Immune reconstitution inflammatory syndrome in cancer patients

Document Sample
Immune reconstitution inflammatory syndrome in cancer patients Powered By Docstoc

Immune Reconstitution Inflammatory Syndrome in
Cancer Patients With Pulmonary Aspergillosis
Recovering From Neutropenia: Proof of Principle,
Description, and Clinical and Research Implications

Marisa H. Miceli, MD1                                      BACKGROUND. Assessing the outcome of patients with invasive pulmonary asper-
Johan Maertens, MD2                                        gillosis by using conventional criteria is difficult, particularly when clinical and
Kristel Buve , MD2
           ´                                               radiologic worsening coincides with neutrophil recovery. Usually, it is assumed
Monica Grazziutti, MD1                                     that this deterioration is related to progressive aspergillosis, prompting changes
Gail Woods, MD3                                            in patient management. However, its temporal relation with neutrophil recovery
Mazhar Rahman, MD1                                         suggests that it may be caused by an immune reconstitution syndrome (IRIS).
Bart Barlogie, MD, PhD1                                    Galactomannan is an Aspergillus-specific polysaccharide that is released during
Elias J. Anaissie, MD1                                     aspergillosis and is detected by the serum galactomannan test, which has been
                                                           approved by the United States Food and Drug Administration for the diagnosis of
  Myeloma Institute for Research and Therapy,              invasive aspergillosis. In this study, the authors used sequential galactomannan
University of Arkansas for Medical Sciences,               testing to distinguish IRIS responses from progressive aspergillosis.
Little Rock, Arkansas.                                     METHODS. From April 2001 to December 2006, patients with hematologic malig-
 Department of Hematology, University Hospital             nancies underwent galactomannan screening during periods when they were at
Gasthuisberg, Leuven, Belgium.                             risk. The clinical and laboratory findings from patients who had !2 consecutive
  Department of Pathology, University of Arkansas          positive galactomannan assays (optical density, !0.5) were reviewed.
for Medical Sciences, Little Rock, Arkansas.               RESULTS. Nineteen neutropenic patients with aspergillosis developed clinical and
                                                           radiologic pulmonary deterioration during neutrophil recovery. Deterioration
                                                           coincided with microbiologic response, as documented by rapid normalization of
                                                           serum galactomannan, and, in 16 patients, was followed by complete clinical
                                                           response and survival at 3 months, although there were no changes in antifungal
                                                           therapy. The 3 patients who died during the first month had no evidence of
                                                           aspergillosis at autopsy examination.
                                                           CONCLUSIONS. The authors propose that IRIS was responsible for the current find-
                                                           ings and provide a definition for the syndrome. They also recommend serial galac-
                                                           tomannan testing to guide aspergillosis management. Declining galactomannan
                                                           values imply IRIS with an aspergillus response and obviate the need for invasive
                                                           procedures and alternative antifungal therapies, whereas persistent galactomannan
                                                           elevation indicates progressive aspergillosis and requires prompt treatment modifi-
                                                           cation. Cancer 2007;110:112–20. Ó 2007 American Cancer Society.

                                                           KEYWORDS: galactomannan, hematologic malignancies, immune reconstitution
                                                           syndrome, invasive aspergillosis.
Address for reprints: Elias J. Anaissie, MD,
Myeloma Institute for Research and Therapy, Uni-
versity of Arkansas for Medical Sciences, 4301
West Markham, Slot 816, Little Rock, AR 72205;
Fax: (501) 686-6442; E-mail: anaissieeliasj@
                                                           I nvasive pulmonary aspergillosis is a life-threatening infection in
                                                             patients with hematologic malignancies who are undergoing mye-
                                                           losuppressive chemotherapy.1 Phagocytic cells (neutrophils and the
                                                           macrophage/monocyte system) are the key immune defenses against
Received February 14, 2007; revision received              aspergillosis, as demonstrated previously by experimental studies,2
February 28, 2007; accepted March 1, 2007.                 which showed the increased susceptibility of neutropenic patients to

ª 2007 American Cancer Society
DOI 10.1002/cncr.22738
Published online 24 May 2007 in Wiley InterScience (
                                                                               Aspergillosis and IRIS/Miceli et al.   113

