Incidence and prognostic value of respiratory events in acute ... - Nature

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Incidence and prognostic value of respiratory events in acute leukemia D Chaoui1, O Legrand1, N Roche2, M Cornet3, A Lefebvre2, R Peffault de Latour1, L Sanhes1, G Huchon2, J-P Marie1 and A Rabbat2 1 Department of Hematology, Hoˆtel-Dieu, Paris, France; 2Department of Respiratory and Critical Care Medicine, Hoˆtel-Dieu, Paris, France; and 3Department of Microbiology, Hoˆtel-Dieu, Paris, France

Acute respiratory failure and infectious pneumonia are the major causes of death during induction chemotherapy of acute leukemia. However, the causes, incidence and prognostic value of all respiratory events (REs) occurring in this context have never been assessed prospectively. We recruited 65 consecutive patients with newly diagnosed acute leukemia into a 1-year prospective study (December 2000–November 2001) to evaluate the incidence and prognostic value of these events. REs were frequent: 38 were recorded in 30 patients. There was a significant relationship between REs and pre-existing respiratory disease and/or smoking. REs were caused by infection in 34% of cases, by an established cause other than infection in 42% and had an undetermined cause in 24%. Poor early outcome (death within 45 days of starting induction chemotherapy) in patients experiencing an RE was independently associated with a 425/min respiratory rate (P ¼ 0.003) and the nonachievement of complete remission (CR) (Po0.0001). Predictors of overall survival in the entire patient population were the absence of CR (Po0.0001), REs (P ¼ 0.02) and a X2 performance status (P ¼ 0.03). In conclusion, REs are frequent during induction chemotherapy of acute leukemia and represent an independent prognostic factor of poor outcome, regardless of their cause. Leukemia (2004) 18, 670–675. doi:10.1038/sj.leu.2403270 Published online 5 February 2004 Keywords: acute leukemia; neutropenia; pulmonary complications; prognosis

Introduction The prognosis of acute leukemia remains poor despite improvements in supportive therapy. Treatment fails in over half of patients. Resistance to treatment occurs in 25–35% of cases and the death rate during aplasia is 15–25%. Moreover, the complications of intensive chemotherapy and, in particular, infections during chemotherapy-induced neutropenia compromise the benefits of curative treatment.1,2 Patients with acute leukemia often experience severe respiratory complications such as acute respiratory failure and infectious pneumonia.3–4 High mortality rates (80–90%) have been reported in patients requiring mechanical ventilation.5 Published studies dealing with pulmonary complications in acute leukemia are retrospective studies and have focused only on pulmonary infiltrates of infectious origin.4–6 Since any respiratory event (RE), even when initially minor, may precede severe respiratory complications, we hypothesized that the occurrence of any RE may be of prognostic value. Thus, the aim of this prospective study was to determine the incidence, cause and prognostic value of all REs occurring during induction chemotherapy in patients with acute leukemia. Correspondence: Dr A Rabbat, Department of Respiratory and Critical Care, Hoˆpital Hoˆtel Dieu, 1 place du Parvis Notre Dame, Paris 75004, France; Fax: þ 33 1 42348199; E-mail: antoine.rabbat@ htd.ap-hop-paris.fr Received 12 June 2003; accepted 18 November 2003; Published online 5 February 2004

Patients and methods

Patients This was a prospective study of all consecutive adult patients with acute leukemia diagnosed between December 1, 2000 and November 31, 2001 in the Hematology Department of a university teaching hospital. The diagnosis of acute leukemia was based on the French–American–British (FAB) criteria. Immunophenotyping was performed using flow cytometry.

