Two different, concomitant

visceral mycoses at  rst AIDS

presentation, including

Candida albicans esophagitis

Roberto Manfredi, MD,

Leonardo Calza, MD

Department of Clinical and Experimental Medicine,

Division of Infectious Diseases, “Alma Mater

Studiorum” University of Bologna, S. Orsola

Hospital, Bologna, Italy

Key words:

Visceral candidiasis, visceral cyiptococcosis, dual

fungemia, recently diagnosed HIV infection,

“AIDS presenters”

ABSTRACT

BACKGROUND: During the last decade, the availability of highly active

antiretroviral therapy (HAART) profoundly modifi ed the natural history of

HIV infection, leading to a dramatic drop of the incidence of opportunistic

complications associated with the most severe immunodefi ciency, also including

visceral candidiasis and cryptococcosis. In the same period, the number of “AIDS

presenters” concurrently increased, including subjects newly diagnosed as HIV-

positive when already suffering from AIDS, which could not take advantage of

HAART, due to a missed-neglected HIV disease.

CASE REPORTS: Two extraordinarily infrequent episodes visceral co-infection

and fungemia due to two different opportunistic yeasts (Candida albicans and

Cryptococcus neoformans), are reported, since they occurred as the fi rst clinical

clue of a HIV disease which remained undiagnosed. These two patients were

initially referred due to a severe, generalized illness associated with prolonged

fever, weight loss, dysfagia, and pancytopenia with predominant lymphocyopenia.

After the initial workup, a Klebsiella pneumonae-Stenotrophomonas maltophilia

pneumonia was diagnosed in the fi rst patient, while a persistent headache allowed

an early identifi cation of cryptococcal meningoencephalitis in the second patient.

An esophageal candidiasis was found in both cases through microscopic, cultural,

and histopathologic examination of biopsy specimens. Later, repeated blood

cultures proved positive for both Candida albicans and Cryptococcus neoformans

in both patients; in the second subject, the search of cryptococcal polysaccharide

antigen was also positive on both serum and cerebrospinal fl uid. Both our “AIDS

presenters” had a very advanced immunodefi ciency, as expressed by an initial

CD4+ count of 44 and 13 cells/μL, respectively. As soon as a diagnosis of serious

dual Candida-Cryptococcus co-infection was confi rmed, liposomal amphotericin

B was immediately started, and changed with fl uconazole after three weeks,

following the rapidly favorable clinical-mycological response. The HAART

initiation (lamivudine-tenofovir-lopinavir/ritonavir in the fi rst case; emtricitabine-

tenofovir-atazanavir/ritonavir in the second patient), was postponed of two weeks

compared with antifungal therapy in order to prevent infrequent, but possible

immune reconstitution signs and symptoms. HAART administration was well

tolerated, and led to the recovery of a CD4+ count >200 cells/μL after 11 and 15

months, respectively. The subsequent follow-up (which presently reaches 28 and

37 months, respectively), failed to show any relapse of initially diagnosed viceral

mycoses, and other opportunistic diseases.CONCLUSION: Decrease of plasma

plasminogen activator inhibitor-1 concentration after administrations of interferon

alpha probably refl ects interferon infl uence to plasminogen activator inhibitor-1

synthesis in the liver.

DISCUSSION:

Multiple, concomitant, or subsequent AIDS-related diseases

occurring in the same patient have been occasionally described as anecdotal reports,

but the concurrent retrieval of two different visceral-disseminated opportunistic

mycoses appears of extremely rare occurrence. Clinicians dealing with “AIDS

presenters” cannot feel satisfi ed with the identifi cation of oneAIDS-defi ning illness,

until all other possibleAIDS-associated disorders have been carefully excluded. On

the other hand, further efforts in term of informational and educational campaigns

are still strongly needed, and should be targeted on behaviours and situations at

risk of a missed or delayed recognition of HIV infection, which is responsible for

an increased risk of spread of HIV itself, and especially late presentations of a far

advanced, and often life-threatening HIV disease.

