Estimated burden of fungal infections in Italy

Matteo Bassetti 1, Alessia Carnelutti 1, Maddalena Peghin1, Franco Aversa2,

Francesco Barchiesi3, Corrado Girmenia4, Livio Pagano 5, Maurizio Sanguinetti 6,

Anna Maria Tortorano7, Maria Teresa Montagna8, Pierluigi Viale9,

Claudio Viscoli 10, David W. Denning 11, 12

1 Infectious Diseases Clinic, Department of Medicine University of Udine and Azienda Sanitaria

Universitaria Integrata, Udine, Italy2 Department of Clinical and Experimental Medicine, Hematology and BMT Unit , University of Parma ,

Parma , Italy

3 Dipartimento di Scienze Biomediche e Sanità Pubblica, Clinica Malattie Infettive, Università Politecnica

delle Marche, Ancona, Italy

4 Dipartimento di Ematologia, Oncologia, Anatomia Patologica e Medicina Rigenerativa, Azienda

Policlinico Umberto I , Sapienza University , Rome , Italy

5 Istituto di Ematologia, Università Cattolica S. Cuore, Roma, Italy

6 Institute of Microbiology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario

Agostino Gemelli, Rome, Italy

7 Department of Biomedical Sciences for Health, Università degli Studi di Milano, Via Pascal 36, 20133,

Milan, Italy

8 Department of Biomedical Science and Human Oncology - Hygiene Section, University of Bari, Bari,

Italy

9 Infectious Diseases Unit, Department of Medical and Surgical Sciences, Hospital S. Orsola-Malpighi,

University of Bologna, Bologna, Italy

10 Infectious Diseases Unit, IRCCS AOU San Martino-IST, University of Genoa (DISSAL), Genoa, Italy

11 Global Action Fund for Fungal Infections (GAFFI), Rue de l'Ancien-Port 14, 1211 Geneva 1, Geneva,

Switzerland

12 National Aspergillosis Centre, University Hospital of South Manchester, The University of

Manchester, Manchester Academic Health Science Centre, Manchester M23 9LT, UK

Running Head: Fungal infections in Italy

Conflict of Interest: Dr. Bassetti has participated in advisory boards and/or received

speaker honoraria from Achaogen, Angelini, Astellas, AstraZeneca, Bayer, Basilea,

Gilead, Menarini, MSD, Pfizer, The Medicine Company, Tetraphase and Vifor.

Corresponding Author:Prof. Matteo Bassetti

Clinica Malattie Infettive

Azienda Sanitaria Universitaria Integrata, Presidio Ospedaliero Universitario Santa Maria della Misericordia

Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy

Phone +39 0432 559355

Fax +39 0432 559360

Email: mattba@tin.it , matteo.bassetti@uniud.it

Abstract

Introduction

Fungal infections are a significant and increasing public health problem worldwide,

that range in severity from mild superficial infections that affect a large proportion of

the otherwise healthy population to life-threatening invasive diseases limited mostly

to vulnerable immunosuppressed patients (1).

Patients that are at risk for fungal infections, those hospitalised with serious underlying

diseases, such as those with HIV infection, haemato-oncological malignancies,

recipients of immunosuppressive therapies, solid-organ or hematopoietic stem cell

transplant (HSCT) recipients (2).

The incidence of fungaemia is growing and has dramatically increased within the past

two decades. Such infections have been attributed to the common practice of

prolonged hospitalisation of highly susceptible patients receiving advanced medical

treatment; such conditions render patients more susceptible to invasive fungal

infections (3,4)

The populations of patients at risk have expanded to include those with usually

multiple underlying medical conditions, such as diabetes mellitus, chronic obstructive

pulmonary diseases and those receiving corticosteroids (3,4)

The current number of fungal infections occurring each year in Italy is not known. The

aim of this work was to estimate the burden of fungal infections in Italy, a country,

with a population of 61 millions. As invasive fungal infections are not reportable, exact

data are not available. For this reason, we have taken different approaches to explore

the current number of invasive fungal infections. First, we have estimated fungal

infections based on populations at risk, with data from published Italian or

international cohort studies and clinical trials.

Material and methods

The burden of serious fungal infections was estimated for general healthy population

and for specific at-risk groups, including patients affected by HIV infection, respiratory

diseases (COPD, asthma and tuberculosis), solid organ or hematologic malignancy and

critical illness.

Demographic data regarding Italian population were obtained from the Italian National

Statistical Institute (ISTAT) (5).

