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Keywords:

  • Definition;
  • haematological malignancies;
  • invasive pulmonary aspergillosis;
  • radiological findings

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Financial Disclosures
  8. Transparency Declaration
  9. References

Clin Microbiol Infect 2012; 18: 990–996

Abstract

The European Organization for Research and Treatment of Cancer and the Mycosis Study Group (EORTC-MSG) radiological definitions of invasive pulmonary aspergillosis (IPA) may lack diagnostic sensitivity. We evaluated applying less restrictive radiological criteria, when supported by specific microbiological findings, to define IPA in acute myeloid leukaemia (AML), lymphoproliferative diseases (LD) and allogeneic stem cell transplant (allo-SCT) patients. Overall, 109 consecutive episodes of proven/probable IPA in 56 AML, 31 LD and 22 allo-SCT patients diagnosed from February 2006 through to January 2011 were considered. IPA was diagnosed with EORTC-MSG criteria (control group, 76 patients) or without prespecified radiological criteria (study group, 33 patients). The latter differed from the former by the inclusion of patients with pulmonary infiltrates not fulfilling the three EORTC-MSG IPA specific findings of dense, well-circumscribed lesions with or without halo sign, air crescent sign or cavity. All the analysed clinical and mycological characteristics, 3-month response to antifungal therapy and 1- and 3-month cumulative survival were comparable in the control and study groups in AML, LD and allo-SCT patients. Seventeen of 33 (51.5%) patients of the study group fulfilled EORTC-MSG radiological criteria at subsequent imaging performed a median of 15 days (range, 6–40 days) after documentation of the pulmonary infection. Our study seems to confirm the possibility of revising the EORTC-MSG criteria by extending the radiological suspicion of IPA to less specific chest computerized tomography scan findings when supported by microbiological evidence of Aspergillus infection in high-risk haematological patients.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Financial Disclosures
  8. Transparency Declaration
  9. References

Invasive pulmonary aspergillosis (IPA) is a major cause of morbidity and mortality in patients, particularly affected by haematological malignancies and allogeneic stem cell transplant (allo-SCT) [1]. Definitive aetiological diagnosis of IPA necessitates tissue microscopic visualization of the characteristic branching septate hyphae. However, the poor candidacy of many patients with suspected IPA for invasive diagnostic procedures has prompted interest in non-invasive means for diagnosis and most cases of IPA are documented at a level of probable infection by radiological and microbiological findings [2,3]. The need for a standardization of the diagnostic criteria prompted the European Organization for Research and Treatment of Cancer (EORTC) and the Mycosis Study Group (MSG) to develop the consensus definitions for the diagnosis of IPA published in 2002 and updated in 2008 [4,5]. These definitions were developed to facilitate the identification of reasonably homogeneous groups of patients for clinical and epidemiological research and to foster communication between international researchers. According to the updated EORTC-MSG definitions, a diagnosis of probable IPA is based on the documentation of at least one of three specific radiological findings (dense, well-circumscribed lesions with or without halo sign, air crescent sign or cavity) associated with Aspergillus isolation from the respiratory tract and/or positive serum galactomannan (GM) or beta D glucan (BDG) assay [5]. Although the introduction of definitions for invasive fungal diseases has greatly facilitated the conduction of clinical trials on diagnostic and therapeutic modalities for IA, their diagnostic performance in clinical practice is low when compared with autopsy examination [6–9]. The application of specific but not very sensitive diagnostic criteria may negatively impact not only the feasibility of clinical trials, considering the difficulties in the recruitment of eligible patients, but also the epidemiological consciousness of IPA. A recently published retrospective study in patients affected by multiple myeloma showed that less specific radiological images not fulfilling the three above findings, when supported by microbiological examinations, may be used to define an IPA and the authors proposed that the EORTC-MSG definitions be revised with the inclusion of a new category of IPA [10]. The objective of our study was to expand the above experience in patients with multiple myeloma to other patient populations at risk of IPA. In particular, we focused on acute myeloid leukaemia (AML) patients undergoing intensive chemotherapy, outpatients with lymphoproliferative diseases (LD) undergoing chemo-immunotherapy and allo-SCT recipients.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Financial Disclosures
  8. Transparency Declaration
  9. References