INTRODUCTION

Starting with the mid-late nineties, the large-scale

introduction of highly active antiretroviral therapy (HAART),

signifi cantly acted on the natural history and course of

HIV infection in industrialized countries, leading to a rapid

drop of the incidence of all opportunistic disorders, but

principally those linked to a very deep immunodefi ciency (as

measurable by a CD4+ T-lymphocyte count below 50-100

cells/μL) [1-5]. Among these last infectious complications,

we retrieve Cytomegalovirosis, atypical micobacteriosis,

cryptosporidiosis, but also the most frequent fungal infections,

also including visceral or disseminated disease, caused by the

yeasts Candida spp. and Cryptococcus spp. A recent European

multicentre study observed also an evident decline of diagnosis

of AIDS-associated esophageal candidiasis, during the years

following HAART availability [6].

Still today, nearly 25 years after the discovery of HIV as

the causal agent of AIDS, a non-negligible number of patients

(certainly much more elevated in developing countries) [7],

is still unaware or neglected eventual previous exposures

to HIV infection. In other cases, although HIV infection

has been detected and communicated months or often years

before, the relevant patients neglected or refused further

examinations and eventual therapeutic and chemoprophylactic

recommendations, or showed very low levels of adherence to

HAART, all conditions which strongly prompt an increased

risk to develop severe opportunistic disease already included

in the diagnosis of AIDS, after a progressive impairment of

immune defence, as demonstrated by very low CD4+ T-cell

counts [8, 9].

Due to these complex epidemiological and social-health

care motivations, the case of a novel diagnosis of HIV

infection performed when already complicated by an AIDS-

related condition (or even posed only at the time of patient’s

death, when HIV infection is detected on retrospective basis),

are still present occurrences, even after a decade since the

availability of the potent HAART regimens [4, 10-12]. In a

recent survey conducted in a very extensive Italian cohort

based on 3,483 patient with HIV infection or AIDS, the

proportion of “AIDS presenters” increased from a 13.8%

rate observed in the pre-HAART era (until year 1996), up to

32.5% of the period 1997-2000 [4]. A sub-study published as

a part of the Italian multicentre cohort named “ICoNA” [10]

extensively assessed all possible behavioural correlates linked

to a late access to HIV testing among 968 patients with a newly

diagnosed HIV infection, and also analyzed the consequences

on the staging of the underlying, unrecognized and untreated

HIV disease [10]. Other Italian data coming from the National

AIDS Centre in Rome strongly witness a signifi cant increase

of AIDS occurrences burdened by a late HIV serology testing:

in the years ranging from 1996 and 2002, an increased risk

regarded patients with sexual exposure, residence in Italian

regions with a proportionally low HIV fi gures, or immigrating

from developing countries [12]. Among these patients,

pneumocystosis, neurotoxoplasmosis, and Kaposi’s sarcoma

were the most common complications, but the occurrence

of multiple, concomitant AIDS-associated disorders became

apparent [12]. In a Scottish study conducted between years

1999 and 2003, the condition of “AIDS presenter” was related

to heterosexual males and females (compared with homo-

bisexual male) exposure to HIV [11].

Multiple AIDS-related pathologies may be therefore

diagnosed concurrently only at the time of the fi rst contact

of the index, “AIDS-resenting patient” with health care

structures, which usually fi nd a very severe accompanying

immunodefi ciency, and no concomitant antiretroviral and/or

antimicrobial prophylaxis followed in the past. Even fi ve out

of the fi rst ten patients notifi ed with AIDS at our centre in the

fi rst four months of the year 2002 had a missed HIV infection,

already evolved toward AIDS at their fi rst hospitalization,

when three to seven concomitant AIDS-related conditions

were found [13].

Paradoxically, a comparable clinical-therapeutic situation

may be found only in developing countires, where the

assistance, healthcare, economical, and preventive measures

are profoundly different from those active in the Northern-

Western part of the world. [7].

Aim of our contribution is to report two very particular and

infrequent cases of concomitant, visceral and hematologically-

disseminated fungal infection, caused by both Candida

albicans and  Cryptococcus neoformans, occurred in two

patients whose HIV infections remained undiagnosed until

their fi rst hospitalization (“AIDS presenters”), but underwent

a favorable course after a prompt and potent antifungal and

antiretroviral treatment, notwithstanding the severity of

initially recognized conditions, as found upon presentation.

