Clinical Infectious Diseases MAJOR ARTICLE
Human Metapneumovirus Infections Following Hematopoietic Cell Transplantation: Factors Associated With Disease Progression Sachiko Seo,1,2 Ted A. Gooley,3 Jane M. Kuypers,1,4 Zachary Stednick,1 Keith R. Jerome,1,4 Janet A. Englund,5,6 and Michael Boeckh1,3,7 1 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; 2Department of Hematology and Oncology, National Cancer Research Center East, Chiba, Japan; 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Departments of 4Laboratory Medicine, and 5Pediatrics, University of Washington, 6Pediatric Infectious Diseases Division, Seattle Children’s Hospital, and 7Department of Medicine, University of Washington, Seattle
Background. Human metapneumovirus (HMPV) is a newly identified pulmonary pathogen that can cause fatal lower respiratory tract disease (LRD) in hematopoietic cell transplantation (HCT) recipients. Little is known about progression rates from upper respiratory tract infection (URI) to LRD and risk factors associated with progression. Methods. A total of 118 HCT recipients receiving transplantation between 2004 and 2014 who had HMPV detected in nasopharyngeal, bronchoalveolar lavage, or lung biopsy samples by real-time reverse transcription polymerase chain reaction were retrospectively analyzed. Results. More than 90% of the cases were identified between December and May. Among the 118 HCT patients, 88 and 30 had URI alone and LRD, respectively. Among 30 patients with LRD, 17 patients progressed from URI to LRD after a median of 7 days (range, 2–63 days). The probability of progression to LRD within 40 days after URI was 16%. In Cox regression analysis, steroid use ≥1 mg/kg prior to URI diagnosis (hazard ratio [HR], 5.10; P = .004), low lymphocyte count (HR, 3.43; P = .011), and early onset of HMPV infection after HCT (before day 30 after HCT; HR, 3.54; P = .013) were associated with higher progression to LRD. The median viral load in nasal wash samples was 1.1 × 106 copies/mL (range, 3.3 × 102–1.7 × 109) with no correlation between the viral load and progression. Conclusions. Progression from URI to LRD occurred in up to 60% of HCT recipients with risk factors such as systemic corticosteroid use or low lymphocyte counts. Further studies are needed to define the role of viral load in the pathogenesis of progressive disease. Keywords. human metapneumovirus; hematopoietic cell transplantation; lower respiratory tract disease; progression.
Human metapneumovirus (HMPV) is a newly recognized respiratory pathogen first identified in 2001 [1] and is structurally similar to respiratory syncytial virus (RSV) [2]. Serological epidemiology shows a 90% exposure by adulthood [3]. HMPV infection occurs in approximately 5% of hematopoietic cell transplantation (HCT) recipients [4, 5], and can cause severe or sometimes fatal lower respiratory tract disease (LRD) [6– 9]. The mortality rate after HMPV LRD in patients with hematological malignancy or HCT recipients ranges from 10% to 40% [9–12]. To date, most studies in HCT recipients are very small and have focused on the LRD characteristics and outcome [7, 8, 10, 12]. Minimal data exist on the timing of, proportion of, and risk factors for progression from upper respiratory tract infection (URI) to LRD. These data are critical for the design of
Received 23 December 2015; accepted 23 April 2016; published online 3 May 2016. Correspondence: M. Boeckh, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109 ([email protected]). Clinical Infectious Diseases® 2016;63(2):178–85 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected]. DOI: 10.1093/cid/ciw284
178
•
CID 2016:63 (15 July)
•
Seo et al
clinical trials that aim to prevent progression from URI to LRD. The purpose of this study was to examine the seasonality of HMPV infections in HCT recipients and to identify patient, transplantation, and viral risk factors for progression to LRD. METHODS Study Design
This retrospective cohort study includes patients who underwent transplantation between March 2004 and April 2014 at the Fred Hutchinson Cancer Research Center (FHCRC) and had documented HMPV infection during pretransplant conditioning or after transplantation. Only an individual’s first episode of HMPV infection was analyzed. Patients’ demographic data and transplantation information were retrieved from the FHCRC database, and other data related to the clinical course of HMPV infections were collected by medical record reviews. The data about HMPV infection in the community were based on the University of Washington Molecular Virology Laboratory data, which include data from Seattle Children’s Hospital and from samples that were sent to the laboratory from regional providers (http://depts.washington.edu/rspvirus/respiratory.htm).
The study was approved by the FHCRC Institutional Review Board.
All statistical analyses were performed using SAS version 9.3 for Windows (SAS Institute, Cary, North Carolina).
