- Research
- Open access
- Published:
Non-infectious respiratory complications after allogeneic bone marrow transplantation: single center experience in Egypt
The Egyptian Journal of Bronchology volume 18, Article number: 30 (2024)
Abstract
Background
Hematopoietic progenitor cells are infused intravenously, known as hematopoietic stem cell transplantation. The range of pulmonary problems after transplantation of hematopoietic stem cells varies significantly from infectious to non-infectious aetiologies.
Objectives
To study noninfectious respiratory complications in patients subjected to allogeneic bone marrow transplants.
Patients and methods
This retrospective study was carried out on 1000 patients with hematopoietic stem-cell transplantations. These patients were presented with respiratory symptoms suggestive of pulmonary complications following bone marrow transplant.
Result
The number of patients in this period was 1000 patients, and 247 of them had non-infectious pulmonary complications. Number and percent of bronchiolitis obliterans, diffuse alveolar hemorrhage, graft-versus-host disease (GVHD), pulmonary edema, Bronchiolitis obliterans with GVHD, Chemotherapy pneumonitis, Idiopathic pneumonia syndrome and Thoracic air leak syndrome to all number of cases were twenty-five (2.5%), sixteen (1.6%), eighty-one (8.1) sixty-four (25.9%), nineteen (1.9%), twenty-one (2.1%), thirteen (1.3%) and eight (0.8%) respectively, but number and percent of bronchiolitis obliterans, diffuse alveolar hemorrhage, GVHD, pulmonary edema, bronchiolitis obliterans with GVHD, chemotherapy-associated pneumonitis, Idiopathic pneumonia syndrome, and thoracic air leak syndrome to all complicated cases only were twenty-five (10.1%), sixteen (6.5%), eighty-one (32.8%), sixty-four (25.9 %), nineteen (7.7%), twenty-one (8.5 %), thirteen (5.3 %) and eight (3.2%) respectively.
Conclusions
Noninfectious respiratory complications included GVHD, pulmonary edema, bronchiolitis obliterans and diffuse alveolar hemorrhage bronchiolitis obliterans with GVHD, chemotherapy-associated pneumonitis, Idiopathic pneumonia syndrome, and thoracic air leak syndrome. Some of them occurred early, and some occurred late. The incidence of non-infectious respiratory complications is affected by increased patient age and female gender.
Background
Following chemotherapy and radiation treatment, an individual may undergo hematopoietic stem-cell transplantations (HSCT), which administer intravenous hematopoietic progenitor cells to restore marrow function [1]. Multiple myeloma, Hodgkin and non-Hodgkin lymphomas, acute and chronic leukemia, as well as non-malignant conditions such as aplastic anemia and congenital immuno-deficiency syndromes, all are treated with HSCT [2].
The patient (autologous), a sibling or unrelated individual (allogeneic), or an identical twin (syngeneic) may serve as the donor source [3]. Following HSCT, engraftment involves the restoration of the neutrophil and platelet counts, which normally occurs three weeks later [4]. With the prudent use of broad-spectrum antibiotic prophylaxis, the range of pulmonary problems after hematopoietic stem cells has shifted increasingly from infectious to non-infectious aetiologies in recent years [5, 6]. The frequency of infection complications following HSCTÂ has reduced because of improvements in the preventative regimen. The importance of non-infectious complications has increased because the frequency of non-infectious consequences has remained constant [7, 8].
The non-infectious respiratory complications following HSCT, including diffuse alveolar hemorrhage and idiopathic pneumonia syndrome, chronic progressive small airways disease, including bronchiolitis-obliterans syndrome, [8] and vascular problems such as pulmonary veno-occlusive diseases and cytolytic thrombosis [7].
Graft versus host disease is a common complication of allogeneic bone marrow transplants. It attacks the new bone marrow cells against the receiver's organs [9].
The purpose of this work is to determine non-infectious respiratory complications based on the onset of the disease into the peri engraftment period (0-30), early posttransplantation (31-100), late post-transplant (after 100 days) in patients subjected to allogeneic bone marrow transplant.
Patients and methods
The retrospective cohort study was conducted from 2009 to 2019 at Nasser Institute and Tanta University Chest Hospital. The inclusion criteria included patients above 18 years who underwent allogeneic bone marrow transplants.
