically ill patients requiring intensive
care
• Children with chronic pulmonary diseases

– Mycoses may occur in children and adolescents with
chronic sinopulmonary infection and lung destruction, as it
may be associated with congenital B cell defects, the
hyper-IgE syndrome, and, most commonly, cystic fibrosis.
– Non-invasive fungal diseases associated with the
colonization of the respiratory tract by Aspergillus spp. and
other moulds such as allergic bronchopulmonary
aspergillosis and aspergilloma formation clearly
predominate in this setting.
Recent advances in early diagnosis and
preemptive therapy
• Early diagnosis and rapid initiation of effective
antifungal chemotherapy is paramount to the
successful management of invasive mycoses
– Improved blood culture detection technique
– HRCT
– MRI
– nucleic acid amplification based systems
Diagnostic Methods for Invasive Aspergillosis
CT Scan (1,3)-ß-D-glucan assay
 Nodules or patchy consolidations  Excellent negative predictive value
 Halo sign: attenuated area around a nodule  False positives:
 Specific to IA? - in the setting of  Albumin
immunocompromise  Immunoglobulin
 Sensitivity varies with timing relative to  Hemodialysis
diagnosis (high early)
Galactomannan assay PCR detection of fungal DNA

 Sensitivity 0.73, specificity 0.81 (proven IA)  Sensitivity 100% for IA (preceding
 False positives: symptoms by a median of 2 days)
 Lowered threshold for test positivity  Requires further standardization
 Bifidobacterium lipoglycan and validation
 Concurrent use of ß-lactam antibiotics,
particularly piperacillin-tazobactam
Perlroth J et al. Med Mycol. 2007;45:321-46.

IFI Management
Antifungal Agents - Sites of Action
ß-1, 3 glucan
polysaccharide
phoB
Am
Ergosterol
Ergosterol
Cell Membrane
Phospholipid
Phospholipid bilayer
bilayer
Azoles
Ec
hi
no
ca
nd
in
s
Adapted from Metcalf SC, Dockrell DH. J Infect. 2007;55:287-99.
Drug Classes and Agents
Polyenes Expanded-spectrum azoles
• Amphotericin B (AMB) • Voriconazole
• Lipid-based formulations • Posaconazole
 ABLC • Ravuconazole*
 ABCD
 L-AMB
Azoles Echinocandins
• Fluconazole • Caspofungin
• Itraconazole • Micafungin
• Anidulafungin
*Not yet approved

ABLC = Amphotericin B lipid complex; ABCD = Amphotericin B colloidal dispersion; L-AMB: Liposomal
amphotericin B
Metcalf SC, Dockrell DH. J Infect 2007;55:287-299; Petrikkos G, Skiada A. Internat J Antimicrob Agents 2007;30:108-117
IFI Management
No
Disease progression
disease Prophylactic Asymptomatic high-risk patient
Markers Asymptomatic + colonization

Preemptive OR novel diagnostic
Signs & symptoms Empirical High risk: Antibiotic + fever
Evidence of infection
Full-blown disease Therapy + clinical disease
Sequelae
Wingard JR. Best Pract Res Clin Haematol 2007;20:99-107; Bow EJ. Hematol. 2006;1:361-7.
Pediatric pharmacology of established
antifungal agents
• Amphotericin B deoxycholate
– Primarily acts by binding to ergosterol in the fungal cell
membrane, leading to pore formation and ultimately, cell
death
– Possesses a broad spectrum of antifungal activity that
includes most fungi pathogenic in humans. However, some
of the emerging pathogens such as A. terreus, Tr. beigelii,
Scedosporium prolificans and certain Fusarium spp. may
be microbiologically and clinically resistant

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Invasive fungal infections in

• The yeast-like fungi Cryptococcus neoformans

• hematologic malignancies, either primary or relapse,

– Invasive candidiasis in preterm infants is most commonly

– Malassezia spp. are lipophilic commensal yeasts that

• Children with acquired immunodeficiencies

– Invasive candidiasis in neutropenic children may

• Children with chronic pulmonary diseases

Galactomannan assay PCR detection of fungal DNA

Perlroth J et al. Med Mycol. 2007;45:321-46.

*Not yet approved

disease Prophylactic Asymptomatic high-risk patient

Markers Asymptomatic + colonization

Signs & symptoms Empirical High risk: Antibiotic + fever

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