Sie sind auf Seite 1von 38

Blok

26
Agustus 2014

Introduc5on
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.

Classica(on of fungi associated with human infec(on


(mycoses)

Cutaneous Supercial Fungal Infec(on


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.

Kera5n-containing structures such as hair shaFs, nails, and


skin are aected.
Dermatophyte skin infec5on (some5mes called ringworm)
is commonly named aFer the area aected
E.g. 5nea capi5s (head) or 5nea corporis (body).

Systemic Fungal Infec(on


The systemic fungi: Coccidioides immi7s, Paracoccidioides
braziliensis, and Histoplasma capsulatum.
Thermally dimorphic fungi (have both yeast-like and
lamentous forms).
Environmental organisms, which enter the body usually via
inhala5on.
Infec5on is geographically circumscribed and oFen clinically
mild.
Severe disseminated disease can occur, however, par5cularly in
immunocompromised pa5ents.

Systemic Fungal Infec(on


The main fungi that cause disease in immunocompromised
the yeasts C. albicans, and
related species such as Candida krusei.

Aspergillus species
important environmental lamentous fungi,
may cause pulmonary or disseminated infec5on.

The yeast-like fungi Cryptococcus neoformans


can cause chronic meningi5s in HIV

Pediatric popula(ons at risk for invasive


infec(ons
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 popula(ons at risk for invasive infec(ons

Risk factors for invasive Candida infec(on

Risk factors for invasive Aspergilus infec(on

hematologic malignancies, either primary or relapse,


allogeneic bone marrow transplanta5on
granulocytopenia,
cor5costeroids for malignancy
autoimmune disease,
immunosuppressive therapies,
immunodeciencies, such as chronic granulomatous disease,
severe combined immunodeciency
organ transplanta5on, such as heart-lung transplanta5on
Cushing syndrome because of its endogenous high secre5on of
cor5sol can favor development of IA.

Risk factors for invasive Aspergilus infec5on

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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 913% of all bloodstream isolates in
NICUs

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
Invasive candidiasis in preterm infants is most commonly
due to C. Albicans and C. parapsilosis [43, 47] 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.

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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.

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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.

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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.

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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.

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
Similar to histoplasmosis [121, 122], 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

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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 fluconazoleresistant 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 [145, 146] makes a major contribution
to the increased susceptibility of patients with advanced HIV infection
to invasive aspergillosis

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents
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 hyperIgE 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.

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents

Epidemiology and presenta(on of invasive fungal


infec(ons in pediatric pa(ents

Recent advances in early diagnosis and


preemp(ve 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

Pediatric pharmacology of established


an(fungal 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