Those individuals come with respiratory symptoms suggestive of pulmonary complications after a bone marrow transplant. The local ethics committee of our center has approved the research protocol number (33468). Patients were followed for 6 months at Nasser Institute. All the studied patients received prophylactic antibiotics, antifungal, and antiviral as a part of the protocol. 1000 patients were examined, and 247 of them had non-infectious complications. The exclusion criteria were patients with incomplete data.
The data related to HSCT were collected from paper-based medical records.
Data included: history taking, baseline investigations included: [complete-blood-count, aspiration of bone-marrow, biopsy from bone-marrow, tests for the functioning of the liver, such as (ALT and AST), renal function tests including (bilirubin, urea and creatinine), electrolytes including (Na, Ca, K and alkaline phosphatase), fasting and post prandial glucose level, blood Group, R.H. and HLA typing, virology including (HBV, HCV, HIV, Toxoplasma virus, cytomegalo virus), electro cardiograph, echocardiography, chest X ray: postero anterior view, abdominal and pelvic ultra sounography.], diagnosis, chest conditions, comorbidity (D.M., HTN, renal disease, hepatic disease, cardiac disease), a drug used and radiotherapy (dose, type)
Diagnosis: criteria of diagnosis of some common non-infectious pulmonary complications:
Pulmonary edema
Clinical: Standard clinical indicators among individuals with dyspnea include gaining weight, bilateral lung rales, and hypoxemia.
Radiological: Bilateral interstitial infiltration, mainly peri-hilar, either with or without pleural effusion, is among the anomalies seen on chest radiographs [3].
Diffuse alveolar hemorrhage (DAH)
Clinical: fast onset of hypoxemia, nonproductive coughing, fever, and dyspnea; hemoptysis is uncommon.
Radiological: Typically, the infiltrations are bilaterally and mostly central [10].
Graft versus host disease
Clinical: Dyspnea, nonproductive coughing, crepitations, and chest wheezing are all respiratory manifestations and warning indications.
Radiological: Focal or diffused infiltration has been identified on HRCT and chest imaging.
PFT
A decline in vital capacity and forced expiratory volume in the initial second, followed by a sharp decline in the forced expiratory volume in the initial second/vital capacity ratios, indicative of airway obstruction, are shown during pulmonary function testing [9].
Bronchiolitis obliterans
Clinical: increasing dyspnea with a cough that is dry and wheezing upon expiration.
Radiological: Radiology of the chest reveals hyperinflation. On an expiratory scan, C.T. scans may reveal trapped air and a mosaic pattern.
Pulmonary function tests (PFT) indicated air flow restriction. Normal lung volumes reduced, forced expiratory volume in the initial second, and reduced forced volume capacity are the norms for diffusing capacity. Clinical signs, anomalies in the HRCT, and abnormal PFT results are used to make the diagnosis of B.O. [11].
Chemotherapy-associated pneumonitis
Clinical: nonproductive cough and increasing dyspnea.
Radiological; bilateral interstitial infiltrates [12].
Idiopathic pneumonia syndrome (IPS) Clinical: dyspnea, hypoxemia, nonproductive coughing.
Radiological: non-lobar radiograph infiltrations [13].
Thoracic air leak
Clinical: acute chest pain and dyspnea
Radiological: On a C.T. scan, the air in the mediastinum, pleural space, and sub-cutaneous tissues are all clearly visible [3].
The most probable etiology of respiratory complication (original disease, therapy, transplant).
Statistical analysis
Statistical analysis was done by SPSS v26 (IBM Inc., Chicago, IL, USA). Quantitative variables were presented as mean and standard deviation (S.D.). Qualitative variables were presented as frequency and percentage (%).
Result
The number of patients in this period with non-infectious complications was 247(24.7%); the mean values of age in years were (28.92 ± 9.02) 156 were male, while 91 were female. Regarding smoking status, 215 nonsmokers, 30 were ex-smokers, and 2 were smokers. Regarding comorbidities, 236 had no comorbidities, 6 were asthmatic, 2 had D.M., and 3 had HTN. 19% were transplanted due to aplastic anemia, 2.4% were transplanted due to B thalassemia major, 2.4%were transplanted due to Fanconi anemia, 61.1 %were transplanted due to leukemia, 7.3% were transplanted due to lymphoma, 6.1 % were transplanted due to myelodysplastic syndrome, 0.8due to myelofibrosis and 0.8 due to Paroxysmal nocturnal hemoglobinuria Table 1.
