Opportunistic fungal infections

Opportunistic Fungal
Infections
Dr. Suprakash Das
M.D (Microbiology)

The HIV Pandemic
 The pandemic of human immunodeficiency virus (HIV) is one of
the biggest health crises ever faced by mankind.
 Overall, 34.0 million people were living with HIV at the end of
2011.
 Sub-Saharan Africa remains the most severely affected, with almost
1 in 20 adults (4.9%) living with HIV.
 AIDS is an advanced clinical manifestation of infection with human
immunodeficiency virus (HIV), characterized by low lymphocyte
count CD4 + below 200 / mm³.
 Patients with human immunodeficiency virus (HIV) infection often
develop complications and multiple comorbidities, among them
opportunistic infection (OI).
 From the mid-90s, the widespread use of HAART deeply influenced
the reduction of mortality associated with OI in HIV-infected
patients, in countries where these therapies are affordable and cheap.

The HIV Pandemic
 Despite the HAART era, the OIs continue to cause
considerable morbidity and mortality in HIV-infected
patients.
 This is due to three primary reasons:
1) Asymptomatic patients seek medical assistance only when
an OI becomes an indicator of AIDS;
2) Other patients do not make use of HAART for
psychosocial and economic factors; and
3) There are still those who do not have a good response to
antiretroviral agents due to poor adherence, drug toxicity,
drug interactions or unexplained biological factors.
 The highest incidence of opportunistic infections was
reported in the group of patients with CD4 lymphocyte
levels below 200 cells / mm³.

The HIV Pandemic
 Studies show that the major co-morbidities associated with
AIDS are
 Candidiasis, followed by
 Tuberculosis,
 Pneumocystosis,
 Toxoplasmosis,
 Herpes,
 Kaposi's sarcoma,
 Cryptococcosis, and
 Infections by protozoa.
 Although most OIs occur in patients with CD4 cell counts
below 200/mm3, a small residual risk remains even in those
with higher counts.

The HIV Pandemic
 A recent analysis of patients with CD4 cell
counts >200/mm3 found that
Esophageal candidiasis,
Kaposi Sarcoma and
Pulmonary tuberculosis
were the most common opportunistic conditions
in this population.

Oral-Esophageal Candidiasis
 Oral- esophageal Candidiasis is a fungal infection, caused by
Candida sp, with C. albicans being the species most commonly
isolated.
 This fungus normally lives in mucosa and only causes disease
when there are pre-existing conditions that favors its growth.
 Oropharyngeal candidiasis (OPC) and oral- esophageal candidiasis
(OEC) are by far the most common fungal infections in patients
infected by the human immunodeficiency virus (HIV) or acquired
immune deficiency syndrome (AIDS).
 They are indicators of profound immunodeficiency and are more
frequently observed in patients with T-CD4 + lymphocyte count of
< 200 cells, being OEC found in a more advanced stage of AIDS
than OPC.
 The oral cavity is colonized in about 40-60% of healthy people.

 In HIV+ individuals, the asymptomatic colonization rate is
higher, being approximately 76%.
 The genus Candida is currently classified in the Saccharomycetes
class and Saccharomycetaceae family based in its gene sequence.
 The genus Candida is comprised of a dichotomous unicellular
yeast specie measuring approximately 2 to 6 μm that
reproduces by budding, being able to grow either as yeast or as
a pseudohypha; most of the species forms pseudohyphas and
hyphas in the tissues.
 The colonies vary in color from white to tan and they can have
either a smooth or rough surface.
 Oropharyngeal candidiasis is the opportunistic infection most
frequently found in individuals that have AIDS.
 The disease occurs in up to 90% of patients during the progression
of the HIV infection.