aspergillosis and a strong relation between aspergillo-      MATERIALS AND METHODS
sis outcome and the resolution of neutropenia.3 Two          This study was conducted at the University of Arkan-
studies reported on 11 patients who had worsening            sas for Medical Sciences from November 2003 to
clinical and radiologic pulmonary findings after neu-        September 2006 and was approved by the Institu-
trophil recovery.4,5 Typically, this deterioration is con-   tional Review Board. The medical records of 67
sidered progressive aspergillosis6 and prompts               patients with !2 consecutive positive galactomannan
invasive diagnostic procedures and treatment modifi-         indices (optical density !0.5) were reviewed; 22
cations, such as the use of cytokines, granulocyte           patients were excluded, including 14 patients who
transfusions and/or surgery, and the addition of new         were receiving piperacillin-tazobactam and 8 patients
antifungal agents.6,7 For example, Caillot et al.            who did not undergo optimal radiologic testing and/
described a 4-fold increase in infiltrate size coinciding    or follow-up. In addition, 13 cancer patients with
with neutrophil recovery among 25 patients who had           pulmonary aspergillosis who were cared for at the
invasive pulmonary aspergillosis. On the assumption          University Hospital Gasthuisberg (Leuven, Belgium)
that they had refractory aspergillosis, patients under-      from April 2001 to December 2006 and who met our
went modification of antifungal therapy and surgery.7        inclusion criteria were identified, and their medical
Similar patients usually are enrolled in salvage trials      records were reviewed.
of antifungal therapy in which refractory aspergillosis           Galactomannan testing was performed and
is defined as progression of clinical or radiographic        reported according to the manufacturer’s instructions
signs despite !7 days of standard antifungal therapy.6       (Platelia Aspergillus EIA; Bio-Rad, Redmond, WA).
Pivotal trials continue to use this enrollment strategy8     Sera with an index !0.5 were retested the next day
despite its major pitfalls, as reported by Almyroudis        and were considered positive if the galactomannan
et al.6 We propose that the temporal association of          index was !0.5.
pulmonary deterioration with neutrophil recovery, in              Neutropenia was defined as an absolute neutro-
fact, may be caused by the restored ability to mount         phil count (ANC) <1000 cells/lL. Invasive pulmonary
an inflammatory response, in a manner reminiscent            aspergillosis was defined according to European
of the immune reconstitution inflammatory syndrome           Organization for Research and Treatment of Cancer/
(IRIS) in patients with the human immunodeficiency           Mycoses Study Group criteria.15 Successful outcome
virus (HIV) who respond to highly active antiretroviral      was defined as a persistently negative galactomannan
therapy (HAART).9,10 In the latter population, the di-       index with survival at 3 months in the absence of
agnosis of IRIS is supported by new symptoms con-            new extrapulmonary lesions of aspergillosis (eg, a
sistent with an infectious/inflammatory condition            culture-positive skin lesion and/or a skin lesion with
that is related temporally to the initiation of HAART        hyphal tissue invasion consistent with aspergillosis)
and a robust decrease in the HIV-RNA level, which is         or a negative autopsy for aspergillosis in the event of
a pathogen-specific, reproducible, and quantitative          death. Failure was defined as a persistently positive
test.9,10 In contrast, the assessment of aspergillosis       galactomannan index and/or death, unless autopsy
response still relies on unvalidated, complex, compos-       examination failed to reveal aspergillosis.
ite endpoints (clinical, radiologic, and rarely histologic        Pulmonary IRIS was defined as a new onset of or
or microbiologic), which mostly are nonpathogen-             worsening clinical and radiologic pulmonary findings
specific, qualitative, and observer-dependent.11 The         consistent with an infectious/inflammatory pulmo-
United States Food and Drug Administration-                  nary condition temporally related to neutrophil
approved diagnostic test for aspergillosis is based on       recovery with evidence of microbiologic response (a
galactomannan, an Aspergillus-specific polysaccha-           decrease !50% in serum galactomannan index titers
ride that is released during invasive infection. The test    on 2 consecutive tests within 4 days of each other)
is reported as a galactomannan index, is quantitative        despite no change in antifungal therapy. The defini-
and reproducible,12 and appears to correlate with            tion also required absence of new extrapulmonary
aspergillosis burden and outcome.13,14                       lesions of aspergillosis (eg, new skin lesions as
     Herein, we report the development of IRIS in can-       described above) and/or other processes, such as
cer patients with invasive pulmonary aspergillosis           newly acquired infection, failure of treatment of a
who were recovering from neutropenia and offer a             known infection, or medication side effects.
galactomannan-based strategy to distinguish respond-
ing pulmonary aspergillosis with IRIS from progres-          RESULTS
sive aspergillosis. We also describe the incidence,          Nineteen neutropenic patients with proven/probable
clinical and radiologic findings, and favorable out-         invasive pulmonary aspergillosis fulfilled the IRIS crite-
come of patients with aspergillosis-related IRIS.            ria, including 11 patients with acute leukemia (58%), 6
114     CANCER   July 1, 2007 / Volume 110 / Number 1