This is a retrospective evaluation of a cohort of 109 consecutive episodes of proven/probable IPA in patients affected by AML or LD or submitted to allo-SCT who were cared for at the Department of Hematology of the Azienda Policlinico Umberto I of Rome, from February 2006 through to January 2011. Informed consent for the use of clinical data for scientific purposes had been obtained from the patients. This was a non-interventional retrospective study and the collection and storage of data were performed by the investigators directly involved in patient care using current techniques of privacy assurance; thus Ethics Committee approval was not necessary.

At first documentation of IPA, cases were included in the ‘control group’ when radiological findings fulfilled the EORTC-MSG criteria (dense, well-circumscribed lesions with or without halo sign, air crescent sign or cavity) [5] or in the ‘study group’ when other radiological findings such as consolidation, ground-glass opacities and micronodules <1 cm were documented. In both groups Aspergillus infection was microbiologically documented by culture isolation of the fungus from the respiratory tract or by GM assay. GM testing was performed according to the manufacturer’s instructions (Platelia Aspergillus EIA; Bio-Rad, Marnes-La-Couquette, France). A positive GM test result was defined as an optical density index of ≥0.5 in serum and ≥1 in bronchoalveolar lavage or sputum.

The following predefined, structured fungal diagnostic strategies adapted to various categories of patients have been applied at our centre since 2006.

  •  AML patients with chemotherapy-induced neutropenia underwent a clinically driven diagnostic approach as detailed elsewhere, avoiding GM surveillance during the whole neutropenia period [11].AML neutropenic patients with persisting fever after 4 days of antibacterial therapy or relapsing fever after 48 h of defervescence underwent an intensive diagnostic work-up (IDWU). IDWU included three blood cultures, GM serum detection over three consecutive days, CT scan of the chest and other examinations as indicated.
  •  In outpatients with LD, pulmonary infiltrates suggestive of an IPA according to the above EORTC-MSG criteria, as well as other pulmonary infiltrates not responding to antibiotic therapy, were further investigated with cultures and GM assay from respiratory specimens (bronchoalveolar lavage or sputum) and with GM serum detection.
  •  Patients submitted to allo-SCT underwent antifungal surveillance until day 100 after transplant or longer in the event of graft versus host disease (GVHD). Surveillance was based on the serum detection of GM (twice per week for hospitalized patients and at least once per week for outpatients) and on the detection of respiratory tract colonization by filamentous fungi (sputum and nasal swab samples). In the event of a single positive serum GM assay result or a culture positive for moulds during surveillance or clinical findings possibly related to an IFD, an IDWU was performed as detailed above.

Mould-active antifungal therapy (voriconazole, liposomal amphotericin B, caspofungin or itraconazole) at standard recommended doses for therapy of aspergillosis was started on first documentation of IPA. All patients in both groups underwent radiological re-evaluations to monitor the evolution of the pulmonary infection. Generally, all patients underwent a first repeat CT scan within 3 weeks from the start of antifungal therapy and subsequently according to clinical judgement. Response to antifungal therapy was defined as complete or partial if a >90% or <90% and >50% reduction in size of the pulmonary lesions was obtained within 3 months from the diagnosis, respectively [12].

Variables considered at diagnosis of IPA or within 3 months from IPA diagnosis included demographic characteristics, underlying haematological disease, concomitant pulmonary diseases or respiratory infections other than IPA, presence of neutropenia (absolute neutrophil count, ANC <500/cmm) or severe neutropenia (ANC <100/cmm), duration of neutropenia before and after diagnosis of IPA, mould-active prophylaxis, radiological and microbiological findings, antifungal therapy, response to antifungal therapy and survival at 3 months. Patients in the ‘study group’ were monitored for 3 months from IPA diagnosis to eventually detect the evolution of aspecific radiological manifestations to pulmonary lesions specific of IPA according to EORTC-MSG definitions.