 The occurrence of OPC, besides being associated with
 TCD4+ lymphocytes level under 200cells/mm3, is also
correlated to
 High viral load (>10.000 copies/ml) and
 HIV disease progression.
 Although the C.albicans species seems to be prevalent in
OPC, the epidemiology of this infection is rapidly evolving
and non- albicans Candida species, as well as rare yeast
forms, are appearing as the main opportunistic pathogen.
 The most common non-albicans Candida species are
 C. glabrata,
 C. parapsilosis,
 C. tropicalis and
 C. krusei, often isolated in oral and systemic candidiasis.

 Esophageal candidiasis is the main AIDS- defining
disease-
 [Certain serious and life-threatening diseases that occur
in HIV-positive people are called "AIDS-defining"
illnesses. When a person gets one of these illnesses, he
or she is diagnosed with the advanced stage of HIV
infection known as AIDS.]
 Its prevalence varies from 10% to 16%.
 In the esophagus C. albicans was the microorganism
most often isolated, followed by
 C. dubliniensis,
 C. glabrata,
 C. krusei and
 C. tropicalis

Pathogenicity-
 The protections against the conversion from colonizing yeast to
opportunistic/ invasive pathogen are provided by both, the systemic
and local immunity.
 The Th-1 type immunity provided by T CD4 lymphocytes is a
critical protection component, and
 the secondary defense is provided by TCD8 lymphocytes and oral
epithelial cells by a variety of mechanisms.
 Researchers have shown that cytokines, especially interferon
gamma, can inhibit the transformation of candida blastoconidea to
the more invasive hyphae phase.
 The decrease in levels of E- cadherin and a loss of TCD4+ cells in
the mucosa are associated with acute episodes of OPC.
 The most commonly described cause of a high rate of yeast in the
GI tract and of oral candidiasis is antibiotics use.
 The eradication of bacterial competition is, almost certainly, the
most important mechanism by which the antibiotics affect the
candida quantity in vivo.

Pathogenicity-
 It is believed that various secondary lines of defense are
important for the protection against candida when the primary
defense done by the T CD4+ cells is insufficient.
 This secondary line of defense includes T CD8+ cells and oral
epithelial cells.
 In individuals susceptible to OPC, the T CD8+ cells migration
to outside the epithelial tissue is inhibited because of the
reduction of E-cadherin with subsequent decrease in epithelial
cells activity level against candida, resulting in the disease.
 E-cadherin in normal levels promotes the migration of TCD8+
to outside the epithelial tissue to fight against candida.

Pathogenicity-
 A variety of virulence factors contribute to the
pathogenicity of Candida spp. including
the capacity to modify cellular morphology,
ability to adhere to epithelial cells and the
capacity to secrete extracellular enzymes,
like phospholipases and aspartyl proteinases.
 Tobacco use is a predisposing factor.
 In contrast to the oropharyngeal candidiasis, little
is known about the host factors and operational
yeast in the pathogeny of esophageal candidiasis
and experimental models have not been
established.

Clinical Presentation
 There are different types of oropharyngeal candidiasis and they are
classified in three groups:
1) Acute candidiasis,
2) Chronic candidiasis and
3) Angular cheilitis (stomatitis).
 Acute candidiasis is divided in
a) Pseudomembranous candidiasis,
b) Acute atrophic candidiasis (induced by dentures) and
c) Median rhomboid glossitis.
 Among HIV+ individuals, the erythematous, pseudomembranous
and angular cheilitis types are more evident.
 Pseudomembranous candidiasis is considered the most prevalent
fungal infection in patients infect by HIV and has been associated
with the progression of the disease;
 Also it is utilized as a clinical marker to define the severity of the
HIV infection.

 Pseudomembranous candidiasis is clinically characterized
as white- yellowish plaques, with a gelatin consistency.
 The plaques are composed by entwined hypha mass, yeasts,
desquamated epithelial cells and necrotic tissue fragments.
 These plaques can be removed by regular scratching with a
rigid instrument or by friction with a dry gauze compress or
a cotton swab,
 leaving as a result an erythematous, hyperemic, eroded or
ulcerated surface with hemorrhage points.
 In most cases, these lesions are asymptomatic, with the
exception of more severe cases where patients complain of
sensibility, burning and dysphagia.