patients with myeloma (32%), and 1 patient each with        after methylprednisone in 2 patients with impending
non-Hodgkin lymphoma and chronic myelogenous                respiratory failure (providing further support for the
leukemia. The median patient age was 56 years (range,       immune-related nature of this syndrome).
18–73 years), and there were 12 men and 7 women                  Worsening of pulmonary findings of aspergillosis
(Table 1). Aspergillosis developed after stem cell trans-   during neutrophil recovery has been reported among
plantation (autologous in 4 patients and allogeneic in      patients with hematologic cancer4,7 but almost always
3 patients) or after conventional chemotherapy (12          was considered evidence of progressive infection.
patients). The mean days to clinical and radiologic         However, because of the absence of microbiologic
findings of IRIS after an ANC >100/lL and an ANC            documentation in those reports, it remains unclear
>500/lL was 3.5 days (median, 3 days; range, from À7        whether patients had resolving aspergillosis with IRIS
days to 18 days) and 2 days (median, 1 day; range,          or progressive infection. In another report, 3 patients
from À8 days to 115 days), respectively. Clinical dete-     with pulmonary aspergillosis developed respiratory
rioration included worsening or new onset of hypoxia        failure during neutrophil recovery; 2 of those patients
requiring oxygen therapy (12 patients), including me-       responded to methylprednisone without changes in
chanical ventilation in 4 patients, cough (8 patients),     antifungal therapy, suggesting that deterioration was
chest pain (6 patients), dyspnea (5 patients), and          related to the resolution of neutropenia.4 Our data
hemoptysis (3 patients). Radiologic findings consisted      support the latter findings and now provide evidence,
of increasing and/or new onset pulmonary infiltrates        for the first time, that pulmonary deterioration can be
in 14 patients, pleural effusions in 10 patients, nodular   immune-related with infection response and not re-
lesions in 9 patients, intrathoracic lymphadenopathy        fractory aspergillosis.11 Indeed, patients who have wor-
in 3 patients, and cavitation in 1 patient. At diagnosis,   sening clinical and radiologic findings always are
all 19 patients had !2 consecutive positive serum           considered to have progressive infection, prompting
galactomannan tests, prompting the initiation of anti-      changes in their management. Then, the subsequent
mould therapy. Declining titers of sequential serum         clinical and radiologic improvements are considered
galactomannan were observed during clinical and             proof of efficacy of this agent (often leading to regula-
radiologic deterioration.                                   tory approval), without any consideration for the pos-
     Three patients died during the first month of fol-     sibility that deterioration leading to enrollment, in
low-up (Patients 12, 14, and 16); autopsies on those        fact, may be aspergillosis-related IRIS with response
3 patients failed to demonstrate invasive aspergillo-       occurring prior to investigational therapy.
sis. At 1-month follow-up, the remaining 16 patients             The incidence of HIV-associated IRIS is from 10%
improved without changes in antifungal therapy or           to 25%,9 and pulmonary IRIS has been associated with
additional therapies, such as cytokines or surgery; at      various pathogens, including Aspergillus spp.16 HIV-
3 months, all 16 patients were alive without clinical,      associated IRIS appears to develop later (mean, % 33
radiologic, or microbiologic evidence of aspergillosis.     days; range, 8–150 days after HAART)9 than among
The serum Aspergillus galactomannan index was also          our patients (mean, 2 days; range, from À8 days to
negative. It is noteworthy that 2 patients with my-         115 days after the resolution of neutropenia). It
eloma (Patients 1 and 5) received intravenous               remains to be determined whether IRIS in our patients
methylprednisone for impending respiratory failure.         was caused by neutrophil recovery only or by the
                                                            combined effect of recovery and antifungal therapy.
                                                                 Second, we provide a definition of pulmonary IRIS
DISCUSSION                                                  among cancer patients that was adapted from the def-
Several new findings emerge from this study. First, we      inition proposed for patients with HIV10 (Table 2).
provide a proof of principle for pulmonary IRIS among       Similar to the definition of HIV-IRIS, our definition is
patients with hematologic cancer and invasive pulmo-        clinical, includes a microbiologic marker of response
nary aspergillosis who are recovering from neutrope-        (serum galactomannan index), but also requires meas-
nia. The immune-related nature of the pulmonary             uring the key immune parameter in aspergillosis
deterioration is supported by 1) the temporal associa-      among neutropenic patients, ie, the neutrophil count.
tion with neutrophil recovery, 2) the robust microbio-           Third, we describe the clinical and radiologic
logic response (decrease in galactomannan index             spectrum of IRIS in 19 cancer patients with pulmonary
titers), 3) the absence of new lesions from aspergillosis   aspergillosis who were recovering from neutropenia
or other processes, 4) the subsequent resolution of         and report that IRIS may not be uncommon among
aspergillosis without treatment modifications (con-         such patients. Fourth, our data suggest that cancer
firming that the deterioration was not related to pro-      patients with pulmonary aspergillosis and IRIS may
gressive aspergillosis), and 5) the improved outcome        have a good prognosis, similar to that for HIV-infected
Cancer Patients With Invasive Pulmonary Aspergillosis and Immune Reconstitution Inflammatory Syndrome After Neutrophil Recovery*

                                                                                                                                                               Pulmonary IRIS featuresy

                        Underlying                                                                                                                                                       Temporal relation
                        disease and                                                                   Date of                                                                            to neutrophil         Resolving
Patient sex    Age, y   status         Therapy               Findings at diagnosis                    IRIS          Clinical deterioration        Worsening radiology                    recovery              antigenemia

