Esophagus

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

Two different,

concomitant visceral mycoses

at first AIDS presentation,

including Candida

albicans esophagitis

Key words:

Visceral candidiasis, visceral cyiptococcosis, dual

fungemia, recently diagnosed HIV infection,

“AIDS presenters”

Conflict of interest, sponsorship, financial

support, acknowledgements:

none

ABSTRACT

Background: During the last decade, the availability of highly active antiretroviral

therapy (HAART) profoundly modified the natural history of HIV infection, leading

to a dramatic drop of the incidence of opportunistic complications associated

with the most severe immunodeficiency, 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 first 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 first patient, while a persistent headache allowed

an early identification 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 fluid. Both our “AIDS

presenters” had a very advanced immunodeficiency, 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 confirmed, liposomal amphotericin

B was immediately started, and changed with fluconazole after three weeks,

following the rapidly favorable clinical-mycological response. The HAART

initiation (lamivudine-tenofovir-lopinavir/ritonavir in the first 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.

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 satisfied with the identification of one AIDS-defining illness, until all

other possible AIDS-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),

significantly 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 immunodeficiency (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 significant 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 figures, 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 first contact

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

structures, which usually find a very severe accompanying

immunodeficiency, and no concomitant antiretroviral and/or

antimicrobial prophylaxis followed in the past. Even five out

of the first ten patients notified with AIDS at our centre in the

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

already evolved toward AIDS at their first 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 first 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 first

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 confirmed HIV-1 infection, and a severe, concurrent

immunodeficiency 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 first patient a severe polymicrobial

pneumonia was confirmed, on the ground of radiological

imaging, and the concurrent isolation of Klebsiella pneumoniae

and Stenotrophomomonas maltophilia from bronchoalveolar

lavage fluid 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, confirmed on the

ground of microscopical and culture identification of this last

yeast from cerebrospinal fluid, 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

fluids (cerebrospinal fluid and serum).

    In the next few days, after diagnosing a serious oropharyngeal

candidiasis, appropriate endoscopy followed by microscopic,

culture, and histopathologic studies, confirmed an extensive

esophageal candidiasis caused by Candida albicans. In the first

patient, also two blood sets yielded repeated positive Candida

albicans and Cryptoccoccus neoformans culture, therefore

confirming 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 fluid, 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 confirmed as a cerebral and systemic

disease in the second observed patient, while the first 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, imidazoles-

triazoles, and flucytosine), both our patient were given i.v.

liposomal amphotericin B at 3 mg/Kg/die for three weeks,

followed by fluconazole (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 first

observed patient. >From a clinical and mycological point of

view, the treatment with liposomal amphotericin B followed

by fluconazole, 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

first 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 first 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-defining 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

difficulties 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 identification of a prominent AIDS-defining 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-defining 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 benefit 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 five particular “AIDS presenters” observed in early

2002 suffered from multiple, concomitant AIDS-defining

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 benefited 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 first 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 has

been reported as a part of a mycological surveillance study 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 insufficient 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 justifies 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