CASE REPORTS

Two patients with rare clinical presentations of AIDS

recently came to our attention. They were characterized by

a concomitant visceral and invasive Candida albicans plus

Cryptococcus neoformans infection, both occurred as the

earliest major opportunistic disorders which prompted the fi rst

recognition of an HIV infection who remained undiagnosed

until this late disease stage.

Due male subjects aged 48 and 56 years respectively,

who were not aware of their HIV seropositivity condition

although reporting some possible at risk bisexual contact

during previous years, were referred to our tertiary care

centre after a diagnosis of persisting, irregular pyrexia not

responsive to broad-spectrum empiric antibiotic therapy,

cachexia, pancytopenia with prevailing lymphocytopenia,

moderate anemia, severe dysfagia with related weight loss

exceeding 15% of baseline body weight, all occurred during

the past six months. After obtaining the informed consent, the

preliminary workup disclosed a confi rmed HIV-1 infection,

and a severe, concurrent immunodefi ciency documented

by a CD4+ T-lymphocyte count of 44 and 13 cells/μL,

respectively. Subsequently, the quantitative assay of HIV
viral load, showed a situation compatible with a long-term,
never treated HIV infection (HIV-RNA 68,000 and 36,000
copies/mL, respectively), in absence of mutations of both
reverse transcriptase and protease gene, after obtaining a viral
genotypization assay.
Moreover, in the fi rst patient a severe polymicrobial
pneumonia was confi rmed, on the ground of radiological
imaging, and the concurrent isolation of Klebsiella pneumoniae
and Stenotrophomomonas maltophilia from bronchoalveolar
lavage fl uid and transbronchial biopsy specimens, while a
persisting headache associated with nausea and intermittent
vomiting prompted a contrast-enhanced CT scan of the
brain and a lumbar puncture, which led to a diagnosis of a
serious cryptococcal meningoencephalitis, confi rmed on the
ground of microscopical and culture identifi cation of this last
yeast from cerebrospinal fl uid, and the concurrent yield of
cryptococci from blood cultures conducted on a standard agar-
Sabouraud medium. The search of the polysaccharide antigen
of Cryptococcus neoformans tested positive in both examined
fl uids (cerebrospinal fl uid and serum).
In the next few days, after diagnosing a serious oropharyngeal
candidiasis, appropriate endoscopy followed by microscopic,
culture, and histopathologic studies, confi rmed an extensive
esophageal candidiasis caused by Candida albicans. In the fi rst
patient, also two blood sets yielded repeated positive Candida
albicans and Cryptoccoccus neoformans culture, therefore
confi rming the severe dissemination of the two different
opportunistic yeast infections. The Cryptococcus neoformans
antigen search proved positive on the serum only, while the
same search repeated on cerebrospinal fl uid, bronchoalveolar
lavage, and urine, tested negative, as well as the microscopical
and culture search.
While a visceral and disseminated candidosis was
diagnosed in both patients thanks to an evident esophagitis
associated to blood cultures positive for Candida albicans,
the disseminated cryptococcosis was confi rmed as a cerebral
and systemic disease in the second observed patient, while the
fi rst patient suffered from an apparently isolated cryptococcal
fungemia.
After posing a diagnosis of concomitant visceral
candidiasis and cryptococcosis determined by yeast strains
which proved sensitive to all tested antinfungal compounds
at the in vitro susceptibility assays (polyenes, imidazolestriazoles,
and fl ucytosine), both our patient were given i.v.
liposomal amphotericin B at 3 mg/Kg/die for three weeks,
followed by fl uconazole (at 800 mg/day i.v. for four weeks,
and 400 mg/day orally for further eight weeks). Appropriate
antimicrobial chemotherapy was also started for the treatment
of the other bacterial infections, which concurred in the fi rst
observed patient. >From a clinical and mycological point of
view, the treatment with liposomal amphotericin B followed
by fl uconazole, achieved a complete cure associated with a
stable disappearance of all the signs and symptoms observed

upon admission, and in absence of disease recurrences during

the subsequent follow-up, which presently reaches 24 and 33

months, respectively.