Induction chemotherapy and first-line antimicrobial treatments Treatment was as follows: anthracyclines and cytosine arabinoside with or without etoposide for acute myeloblastic leukemia (AML), anthracyclines with or without cytosine arabinoside and all-trans-retinoid acid for acute promyelocytic leukemia, and prednisone, vincristine, cyclophosphamide and anthracyclines for acute lymphoblastic leukemia (ALL). Neutropenic patients with fever received broad-spectrum antibiotic regimens containing a b-lactam and an aminoglycoside. If fever did not resolve within 3–5 days, antifungal treatment (amphotericin B) was initiated. Granulocyte colony-stimulating factor was administrated to patients with ALL from day 15 after the onset of induction chemotherapy until neutrophil recovery. Prophylactic cotrimoxazole was administrated from the onset of chemotherapy until the end of treatment. All neutropenic patients received decontaminated feeding and were isolated in rooms ventilated with HEPA filtration, in which visitors wear nasal masks and gloves.

Definition and diagnosis of REs An RE was defined as any episode of new respiratory symptom or sign such as dyspnea, cough, sputum, chest pain, rales, hemoptysis, pulmonary infiltrate on chest X-ray or oxygenation impairment. Chest X-ray was performed in all patients with respiratory symptoms or fever. Each RE was confirmed and monitored by a hematologist and a lung specialist. All patients underwent at least three sets of blood culture tests, cytobacteriological analysis of urine, a serum test for Aspergillus antigen (Platellias Bio-Rad; Marne la Coquette, France). If these investigations failed to identify the cause of the RE or if the chest X-ray was abnormal, a computed tomography (CT) scan of the lungs was performed. Then a spiral CT scan was performed when no pulmonary infiltrate was present or when pulmonary embolism was clinically suspected. Finally, a guided bronchoalveolar lavage (BAL) was performed in pneumonia cases (as defined by the presence of any infiltrate) after obtaining the consent of the patient and of the hematologist in charge. The aspect of the BAL fluid (BALF) was recorded. BALF smears were

Respiratory events in acute leukemia D Chaoui et al

671 Table 1

Criteria for diagnosing the etiology of respiratory diseases Criteria

Infectious diseases Bacterial pneumonia

Pathogen concentration 4103 colony-forming units/ml on telescopic-plugged catheter or 4104 colonyforming units/ml in BALa, or positive blood culture with a pulmonary infiltrate and no other focus of infection.7,8

Invasive pulmonary aspergillosis

Proven, probable or possible according to the EORTC/MSGb consensus criteria9

Candida pneumonia

Proven: Histological criteria of invasive pneumonia present, isolation of Candida Probable: Pulmonary infiltrate with isolation of Candida but no other pathogen

Noninfectious diseases Cardiac dysfunction with pulmonary edema

Left ventricular function o60% and/or resolution or improvement of RE with diuretics

Alveolar hemorrhage

Bloody BAL with 420% of siderophages

Pulmonary embolism

Positive spiral CT scan or high probability on V/Q lung scan

Pneumothorax

Pleural air leak on radiological or HRCTc examination

Leukostasis

WBC 4100 109/l; pulmonary symptoms (dyspnea, diffuse pulmonary rates and diffuse interstitial infiltrates on chest X-ray); 475% of blast cells on BAL; no other identified cause

Undetermined cause

No microorganism foundd; no specific diagnosis of noninfectious disease

a

BAL: bronchoalveolar lavage. European Organization for the Research and Treatment of Cancer/Mycosis Study Group. HRCT: high-resolution computed tomography. d REs cured by antibiotics but with no microbiological documentation were included in undetermined causes. b c

stained for a differential cell count and to identify usual and opportunistic pathogens (mycobacteria, viruses, fungi, parasites). BALF aliquots were cultured to identify pathogens. When Legionella pneumophila was suspected, BAL was cultured on specific ground and urine was tested for the antigen. Microbiological sputum examination was performed when sputum was available. A multidisciplinary team (a hematologist, a pulmonologist, a specialist of infectious diseases and a radiologist) reviewed all patients each week, recording RE occurrence and establishing RE cause. REs were classified into three categories according to the criteria given in Table 1: (i) infectious origin; (ii) noninfectious origin; and (iii) undetermined origin.