1       W      61       Recurrent      3/27/04:              4/12-22/04: Positive GMI (peak,          5/3-17/04     Cough, crackles, wheezing,    5/3/04: CT shows extensive             5/1/04: ANC >500;     4/19/04: GMI
                          myeloma         Chemotherapy;         4.14; 4 tests), cough, crackles;                      hypoxia requiring O2, and      bilateral effusions, infiltrates,      5/5/04: ANC           decreased >50%
                                          4/1-24/04: ANC        4/5/04: CT shows apical                               IV methylprednisone            nodules; 5/17/04: CT shows             >4000                 GMI decrease;
                                          <100                  scarring, Voriconazole                                                               new mediastinal and                                          4/22/05: Negative
                                                                400 mg/d (started 4/13/04)                                                           precarinal lymph nodes                                       GMI
2       W      60       Recurrent      7/8/04: ASCT;         7/14-31/04: Positive GMI (peak,          8/5-19/04     Elevated fever, worsening     8/20/04: CT shows worsening            7/20/04: ANC >500;    7/29/04: GMI
                          myeloma         7/13-19/04: ANC       2.64; 7 tests); 7/14-19/04: Fever                      hypoxia                       infiltrates                            7/24/04: ANC          decreased >50%;
                                          <100                  and hypoxia, CT shows                                                                                                       >4000                 8/3/04: Negative
                                                                infiltrates and effusions;                                                                                                                        GMI;
                                                                Voriconazole 600 mg/d (7/19-
                                                                23/04), Ambisome 150 mg/d
                                                                (started 7/23/04)
3       M      67       Recurrent      12/20/04:             Minimal crackles; 12/30/05: CT           1/12-18/05    Fever, cough, crackles,       1/12/05: CT shows bilateral            1/5/05: ANC >500;     1/13/05: Negative
                          myeloma         Chemotherapy;         shows minimal bilateral                               wheezing, hypoxia              alveolar opacities and                 1/8/05: ANC           GMI
                                          12/28/04-1/3/05:      interstitial infiltrates; 12/30/04-                                                  effusions, new right lung              >4000
                                          ANC <100              1/5/05: Positive GMI (peak, 6.5;                                                     nodule
                                                                5 tests), Ambisome 200 mg/d
                                                                (started 1/3/05)
4       W      73       Myeloma in     3/17/05: ASCT;        3/25/05: RML rales and hypoxia,          3/31/        Cough, bilateral crackles,     4/7/05: CT shows stable                3/28/05: ANC >500;    4/1/05: GMI
                          remission       3/21-27/05: ANC       CT shows bilateral upper lobe            05-4/7/05   wheezing, hypoxia               infiltrates; new pretracheal,          3/31/05: ANC          decreased >50%;
                                          <100                  infiltrates; 3/25/05-4/3/05:                                                         precarinal and                         >4000                 4/4/05: Negative
                                                                Positive GMI (peak, 3.3; 6                                                           aortopulmonary window                                        GMI
                                                                tests), Voriconazole 600 mg/d                                                        lymph nodes
                                                                (started 3/29/05)
5       M      72       Myeloma in     8/29/05: ASCT;        9/2/05: ANC 400, GMI 5.8, fever;         9/11-15/05    Elevated fever, wheezing,     9/11/05: CT shows new,                 9/9/05: ANC >500;     9/12/05: Negative
                          remission       9/4-8/05: ANC         9/2-7/05: Positive GMI (peak, 6;                       and worsening hypoxia         diffuse, bilateral                     9/10/05: ANC          GMI
                                          <100                  3 tests); 9/9/05: ANC >1000,                           requiring ICU transfer        infiltrates and nodules                >4000
                                                                fever, CT shows scarring LLL;                          and IV methylprednisone
                                                                Voriconazole 400 mg/d (9/9-
                                                                11/05), Ambisome 300 mg/d
                                                                (started 9/12/05)
6       M      58       Recurrent      12/5/05: ASCT;        12/20-24/05: Fever, cough, and           12/25/05-     Mechanical ventilation for    12/26/05: CT shows                     12/25/05: ANC >500;   1/2/06: GMI
                          myeloma         12/14-24/05: ANC      crackles; CT shows bilateral             1/7/06       respiratory failure            worsening bilateral                    12/29/05: ANC         decreased >50%;
                                          <100                  lower lobe consolidations; 12/                                                       infiltrates, new effusions             >4000                 2/26/06: Negative
                                                                20/05-1/2/06: Positive GMI                                                                                                                        GMI
                                                                (peak, 6.3; 8 tests);
                                                                                                                                                                                                                                       Aspergillosis and IRIS/Miceli et al.

                                                                Voriconazole 400 mg/d
                                                                (started on 12/22/05)


                                                                                                                                                                Pulmonary IRIS featuresy

                       Underlying                                                                                                                                                        Temporal relation
                       disease and                                                                                                                                                       to neutrophil       Resolving
Patient Sex   Age, y   status            Therapy               Findings at diagnosis                 Date of IRIS Clinical deterioration            Worsening radiology                  recovery            antigenemia

7       M     53       Recurrent AML     10/22/06:             10/31/06: Fever, dyspnea, and         11/18/06-     Mechanical ventilation for       CT not feasible; daily chest         11/20/06:           11/22/06: GMI
                                            Chemotherapy;         cough; CT shows bilateral lower       12/5/06      respiratory failure              x-ray; progression of                 ANC >500;           decreased >50%;
                                            10/31/06-11/18/       lobe consolidations; 10/31/06-                                                      pulmonary infiltrates                 11/24/06: ANC       11/28/06: Negative
                                            06: ANC <100          11/18/06: Positive GMI (peak,                                                                                             >4000               GMI
                                                                  8.2; 21 tests); Ambisome 5 mg/
                                                                  kg/d (started 11/3/06)
8       W     52       NHL in            7/22/06: Allo-SCT;    9/16/06: Fever, dry cough, and        12/4-15/06    Pleuritic chest pain, hypoxia    12/6/06: CT shows increased          12/3/06: ANC        12/1/06: GMI
                         remission          7/21/06-12/1/06:      dyspnea; CT shows 2 nodules                         requiring O2 , worsening         volume of previous lesions,          >500; 12/8/06:      decreased >50%;
                                            ANC <100              with halo sign in RUL; 9/16/06-                     productive cough                 new nodular lesion in LLL            ANC >4000           12/4/06: Negative
                                                                  12/3/06: Positive GMI (peak,                                                                                                                  GMI
                                                                                                                                                                                                                                     July 1, 2007 / Volume 110 / Number 1