Data on the HIV/AIDS population were obtained from the Epicentro-National Institute

of Health (Istituto Superiore di Sanità-ISS) (6) and recent published data estimating

adult HIV prevalence in Italy (7).

Tuberculosis statistics were taken from the Epicentro-National Institute of Health (ISS)

(6) and World Health Organization (WHO) reports (8). COPD and asthma prevalence in

Italy were obtained from the Health Examination Survey (OEC/HES) 2008-2012(9).

Solid organ cancer and haematological diseases cases were taken from Associazione

Italiana Oncologia Medica (AIOM) (10) and Associazione Italiana dei Registri Tumori

(AIRTUM) reports (11).

Country’s profile, populations and rates required to calculate burden of serious fungal

infections are reported in Table 1.

We conducted an extensive literature review and published epidemiology papers

reporting fungal infections incidence and/or prevalence in Italy were identified.

Where no national data existed, authors reviewed data from published single-center or

multicentre trials and from public health institutions in Italy. Moreover, in selected

cases, when Italian data were not available, we calculated Italian fungal burden based

on fungal infection incidence in other European countries.

RESULTS

Country profile

Italy is a country with an estimated population of 61 million people, represented by

adults ( 14 years) in up to 85% of cases. Of the general population, approximately 13

million (22%) are older than 65 years. Chronic obstructive pulmonary disease

prevalence has been estimated in 3.5-5% in men and 2.3 - 3.3% in women overall

among adult population, with the large majority of patients in classified as GOLD stage

I. The number of HIV-infected patients ranged between 114.000 and 156.000 people,

with approximately 84% of patients receiving ARV (7). Solid organ cancer prevalence is

3.037.127 cases, accounting for approximately 5% of overall population (11). The exact

prevalence of patients with hematological malignancies is not available, but an

estimated number of 31.300 new diagnosis per year, mainly represented by non-

Hodgkin lymphoma and acute leukemia has been reported in Italian registries (11). The

number of autologous and allogeneic HSCTs is available at the registry of the Gruppo

Italiano Trapianto di Midollo Osseo (GITMO) and accounted in 2016 for 2905 and 1796

transplants, respectively (www.gitmo.it). Country’s profile, populations and rates

required to calculate burden of serious fungal infections are reported in Table 1.

Prevalence rates previously reported used to estimate the burden of serious fungal

infections are reported in Table 2.

SUPERFICIAL MYCOSIS

Dermatomycosis and onychomycosis

The most recent epidemiological data concerning the most common superficial fungal

infection, tinea pedis, unfortunately date back to the Achilles foot screening project

conducted in the spring of 1997 and 1998 in several European countries, including Italy

(12). The overall prevalence of tinea pedis was 22%, ranging from 7% in children up to

29% in the elderly (12). A total of 16.606.000 cases could be expected in Italy

considering the prevalence in the different age groups.

Regarding tinea capitis, the prevalence in children in Italyian population has shown to

be very high with a rate of about 1.003 cases/100.000 consistent with 610.000 cases

(13).

Recent data on epidemiology of onychomycosis in Italy are also available (14).

Onychomycosis was clinically diagnosed in 1175 among the 8331 patients enrolled

(5872 by dermatologists and 2459 by general practitioners). Hands were involved in

17% of the cases and feet 83%. Dermatophytes were isolated in 70.7% of the cases,

yeast in 16.2% and other mould in 13.2%. The prevalence increased with age from

1.9% in children to 20.7% in subjects over 60 years. Although applying data from both

studies to Italian population may introduce a bias (since most of the patients were

enrolled by dermatologists), we can expect about 7.929.000 cases of onychomycosis.

INVASIVE MYCOSIS

MUCOSAL INFECTIONS

Vulvo-vaginal candidosis

Vulvovaginal candidosis (VVC) and recurrent vulvovaginal candidosis (rVVC), both

caused by several Candida species, in particular C. albicans, is a significant problem

worldwide, including Italy (15). It is estimated that 75% of all women experiences VVC

at least once during their lifetimeve, and about half of them have at least one

recurrence (16). Moreover, up to 8% of these women will suffer from rVVC (13). The

most important pathogen is C. albicans, followed by other species, in particular C.

glabrata which is fluconazole resistant.

An epidemiological survey on 6010 women aged 16–65 years from six countries

published by Foxman et al. (18) estimated the prevalence rate in 9%. An Italian survey,

published in 2003 by Corsello et al. (19) on 931 women from eight different hospitals

reported a rate of rVVC of 8.2% (77/931). C. albicans was the predominant species

(77.1%), followed by C. glabrata (14.6%) and C. krusei (4.0%). Taking into account that

these data are form selected Italian centers, we used a conservative approach and we

estimated a 6% rVVC rate among adult women, resulting in 1.580.241 affected women

at a rate of 2590 per 100 000 person-years.