Prospective data collection At the time of acute leukemia diagnosis, recorded items were any pre-existing respiratory disease (asthma, chronic obstructive pulmonary disease, tuberculosis), cigarette smoking expressed in pack-years, pre-existing cardiac disease and left ventricular function (as assessed by isotopic ventriculography), any steroid medication, and all established hematological prognostic factors, that is age 4/p60 years, WHO performance status (PS) X/o2, morphologic subtype, cytogenetic abnormalities,10,11 secondary/de novo acute leukemia, WBC 4/ p20.109/l, P-glycoprotein activity and CD34 expression. Clinical, biological and radiological data relating to the RE were evaluated, as well as the response to antibacterial and antifungal treatment. Acute respiratory failure was defined as the need for mechanical ventilation (invasive or noninvasive) or a PaO2/FIO2 o200 mmHg. The prognostic value of REs was assessed on the basis of overall survival and survival rate at day 45 of starting induction chemotherapy. This time point was chosen since it allows to

know whether patients have achieved complete hematological remission (bone marrow total blasts o5%, normal blood cell count), and thus if death is related to the RE or to disease progression.

Statistical analysis Risk factors for RE and death within 45 days (for patients with RE) of initiating induction therapy were studied by univariate analysis using Student’s t-test for continuous variables, the w2test for categorical variables and Fisher’s exact test for small expected frequencies. Significant differences (Po0.05) observed on univariate analysis were evaluated by logistic regression (multivariate analysis). Prognostic factors were assessed using the log-rank test. Significant prognostic factors (Po0.05) found in univariate analysis were evaluated by multivariate analysis using Cox’s proportional-hazards model. We used the Statview software (version 5.0) for statistical analysis (SAS Institute Inc., CA, USA).

Results

Patient characteristics and risk factors for REs During the 1-year study period, acute leukemia was diagnosed in 67 patients. Two patients were not included because of progressive breast cancer in one case and of HIV infection in the other. Sex ratio was 36/29 (men/women). Median age was 55 years (range, 17–85 years). The number of patients according to leukemia FAB classification was: 39 AML (60%), eight ALL (12%), 11 patients (17%) with acute leukemia secondary to myelodysplastic syndrome and seven patients (11%) with acute leukemia secondary to myeloproliferative syndrome. Median Leukemia


672 Table 2

Characteristics of patients With a respiratory event 30 57 14 18

De novo acute leukemia: AML+ALL, n (%) Secondary acute leukemia: MDS+MPS, n (%) AML 3, n (%)

16 (24%) 11 (17%) 3 (5%)

26 (40%) 7 (11%) 2 (5%)

NSa NSa

Glucocorticoid-containing regimen, n (%) Palliative treatment, n (%)

8 (12%) 4 (6%)

6 (9%) 3 (5%)

NSa NSa

WBC 420 109/l, n (%) Lactic dehydrogenase 41000 UI/l, n (%)

15 (23%) 18 (28%)

18 (28%) 18 (28%)

NSa NSa

8/12/7

6/17/6

NSa

19 (29%)

28 (43%)

NSa

6 (26%)

2 (9%)

NSa

Pre-existing heart disease, n (%) Left ventricular function impairment o60%, n (%)

16 (25%) 7 (11%)

13 (20%) 7 (11%)

NSa NSa

Pre-existing respiratory disease and/or smoking 420 packs per year, n (%)

16 (25%)

6 (9%)

0.002a

CD 34+, n (%) P-gp activity +, n (%)

35 52 22 10

(54%) (17–85) (34%) (15%)

P-vaue

Patients, n (%) Age in years, median and range Sex male, n (%) Performance status X2, n (%)

Cytogenetic prognosis, n: favourable/intermediate/unfavorable

(46%) (20–78) (21%) (28%)