The endpoint of this study was to compare the variables of cases and controls. Categorical data were analysed using chi-squared or Fisher’s exact tests as appropriate and continuous variables were compared using the t-test. Cumulative survival curves were calculated using the Kaplan–Meier method and compared by the log-rank test, taking into account the date of diagnosis of IPA and the date of death or last follow-up, censored at 3 months after the diagnosis of IPA. All analyses were performed using SPSS statistical software, version 17.0 for Windows (SPSS, Bologna, Italy). p ≤0.5 was considered to be statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Financial Disclosures
  8. Transparency Declaration
  9. References

During the 5-year period, 109 consecutive episodes of probable IPA in 56 (51.4%) patients affected by AML and submitted to intensive chemotherapy, 31 (28.4%) patients affected by LD and submitted to chemo-immunotherapy and 22 (20.2%) allo-SCT recipients were considered. The demographic, clinical, radiological and microbiological manifestations, and 1- and 3-month survival of patients are detailed in Table 1.

Table 1.   Clinical, radiological and microbiological findings among patients with acute myeloid leukaemia (AML) or lymphoproliferative disease (LD) or submitted to allogeneic stem cell transplant (SCT) and proven/probable invasive pulmonary aspergillosis (IPA): comparison of cases by EORTC-MSG prespecified radiological criteria (control group)a versus cases without prespecified radiological findings (study group) at diagnosis
Characteristic at diagnosisAML (n = 56)LD (n = 31)Allogeneic SCT (n = 22)Total cases (n = 109)
Control group (n = 42)Study group (n = 14)pControl group (n = 23)Study group (n = 8)pControl group (n = 11)Study group (n = 11)pControl group (n = 76)Study group (n = 33)p
  1. ANC, absolute neutrophil count.

  2. NP: statistical comparison was not performed because by definition the two groups had been stratified according to different radiological findings

  3. aEORTC-MSG radiological criteria of pulmonary invasive aspergillosis were: dense, well-circumscribed lesions with or without halo sign, air crescent sign and cavity.

  4. bIn each patient more than one radiological finding may have been observed at computerized tomography examination but only the predominant finding was indicated.