 Acute erythematous candidiasis is a symptomatic lesion, generally
associated with a burning sensation in the mouth or tongue.
 The tongue can be a brilliant red similar to the observed with low
vitamin B12 serum levels, low folate and low ferritin .
 There is intense sensibility due to the numerous erosions dispersed in
the mucosa and due to the associated inflammation,
 most commonly located along the dorsum of the tongue, occurring
also in the soft and hard palate.
 These lesions can cause a burning sensation when there is ingestion
of hot or acidic aliments.
 It can occur independently or simultaneous to the pseudomembranous
form.
 The oral symptoms of the acute erythematous candidiasis are much
more accentuated due to the numerous erosions and the intense
inflammation.

 Angular cheilitis is a chronic inflammatory lesion
characterized clinically by
 Erythema,
 Maceration,
 Crusts and fissures.
 It affects the labial commissure and
 many times it is symptomatic and bilateral causing
discomfort.
 It can occur with or without erythematous or
pseudomembranous candidiasis, and
 It can persist for a long time period if left without treatment.
 The differentiation between each clinical subtype of
candidiasis is done by the appearance of the lesion and by
the symptoms described by the patient.

 This way, the candidiasis should be differentiated from
 Lichen planus,
 Leucoplasia,
 Fordyce granules,
 Eschar associated with chemical burns,
 Traumatica ulcers,
 Syphilitic plaques,
 Keratotic lesions and
 Discoid lupus erythematosus.

 In regards to esophageal candidiasis, it mostly
presents with
 Odynophagia,
 Dysphagia and
 Retrosternal pain.
 The differential diagnosis of OEC should include
 Gastroesophageal reflux disease (GERD),
 Idiopathic ulcers associated with HIV and
 Viral esophagitis due to cytomegalovirus or herpes
simplex virus.

Diagnosis-
 The diagnosis of OPC is generally clinical and followed
immediately by empiric antifungal therapy.
 Initially, the clinical story should be collected, followed by a
detailed mouth analysis including observation of the soft and
hard palate and examination of the oral mucosa, after
removing any prosthetics that the patient might have.
 Predisposing factors must be identified.
 In case of recurring candidiasis, candidiasis resistant to
previous treatment and/or patients repeatedly exposed to
fluconazol (and/ or imidazole derivatives),
 The identification of yeasts through fungal direct exam,
cultures and susceptibility tests to antifungal agents are
recommended due to the possibility of infection by Candida
spp resistant to one or a varitety of triazole drugs.

Diagnosis-
 In cases of esophageal candidiasis in HIV+ patients, the presumptive
diagnosis can be generally done after the beginning of typical
symptoms or by the presence of oral candidiasis associated with
esophageal symptoms and the antifungal treatment can be
empirically initiated.
 An endoscopy before the beginning of antifungal therapy can be
done in those individuals without concurrent OPC or those with
atypical symptoms.
 If the patients does not improve with adequate systemic antifungal
therapy an endoscopy is recommended so that other causes of
esophagitis mentioned earlier can be excluded.
 The endoscopy can reveal white plaques that may or may not be
accompanied by ulcerated lesions.
 It is also recommended that a sample be obtained for microscopic
exam, culture and a mucosa biopsy

Treatment-
 Fluconazole continues to be the antifungal drug of
choice for OPC and OEC treatment.
 Fluconazole is a fungistatic against Candida spp. with
an oral bioavailability superior to 80%, which is not
influenced by concomitant food ingestion or gastric pH.
 Its penetration in the saliva is excellent.
 Fluconazole, in the dosage of 100mg/day during 7 to
14 days is recommended as the first choice drug for
OPC treatment.
 Posaconazole (200mg in the first day and 100mg/
day for the remaining days) is also an alternative to
fluconazole; it is considered a therapy option in cases
with fluconazole resistant Candida sp.

