INVASIVE FUNGAL INFECTIONS, FEBRILE NEUTROPENIA, AND MALARIA
INVASIVE FUNGAL INFECTIONS
GENERAL OVERVIEW
TYPES OF FUNGAL INFECTIONS
The fungal diseases can be of different spectrum and not all of them are associated with infections.
They can be divided into three major groups, which are:
• Allergies: they are
hypersensitivity reactions
(type I) to mould spores;
the typical example is the
hay fever.
• Mycotoxicosis: it is caused by ingestion of fungal toxins in contaminated food or mushrooms;
this is often observed in individuals that took fungi in the forest by themselves, and then cook
and eat them.
• Mycoses: they are invasive and infectious diseases of living tissues
caused by fungi; they can be divided into:
Superficial mycoses: they affect skin, hair, and nail beds; they
are named tineas.
Subcutaneous mycoses: they affect muscles and connective
tissue underneath the skin; an example is the sporotrichosis,
or rose-gardener’s disease, which is caused by the
Sporothrix shenckii; this disease develops when the fungus
enters the skin through a small cut or scrape; it causes
ulcerations, but it does not invade internal organs.
Systemic mycoses: they are infections of the internal organs;
they are divided into primary and opportunistic infections.
The number of fungal infections occurring worldwide is of about 150-300
million cases per year; however, more than 99% of them are caused by 30 species. Which means that
only few fungi are pathogenic to humans. The annual number of deaths is of 1.7 million, which is
similar to TB and 3-times higher than malaria.
The main reason why not all fungi can cause infections in humans is
related to the fact that they are not adapted to live at 37°C (body
temperature). There are some fungi, like the Ophiocordyceps
unilaterali (zombie-ant fungus) that is able to control the nervous
system of the infected ant, maintaining it attached to the leaf, until
it germinates and release the spores (it is thought that a possible
cause of dinosaurs’ extinction was a fungal infection). It is believed
that more pathogenic fungal species will arise in the next years due to the global warming.
FUNGAL MORPHOLOGY
The fungal morphology is different respect to the bacteria one. Indeed, they are eukaryotes that can
be unicellular or not. There are three main types of fungal morphology, which are:
• Yeasts: they are the most common cause of
fungal infections; they are usually unicellular
organisms that can form pseudohyphae;
usually, the yeast is the colonising form, while
the hyphae are the invasive form; an example
is C. albicans.
• Moulds: they are fungi that produce spores
that are release in the air; these spores can be
taken up by macrophages in lungs, and they
, are typically destroyed; an example is Aspergillus; note that hyphae have branching
characteristics that help histopathology in identification of the type of fungal pathogen.
• Dimorphic state: they can be present either in a mould-like form or in a yeast form; the mould
can release spores that invade the host, and due to the warmer temperature, it can germinate,
thus creating an invading yeast; an example is coccidiomycosis.
PRIMARY AND OPPORTUNISTIC INFECTIONS
The systemic mycoses are divided into primary and opportunistic infections. The primary endemic
fungal infections are rarer and more specific of determined ecological niches. They are mostly found
in Africa, South America, and some regions in Asia, as well as
in some areas of the Po valley. Examples are blastomycosis,
coccidiomycosis (observed in Arizona and US desert areas),
histoplasmosis, and emergomycosis. For that reason, asking
patients where they have been, is important to rule in or rule
out these fungal infections.
The primary systemic mycosis are infections that occur both in
immunocompromised and immunocompetent patients.
Despite being endemic in specific area, global warming may
increase the widespread of these diseases. Typically, in the
endemic area they are present as dimorphic fungi, but they
can spread in a mould-like form at environmental
temperature or yeast-like form at 37°C.
The opportunistic infections mainly occur in
immunocompromised patients. The most common are
invasive candidiasis, cryptococcosis (cryptococcal meningitis), aspergillosis, and rarer molds (e. g.
mycormycosis, fusariosis, scedosporium, etc.).
CRITICAL PATHOGENS AND ANTIGUNGAL AGENTS
The WHO provides a list of priority fungal pathogens and in the group of critical priority C. albicans,
and C. auris are found, together with C. neoformans and A. fumigatus. The C. auris was recently
discovered in a group of Japanese patients,
and it was later found in 5 continents, it is
acquired via human-to-human transmission.
It is also MDR.
As regards antifungal agents, they typically
target either the cell wall (-1,3 glucan
synthase, echinocandins) or the cell
membrane (ergosterol biosynthesis, azoles,
amphotericin B). Only flucytosine acts on
DNA synthesis (thymidylate synthase
inhibitor). They are quite effective, and
resistance is rarely observed (despite being
increased recently). The problems are that
they have a high number of side effects (e. g. cyt-P450 interaction) and toxicities (e. g. nephrotoxicity).
Moreover, the problem in developing of new antifungal is that fungi are eukaryotes, and therefore it
should be created a drug that affect only fungi, not human cells.