Sex, n male (%)28 (66.7)6 (42.9)0.112 (52.2)5 (62.5)0.79 (81.8)5 (45.5)0.249 (64.5)16 (58.5)0.1
Age, median years (range)54 (24–77)55(30–77)0.964 (28–74)69 (59–79)0.0634 (27–65)46 (2–66)0.855 (24–77)57 (2–79)0.8
Acute leukaemia, n cases (%)42 (100)14 (100)////7 (63.6)8 (72.7)149 (64.5)22 (66.7)1
Chronic lymphocytic leukaemia, n cases (%)// 9 (39.1)2 (25)0.72 (18.2)2 (18.2)111 (14.5)4 (12.1)1
Lymphoma, n cases (%)// 12 (39.1)6 (62.5)0.400/12 (15.8)6 (18.2)0.8
Other haematological diseases, n cases (%)// 200.62 (18.2)1 (9.1)14 (5.3)1 (3.0)1
Baseline chronic pulmonary disease, n cases(%)5 (11.9)2 (14.3)0.610 (43.5)3 (37.5)12 (18.2)1 (9.1)117 (22.4)6 (18.2)0.8
Neutropenia (<500 neutrophils/mm3) at diagnosis of IPA, n cases (%)42 (100)14 (100)16 (26.1)1 (12.5)0.66 (54.5)4 (36.4)0.754 (71.0)19 (57.6)0.2
Severe neutropenia (<100 ANC/mm3) at diagnosis of IPA, n cases (%)42 (100)14 (100)11 (4.3)015 (45.5)4 (36.4)147 (61.8)18 (54.5)0.5
Time with ANC <500/cmm before diagnosis of IPA, median (range) days12 (7–40)14 (8–20)0.87 (4–35)10/15 (3–22)19 (12–90)0.212 (3–40)14 (8–90)0.08
Time with ANC <100/cmm before diagnosis of IPA, median (range) days10 (5–25)10 (7–18)14 (4)//16 (3–20)9 (8–60)0.310 (3–25)10 (7–60)0.1
Time with ANC <500/cmm after diagnosis of IPA, median (range) days8 (2–35)11.5 (4–14)0.56 (2–15)//8(1–14)9 (8–14)0.98 (1–35)10.5 (4–14)0.3
Time with ANC <100/cmm after diagnosis of IPA, median (range) days6 (1–18) in 42 pts7.5 (2–11) in 14 pts0.23 in 1 pt//7 (4–14) in 5 pts9.5 (6–11) in 4 pts0.96 (1–18) in 47 pts7.5 (2–11) in 18 pts0.1
Mould-active antifungal prophylaxis, n cases (%)15 (35.7)4 (28.6)0.700 1 (9.1)2 (18.2)116 (21.0)6 (18.2)0.8
Radiological findings, n cases (%)b
 EORTC-MSG specific findings  NP  NP  NP  NP
  Macronodules with halo sign23 (54.8)0 1 (4.3)0 2 (18.2)0 26 (34.2)0 
  Macronodules without halo sign17 (40.5)0 21 (91.3)0 9 (81.8)0 47 (61.8)0 
  Cavity or air crescent sign2 (4.8)0 1 (4.3)0 00 3 (3.9)0 
 Aspecific findings
  Consolidation06 (42.9) 07 (87.5) 04 (36.4) 017 (51.5) 
  Ground-glass opacities02 (14.3) 01 (12.5) 02 (18.2) 05 (15.1) 
  Micronodules06 (42.9) 00 05 (45.5) 011 (33.3) 
 Mycological criteria, n cases (%)
  GM from serum38 (90.5)10 (71.4)0.116 (69.6)4 (50)0.49 (81.8)8 (72.7)163 (82.9)22 (66.7)0.08
  GM from BAL or sputum7 (16.7)3 (33.3)0.79 (39.1)6 (75)0.12 (18.2)2 (18.2)118 (23.7)11 (33.3)0.3
  Culture from BAL or sputum4 (9.5)2 (14.3)0.67 (30.4)4 (50)0.42 (18.2)1 (9.1)113 (17.1)7 (21.2)0.6
  Histopathological testing with GM and or culture2 (4.8)1 (7.1)11 (4.3)1 (12.5)0.52 (18.2)1 (9.1)15 (6.6)3 (9.1)0.7
 Serum GM peak, median value (range)1.2(0.6–4.4)1.2(0.5–5)0.71.8(0.6–5.1)1.5(0.8–2.8)0.81.6(0.8–4.6)1.8(0.7–3.8)0.71.6(0.6–5.1)1.4(0.5–5.1)0.6
 Primary antifungal treatment, n cases (%)
  Voriconazole32 (76.2)10 (71.4)0.220 (87)6 (75)0.38 (72.7)7 (63.6)0.560 (78.9)23 (69.7)0.1
  Liposomal Amphotericin B10 (23.8)4 (28.6) 00 2 (18.2)2 (18.2) 12 (15.8)6 (18.2) 
  Itraconazole00 3 (13)2 (25) 00 3 (3.9)2 (6.1) 
  Caspofungin00 00 1 (9.1)2 (18.2) 1 (1.3)2 (6.1) 
 Complete/partial response after 3 months antifungal therapy25 (59.5)10 (71.4)0.217 (73.9)5 (62.5)0.37 (63.6)6 (54.5)0.549 (64.5)21 (63.6)0.17
 1-month cumulative survival, %85.785.7178.387.50.572.71000.0781.690.90.2
 3-month cumulative survival, %61.971.40.556.562.50.763.681.80.360.572.70.2