In the meantime, two weeks after antifungal and

antimicrobial chemotherapy, HAART was introduced (a

lamivudine-tenofovir-lopinavir/ritonavir combination in the

fi rst case; an emtricitabine-tenofovir-atazanavir/ritonavir

association in the second patient), and taken with compliance

levels exceeding 95% (as evaluated on the basis of self-

assessment, and the direct drug distribution and accountability

carried our at least monthly by our services). As a consequence

of potent HAART activity, our patients reached an undetectable

HIV viremia after six and nine months respectively (HIV-RNA

<50 copies/mL, as measured with the ultrasensitive branched-

DNA technique), while CD4+ T-lymphocyte count overcome

the “safety” level posed at 200 cells/μL after 11 and 15 months

of HAART administration, respectively in the fi rst and in the

second described patient.

DISCUSSION

The recent increased frequency of the so-called “AIDS

presenters” i san only apparently paradoxical phenomenon,

since it is strongly supported by at least two favoring

conditions: patients who are not aware of their HIV serostatus,

or subjects who despite a previous diagnosis of HIV infection

neglected all further monitoring and pharmacologic therapy,

notwithstanding the progressive development of very effective

control and treatment measures which occurred over time. On

the ground of these premises, the “AIDS presenters” could

not take any sort of advantage from the introduction of very

potent and effective antiretroviral agents (HAART), which are

available since around ten years [5, 9, 10, 12].

The occurrence of multiple AIDS-defi ning disorders

(either concomitant or subsequent over time), have been

reported as single reports or small patient series, usually

aimed to underline the diagnostic and differential-diagnostic

diffi culties encountered in the clinical management of these

patients [7, 14, 15]. In fact, the majority of multiple, eventually

concomitant disorders is and remains at elevated risk to be

underestimated due to lack of recognition, especially after the

early identifi cation of a prominent AIDS-defi ning illness, and

again when signs and symptoms of different opportunistic

disorders may very frequently overlap, making their respective

recognition less easy [2, 4, 5, 16-19]. Infrequently, multiple

AIDS-associated diseases also interested pediatric patients

with vertically-transmitted HIV infection [20].

On the other hand, partially different is the situation

pertaining to HIV-associated malignanicies, which showed

a progressively reduced incidence in the HAART era,

predominantly in the case of Kaposi’s sarcoma, and less

evident for lymphomas as a whole, while this tendency seems

unfortunately balanced by the emerging of solid tumors,

which are not part of the list of AIDS-defi ning diseases [5,

21, 22]. Also in our experience an increased frequency of

dual neoplastic disorders and an overall increase of frequency

of malignancies, may be a rough indicator of the increased

survival of HIV-infected patients, concurrent with permaining

supporting factors, such as HIV infection itself, and immune

system dysregulation [23].

When focusing our attention on opportunistic fungal

infections, a concurrent diagnosis of two different, visceral

and invasive mycoses caused by two different opportunistic

yeasts (Candida albicans and Cryptococcus neoformans in our

cases), has very limited literature equivalents, taking also into

consideration that the main localization of visceral candidiasis

(the esophageal one), seemed to have a benefi t during the HAART

era, based on its progressive reduction of incidence [6].

In our experience, when considering only fungal

opportunism observed during HIV infection, our single

report of the year 2002 [24] described a visceral candidiasis

(esophagitis plus fungemia), associated with a cryptococcosis

(only blood culture isolation and positive serum antigenemia),

concurrent with a pulmonary atypical mycobacteriosis [24],

while fi ve particular “AIDS presenters” observed in early 2002

suffered from multiple, concomitant AIDS-defi ning diseases

(from a minimum of three, to a maximum of seven) [13], but

thanks to the administration of adequate antimicrobial and

chemoprophylactic treatments, and the resort to potent HAART

regimens, all of them benefi ted from a slow, but progressive

ameliorement of their clinical situation, paralleling the

improvement of HIV-related virological and immunological

situation (characterized by a CD4+ T-lymphocyte count

recovery ranging from 60% and 500% versus baseline levels,

and a reduction of HIV plasma viremia ranging from 1.5 to 3.5

Log10 HIV-RNA copies/mL versus baseline values, within 3-

6 months of HAART initiation [13].

In the past, but still today, necropsy studies allow to identify

AIDS-related disorders and/or disease localizations never

diagnosed during the patients’ lifetime [19]. When excluding

our detailed case report published four years ago (in the year

2002) [24], the only remaining report dealing in some way with

a dual fungemia during HIV infection is of the year 2001, and

regards  the associated isolation of two different Candida spp.