There were 39.3% survived and 60.7% died. 78.1% didn't need mechanical ventilation and 21.9 % needed mechanical ventilation Table 2.
The number and percentage of bronchiolitis obliterans, diffuse alveolar hemorrhage, graft versus host disease (GVHD), pulmonary edema, and patients with both bronchiolitis obliterans and GVHD in relation to cases with non-infectious complications were 10.1%, 6.5%, 41.3%, 34.4%, and 7.7% respectively Table 3.
There was a significant increase in age in patients with GVHD, but there was a significant decrease in patients with pulmonary edema. There was an insignificant difference in sex in patients with different non-infectious respiratory complications. All cases of diffuse alveolar hemorrhage and pulmonary edema occurred early, while all cases of bronchiolitis obliterans occurred late, but 27.3% of GVHD occurred early, and 72.7% occurred late. Also, for cases with bronchiolitis obliterans and GVHD, 33% occurred early, 67% occurred late chemotherapy chemotherapy-associated pneumonitis, 80.95% occurred early, and 19.05% occurred late. In idiopathic pneumonia syndrome, 69.23% occurred early, and 30.77% occurred late; in thoracic air leak syndrome, 25.00% occurred early, and 75.00% occurred late. There was a significant increase in mortality in patients with GVHD, followed by patients with both bronchiolitis obliterans and GVHD. Bronchiolitis obliterans patients, then pulmonary edema patients, then patients with diffuse alveolar hemorrhage, then idiopathic pneumonia syndrome, then chemotherapy-associated pneumonitis, and the lowest mortality was in patients with thoracic air leak syndrome Table 4.
Discussion
In the present study, as regards the number of cases 247 were complicated with non-infectious respiratory complications.
In contrast, this incidence was much higher than Onizuka et al. [14], identifying 535 patients with non-infectious pulmonary complications among 13,573 individuals (3.9%), according to data from 2001 to 2009 from the Japan Transplant registry. At 100 days, a year, and three years following HSCT, this cohort's cumulative frequency of non-infectious pulmonary problems was 2.1%, 3.7%, and 4.1%, respectively. The higher incidence in our study may be as it is single center experience.
In the present study, the mean value of age was range (18 – 58) and the mean (was 28.92 ± 9.02) Onizuka et al. [14] found that high recipient age was significantly correlated with a raised risk of non-infectious pulmonary complications.
While Patriarca et al. [15] observed an insignificant difference according to age among individuals with and without late-onset non-infectious respiratory issues.
In the present study, the frequency of non-infectious respiratory complications was higher in females than in males.
Bergeron et al. [16] agreed with the present study and reported that female was significantly associated with non-infectious respiratory issues compared to males. In contrast, Patriarca et al. [15] observed that males represented most individuals with noninfectious respiratory complications.
In the current study, the incidence of nonsmokers was higher than smokers.
This result, agreed with Ho et al. [17], showed that smoking is not associated with the development of severe pulmonary complications.
In the present study, the indication of bone marrow transplant in a patient with non-infectious complications was 61.1% leukemia, 7.3% lymphoma, 19% aplastic anemia, 2.4% Fanconi anemia, 6.1% myelodysplastic syndrome, 0.8% paroxysmal nocturnal hemoglobinuria, 0.8% myelofibrosis and 2.4 % in B thalassemia major.
In agreement with this study, Ueda et al. [18] reported insignificant differences among individuals with and without noninfectious respiratory complications regarding the indication of stem cell transplantation.
In the current work, the number of people who survived was 97 (39.3 %), while the number of those who died was 150 (60.7%), mainly of those complicated with late-onset noninfectious pulmonary complications; this may be due to the presence of cGVHD.
In agreement with the present study, Bergeron et al. [16] stated that the occurrence of late-onset noninfectious pulmonary complications was associated with an increased hazard of death. In contrast to this result, Sakaida et al. [19] reported a non-significant difference in mortality among individuals with and without late-onset noninfectious respiratory complications. A smaller sample size is a suitable explanation for this difference.
In the present study, patients who didn't need mechanical ventilation were 193 (78.1%) while those need mechanical ventilation were 54 (21.9%)
Sadon et al. [20] considered that Higher morbidity and death rates and poor outcomes were predicted by mechanical ventilation.