Laboratory Testing
RESULTS
Nasopharyngeal samples were collected when HCT recipients had URI symptoms. We also collected a bronchoalveolar lavage (BAL) sample when patients had lower respiratory tract symptoms and a radiographic abnormality. Follow-up nasopharyngeal samples were obtained in a subset of patients. We initially applied direct fluorescent antibody testing and individual reverse transcription polymerase chain reaction (RT-PCR) assay to detect HMPV and started multiplex PCR testing in 2008 [13, 14]. Samples were considered positive if the PCR amplification plot crossed the threshold at 365
48 (41)
40 (46)
8 (27)
1.1 × 106 (3.3 × 102–1.7 × 109)
2.6 × 106 (3.3 × 102–1.7 × 109)
4.2 × 105 (5.4 × 102–1.3 × 108)
None
82 (69)
66 (75)
16 (53)
Any pathogen
36 (31)
22 (25)
14 (47)
≥70
76 (78)
57 (80)
19 (73)
1000 × 106/L
89 (84)
68 (87)
21 (75)
≤1000 × 106/L
17 (16)
10 (13)
7 (25)
>300 × 106/L
83 (78)
65 (83)
18 (64)
≤300 × 106/L
23 (22)
13 (17)
10 (36)
GVHD prophylaxis
.64
Others Days between HCT and infection
.027
Quantitative viral load at diagnosis, median (range) Copathogen
.58
%TLC pre HMPV LRD
1.00
White blood cell count at diagnosis
.15
Neutrophil count at diagnosis
.14
Lymphocyte count at diagnosis
•
CID 2016:63 (15 July)
.15 .038
%FEV1/FVC pre HMPV LRD
180
P Value
.06
•
Seo et al
Table 1
continued.
Characteristic
Total (N = 118)
URI Alone (n = 88)
LRD (n = 30)
>300 × 106/L
65 (61)
53 (68)
12 (43)
≤300 × 106/L
41 (39)
25 (32)
16 (57)
None
59 (50)
44 (50)
15 (52)
1000 × 106/L
1.00
≤1000 × 106/L
2.71
Lymphocyte count at diagnosis >300 × 106/L
1.00
≤300 × 106/L
3.43
Monocyte count at diagnosis >300 × 106/L
1.00
≤300 × 106/L
2.31
Steroid dose before diagnosis None
1.00
30
1
≤30
1.89
1
Lymphocyte count at diagnosis >300/µL
1
≤300/µL
2.60
1 2.60
Steroid dose before diagnosis
Human Metapneumovirus Infections Following Hematopoietic Cell Transplantation: Factors Associated With Disease Progression Sachiko Seo,1,2 Ted A. Gooley,3 Jane M. Kuypers,1,4 Zachary Stednick,1 Keith R. Jerome,1,4 Janet A. Englund,5,6 and Michael Boeckh1,3,7 1 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; 2Department of Hematology and Oncology, National Cancer Research Center East, Chiba, Japan; 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Departments of 4Laboratory Medicine, and 5Pediatrics, University of Washington, 6Pediatric Infectious Diseases Division, Seattle Children’s Hospital, and 7Department of Medicine, University of Washington, Seattle
Background. Human metapneumovirus (HMPV) is a newly identified pulmonary pathogen that can cause fatal lower respiratory tract disease (LRD) in hematopoietic cell transplantation (HCT) recipients. Little is known about progression rates from upper respiratory tract infection (URI) to LRD and risk factors associated with progression. Methods. A total of 118 HCT recipients receiving transplantation between 2004 and 2014 who had HMPV detected in nasopharyngeal, bronchoalveolar lavage, or lung biopsy samples by real-time reverse transcription polymerase chain reaction were retrospectively analyzed. Results. More than 90% of the cases were identified between December and May. Among the 118 HCT patients, 88 and 30 had URI alone and LRD, respectively. Among 30 patients with LRD, 17 patients progressed from URI to LRD after a median of 7 days (range, 2–63 days). The probability of progression to LRD within 40 days after URI was 16%. In Cox regression analysis, steroid use ≥1 mg/kg prior to URI diagnosis (hazard ratio [HR], 5.10; P = .004), low lymphocyte count (HR, 3.43; P = .011), and early onset of HMPV infection after HCT (before day 30 after HCT; HR, 3.54; P = .013) were associated with higher progression to LRD. The median viral load in nasal wash samples was 1.1 × 106 copies/mL (range, 3.3 × 102–1.7 × 109) with no correlation between the viral load and progression. Conclusions. Progression from URI to LRD occurred in up to 60% of HCT recipients with risk factors such as systemic corticosteroid use or low lymphocyte counts. Further studies are needed to define the role of viral load in the pathogenesis of progressive disease. Keywords. human metapneumovirus; hematopoietic cell transplantation; lower respiratory tract disease; progression.