Strains (Candida albicans and Candida glabrata), incidentally

retrieved during an estensive 12-year-long surveillance study

of fungemia, conducted at an oncology reference centre [25].

As a consequence, in the herewith described cases the

diagnosis of Candida albicans esophagitis and fungemia

found in both presented cases, together with a concomitant

cryptococcosis (meningoencephalitis and fungemia in one

case, isolated fungemia in the fi rst patient), appears to represent

an extraordinary occurrence, in absence of other literature

evidences, when excluding another, previous single case

report coming just from our institution [24], and the episodes

of hematogenous mixed Candida albicans-Candida glabrata

co-infection encountered in an hospitalized patient, with all

clinical and microbiological details lacking, since this case

of the trend of fungemias in a large Hospital setting [25].

The availability of a large spectrum of potent antiretroviral

compounds and their associations (HAART), which are of

common use since more than a decade in developed countries,

unfortunately does not seem to be related to the persisting

reports of cases of HIV infection detected only in a very

advanced stage, which continue to occur in subjects who

remain unaware of their condition, in subjects who refused

controls and/or treatments after receiving their diagnosis of

HIV seropositivity, or patients who carried our their HAART

regimen and/or their chemoprophylactic recommendations

with very low and insuffi cient adherence levels [8, 9].

This worrying tendency seems related to some global

epidemiological and social-health care issues, although we

are also aware that the introduction of HAART did not modify

the proportional distribution of the majority of AIDS-related

disorders over years [8, 9], while the very limited HAART

availability in developing countries justifi es the persistence

of multiple co-infections, including fungal ones [7]. A very

recent experience performed on male HIV-infected subjects

demonstrated that HAART administration gives a potent

initial protection, but could not ensure a long-term one, when

the development of different AIDS-associated diseases is

of concern, in particular those related to malignancies or a

primary role of HIV itself [22]. As a result, when considering

also the present, increased life expectancy of HIV-infected

population, the relationship between viral replication and

immunoreconstiution guaranteed by HAART administration,

and long-term disease evolution and outcome, deserve further

studies encompassing “hard” and “late” clinical end-points.

When considering the current clinical-therapeutic

management, an “AIDS presenter” patient with a very low

initial T-lymphocyte CD4+ count, it seems reasonable to

avoid the concurrent initiation of HAART and antiinfective

treatments, by administering all antimicrobial treatments

deserved for opportunistic complication immediately, and

waiting some days (or preferably a few weeks) for HAART

introduction (as done in the two reported cases), in order to

reduce the risk to develop an infrequent, but possible “immune

reconstitution syndrome”, related to a rapid recovery of

immune system competence, which may become responsible

for clinical complication related to an exaggerated immune

reactivity, but also for some degree of pathomorphism of

AIDS-associated mycoses, as documented by the emerging of

clinical and laboratory confounding factors [26].

A prompt recognition and a rapid and effective treatment

of all known HIV-infected patients represent an absolute

priority, in order to avoid late diagnoses of HIV disease,

and to limit the phenomenon of  “AIDS presenters” and its

severe correlates. Unfortunately, we have a signifi cant clue

of this phenomenon, represented by the persisting reports

of a proportionally increased rate of subjects at risk of a late

diagnosis of HIV disease and its broad-spectrum complications

become more and more easy to be administered, due to the

increased availability of novel drugs, and drug formulations,

which can enhance patient compliance also when concomitant

unfavorable clinical conditions are of concern.

To conclude, we strongly believe that preventive,

informational and educational efforts should not be abandoned,

but targeted as far as possible towards the different needs of

populations who represented and still represent people at risk

for HIV infection and reduced awareness of their condition [5,

10-12], to avoid cases of neglected or late diagnosis of HIV

disease, which are responsible for the continued spread of HIV

into the general population, and are at very increased risk to

develop life-threatening opportunistic complications, even in

associations never seen before (including the pre-HAART era),

like the case of dual, concurrent, visceral and disseminated

yeast infection. In fact, even in the third millennium these

last complications remain burdened by an increased risk of

late recognition, elevated mortality, and possible permanent

sequelae.

REFERENCES