Without a respiratory event

NSb NSa NSa

a 2

w test. Student’s t-test. MDS: myelodysplastic syndrome; MPS: myeloproliferative syndrome; RE: respiratory events; NS: nonsignificant. Number of patients for whom results are available: cytogenetics, n ¼ 56; CD 34+, n ¼ 47; P-gp activity, n ¼ 23; left ventricular function, n ¼ 59 (not available for four patients in RE group). b

follow-up was 574 days (range, 3–751 days). In all, 30 patients (46%) experienced at least one RE (six patients with two REs, one patient with three REs) during induction chemotherapy. Patient characteristics according to the presence or absence of RE are given in Table 2. Pre-existing respiratory disease and/or smoking was the only factor significantly related to RE occurrence (16/30 vs 6/35, P ¼ 0.002; odds ratio: 5.5; 95% confidence interval (CI): 1.8–17.2). Only one of the 12 smokers had chronic obstructive pulmonary disease. Other respiratory disorders included asthma (n ¼ 2), tuberculosis (n ¼ 1) and chronic restrictive respiratory failure (n ¼ 1).

Etiology of REs The cause of the 38 REs was infectious in 34% of cases, an established cause other than infection in 42% and an undetermined cause in 24%, as detailed in Table 3. Among the nine patients with undetermined etiology, eight (21%) were cured by antibiotics and could be considered as probable bacterial pneumonia, increasing the proportion of infectious causes of REs to 55%. Infection was due to Aspergillus in seven cases (ie an incidence of 10 or 6% if considering only the five proven and probable cases). Of the 38 REs, 14 were recorded at diagnosis of acute leukemia and 24 occurred after starting induction chemotherapy. All but two REs of undetermined etiology (ie 7/9) were present at diagnosis. REs of noninfectious origin occurred within 10 days in all cases but one (15/16). REs of fungal origin occurred after a median of 17 days (range, 4–30 days). Five of the seven cases of pulmonary aspergillosis occurred after more than 10 days (Figure 1). The incidence of pre-existing respiratory disease or smoking was similar in the infectious and nonLeukemia

infectious groups. There was no relationship between these two groups and left ventricular systolic function impairment, even for REs due to cardiac disease.

Factors predicting poor early outcome of patients with REs Death within 45 days of starting induction chemotherapy occurred in 18 patients (27.7%). Of the 30 patients with REs, 16 were dead at day 45 (54%). Of these 30 patients, 10 achieved complete remission (CR), 10 did not and 10 died before hematopoietic recovery and evaluation of response to chemotherapy. All of the 10 patients with REs who achieved CR were alive at day 45, while six of the 10 patients with REs who did not achieve CR died before day 45, all these deaths being related to leukemia progression. Death was clearly related to the RE in the 10 patients who died before hematopoietic recovery and evaluation of response to chemotherapy: two patients with pulmonary aspergillosis, one Candida pneumoniae, three patients with pulmonary bacterial infection and four patients with an RE of noninfectious origin. In the group of patients without RE (n ¼ 35), 12 did not achieve a CR including two patients who died of leukemia progression and 23 achieved CR and were alive at day 45 (Figure 2). In patients with an RE, factors that were significantly related to death by day 45 in univariate analysis were: more than a single pulmonary infiltrate (P ¼ 0.01), high respiratory rate (425/min) (Po0.0001), age 460 years (P ¼ 0.003), PS X2 (P ¼ 0.0005) and absence of CR (Po0.0001). In multivariate analysis, high respiratory rate (425/min) (P ¼ 0.0025) and absence of CR (Po0.0001) were the only independent determinants of a poor


673 Table 3 Cause of respiratory events occurring during induction chemotherapy N (%), total ¼ 38

Cause Infectious RE Proven

65 patients

13 (34%) 5 2 7 (18%) 3 (8%)

Bacteriaa Fungi (Aspergillus fumigatus)

Probable

Fungib (Aspergillus)

Possible

Fungi (two Aspergillus, one Candidac)

35 no RE

Acute respiratory failure 20/30 patients (66%)

3 (8%)