Human metapneumovirus (HMPV) is a newly recognized respiratory pathogen first identified in 2001 [1] and is structurally similar to respiratory syncytial virus (RSV) [2]. Serological epidemiology shows a 90% exposure by adulthood [3]. HMPV infection occurs in approximately 5% of hematopoietic cell transplantation (HCT) recipients [4, 5], and can cause severe or sometimes fatal lower respiratory tract disease (LRD) [6– 9]. The mortality rate after HMPV LRD in patients with hematological malignancy or HCT recipients ranges from 10% to 40% [9–12]. To date, most studies in HCT recipients are very small and have focused on the LRD characteristics and outcome [7, 8, 10, 12]. Minimal data exist on the timing of, proportion of, and risk factors for progression from upper respiratory tract infection (URI) to LRD. These data are critical for the design of
Received 23 December 2015; accepted 23 April 2016; published online 3 May 2016. Correspondence: M. Boeckh, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109 ([email protected]). Clinical Infectious Diseases® 2016;63(2):178–85 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail [email protected]. DOI: 10.1093/cid/ciw284
178
•
CID 2016:63 (15 July)
•
Seo et al
clinical trials that aim to prevent progression from URI to LRD. The purpose of this study was to examine the seasonality of HMPV infections in HCT recipients and to identify patient, transplantation, and viral risk factors for progression to LRD. METHODS Study Design
This retrospective cohort study includes patients who underwent transplantation between March 2004 and April 2014 at the Fred Hutchinson Cancer Research Center (FHCRC) and had documented HMPV infection during pretransplant conditioning or after transplantation. Only an individual’s first episode of HMPV infection was analyzed. Patients’ demographic data and transplantation information were retrieved from the FHCRC database, and other data related to the clinical course of HMPV infections were collected by medical record reviews. The data about HMPV infection in the community were based on the University of Washington Molecular Virology Laboratory data, which include data from Seattle Children’s Hospital and from samples that were sent to the laboratory from regional providers (http://depts.washington.edu/rspvirus/respiratory.htm).
The study was approved by the FHCRC Institutional Review Board.
All statistical analyses were performed using SAS version 9.3 for Windows (SAS Institute, Cary, North Carolina).
Laboratory Testing
RESULTS
Nasopharyngeal samples were collected when HCT recipients had URI symptoms. We also collected a bronchoalveolar lavage (BAL) sample when patients had lower respiratory tract symptoms and a radiographic abnormality. Follow-up nasopharyngeal samples were obtained in a subset of patients. We initially applied direct fluorescent antibody testing and individual reverse transcription polymerase chain reaction (RT-PCR) assay to detect HMPV and started multiplex PCR testing in 2008 [13, 14]. Samples were considered positive if the PCR amplification plot crossed the threshold at 365
48 (41)
40 (46)
8 (27)
1.1 × 106 (3.3 × 102–1.7 × 109)
2.6 × 106 (3.3 × 102–1.7 × 109)
4.2 × 105 (5.4 × 102–1.3 × 108)
None
82 (69)
66 (75)
16 (53)
Any pathogen
36 (31)
22 (25)
14 (47)
≥70
76 (78)
57 (80)
19 (73)
1000 × 106/L
89 (84)
68 (87)
21 (75)
≤1000 × 106/L
17 (16)
10 (13)
7 (25)
>300 × 106/L
83 (78)
65 (83)
18 (64)
≤300 × 106/L
23 (22)
13 (17)
10 (36)
GVHD prophylaxis
.64
Others Days between HCT and infection
.027
Quantitative viral load at diagnosis, median (range) Copathogen
.58
%TLC pre HMPV LRD
1.00
White blood cell count at diagnosis
.15
Neutrophil count at diagnosis
.14
Lymphocyte count at diagnosis
•
CID 2016:63 (15 July)
.15 .038
%FEV1/FVC pre HMPV LRD
180
P Value
.06
•
Seo et al
Table 1
continued.
Characteristic
Total (N = 118)
URI Alone (n = 88)
LRD (n = 30)
>300 × 106/L
65 (61)
53 (68)
12 (43)
≤300 × 106/L
41 (39)
25 (32)
16 (57)
None
59 (50)
44 (50)
15 (52)
1000 × 106/L
1.00
≤1000 × 106/L
2.71
Lymphocyte count at diagnosis >300 × 106/L
1.00
≤300 × 106/L
3.43
Monocyte count at diagnosis >300 × 106/L
1.00
≤300 × 106/L
2.31
Steroid dose before diagnosis None
1.00
30
1
≤30
1.89
1
Lymphocyte count at diagnosis >300/µL
1
≤300/µL
2.60
1 2.60
Steroid dose before diagnosis