Oral candidosis and oesophageal candidosis

The incidence of oral candidosis and esophageal candidiasis has declined in the current

era of antiretroviral therapy (ARV), but they still remain two clinically relevant diseases

in the global HIV setting (20). In HIV infection, oral candidiasis is estimated to occur at

least once in 90% of those without ARV, and esophageal candidiasis in 20% of patients

without ARV and 5% of patients on ARV. Using theseis assumptions, 1.763 cases of oral

candidiasis and 1.413 cases of esophageal candidiasis are annually expected.

Another major patient group at risk for oral candidosis is those with cancer. According

to an Italian survey (21), 30%-40% of patients with head and neck cancer were found

to have oral candidosis. A review of oral fungal infections in patients receiving cancer

therapy highlights the prevalence of clinical oral candidosis was 7.5% pre-treatment,

39.1% during treatment, and 32.6% after the end of cancer therapy (22) These rates

may be used as an estimate for current calculation. Assuming that the majority of

cancer patients (90%) receive anticancer treatment, the number of oral candidosis is

estimated at 1.066.031 episodes per years.

The number of oral or oesophageal candidiasis related with transplanted patients or

those taking inhaled corticocosteroids are unknown in Italy.

INVASIVE FUNGAL INFECTIONS

Candidemia and Candida peritonitis

Recent national surveys show that rate of candidemia ranges from 0.79 to 2.2 /1000

per hospital admission (23) (24) (25). In keeping with the worldwide trend (26) , a

recent 1-year prospective survey of candidemia in Italy (comparison of the 1997-1999

and 2009 data on episodes of candidemia) revealed a three-fold increase in incidence

(from 0.38 to 1.19 per 1.000 admissions) (27). In 2015 about 8.930.979 hospital

admissions were recorded in Italy. Therefore we estimate that candidemia around

13.351 episodes of candidemia, yielding an annual incidence of 21.8 cases/100 000

inhabitants (24), which is higher than in most other European countries (27)(29).

Of interest that in itakylian setting, internal medicine wards represent a significant

reservoir of patients with candidaemia, with a prevalence ranging from 24 to 57% (23).

Candida albicans represents the most commonly isolated species followed by Candida

parapsilosis (30).

Intraabdominal candidiasis (IAC), including Candida peritonitis, is the second most

frequent form of invasive candidiasis (31). Concomitant candidemia is occurring

uncommon in a low percentage of these patients (10-15%). Based on previous studies

(31), we estimated one case of intra-abdominal candidiasis for every six patients with

candidaemia. Therefore, a total of 2.225 IAC are expected annually in Iitaly.

Cryptococcosis

According to the Istituto Superiore di Sanità data, 832 cases of cryptococcosis were

diagnosed in the period 1999-2015 among the 24 163 patients with diagnosis of AIDS,

an incidence with a rate of 3.4% (32). A total of 789 new cases of AIDS were diagnosed

in Italy in 2015 (32). Therefore, about 30 cases of cryptococcosis is expected to occur in

this patient population. In addition, other 21 cases in HIV negative patients have to be

added as 41% of cases analysed during the second prospective survey on

cryptococcosis in Italy occurred in HIV negative patients (33). In conclusion, the burden

of cryptococcosis in Italy is estimated to be of about 51 cases/year.

Pneumocystis jirovecii pneumonia

Pneumocystis jirovecii pneumonia (PJP) is a disease of patients with T cell deficiencies

and is emerging as a concern in patients with non–HIV-related immune deficiencies, in

high-resource countries.

In the HIV setting, data exist and can be extrapolated from official governmental

documents (34). In the years 2011-2012 and 2013-2014, a total of 2707 and 2505,

respectively, new cases of AIDS were notified. The AIDS-defining condition was PJP in

21.8% and 24.6% of the cases in the 2 periods, which allow estimating a total number

of 1206 cases of PJP over 4 years or about 300 per year.

Outside of the HIV-positive population, data about incidence and prevalence of PCP in

Italy do not exist. The main reason is the lack of any central surveillance system

among cancer patients and among the increasing population of recipients of biological

response modifiers. Since in developed countries patients with proven PCP are mainly

non-AIDS patients (60%)(35) we estimated that non–HIV patients with PCP and are

likely to be 450 per year in Italy.