Overall, 14 (25%) AML patients, 8 (25.8%) LD patients and 11 (50%) allo-SCT recipients presented at first evidence of IPA with radiological findings not fulfilling the EORTC-MSG definitions (study group). No statistically significant difference was observed for all the analysed characteristics, other than radiological findings, between the control group and study group in the three categories of patients. The radiological findings more frequently observed at diagnosis of IPA were macronodules with halo sign in AML patients (23 of 56 patients, 41.1%), and macronodules without halo sign in both LD and allo-SCT patients (21 of 31 patients, 67.7%, and nine of 22 patients, 40.9%, respectively). Diagnosis of IPA was successively proven by histopathological documentation of fungal tissue infiltrate associated with microbiological evidence of Aspergillus infection, in five and three patients of the control group and study group, respectively.

The correlation between ANC and radiological findings at onset of IPA in the overall population showed that, out of 73 neutropenic patients (ANC ≤500/cmm), macronodules without halo sign, macronodules with halo sign and micronodules were the most frequent predominant findings, accounting for 38.4%, 32.9% and 11.0% of cases, respectively, whereas, out of 37 non-neutropenic patients (ANC >500/cmm), macronodules without halo sign, consolidations and micronodules accounted for 51.3%, 27.0% and 8.1% of the cases, respectively. In particular, macronodules with halo sign were observed in 24 of 73 (32.9%) neutropenic patients and in two of 37 (5.4%) non-neutropenic patients (p =0.001).

Voriconazole was the most frequently used primary treatment for IPA and treatment practices did not differ in cases and controls. The 3-month response to antifungal therapy and cumulative survival of cases and controls at 1 and 3 months evaluation was comparable in all three groups.

Evolution of radiological findings in the overall population of patients in the study groups is detailed in Fig. 1. At a repeat imaging, radiological findings specific to IPA, according to EORTC-MSG criteria, were documented in 17 of 33 (51.5%) patients [6 of 14 (42.9%) AML patients, 4 of 8 (50%) LD patients, and 7 of 11 (63.6%) allogeneic SCT patients]. This evolution was documented with CT exams performed a median of 11 days (range, 5–28 days), 18 days (range, 9–37 days) and 20 days (range, 7–40 days) after their first CT exam in AML, LD and allo-SCT patients, respectively. Macronodules without halo sign represented the most frequent radiological finding specific for IPA at a repeat imaging. Overall, radiological findings fulfilled the EORTC-MSG criteria in 76 of 109 (69.7%) patients at first evidence of IPA and in 93 of 109 (85.3%) patients when considering repeat imaging performed a median of 15 days (range, 6–40 days) after documentation of the pulmonary infection.

image

Figure 1.  Evolution of radiological findings at a repeat imaging in patients without prespecified EORTC-MSG radiological criteria at diagnosis of invasive pulmonary aspergillosis.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Financial Disclosures
  8. Transparency Declaration
  9. References

The enrollment of patients with IA in clinical trials may be difficult when restrictive eligibility criteria are applied. In the three largest prospective studies on treatment of IA with voriconazole, liposomal amphotericin B and caspofungin, respectively [2,3,13], which represented the basis for current Aspergillus infections treatment guidelines [14,15], the recruitment criteria considered the original EORTC-MSG definitions [4]. According to these original definitions any new pulmonary infiltrate, when associated with microbiological evidence of Aspergillus infection, was sufficient to define a diagnosis of probable IPA. Furthermore, in the studies on voriconazole and liposomal amphotericin B, 34% of 277 cases and 60% of 201 cases, respectively, were upgraded to have probable IPA on the basis of the presence of a halo or air crescent sign, despite lack of microbiological support, in order to increase the capacity for recruitment of patients [1,2]. On the contrary, in the EORTC study on caspofungin first-line therapy for IA [13], patients with possible infection (i.e. those with a halo sign only, without microbiological confirmation, or with host factors and clinical signs or symptoms compatible with IA but again without microbiological confirmation) were allowed to start treatment, but in the event of lack of upgrade of the cases to proven or probable IA based on culture or serological tests within 7 days they were discontinued from the efficacy study. These strict eligibility criteria probably justify the slow recruitment in this study: 61 evaluable cases from 23 European centres in 2 years.