Treatment-
 Intravenous formulations can be used in severe esophagitis cases.
 Voriconazole, 200mg two times per day for 14 to 21 days, is as
efficient as fluconazole,
 but it is associated with a higher incidence of adverse effects and a
higher potential for drug interactions, visual alterations and
phototoxicity in ambulatory patients.
 Echinocandins were evaluated for the treatment of OEC associated
with AIDS, especially comparing it to fluconazole.
 Intravenous caspofungin, micafungin and anidulafangin can be
used, however,
 these agentes have a higher recurrence rate then fluconazole, are
more expansive and are not available in an oral formulation.

Pneumocystis jirovecii pneumonia (PCP)
 Pneumocystis jirovecii pneumonia (PCP) is a potentially life-
threatening fungal infection seen in immunocompromised
individuals.
 In 1940s, Pneumocystis was recognized as a pathogen for
pneumonia in malnourished or premature infants.
 Then, prior to 1980s, PCP was recognized as a rare but fatal
infection primarily among patients with acute leukemia and other
hematological malignancies.
 In 1980s, the worldwide epidemic of human immunodeficiency
virus (HIV) dramatically increased the prevalence of PCP.
 Because of the progress in the antiretroviral therapy (ART) and the
use of routine prophylaxis against PCP, the incidence of PCP in
HIV-infected population was reduced in most of the industrialized
countries.
 However, PCP still remains to be the most common opportunistic
infection among patients with acquired immunodeficiency syndrome
(AIDS) in many countries.

 Pneumocystis jirovecii lives almost exclusively in the pulmonary alveoli in
human.
 Morphological studies have revealed three distinct stages:
1) the trophozoite (trophic form), in which it often exists in clusters,
2) the sporozoite (precystic form), and
3) the cyst, which contains several intracystic bodies (spores).
 The trophic form, which adheres tightly to alveolar type I epithelial cell,
is 1–4 μm in diameter and the mature cyst is 8–10 μm in diameter.
 During infection of the lung, the trophic forms predominate over the cyst
forms by ∼10:1.
 Based on serologic testing, most children acquire infection with P.
jirovecii by age 4.
 In HIV-infected patients, the rates of colonization were reported to be as
high as 69%.
 PCP or those colonized with Pneumocystis may result in person-to-
person transmission.

Host Response to Pneumocystis-
 The host immune response during PCP involves complex interactions
between CD4+ T cells, CD8+ T cells, neutrophils, alveolar
macrophages, and soluble mediators that facilitate the clearance of the
infection.
 Alveolar macrophages serve as the primary host defense against P.
jirovecii, playing an important role in the recognition, phagocytosis,
and degradation of the organisms.
 In response to proliferation of Pneumocystis, the uptake of the
organisms by macrophages occurs through multiple receptor systems,
including
 the action of mannose receptors that interact with glycoprotein A or
major surface glycoprotein (MSG) on the surface of Pneumocystis, and
 the interaction between (1→3)-β-d-glucan (β-d-glucan) of
Pneumocystis and the macrophage surface receptors, dectin-1 and Toll-
like receptor 2.

Host Response to Pneumocystis-
 CD4+ T lymphocytes, the count of which decreases in
HIV infection, are essential to eradicate P. jirovecii
infection and contribute to inflammatory lung damage.
 CD4+ T cells proliferate in response to Pneumocystis
antigens and generate interferon (IFN)-γ,
 which induces further recruitment of macrophages.
 Interleukin-8 (IL-8), which is released from epithelial
cells and macrophages, strongly enhances the
recruitment of neutrophils that not only contribute to
the organism clearance but also mediate lung injury
through the release of proteases and oxygen radicals.
 Severe PCP is characterized by neutrophilic lung
inflammation that may result in diffuse alveolar
damage, impaired gas exchange, and respiratory failure.