Aspergillosis

Incidence of invasive aspergillosis (IA) in Italy is extremely difficult to estimate due to

the lack of a national registry. The largest study that evaluated the incidence of IFI in

patients with hematological malignancies that received conventional chemotherapies

(transplant procedures were excluded) was SEIFEM published in 2004. study SEIFEM

was, a retrospective cohort study of patients admitted to 18 hematology wards in Italy

between 1999 and 2003 (36). A total of 11.802 patients affected by acute and chronic

leukemia, lymphomas and myeloma were collected. Overall, Aspergillus spp. was

found responsible for 58% of the 538 cases of proven/probable IFI, accounting for 90%

of all infections caused by molds. To Of note, the incidence widely varied depending on

the hematologic malignancy and its stage. The majority of IFIs were reported in acute

myeloid leukemia patients (71% of all cases) and particularly after the the first

induction chemotherapy (43% of all cases). After the introduction of anti-mold

prophylaxis (i.e. posaconazole) the incidence of IA in patients with AML treated in the

first induction phase of remission has progressively reduced, with an estimated

incidence of cases of IA 6% in this population according to Caira et al. (37).

Incidence of IA has been reported to be lower in patients affected by acute and chronic

lymphoproliferative disorders, ranging between 2.8 and 3% (38, 39)

Assuming an incidence of AML of 3.4-4.4 per year, with approximately 2300 new cases

per year based on total Italian population, we have estimated 141 new cases of IA per

year among patients with AML. Regarding the other hematological malignancies

overall, an estimated number of new cases of 31.300 per year have been reported by

Italian registries, deriving an estimated number of IA of 907 cases per year.

Pagano et al. retrospectively analysed the incidence of proven or probable IFI among

hematopoietic stem cell transplant (HSCT) recipients in Italy during the period 1999-

2003. Among 3228 patients, IFI occurred in 121 patients (incidence 3.1%) and

Aspergillus spp. accounted for the large majority of episodes overall (86 cases, 2.6% of

patients) (40). A recent European study by Harrison et al. reported an overall 1-year

incidence of IFIs after HSCT of 10.3%, with up to 70% of cases represented by IA (41).

In Italy a total of approximately 1750 allogeneic HSCT and 3000 autologous HSCT per

year have been performed in the last years, with an estimated of 120 cases of IA per

year in allogeneic HSCT (about 7% of transplants) and 15 cases of IA per year in

autologous HSCT (about 0.5% of transplants). (Girmenia C, Raiola AM, Piciocchi A, et al.

Incidence and outcome of invasive fungal diseases after allogeneic stem cell

transplantation: a prospective study of the Gruppo Italiano Trapianto Midollo Osseo

(GITMO). Biol Blood Marrow Transplant. 2014 Jun;20(6):872-80.)

Another population frequently affected by IA is represented by solid organ recipients,

but data in Italy are limited and incidence is not known.

Grossi et al. in a large, retrospective Italian study including 1963 patients undergoing

thoracic organ transplantation in 12 Italian centers between 1985 and 1997, reported

53 IFIs, represented by aspergillosis in 34 cases (64.1%) (42)

Sganga et al. retrospectively analyzed 215 consecutive liver transplant patients

between 2003 and 2012. Overall, 4 (1.9%) cases of IA have been reported (43)

The Transplant-Associated Infection Surveillance Network (TRANSNET) reported an

overall 12-month cumulative incidence for any IFI of 3.1% among solid organ

transplant recipients in United States. 12-month cumulative incidence of IA was 0.7%,

even with considerable site-to-site variability (44).

Considering a total amount number of solid organ transplants of 2825 per year,

considering a 12-month incidence of IA of approximately 0.7%, we estimated a total

amount of 20 cases of IA per year among solid organ transplant recipientsin these

patients.

An emerging burden of disease is represented by aspergillosis among non-neutropenic

patients with underlying pulmonary disease, mainly represented by COPD. Other well

recognized predisposing conditions are steroid treatment and intensive care unit

admission.

A recent study conducted among five Swiss university hospitals during a two-year

period found an incidence of aspergillosis of 1.2/10.000/admissions (45) .

Considering an amount ofAs there are approximately 13 million admissions per year in

Italy (9), we have estimated a burden of 1560 cases per year of aspergillosis among

non-neutropenic patients in Italy, most of which probably complicate COPD or critical

care. Overall, the burden of IA in Italy is approximately 4280 cases annually (4.6 per

100 000).