The definitions of probable IPA according to the revised EORTC-MSG criteria [5] are even more restrictive if we consider that pulmonary infiltrates other then macronodules with or without halo-sign, air crescent sign and cavity are no longer considered for any diagnosis of pulmonary fungal infection. Presumably, clinical trials will dramatically suffer the problem of recruitment of patients with the application of these revised definitions, unless extension of eligibility criteria is applied. On the other hand, any subjective modification of the standard recruitment criteria would affect the comparability of the studies against the aim of the EORTC-MSG efforts to facilitate the identification of reasonably homogeneous groups of patients for clinical and epidemiological research.

A recently published retrospective study from the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, showed that the features of multiple myeloma patients with probable IPA according to the revised EORTC-MSG radiological criteria are comparable to those of patients without specific radiological findings [10]. Out of 116 episodes of IPA, 30% of cases presented with radiological findings not fulfilling the above specific EORTC-MSG diagnostic criteria of probable IPA. No significant difference in the host, clinical and mycological characteristics, as well as in survival, was observed in the two groups. The authors proposed that the EORTC-MSG definitions be revised, with the inclusion of a new category of IA giving a greater weight to Aspergillus-specific microbiological criteria, and suggested expanding their experience in patients with multiple myeloma to other patient populations at risk of IA. Our data in AML, LD and allo-SCT patients confirm these results, although the single-centre experience, the small numbers in the subgroups and the retrospective evaluation of outcomes represent a limitation for any comparison. Both studies suggest that patients with haematological malignancies at risk of invasive mycoses developing any type of pulmonary infiltrate when associated with microbiological evidence of Aspergillus infection should be considered to be probably affected by IPA. This was demonstrated by the comparable characteristics, response to antifungal therapy and outcome of patients with and without specific radiological findings and by the evolution in more than 50% of cases of aspecific pulmonary infiltrates to radiological findings of IPA according to the EORTC-MSG criteria, suggesting that these cases might be an early phase of the disease. The inclusion of these cases in studies on IA should be considered not only for the speed, efficiency and costs of randomized clinical trials of novel therapies but also for epidemiological reasons in order to avoid underestimating infective complications that deserve proper prevention strategies.

In conclusion, considerable uncertainty and controversy exists regarding the best method for establishing a diagnosis of IPA in haematological patients. This is important in clinical research, considering that a crucial goal when performing a randomized clinical trial is to limit diagnostic uncertainty while assuring an adequate enrollment of patients. This was the spirit of the EORTC-MSG criteria, which have been defined for research only and not for clinical use. However, the revised EORTC-MSG definitions provide highly restrictive radiological criteria for diagnosis of probable IPA and their applicability in future clinical and epidemiological research might be limited. Our study seems to confirm that microbiological evidence of Aspergillus infection in high-risk haematological patients may support the possibility of extending the radiological suspicion of IPA to less traditional chest CT findings. The application of the original EORTC-MSG definitions of probable IPA published in 2002 might be reconsidered [4]. Further study is needed to validate and standardize new imaging findings for their use in clinical practice and enrollment in clinical trials and to support a revision of the current EORTC-MSG diagnostic criteria of IPA.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Financial Disclosures
  8. Transparency Declaration
  9. References
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