Candidiasis in HIV/AIDS

Doni Priambodo Wijisaksono

Subdivision of Tropical Medicine and Infectious Diseases

Internal Medicine Department
Faculty of Medicine Gajah Mada University / Dr Sardjito General Hospital Jogjakarta
 Increases in the prevalence of systemic
Candida infections
3.5
(episodes/10,000 patient-days/year)

3.0
Incidence of candidaemia

2.5

2.0

1.5

1.0

0.5 Europe Data

0
1999 2000 2001 2002 2003

Year Bassetti M, et al. BMC Infect Dis 2006; 6:21

 Candidiasis is now known to
be the most common
opportunistic fungal infection
in HIV-positive Patients.
 The spectrum of Candida infection is diverse,
starting from asymptomatic Colonization to
Oropharyngeal Candidiasis (OPC),
esophagitis,onychomycosis,
vulovaginitis, cutaneous Candidiasis and systemic
candidiasis or invasive candidiasis including
candedemia
(7, 8, 9). Oropharyngeal candidiasis,often the first
sign of HIV infection
 c. Albicans in aids patients
In immunocompromised patients, when body
resistance is low as in leukemia or HIV/AIDS,
Candida albicans can enter the bloodstream and
causes systemic infection
The more debilitated the host the more invasive
the disease
Candida albicans is one of several mycoses
(fungal disease) that account for most deaths
associated with AIDS
So common in HIV+ individuals that their
mycoses are part of what defines end-stage AIDS
 Overview
Candida ssp is an
opportunistic fungus
(yeast)
Candida albicans is the
most common etiology of
esophagitis in patients with
AIDS
Candida tropicalis, Candida
Krusei, Candida glabrata,
and Candida parapsilosis
can also cause esophagitis
Esophageal Candidiasis
Oropharyngeal candidiasis (thrush)
Yeast infection that develops in
the mouth
White plaques in mouth,
tongue, gums, palate, and/or
pharynx
Preventable by practicing good
oral hygiene
To prevent from spreading to
infants: treat vaginal yeast
infections during last 3 months
of pregnancy, wash bottles and
pacifiers, and do not reuse
bottles more than an hour after
a baby has drank from it
Ocular candidiasis
Characterized by cloudy
vision, and lesions within
the eye
Caused through the spread
of Candida in the blood
stream, indwelling
catheters, IV drug abuse,
ocular trauma/surgery
Prevention: avoid IV drug
abuse
Treatment: Amphotericin B
 Relationship between hospital mortality and the timing of
appropriate antifungal treatment

35
Hospital mortality (%)

30
25
20
15
10
5
0
< 12 1224 2448 > 48

Delay in start of antifungal treatment (hours)

Initiation of therapy > 12 h after the first positive blood sample was associated
with a greater risk of mortality than appropriate therapy given within 12 h

Morrell M, et al. Antimicrob Agents Chemother 2005; 49:36405

The Action of Therapy:
IDSA Guidelines 2009
 Systemic antifungal agents

3 major categories
1. The Polyenes (Amphotericin B)
2. Triazoles (fluconazole, itraconazole,
voriconazole, posaconazole)
3. Echinocandins (caspofungin, anidulafungin,
micafungin)
 IMUNOPATOGENESIS (Guntur, 2000)

C3a, C5a LPS APC SUPER ANTIGEN

IMUNO.COM
LPS bp

C7a CD 4+ TCR
CD 14
TLR 4 IL - 10 IL
IFN - g -4
TLR2 TH - 1 TH - 2 IL - 5 B cell
IL - 6
CSF Ig
IL 8
SEPSIS
IL 6 IL-2
IL -1 N
Compl.
TNF - a CD 8+
MOD NK
TF-VIIA
PaI-1 PGE 2 NO ICAM -1

SHOCK
SEPTIC
 Innate and Adaptive Immunity to Fungus

Different fungus infect humans and may live

both in extracellular tissue and within
phagocytes
Principal mediators of innate immunity to
fungus are macrophages and neutrophils
Cell-mediated immunity is the major
mechanisms of adaptive immunity against
fungal infection
Figure 1. Pathogens causing invasive fungal infections (Pappas et al. 2006) PCP,
Pneumocystis jiroveci (carinii
 Candida is the third most common
cause of BSI in the ICU

40 35.9%
35
Cause of nosocomial BSI in the ICU
(US; 1995-2002)
30
Cause of infection (%)

25

20 16.8%

15
10.1% 9.8%
10
3.7%
5

0
CoNS Staph Candida Enter E.Coli
BSI=Blood stream infection.
ICU=Intensive care unit.
Wisplinghoff H et al. Clin Infect Dis. 2004;39:309-317.
 Recommended duration of therapy or
candidemia :