INVASIVE CANDIDIASIS
AETIOLOGY
The invasive candidiasis can be caused by the passage of Candida from the GI tract to the
bloodstream. Indeed, it was seen from an experiment performed by a German resident in the 1969
,that the Candida that overgrowth in the GI tract during antimicrobial therapy in ICU patients may
cause systemic infections (he inoculated himself by eating 400 plates of Candida, 1017 cells). For that
reason, Candida is one of the most detected
pathogens in the blood in ICU patients.
The invasive candidiasis is linked to medical
progress/technology. In several developed
countries, it is the 3rd-4th most common cause of
bloodstream infection (BSI, 18% of all ICU
infections). Most infections start with colonisation
(60% of hospitalised patients), typically of the
intestine. Most infections are caused by 1 of these
6 species, which are:
• C. albicans: it is the most common and with
high virulence.
• C. glabrata: it is MDR to fluconazole; it has low virulence.
• C. tropicalis: it has high virulence, potential human-to-human transmission.
• C. parapsilosis: it is a high biofilm producer; it is typically observed in case of catheter
infection (healthcare workers hands); it has lower virulence.
• C. krusei: it is fluconazole resistant, breakthrough infections.
• C. auris: it is an emerging MDR pathogen, which spread human-to-human, and survives to
harsh environments.
These species may vary among continents, countries, and hospitals.
PATHOGENESIS
The invasive candidiasis should be seen as a continuum of infection. It begins from a colonization of
the host, which may occur in the mouth, intestine, genital tract, or skin. At first the colonisation causes
a local infection that is presented
in different ways according to the
affected site. Examples of local
infections can be oropharyngeal
candidiasis, candidemia,
vulvovaginal candidiasis, and
cutaneous candidiasis.
Once Candida moves in the
blood it will cause a
disseminated disease, which
may affect multiple internal organs. In the case of Candida in the intestine, the dissemination may
cause different symptoms. Firstly, if the Candida moves in the abdominal cavity it may result in
abdominal abscess, pancreatitis, and peritonitis. This is often observed in case of leaky gut. If Candida
moves in the bloodstream, it may affect multiple organs, which are:
• Bone: it causes osteomyelitis and spondylodiscitis.
• Brain: it causes brain abscess and meningoencephalitis.
• Eye: it causes choroiditis, retinitis, and endophthalmitis.
• Heart: it causes endocarditis.
• Kidney: it causes candiduria, pyelonephritis, pyonephrosis, and renal abscess.
• Liver and spleen: it causes chronic disseminated candidiasis and focal abscess.
• Lung: it causes focal abscess.
CANDIDIASIS PRESENTATIONS
The candidiasis can be presented in different forms. In the mucocutaneous and semi-invasive forms,
the patient presents mucosal lesions, which are inflamed, painful, and whitish due to the presence of
, fungal biofilm. An example is the oesophageal candidiasis, which is mainly observed in a HIV patient.
Other manifestations can be observed in the throat, tongue, and vulvovaginal tract.
The cutaneous manifestations of Candida infection
are related to different signs. In case of no
disseminated disease, larger and less diffused areas of
ecchymosis are observed. Conversely, in disseminated
disease multiple and more diffused petechiae are
present (mainly in neutropenic patients). Typically,
invasive candidiasis is developed by patients with
leaky gut or neutropenia. The HIV patients have
typically recurrent semi-invasive forms.
Other clinical presentations include:
• Fever and haemodynamic instability.
• Skin lesion in neutropenic patients.
• Eye lesion: chorioretinitis, endophthalmitis;
it is difficult to treat since there are few
antifungals can penetrate the eyes.
• Endocarditis: common in injection-drug users
and prosthetic valves patients.
In neutrophil recovery patients (e. g. chemotherapy patients after prolonged neutropenia), invasive
candidiasis can be presented as hepatosplenic candidiasis. The Candida has a great propensity to
colonise the liver and the spleen. In this condition, the infection
remains undetected during the neutropenic stage, but then once
recovery occurs, neutrophils start the inflammatory reaction,
causing pain and fever. This infection can be observed in
abdominal CT or detected due to increase liver alkaline
phosphatase and fever.
DIAGNOSIS
The diagnosis of invasive candidiasis is difficult since most of the blood cultures result negative; the
positivity ranges between 21%-71%, and longer times for positivity is required (2-5 days). There are
some techniques used to improve blood culture positivity,
such as high-volume culture (40-60mL), frequent sampling
if febrile, and specialised culture techniques (lysis
centrifugation).
The candidiasis is also diagnosed when positive cultures are
observed in sterile sites or newly placed drains (e. g.
intrabdominal, intrathoracic sites). Note that Candida rarely
causes respiratory infections, and therefore if
bronchoalveolar lavage results positive to Candida, it is
sufficient to change the ventilator, and antifungals are not
required.
To isolate yeasts, commercial ID systems (e. g. MALDI-TOF)
are used. The identification is useful to obtain susceptibility
testing. There are however some pathogens that can be misidentified through MALDI-TOF (e. g. C.
auris).
Another method used to diagnose candidiasis is histopathology. There are specific dyes that can be
used to observe the Candida in the infected tissue, both in its amorphous and hyphae forms. Examples
are the Grocott-Gömöri methenamine silver stain (used to identify hyphae) and Calcofluor White
stain. The histopathological sample is taken from a biopsy of the infected tissue.
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