In our study, all cases of pulmonary edema and diffuse alveolar hemorrhage occurred early, while all cases of bronchiolitis obliterans occurred late, but 77.9 % of GVHD occurred late, and 24.6% occurred early. The occurrence of bronchiolitis obliterans was late mainly because it was a complication of GVHD. This agreed with many studies that revealed that bronchiolitis obliterans syndrome is now recognized as the majority of late-onset noninfectious respiratory complications. Filipovich et al. [21], Jagasia et al. [22], Shulman et al. [23]. In agreement with this study, Patel et al. [24] showed that with a median time to start of 50 days after an allogeneic transplant of stem cells, diffuse alveolar hemorrhage was more inclined to emerge sooner in the posttransplantation course.
In the current research, participants with graft versus host diseases and bronchiolitis obliterans had a substantial age rise. In agreement with the present study, Yoshihara et al. [25] found that potential risk factors for developing bronchiolitis obliterans included older recipients and donor age.
In the present study, thoracic air leak syndrome occurred late and mainly in males (62.5%); the mean age was (36.6±13.61).
In agreement with this study, Sakai R. et al. [26] found late onset of air leak syndrome and male predominance. In contrast to this result, Moon, M.H. et al. [27] found more females with air leak syndrome than males.
Limitations
It was a single-center study, and the results may differ elsewhere. The retrospective nature of the study is insufficient to establish a causal relationship. This study was done on allogeneic patients, which may affect the results. There was little information on therapy management because most of these treatments are currently being studied and tested, so there's no official guide to treat these complications.
Conclusion
Noninfectious respiratory complications included GVHD, pulmonary edema, bronchiolitis obliterans and diffuse alveolar hemorrhage bronchiolitis obliterans with GVHD, chemotherapy-associated pneumonitis, Idiopathic pneumonia syndrome, and thoracic air leak syndrome. Some of them occurred early, and some occurred late. The incidence of non-infectious respiratory complications is affected by the increase in the patient's age and the increase in the female gender.
Availability of data and material
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Abbreviations
- GVHD:
-
Graft versus host disease
- HSCT:
-
Haematopoietic stem-cell transplantations
- ALT:
-
Alanine transaminase
- AST:
-
Aspartate aminotransferase
- R.H.:
-
Rhesus
- HLA:
-
Human leukocyte antigens
- HBV:
-
Hepatitis B virus
- HCV:
-
Hepatitis C virus
- HIV:
-
Human immunodeficiency virus
- DM:
-
diabetes mellitus
- HTN:
-
Hypertension
- DAH:
-
Diffuse alveolar hemorrhage
- CT:
-
Computed tomography
- PFT:
-
Pulmonary function tests
- IPS:
-
Idiopathic pneumonia syndrome
References
Sirithanakul K, Salloum A, Klein JL, Soubani AO (2005) Pulmonary complications following hematopoietic stem cell transplantation: diagnostic approaches. Am J Hematol 80:137–146
del Campo L, León NG, Palacios DC, Lagana C, Tagarro D (2014) Abdominal complications following hematopoietic stem cell transplantation. Radiographics 34:396–412
Peña E, Souza CA, Escuissato DL, Gomes MM, Allan D, Tay J et al (2014) Noninfectious pulmonary complications after hematopoietic stem cell transplantation: practical approach to imaging diagnosis. Radiographics 34:663–683
Levine DS, Navarro OM, Chaudry G, Doyle JJ, Blaser SI (2007) Imaging the complications of bone marrow transplantation in children. Radiographics 27:307–324
Astashchanka A, Ryan J, Lin E, Nokes B, Jamieson C, Kligerman S et al (2021) Pulmonary Complications in Hematopoietic Stem Cell Transplant Recipients-A Clinician Primer. J Clin Med 10(15):3227
Yanik G, Kitko C (2013) Management of noninfectious lung injury following hematopoietic cell transplantation. Curr Opin Oncol 25:187–194
ZazaDitYafawi J, Shehada E, Soubani A (2012) Pulmonary complications following hematopoietic stem cell transplantation. Hematopoietic Stem Cells: New Research New York. Nova Publishers, NY, pp 1–49
Chi AK, Soubani AO, White AC, Miller KB (2013) An update on pulmonary complications of hematopoietic stem cell transplantation. Chest 144:1913–1922
Yen KT, Lee AS, Krowka MJ, Burger CD (2004) Pulmonary complications in bone marrow transplantation: a practical approach to diagnosis and treatment. Clin Chest Med 25:189–201