Clinical presentation –
 In HIV-infected patients, PCP classically presents with
 Low-grade fever,
 Nonproductive or minimally productive cough,
 Dyspnea, and
 Malaise, which are not specific to PCP.
 Symptoms may be subtle at first but gradually progress and may be
present for several weeks before diagnosis, and up to 7% of the
patients can be asymptomatic.
 Physical examination is also nonspecific.
 The pulmonary auscultation is often normal, but, when abnormal,
 Inspiratory crackles are the most common finding.
 Patients may have signs of respiratory compromise, including
 Tachypnea,
 Tachycardia, and
 Cyanosis.

 Extrapulmonary manifestations of Pneumocystis infection
are not common, but
 Retinitis,
 Thyroiditis,
 Bone lesions, and
 Pneumocystosis of brain, liver, spleen, and kidney have
been described as rare manifestations.
 These findings tend to occur more frequently in patients
who have been on prophylaxis with aerosolized
pentamidine or
 who were extremely immunocompromised, generally from
advanced AIDS.

Diagnosis-
 PCP cannot be cultured routinely; therefore,
 diagnosis requires detection of the organism by microscopic
examination of induced sputum, bronchial alveolar lavage (BAL),
or tissue.
 Examination of induced sputum has variable sensitivity (<50% to
>90%).
 BAL has a high sensitivity for PCP; however, it is an invasive
procedure with potential morbidity in patients with respiratory
compromise.
 Elevated serum lactate dehydrogenase is a nonspecific marker,
which is often elevated in cases of PCP.
 Serum (1→3)-β-D-glucan (β-glucan), a component of the cell wall
of Pneumocystis jirovecii, may also be elevated in patients with
PCP but there is cross reactivity with other fungal diseases.

Diagnosis-
 The microscopic demonstration of the organisms in
respiratory specimens has been the golden standard for
the diagnosis of PCP.
 Cysts can be stained with
 Grocott-Gomori methenamine-silver
 Toluidine blue O
 Calcofluor white.
 Trophic forms, which predominate over the cyst forms
during development of PCP, can be detected with
 Wright-Giemsa and
 Diff-Quik staining.

Diagnosis-
 The visualization of the organism may not be steady
depending upon the skill and experience of the observer.
 Monoclonal antibodies for detecting Pneumocystis have a
higher sensitivity and specificity in induced sputum samples
.
 In HIV-infected patients, microscopic visualization of BAL
specimens has a reported sensitivity of 98% or greater.
 Because bronchoscopy requires specialized personnel and
equipment and carries an associated risk of complications,
sputum induction with hypertonic saline, which has a
diagnostic yield of 50%–90%, could be the initial
procedure used to diagnose PCP.
 The sensitivity may be lower in patients receiving
aerosolized pentamidine for prophylaxis.

 Diagnosis-
 The detection of Pneumocystis DNA in clinical specimens by using
PCR assays is leading to important advances in the clinical diagnosis of
PCP.
 Nested or conventional PCR, which uses PCR primers for the gene for
Pneumocystis mitochondrial large-subunit ribosomal RNA, is a
technically established method and is now widely used in clinical
practice.
 PCR has 94%–100% sensitivity and 79%–96% specificity in the
diagnosis of microscopically positive PCP.
 It has been shown that Pneumocystis DNA can be detected by PCR in
oropharyngeal washes and nasopharyngeal aspirates.
 In HIV-infected patients, PCR of oropharyngeal wash had a
diagnostic sensitivity of up to 88% and a specificity of up to 90% for
PCP, which is comparable to that of microscopic observation of BAL
fluid and may exceed that of microscopic observation of induced
sputum.

Clusters of Pneumocystis jirovecci (Methenamine silver stain - 100 ×).

Aspergillus
 Aspergillus is a genus of mold that is ubiquitous in the environment and
can be isolated from soil worldwide.
 Various species are known to cause human disease but the most
frequent pathogen is Aspergillus fumigatus.
 Human exposure to Aspergillus spp. occurs by inhalation of airborne
conidia.
 In immunocompetent hosts with normal lung architecture, it is rare for
Aspergillus to cause disease.
 In immunocompromised patients or patients with structural lung
abnormalities, Aspergillus is associated with several distinct chest
syndromes:
 Aspergilloma,
 Allergic bronchopulmonary aspergillosis (ABPA),
 Tracheobronchial aspergillosis,
 Chronic necrotizing aspergillosis, and
 Invasive pulmonary aspergillosis (IPA).