                                                                  6.8; 83 tests); Voriconazole 400
                                                                  mg/d (started on 9/16/06)
9       W     36       Recurrent ALL     5/16/06:              6/6/06: Confusion, fever, dyspnea,    6/16-22/06    Increased dry cough,             6/16/06 and 6/23/06: CT shows        6/23/06: ANC        6/20/06: GMI
                                            Chemotherapy;         cough; CT shows nodule in                           persistent fever, pleuritic      new infiltrates with halo in         >500; 6/29/06:      decreased >50%;
                                            5/21/06-6/21/06:      RUL with halo sign; 6/10-21/06:                     pain                             RLL, subpleural and lingula;         ANC >4000           6/22/06: Negative
                                            ANC <100              Positive GMI (peak, 3.1; 12                                                          6/30/06: CT shows air crescent                           GMI
                                                                  tests); Caspofungin 50–70 mg/d                                                       formation in 2 lesions
                                                                  (started on 6/10/06)
10      W     25       Recurrent ALL     1/8/03:               1/30/03: Fever and cough, CT          2/17-28/03    Hypoxia requiring O2,            2/17/03: CT shows further            2/14/03: ANC        2/17/03: GMI
                                            Chemotherapy;         shows small nodular infiltrates                    bilateral crackles                increase of the original lesion      >500; 2/21/03:      decreased >50%;
                                            1/15/03-2/13/03:      in the RUL; 1/30/03-2/20/03:                                                         and new apical infiltrate in         ANC >4000           2/21/03: Negative
                                            ANC <100              Positive GMI (peak, 2.2; 18                                                          right lower mediastinal and                              GMI
                                                                  tests); Ambisome 5 mg/k/d                                                            axillary lymph nodes, pleural
                                                                  (started on 1/30/03); 2/6/03:                                                        fluid
                                                                  CT shows significant increase
                                                                  of the initial lesion and
                                                                  pleuritic fluid
11      M     59       ALL in remission 5/7/03:                6/13/03: Fever, dyspnea, cough;       6/24/03-      Mechanical ventilation for       X-ray shows bilateral, patchy        6/25/03: ANC        6/30/03:GMI
                                           Chemotherapy;          CT not available; chest x-ray         7/3/03       respiratory failure               infiltrates while in mechanical      >500; 7/4/03:       decreased >50%;
                                           5/19/03-6/22/03:       shows bilateral patchy                                                               ventilation; pneumothorax on         ANC >4000           7/30/03: Negative
                                           ANC <100               infiltrates; 6/13/03-7/29/03:                                                        7/2/03                                                   GMI
                                                                  Positive GMI (peak, 2.7; 25
                                                                  tests); Voriconazole 400 mg/d
                                                                  (started on 6/14/03)

                                                                                                                                                              Pulmonary IRIS featuresy

                       Underlying                                                                                                                                                        Temporal relation
                       disease and                                                                                                                                                       to neutrophil         Resolving
Patient Sex   Age, y   status            Therapy                Findings at diagnosis                Date of IRIS Clinical deterioration         Worsening radiology                     recovery              antigenemia