Afessa B, Tefferi A, Litzow MR, Krowka MJ, Wylam ME, Peters SG (2002) Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 166:641–645
Borhani AA, Hosseinzadeh K, Almusa O, Furlan A, Nalesnik M (2009) Imaging of posttransplantation lymphoproliferative disorder after solid organ transplantation. Radiographics 29:981–1000 (discussion 1000-1002)
Dhamija E, Meena P, Ramalingam V, Sahoo R, Rastogi S, Thulkar S (2020) Chemotherapy-induced pulmonary complications in cancer: Significance of clinicoradiological correlation. Indian J Radiol Imaging 30:20–26
Khurshid I, Anderson L (2002) Non-infectious pulmonary complications after bone marrow transplantation. Postgrad Med J 78:257–262
Onizuka M, Fujii N, Nakasone H, Ogata M, Atsuta Y, Suzuki R et al (2022) Risk factors and prognosis of non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation. Int J Hematol 115:534–544
Patriarca F, Skert C, Sperotto A, Damiani D, Cerno M, Geromin A et al (2004) Incidence, outcome, and risk factors of late-onset noninfectious pulmonary complications after unrelated donor stem cell transplantation. Bone Marrow Transplant 33:751
Bergeron A, Chevret S, Peffault de Latour R, Chagnon K, de Margerie-Mellon C, Rivière F et al (2018) Noninfectious lung complications after allogeneic haematopoietic stem cell transplantation. Eur Respir J 51(5):1702617
Ho VT, Weller E, Lee SJ, Alyea EP, Antin JH, Soiffer RJ (2001) Prognostic factors for early severe pulmonary complications after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 7:223–229
Ueda K, Watadani T, Maeda E, Ota S, Kataoka K, Seo S et al (2010) Outcome and treatment of late-onset noninfectious pulmonary complications after allogeneic haematopoietic SCT. Bone Marrow Transplant 45:1719–1727
Sakaida E, Nakaseko C, Harima A, Yokota A, Cho R, Saito Y et al (2003) Late-onset noninfectious pulmonary complications after allogeneic stem cell transplantation are significantly associated with chronic graft-versus-host disease and with the graft-versus-leukemia effect. Blood 102:4236–4242
Sadon AAE-A, El-Hagrasy RS, Saraya MA (2018) Pulmonary complications within the first year after bone marrow transplantation. Egypt J Bronchol 12:233–239
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al (2005) National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11:945–956
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al (2015) National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 21:389–401.e381
Shulman HM, Cardona DM, Greenson JK, Hingorani S, Horn T, Huber E et al (2015) NIH Consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 Pathology Working Group Report. Biology of Blood and Marrow Transplantation 21:589–603
Patel SS, Ahn KW, Khanal M, Bupp C, Allbee-Johnson M, Majhail NS et al (2022) Noninfectious pulmonary toxicity after allogeneic hematopoietic cell transplantation. Transplant Cell Therapy 28:310–320
Yoshihara S, Yanik G, Cooke KR, Mineishi S (2007) Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 13:749–759
Sakai R, Kanamori H, Nakaseko C, Yoshiba F, Fujimaki K, Sakura T et al (2011) Air-leak syndrome following allo-SCT in adult patients: report from the Kanto Study Group for Cell Therapy in Japan. Bone Marrow Transplant 46:379–384
Moon MH, Sa YJ, Cho KD, Jo KH, Lee SH, Sim SB (2010) Thoracic air-leak syndromes in hematopoietic stem cell transplant recipients with graft-versus-host disease: a possible sign for poor response to treatment and poor prognosis. J Korean Med Sci 25:658–662
Acknowledgements
Not applicable.
Funding
None to be declared.
Author information
Authors and Affiliations
Contributions
Study concept and design: M. M., and M. S.; analysis and interpretation of data: S. G., and B. E.; drafting of the manuscript: M. M.; critical revision of the manuscript for important intellectual content: B. E., and S. G.; statistical analysis: M. M.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
The local ethics committee of our center has approved the research protocol number (33468).
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Motawea, M.M., Samra, M.A.E., Ganna, S.A. et al. Non-infectious respiratory complications after allogeneic bone marrow transplantation: single center experience in Egypt. Egypt J Bronchol 18, 30 (2024). https://doi.org/10.1186/s43168-024-00283-0
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s43168-024-00283-0