Aspergillus
Different syndromes have unique risk factors.
 For aspergilloma, structural lung disease, like bullae in
chronic obstructive pulmonary disease, is a major predisposing
condition.
 ABPA has a predilection for patients with cystic fibrosis and
severe asthma.
 IPA, the most severe and most dangerous manifestation of
Aspergillus infection, affects immunocompromised hosts,
particularly patients with absent or abnormal phagocyte
function.
 The classic risk factors for IPA are corticosteroid use and
granulocytopenia from hematologic malignancy or its
therapies.

Aspergillus
 All Aspergillus syndromes have been described in patients with HIV
infection but
 compared to the occurrence of other opportunistic pathogens,
Aspergillus infection is uncommon.
 While IPA was initially included as an AIDS-defining opportunistic
infection by the Centers for Disease Control, it was removed in 1984
when it was found that the incidence of IPA in patients with HIV
infection was 0.1 percent;
 incidence is lower still today because of widespread use of effective
ART.
 Even in patients with very low CD4+ TH counts, IPA is unusual in
the absence of additional risk factors such as neutropenia.

INVASIVE ASPERGILLOSIS
 IA implies invasion of lung tissue by hyphae as
demonstrated on histology.
 The clinical presentation is relatively rapid, ranging from
days to a few weeks.
 It has been studied extensively in the neutropenic host;
however,
 it has also become increasingly recognised in patients
without neutropenia.
 The classic risk factor for IA is neutropenia, and the
likelihood of IA correlates with its duration and depth.
 Platelets may also be important in defence against IA, and
thrombocytopenia tends to parallel neutropenia.
 Angioinvasion is involved in the pathogenesis in
neutropenic hosts and is responsible for the higher
frequency of dissemination to other organs such as skin,
brain or eyes .

 At higher risk for IA are patients undergoing allogeneic HSCT
and patients with prolonged neutropenia following
chemotherapy.
 IA occurs in a wide range of non-neutropenic hosts.
 The most common unifying risk factor is corticosteroid use,
often prior to hospital admission.
 IA has been recognised in solid organ transplant recipients (
particularly lung and heart-lung transplant recipients),
 patients with AIDS, COPD, the critically ill intensive care
unit (ICU) patients,
 patients with liver failure and those with chronic
granulomatous disease.
 In these hosts, in contrast to patients with neutropenia,
angioinvasion is not a common feature.

The symptoms include
 fever,
 cough,
 chest pain, and
 dyspnea (shortness of breath).
 Angioinvasion results in necrosis of tissue, which
may ultimately lead to cavitation (formation of
empty spaces) and/or hemoptysis (coughing up
blood).

 Although there is accumulated experience with diagnostic tests
such as fungal culture, galactomannan (GM) or PCR in
patients with neutropenia, less evidence exists in non-
neutropenic hosts.
 Respiratory samples are better than blood for all tests except
β-D-glucan.
 There are several studies that document the usefulness of
bronchoalveolar lavage (BAL) GM and PCR for the
diagnosis of aspergillosis in lung transplant patients.
 GM sensitivity ranges from 60% to 93%, depending on the
cut-off value used, whereas

 A. fumigatus-specific and panfungal PCR had a
sensitivity of 85% and 100%, respectively.
 Both tests have a better sensitivity than that of
direct microscopy and fungal culture, which is
usually less than 50%.
 BAL GM may also be useful as a prognostic
factor, and an index ≥2.0 was associated with
worse prognosis in patients who were
nonneutropenic.
 In contrast, serum but not BAL GM was a
predictor of prognosis in patients with HSCT.

Opportunistic fungal infections

Opportunistic fungal infections

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