2 weeks after documented clearance of candida

from the blood stream and resolution of
symptoms attributable to candidemia
Journal of Clinical Microbiology 2005;43(12):5848-5859
Spores / Hyphae
 The defect in cellular immunity
characteristic of HIV infection predisposes to
Candida infections. Role of lymphocytes and
polymorphonuclear
leukocytes in defense against infection
with Candida is of great importance, as indicated
by the relatively common occurrence of disseminated
candidiasis in neutropenic patients without defects in
cellular immunity
 Importance of Candidemia
Common BSI in ICU patients, 4th rank due to NNIS

Delayed therapy results in higher mortality than early

appropriate therapy

High mortality 30-40% even antifungal therapy with attributed

mortality 14.5% in adults

Increase in prevalence of non-albicans Candida which may not

response well to amphotericin B or fluconazole

Concern about amphotericin B nephrotoxicity in critically ill

Wisplinghoff H et al. Clin Infect Dis. 2004;39:309-317., Zaoutis TE et al. Clin Infect Dis 2005;41:1232.
Weinberger M et al, J Hosp Infect 2005;61:146.
Q2: What is the most common Candida species
in your institute?

1. Candida albicans

2. Candida tropicalis

3. Candida glabrata

4. Candida parapsilosis

5. I dont know. My institute cant speciate

 Epidemiology of Candida BSI 2001-2004

USA Europe Latin Asia-

America Pacific
C. albicans 51 59.8 51.0 54.8

C. tropicalis 7.1 8.8 7.1 13.2

C. parapsilosis 14.3 12.1 14.3 16.9

C. glabrata 22.3 10.3 6.5 10.1

Pfaller MA et al. Clin Microbiol Infect 2004;10(suppl1):11-23.

 In vitro activity of the Echinocandins versus Common Candida

Species (n) Caspofungin Micafungin Anidulafungin

(mcg/mL) (mcg/mL) (mcg/mL)
MIC50 MIC90 MIC50 MIC90 MIC50 MIC90

C. albicans (733) 0.5 0.5 0.03 0.03 0.03 0.03

C. glabrata (458) 0.5 1 0.03 0.06 0.03 0.03

C. parapsilosis (391) 2 2 1 2 2 2

C. krusei (50) 1 2 0.03 0.06 0.03 0.13

C. lusitaniae (20) 1 2 0.13 0.25 0.06 0.25

C. dubliniensis (18) 0.5 0.5 0.06 2 0.03 0.06

Ostroskey-Zeichner. Antimicrobial Agents Chemother. 2003, p. 31493154

Friend? Or Enemy?
Candida colonization

Superficial infection

Systemic infection
The lancet infectious disease Vol.3 Novermber 2003,p.685-720
 Candida score
Total parenteral nutrition * 1
Surgery * 1
Multifocal Candida colonization * 1
Severe sepsis * 2