12      M     71       Recurrence AML    9/12/03: Allo-SCT;     9/11/03: Fever and dyspnea;          9/23-28/03    Mechanical ventilation for    Chest x-rays show progressive           9/22/03: ANC >500;    9/28/03:GMI
                                            9/8-21/03: ANC         9/12/03: CT shows nodule in                       respiratory failure            increase in radiologic                  9/23/03: ANC          decreased >50%;
                                            <100                   RML and lingula with halo                                                        abnormalities; 10/15/03: CT             >4000                 10/10/03: Negative
                                                                   sign; 9/11/03-10/9/03: Positive                                                  shows cavitation of previously                                GMI
                                                                   GMI (peak, 6.1; 24 tests);                                                       seen nodule, new nodules and
                                                                   Ambisome 5 mg/k/d (started                                                       infiltrates in both lungs, large
                                                                   on 9/12/03)                                                                      bilateral pleural fluid
13      M     18       Recurrent ALL     12/28/03:              1/1/04: Fever, cough, and            1/14-/26/04   Increased cough, hypoxia      1/14/04: CT shows new lesions,          1/14/04: ANC > 500;   1/9/04: GMI
                                            Chemotherapy;          hemoptysis; 1/5/04: CT shows                       requiring O2, pleuritic       pleural fluid, increased volume         1/19/04: ANC          decreased >50%;
                                            12/31/03-1/12/04:      bilateral nodular lesions                          chest pain requiring          of initial lesions                      >4000                 1/13/04: Negative
                                            ANC <100               surrounded by halo;1/1-12/04:                      morphine, crackles                                                                          GMI
                                                                   Positive GMI (peak, 2.1; 10
                                                                   tests); Ambisome 5 mg/k/d
                                                                   (started on 1/3/04)
14      M     68       Newly diagnosed   7/13/02:               8/2/02: Fever, dyspnea; 8/4/02: CT   8/12-17/02    Worsening dyspnea,            8/12/02: CT shows increased             8/8/02: ANC >500;     8/9/02: GMI
                         AML                Chemotherapy;          shows bilateral lower lobe                        hemoptysis, wheezing           volume of initial lesions; new          8/12/02: ANC          decreased >50%;
                                            7/21/02-8/6/02:        consolidations; 8/2-22/02:                                                       pleural fluid                           >4000                 8/23/02: Negative
                                            ANC <100               Positive GMI (peak, 5.2; 19                                                                                                                    GMI
                                                                   tests); Anidulafungin 200 mg/d
                                                                   and Ambisome 5 mg/k/d
                                                                   (started on 8/4/02)
15      W     54       Recurrent AML     4/6/01:                4/30/01: Fever, cough, dyspnea;      5/18-24/01    Worsening cough, hypoxia      5/18/01: CT shows new lesion            5/17/01: ANC >500;    5/15/01:GMI
                                            Chemotherapy;          CT shows consolidation in LUL;                    requiring O2, pleuritic        RUL, pleural fluid, increased           5/23/01: ANC          decreased >50%;
                                            4/15/01-5/15/01:       4/30/01-5/19/01: Positive GMI                     chest pain requiring           volume of initial infiltrate in         >4000                 5/20/01: Negative
                                            ANC <100               (peak, 4.1; 20 tests); Ambisome                   morphine, transfer to ICU      LUL; 6/5/01: CT shows further                                 GMI
                                                                   5 mg/kg/d (started on 8/4/01)                                                    increase of volume lesions in
                                                                                                                                                    both lungs
16      M     67       Recurrent AML     30/10/06:              12/5/06: Fever, dry cough; CT       12/13-22/06    Worsening cough, dyspnea,     12/13/06: CT shows increase of          12/11/06: ANC >500;   12/11/06: GMI
                                            Chemotherapy;          shows consolidation in left                       hypoxia requiring O2,          initial consolidation, new              12/17/06: ANC         decreased >50%;
                                            11/6-12/9/06:          suprahilar region with halo; 12/                  pleuritic chest pain           nodule in RLL, ground-glass             >4000                 12/13/06: Negative
                                            ANC <100               6-12/06: Positive GMI (peak,                      requiring morphine             opacities, bilateral pleural fluid                            GMI
                                                                   1.8; 7 tests); Caspofungin 70/50
                                                                   mg/d (started on 12/5/06)
17      M     60       Chronic-phase     10/6/04: Allo-SCT;     6/13/05: Fever, cough; CT shows     6/29/05-       Worsening dyspnea,            6/29/05: CT shows doubling              6/30/05: ANC >500;    6/21/05:GMI
                         CML                6/1-28/05: ANC         multiple nodules in the right       7/5/05        hemoptysis                     volume of initial lesions,              7/1/05: ANC           decreased >50%;
                                            <100                   lung with halo; 6/13-22/05:                                                      pleural fluid, multiple                 >4000                 6/23/05: Negative
                                                                                                                                                                                                                                       Aspergillosis and IRIS/Miceli et al.

                                                                   Positive GMI (peak, 1.4; 5                                                       mediastinal lymph nodes                                       GMI
                                                                   tests); Caspofungin 70/50 mg/d
                                                                   (started on 6/13/05)


                                                                                                                                                                                                           Pulmonary IRIS featuresy

                                   Underlying                                                                                                                                                                                            Temporal relation
                                   disease and                                                                                                                                                                                           to neutrophil                Resolving
Patient Sex            Age, y      status                  Therapy                      Findings at diagnosis                       Date of IRIS Clinical deterioration                      Worsening radiology                         recovery                     antigenemia

18         M           57           Newly diagnosed 12/12/05:                           1/11/06: Fever, productive cough, 1/20-25/06                  Worsening chest pain,                  1/20/06: CT shows increased                 1/21/06: ANC >500;           1/18/06: GMI
                                      AML              Chemotherapy;                       mild chest pain; CT shows                                    hypoxia requiring O2                    volume of initial nodule,                   1/27/06: ANC                 decreased >50%;
                                                       12/25/05-1/18/06:                   nodule in the RUL with halo;                                                                         progression of infiltrates                  >4000                        1/23/06: Negative
                                                                                                                                                                                                                                                                                                   July 1, 2007 / Volume 110 / Number 1