Noninfectious RE Cardiac diseased ATRA syndrome Pulmonary embolism Leukostasis Alveolar hemorrhage+leukostasis Pneumothorax Undetermined cause

30 RE (46%)

16 (42%) 8 3 1 1 1 2

Intensive care 12/20 patients

Remain in hematology 8/20 patients Return to hematology 5/12 patients

9 (24%) Cured by antibiotics

8 (21%)

a

Bacterial origin: one Escherichia coli; one Pseudomomonas aeruginosa+Enterococcus; one Pseudomomonas aeruginosa+Candida; one Mycoplasma pneumoniae; one Stenotrophomonas maltophilia. b Positive Aspergillus antigen serum test and compatible radiological characteristics. c Candida but no other infectious agent present in blood culture and pulmonary infiltrate. d Cardiac disease: six pulmonary edema; one myocardial infarction; one pericardial effusion.

9 8

Death in intensive care 7/12 patients

Death in hematology Death from disease progression in hematology department department 9/13 patients 2 patients

Figure 2 Outcome of patients with RE (end point: death within 45 days of the start of induction chemotherapy).

absence of CR (Po0.0001), cytogenetic abnormalities (P ¼ 0.0001) and RE (P ¼ 0.007). In multivariate analysis, RE (P ¼ 0.02; RR: 3.66; 95% CI: 1.29–10), absence of CR (Po0.0001; RR: 15; 95% CI: 4–56) and PS X2 (P ¼ 0.03; RR: 2.5; 95% CI: 1–3) were independent determinants of survival (Figure 3a–c).

number of REs

7 6

Discussion

5 4

fungal infections bacterial infections non infectious etiologies

3 2 1 0 RE at diagnosis

RE before day 10

RE after day 10

interval between starting of induction chemotherapy and RE

Figure 1 Time and etiology of RE with respect to the start of induction chemotherapy.

early outcome. Acute respiratory failure occurred in 66% of patients with an RE (20/30); 12 patients were admitted to the intensive care unit and seven died. Need for intensive care and cause of the RE were not related to a poor outcome.

Prognostic factors for overall survival Univariate analysis indicated that the following factors were correlated with overall survival: age 460 years (P ¼ 0.008), secondary acute leukemia (P ¼ 0.002), PS X2 (Po0.0001),

This prospective study found a high rate of REs in patients with newly diagnosed acute leukemia. REs occurred in 46% of the 65 patients, especially in smokers or patients with previous respiratory disease. REs were due to infection in 34% of cases and to another cause in 42%. Irrespective of their cause, REs were of a major prognostic significance. The 24% rate of REs with undetermined etiologies agrees with a recent study of immunocompromised patients.12 However, infectious etiologies and especially proven infections were less frequent in our patients than in that study (34 vs 58%).12 This discrepancy may be related to the markedly heterogeneous immunocompromising conditions in that study (in which only 27% of patients were neutropenic) and to the lower proportion of our patients who underwent FOB (37 vs 67% in Rano’s study).12 Our low rate of FOB can be explained by the low bacteriological diagnostic yield of FOB in neutropenic AL patients undergoing induction chemotherapy and receiving early broad-spectrum antibiotics,13 and the potentially lifethreatening complications of FOB in patients with severe thrombocytopenia, neutropenia and hypoxemia.14 Comparable rates of FOB were reported by Wilhelm et al6 (25%) and Ewing et al5 (43%) in neutropenic patients with acute leukemia. Among infectious etiologies, we found a 6% incidence of proven and probable pulmonary aspergillosis, which agrees with the recently published rates in AML and ALL (8 and 6.3%, respectively).15 Leukemia


674

a 1

No RE

0.8

P = 0.02

0.6 0.4 0.2

RE

0 0

100

200

300

400 days

500

600

700

800

b 1 0.8 0.6

CR

P < 0.0001

0.4

No CR 0.2 0 0

100

200

300

400 days

500

600

700

800

c 1

PS : 0. 1

0.8 0.6

P = 0.03

0.4

PS : 2. 3. 4 0.2 0 0

100

200

300

400 days

500

600

700

800

Figure 3 Probability of overall survival according to whether patients: (a) experienced an RE or not; (b) achieved CR or not; (c) had a PS X2 or o2.