The cutoff point is 3

 The individual Candida strains affecting persons with HIV infection
are not different from those in other immunosuppressed hosts.(19)
C dubliniensis is more commonly identified in HIV-infected persons,
though it is currently indistinguishable from C albicans in its clinical
presentation.(11-13) There are no detectable differences in the
virulence of strains isolated from HIV-infected or HIV-uninfected
persons. Recurrent disease can result from the same or from
different species or strains of Candida.(20-23) The emergence of
different strains or species is more likely in persons with lower CD4
lymphocyte counts and exposure to antifungal therapy.(19) Up to
90% of persons with advanced untreated HIV infection develop
OPC, with 60% having at least 1 episode per year with frequent
recurrences (50-60%).
 Diagnosis The diagnosis of OPC usually is made by its characteristic clinical appearance; recovery of an organism is not
required. Oropharyngeal cultures often demonstrate Candida species, but alone are not diagnostic because colonization is
common.(24) The diagnosis of OPC can be confirmed by examining a 10% potassium hydroxide (KOH) slide preparation of a
scraping from an active lesion. Pseudohyphae and budding yeast are characteristic findings. The appearance of the lesion
and presence of yeast forms on microscopic examination of the oropharynx are sufficient to confirm the diagnosis. A KOH
preparation is not mandatory for diagnosing OPC. A presumptive diagnosis of OPC can be made by visual detection of
characteristic lesions with resolution of those lesions in response to antifungal therapy. Culture usually is not necessary
unless the lesions fail to clear with appropriate antifungal therapy. In patients with poorly responsive OPC, a culture should
be obtained to look for inherently drug-resistant yeast or those that respond poorly to certain azoles (eg, C krusei or C
glabrata). Clinicians should note that many microbiology laboratories report yeast cultures as either C albicans or non-
albicans species based upon the germ tube test, and further characterization requires making a specific request. Biopsy of
oral lesions rarely is helpful or indicated for the diagnosis of oral candidiasis.
A presumptive diagnosis of Candida esophagitis can be made in a patient with dysphagia and/or odynophagia who has OPC.
Barium swallow or upper GI endoscopy can confirm a suspicion of esophageal involvement. These studies are not uniformly
required, however, unless a patient fails to improve with appropriate systemic antifungal therapy.(35) If esophageal
symptoms in a patient with OPC do not resolve despite resolution of the oral lesions, endoscopy is indicated to exclude
other causes of esophagitis (eg, cytomegalovirus, herpes simplex virus, aphthous ulcers) in persons with HIV infection. The
diagnosis of Candida esophagitis is confirmed by the presence of yeast forms on histologic examination of esophageal
lesions. Cultures to look for drug-resistant yeast are warranted for patients who require endoscopy. Barium swallow rarely is
indicated in HIV-infected patients with esophageal disease because it usually is not possible to determine the cause of an
abnormality by its radiologic appearance alone.
The diagnosis of Candida vulvovaginitis is made by the presence of a characteristic clinical appearance and observation of
yeast forms on microscopic examination. A KOH preparation of the vaginal discharge should be made to confirm the
diagnosis of candidiasis and to differentiate from a number of other conditions that can be similar in appearance (eg,
trichomoniasis). Because yeast are normal inhabitants of the vaginal mucosa, routine fungal cultures rarely are helpful when
the KOH preparation is negative. A fungal culture should be obtained if a patient fails to respond to standard antifungal
therapy.
 Infection by HIV-1 is a major risk factor predisposing for fungal infection. However, few studies have
addressed the immunological status of HIV-1 patients suffering fungal infections. This study examines the
status of polymorphonuclear phagocytes (PMN) and T cells in HIV-1-infected patients suffering from
mucosal Candida infections. These patients had a more immature population of blood PMN, as detected
by lower CD18 expression, than HIV asymptomatics or healthy controls. They also had a selective defect in
T cell activation in response to phytohemagglutinin (PHA), but not to stimulation through the T cell
receptor by anti-CD3 crosslinking, when compared to HIV-1 asymptomatic patients. This was shown by a
decrease in cellular proliferation and cell surface expression of CD69, CD25 and CD71 activation antigens.
There was also a severe impairment of IL-2 production upon activation by PHA. IL-10, and TNF secretion
was also reduced, whereas IFN-gamma and IL-5 production was not affected. No correlation with viral
load, CD4 or CD8 T cell number or clinical stage was found. In conclusion, our results indicate that
Candida-infected HIV patients have a selective defect, independent of viral load, CD4 or clinical status,
involving some aspects of T cell activation, IL-2 production being severely impaired.
Eur Cytokine Netw. 2002 Apr-Jun;13(2):215-23
Punzn C, Resino S, Belln JM, Muoz-Fernndez MA, Fresno M
 Is Fungal Pathogenesis Important? How Common are Fungal Diseases?
Candida infection: Invasive and life-threatening fungal infection
Candidaemia occurs at a population rate of 2-11/100,0007, so ~300,000 cases are
predicted worldwide, with a mortality of 30-55%. The numbers rose in the US by
52% between 2000 and 2005.
Around 150,000 of the 7.5 million patients admitted to intensive care (ICU) in
Europe, USA and Japan each year grow Candida in their urine (a rate of 2.7% of
ICU admissions) and is a common finding in hospitalised patients and those with
catheters (~16%)11 especially those in ICU.
Oral, oesophageal and vulvovaginal candidiasis (thrush)
Oral thrush occurs in ~9.5 million people worldwide based on ~90% of HIV/AIDS
patients not taking but needing anti-retroviral therapy, estimated at by the WHO
in 2009.
Oral thrush also occurs in normal babies, people taking inhaled steroids for
asthma, following radiotherapy to the head and neck for cancer, in denture
wearers and in some leukaemia and transplant patients.
Candida infection of the oesophagus (gullet) affects an estimated ~2 million
people as ~20% of HIV/AIDS patients3 not on anti-retroviral therapy, and ~0.5% if
on antiretroviral therapy develop it.
Repeated attacks of vulvovaginal affect at least 75 million women annually as 5
8% have at least 4 attacks annually. About 70% of all premenopausal woman
develop thrush at some point in their lives.
The Fungal Research Trust. How common are fungal diseases? Fungal Research Trust 20th Anniversary meeting. London June 18th 2011.
 Biology of Candida albicans
Commensal Pathogen

A thin-walled dimorphic fungus

Morphogenesis
Unicellular yeast (harmeless)
Filamentous (pathogenic) Figure 1. Yeast in Oral Scraping
Biofilm A sample of an oral scraping contains yeast cells
and pseudohyphae
(www.doctorfungus.org)
Principal Cell Wall Polymers
Glucan
Mannan

Strict aerobe, favors moist surfaces

Commensally found in gut, genitals, and lungs
Body Temp 37 C, neutral pH

Rapid Multiplication & Spread Oral Thrush, atrophic (www.mycolog.com)

 Fungal Pathogen Interactions with the Host immune System
Host immune systems recognize a number of fungal PAMPs, mostly cell wall constituents