                                                       ANC <100                            1/11-22/06: Positive GMI (peak,                                                                                                                                               GMI
                                                                                           3.9; 12 tests); Caspofungin 70/
                                                                                           50 mg/d (started on 1/14/06)
19         M           57           Recurrent AML          8/7/06:                      8/25/06: Fever, dyspnea, cough;    9/5-14/06                  Hemoptysis, hypoxia                    9/8/06: CT shows worsening                  8/31/06: ANC >500;           9/3/06: GMI
                                                              Chemotherapy;                8/28/06: Bilateral lower lobe                                requiring O2 and BiPAP                  of initial lesions, new apical              9/6/06: ANC                  decreased >50%;
                                                              8/14-29/06: ANC              consolidations surrounded by                                                                         infiltrate, bilateral pleural fluid         >4000                        9/6/06: Negative
                                                              <100                         halo; 8/25/06-9/5/06: Positive                                                                                                                                                GMI
                                                                                           GMI (peak, 2.8; 12 tests);
                                                                                           Caspofungin 70/50 mg/d
                                                                                           (started on 8/28/06)

IRIS indicates immune reconstitution inflammatory syndrome; W, woman; ANC, absolute neutrophil count (cells/lL); CT, chest computed tomography scan; IV, intravenous; GMI, serum galactomannan index; ASCT, autologous stem cell transplantation; M, man; RML, right middle lobe;
LLL, left lower lobe; ICU, intensive care unit; AML, acute myeloid leukemia; NHL, non-Hodgkin lymphoma; Allo-SCT, allogenic stem cell transplantation; RUL, right upper lobe; ALL, acute lymphoid lympyhoma; LUL, left upper lobe; RLL, right lower lobe; BiPaP, bilevel positive air pres-
* Patients 12, 14, and 16 died during the first month of follow-up; in those 3 patients, autopsies failed to demonstrate invasive aspergillosis. At 1 month of follow-up, the remaining 16 patients improved without changes in antifungal therapy; at 3 months, all patients were alive without
clinical, radiologic, or microbiologic evidence of aspergillosis. The serum Aspergillus galactomannan index also was negative.
  Pulmonary IRIS was defined as new onset or worsening of clinical and radiologic pulmonary findings consistent with an infectious/inflammatory pulmonary condition temporally related to neutrophil recovery and a decrease !50% in serum GMI titers (2 consecutive tests within 4
days) in the absence of new extrapulmonary lesions of aspergillosis (eg, the aforementioned new skin lesions) and after excluding other causes, such as newly acquired infection, failure of treatment of a known infection, or medication side effects.
                                                                                                                            Aspergillosis and IRIS/Miceli et al.                  119

Definition of Immune Reconstitution Inflammatory Syndrome (IRIS): HIV Patients After HAART vs. Cancer Patients
Following Neutrophil Recovery

Criteria               IRIS in HIV patients                                                        Pulmonary IRIS in cancer patients with aspergillosis

  Clinical             Worsening symptoms of inflammation/infection                                New onset of or worsening clinical and radiological pulmonary findings consistent
                                                                                                     with an infectious/inflammatory pulmonary condition
                       Temporal relationship with starting antiretroviral treatment                Temporal relationship with neutrophil recovery
                       Symptoms not explained by newly acquired infection or disease               Absence of new extrapulmonary lesions of aspergillosis (eg, new skin lesions
                         or the usual course of a previously acquired disease                        above-described) and after exclusion of other causes, such as newly acquired
                                                                                                     infection, failure of treatment of a known infection, or medication side effects
  Laboratory           !1 Log10 decrease in plasma HIV load                                        !50% decrease in serum GMI titers without treatment modifications
  Clinical                                                                                         Subsequent resolution of aspergillosis without treatment modifications
  Laboratory           Increase in CD4 cell count of !25 cells/mm        3
                                                                                                   To be determined but likely to include: Immune function studies such as
                                                                                                      immunophenotype (CD4, CD8, others), cytokines, others
                       Biopsy demonstrating well-formed granulomatous inflammation                 Biopsy demonstrating well-formed granulomatous inflammation or unusually
                          or unusually exuberant inflammatory response                                exuberant inflammatory response

IRIS indicates immune reconstitution inflammatory syndrome; GMI, serum galactomannan index.