Half of the REs of noninfectious origin in our study were related to pulmonary edema. All occurred during the first week after the onset of induction treatment, suggesting that chemotherapy and hydration were involved. They were not predicted by pretreatment isotopic measurement of left ventricular ejection fraction, but this investigation does not allow to rule-out diastolic myocardial dysfunction. In this context, the combination of high volumes of hydration, drugs such as anthracyclines and cytosine arabinoside and anemia could impair cardiopulmonary function. Alternatively, we cannot rule out transient noncardiogenic pulmonary edema in some patients, because no measurement of pulmonary capillary wedge pressure or extravascular lung water was performed. The usual hematological factors predicting outcome for AL were not different in patients with or without REs. Conversely, REs were significantly more frequent in smokers (420 packLeukemia

year) or patients with pre-existing lung disease. There may be several explanations for the increased rate of REs in smokers: (i) cigarette smoke might impair the clearance and detoxification of bacteria, resulting in a higher prevalence of bacterial colonization of proximal or distal airways;16,17 (ii) smoking is associated with immunologic disturbances;18,19 (iii) in healthy long-term smokers, myocardial blood flow is impaired and the degree of impairment correlates with the number of years the patient has smoked;20,21 and (iv) in animal models, cigarette smokes impairs cardiopulmonary function and increases capillary permeability. This could explain the hydration-related pulmonary edema occurring at the onset of chemotherapy.22,23 Unlike Rossini et al,4 we did not find that total blood count, blast count and age were associated with more frequent pneumonia. The presence of an RE during induction chemotherapy was a significant prognostic factor, independent of usual hematological factors. If an RE occurred, hematological factors (no CR) and respiratory rate 425/min were predictors of death by day 45. Two-thirds of the patients with an RE developed acute respiratory failure, suggesting that each RE should be closely monitored by a hematologist and a lung specialist. Admission to the intensive care unit for acute respiratory failure was not significantly associated with a poor outcome, which could be explained by (i) the selection criteria used to decide whether patients should be admitted to the unit (age, disease response to treatment, cytogenetic abnormalities and secondary acute leukemia) and/or (ii) the use of noninvasive mechanical ventilation as first ventilatory support, which improves the prognosis of ICU-admitted patients.24 Outcome did not depend on the cause of the RE (infectious or noninfectious) nor on the type of infection, despite previous demonstration of a poorer prognosis in patients with neutropenia-related fungal infections.6 Our low mortality rate may be due to the weekly screening for aspergillosis antigenemia and to earlier introduction of antifungal treatment (within 3–5 days) than in most institutions (5–7 days) when fever did not resolve with broad-spectrum antibiotics. In addition, two of our seven patients with fungal infections had localized pulmonary aspergillosis and were cured by surgery. Improvement of survival in acute leukemia needs achievement of CR. In fact, remission also appears to be crucial for a favorable outcome of the RE since it implies resolution of neutropenia. Improving survival also requires a better initial management of patients with an RE. This could be achieved by identifying patients at a higher risk of RE and using antimicrobial prophylaxis in smokers and patients with pre-existing pulmonary disease,25,26 earlier systemic antifungal therapy in patients with fungal infection, monitoring of hydration to avoid pulmonary edema and earlier diagnosis of pneumonia by CT scanning in neutropenic patients with unexplained fever for 448 h.27 In conclusion, clinically defined REs are frequent and occur early in the course of acute leukemia. Half are of infectious origin and all are of a major prognostic significance. This stresses the importance of early diagnosis and appropriate management. These results should be confirmed in a multicenter study in which at-risk patients are closely monitored for RE.

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