Allergic Bronchopulmonar aspergillosis (ABPA)

The prevalence of ABPA is still not completely known, likely due to the lack of uniform

diagnostic criteria. It ranges form 2 to 15% in cystic fibrosis patients (46) . An Iitalian

epidemiolgical study involving 3089 CF patients revealed that the prevalence of ABPA

in Italian CF patients was 6.218%, occurring mainly in adolescents and young adults –

an estimated total of 192 ABPA patients (47). This may be an underestimate based on

other modelling and data from France (Armstead, 2013). With respect to asthma,

Denning et al. reviewing the published studies on asthma and ABPA, attempted to

define the global burden of ABPA and found a prevalence of 2.5% (range 0.72%-3.5%).

Based on these data we estimated a total burden of 106.137 cases of ABPA among

adult patients with asthma.

Overall, the burden of IA in Italy is approximately 4280 cases annually (4.6 per 100

000).

Allergic Bronchopulmonar aspergillosis (ABPA)

ABPA was reported in 2.5% (range 0.7%–3.5%) of adults with asthma (48) These data

allowed us to estimate that 106.137 persons in Italy suffer from ABPA.

Severe asthma with fungal sensitivization (SAFS)

Accumulating evidence points to an important role of fungi as exogenous drivers of

asthma, particularly in the segment of the asthmatic population with poorly controlled

disease (49). SAFS refers to patients with severe asthma and evidence of fungal

sensitisation.

In Italy there are 3,272,000 people suffering of asthma, assuming a prevalenze of SAFS

of 6,2% we estimate that 107,997 people suffering of SAFS.

Other invasive mould infections

Scedosporium apiospermum is currently recognized as an important cause of death in

bone marrow transplant recipients, with a frequency of 1:1000 patients (50). A

comparable frequency was observed by Pagano et al. in the GIMEMA retrospective

study in patients with hematologic malignancies, while in the SEIFEM-2004 study only

3 episodes out of 345 mould infections were caused by Scedosporium spp. (0.03%)

(36).

Considering an estimated number on HSCT of approximately 1000 per year, 1-2 cases

of Scedosporium spp. infection per year are expected to be observed in Italy in this

population.

A literature search yielded 83 reports of a total of 177 cases of invasive Fusarium

infection in haematological patients in Italy (51) (40).

In Italy the first attempt to assess the epidemiology of fusariosis in neutropenic

patients with haematological diseases came from a retrospective study including 14

Italian haematology departments of the Gruppo Italiano Malattie Ematologiche

Maligne dell'Adulto (GIMEMA) Infection Programme: over a period of 10 years (1988-

1997) Fusarium infection was documented in 6 out of 351 patients (1,7%) with aplastic

anaemia and AML as the underlying diseases (three cases each), accounting for an

incidence rate 0.06% (0% and 0.08% in ALL and AML respectively) (40). In the

retrospective SEIFEM-2004 survey Fusarium spp. was responsable for 15 episodes

(0,1%) out of 345 mould infections, mostly in AML patients (0,3%) (36). Comparison of

data for 1987 and 2003 on acute leukemia patients (available for six centers only)

revealed increases in the absolute numbers of infections due to Fusarium spp. and

other molds although incidence rates remained stable. Among HSCT patients, 3

Fusarium spp. infections were reported in patients who had undergone allogeneic-

HSCT (incidence rate 0.2%), while no Fusarium spp. infections occurred in the

autologous transplant setting (40). These incidence rates are lower than those

observed in other centers in different countries (0.9-1.1%) (52). Considering the

incidence of AML in Italy and the total number of HSCT, 1-2 cases of fusariosis per year

are expected in both these populations.

Discussion

This is the first attempt to estimate the burden of fungal infections in Italy. Overall,

about 44% of Italians suffer from fungal infections yearly -with 25.145.000 (41,2%) of

with superficial and 2.892.383 (4,7%) of with invasive serious fungal infections,

respectively. There are currently no epidemiology papers that have reported on the

fungal infection rates in Italy, so every estimate is based on modelling. This is in line

with the deterministic model that has consistently been applied in many countries by

the LIFE program (www.LIFE-worldwide.org). This approach was already used in

several reports from other countries (e.g. Portugal, Greece, Canada, UK ) (53-56).

In summary, using local data and available national and international literature

estimates of the incidence or prevalence of fungal infections, almost 28 M or 44% of

the population in Italy are affected each year by a fungal infection. Given these

estimates, increased public health efforts are required to document and control this

substantial burden of disease.

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