patients in whom IRIS was associated with successful                                          patients who have resolving antigenemia and no
immune reconstitution, decreasing HIV viral load, and                                         other evidence of progressive aspergillosis.
a trend toward increased survival.17 Additional experi-                                            Our study should be confirmed by others and
ence will be needed to confirm our findings, because                                          broadened to include other populations at risk.1,3 A
it is likely that some patients with invasive pulmonary                                       prospective validation of our definition also is needed.
aspergillosis and IRIS may not survive in face of over-                                            We conclude that pulmonary IRIS may develop
whelming respiratory deterioration.                                                           among patients with invasive aspergillosis and hema-
      Our findings imply that pulmonary deterioration                                         tologic cancers who are recovering from neutropenia.
among cancer patients with invasive pulmonary                                                 Serial galactomannan testing is critical to distinguish
aspergillosis who are recovering from neutropenia                                             this syndrome from progressive aspergillosis. This
does not necessarily indicate progressive aspergillo-                                         strategy is likely to improve patient outcomes and to
sis, particularly when such deterioration coincides                                           enhance the precision of trials that investigate treat-
with a robust decrease in aspergillus antigenemia.                                            ment strategies for aspergillosis.
Such patients should be continued on the same ther-
apy with consideration for a 3- to 7-day course of                                            REFERENCES
corticosteroids (eg, 2 mg/kg methylprednisone per                                             1.      Perfect JR, Cox GM, Lee JY, et al. The impact of culture iso-
day) for the occasional patient with impending respi-                                                 lation of Aspergillus species: a hospital-based survey of
                                                                                                      aspergillosis. Clin Infect Dis. 2001;33:1824–1833.
ratory failure (Table 1). Corticosteroids have been                                           2.      Robertson MD, Seaton A, Raeburn JA. Phagocytic cell
used successfully in HIV-positive patients who had                                                    responses to Aspergillus fumigatus. FEMS Microbiol Immu-
IRIS associated with various opportunistic infec-                                                     nol. 1989;1:305–306.
tions.17,18 In contrast, persistently elevated galacto-                                       3.      Segal BH, Walsh TJ. Current approaches to diagnosis and
mannan titers suggest progressive aspergillosis and                                                   treatment of invasive aspergillosis. Am J Respir Crit Care
                                                                                                      Med. 2006;173:707–717.
should prompt treatment modification. Hence, we                                               4.      Takuma T, Okada K, Uchida Y, Yamagata A, Sawae Y. Inva-
recommend serial serum galactomannan testing in                                                       sive pulmonary aspergillosis resulting in respiratory failure
patients with pulmonary deterioration. Work-up to                                                     during neutrophil recovery from postchemotherapy neu-
exclude other infections may be needed, although                                                      tropenia in three patients with acute leukaemia. J Intern
breakthrough infections are least likely during neu-                                                  Med. 2002;252:173–177.
                                                                                              5.      Todeschini G, Murari C, Bonesi R, et al. Invasive aspergillo-
trophil recovery. The current findings also imply that                                                sis in neutropenic patients: rapid neutrophil recovery is a
clinical trials of progressive aspergillosis should rely                                              risk factor for severe pulmonary complications. Eur J Clin
on serial galactomannan testing and should exclude                                                    Invest. 1999;29:453–457.
120        CANCER    July 1, 2007 / Volume 110 / Number 1

6.                                         ,
      Almyroudis NG, Kontoyiannis DP Sepkowitz KA, DePauw                    circulating galactomannan by a sandwich enzyme-linked
      BE, Walsh TJ, Segal BH. Issues related to the design and               immunosorbent assay for hematological patients at risk
      interpretation of clinical trials of salvage therapy for inva-         for invasive Aspergillosis. J Clin Microbiol. 1999;37:3223–
      sive mold infection. Clin Infect Dis. 2006;43:1449–1455.               3228.
7.    Caillot D, Couaillier JF, Bernard A, et al. Increasing volume    14.   Woods G, Miceli M, Grazziutti M, et al. Validation of serum
      and changing characteristics of invasive pulmonary aspergil-           aspergillus galactomannan index as a surrogate endpoint
      losis on sequential thoracic computed tomography scans in              for outcome of invasive aspergillosis: clinical and research
      patients with neutropenia. J Clin Oncol. 2001;19:253–259.              implications. Paper presented at: 48th Annual Meeting of
8.    Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive           the American Society of Hematology, December 11, 2006;
      aspergillosis with posaconazole in patients who are refrac-            Orlando, Fla. Abstract 2861.
      tory to or intolerant of conventional therapy: an externally     15.   Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic
      controlled trial. Clin Infect Dis. 2007;44:2–12.                       invasive fungal infections in immunocompromised
9.    Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, et al.             patients with cancer and hematopoietic stem cell trans-
      Immune reconstitution inflammatory syndrome: emer-                     plants: an international consensus. Clin Infect Dis. 2002;34:
      gence of a unique syndrome during highly active antiretro-             7–14.
      viral therapy. Medicine (Baltimore). 2002;81:213–227.            16.   Sambatakou H, Denning DW. Invasive pulmonary aspergil-
10.   Robertson J, Meier M, Wall J, Ying J, Fichtenbaum CJ.                  losis transformed into fatal mucous impaction by immune
      Immune reconstitution syndrome in HIV: validating a case               reconstitution in an AIDS patient. Eur J Clin Microbiol
      definition and identifying clinical predictors in persons              Infect Dis. 2005;24:628–633.
      initiating antiretroviral therapy. Clin Infect Dis. 2006;42:     17.   Shelburne SA, Visnegarwala F, Darcourt J, et al. Incidence
      1639–1646.                                                             and risk factors for immune reconstitution inflammatory
11.   Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole             syndrome during highly active antiretroviral therapy. AIDS.
      versus amphotericin B for primary therapy of invasive                  2005;19:399–406.
      aspergillosis. N Engl J Med. 2002;347:408–415.                   18.   Montaner JS, Lawson LM, Levitt N, Belzberg A, Schechter
12.   Wheat LJ. Rapid diagnosis of invasive aspergillosis by anti-           MT, Ruedy J. Corticosteroids prevent early deterioration in
      gen detection. Transpl Infect Dis. 2003;5:158–166.                     patients with moderately severe Pneumocystis carinii pneu-
13.   Maertens J, Verhaegen J, Demuynck H, et al. Autopsy-                   monia and the acquired immunodeficiency syndrome
      controlled prospective evaluation of serial screening for              (AIDS). Ann Intern Med. 1990;113:14–20.