Bacterial Causing Pneumonia Post Hematopoietic Stem Cell Transplant: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Said Chaaban
,
Andrea Zimmer
,
Vijaya Raj Bhatt
,
Cynthia Schmidt
,
Ruxana T. Sadikot

Allogeneic stem cell transplantation is a lifesaving treatment for many malignancies. Post-transplant patients may suffer from graft versus host disease in the acute and/or the chronic form(s). Post-transplantation immune deficiency due to a variety of factors is a major cause of morbidity and mortality. Furthermore, immunosuppression can lead to alterations in host factors that predisposes these patients to infections. Although patients who receive stem cell transplant are at an increased risk of opportunistic pathogens, which include fungi and viruses, bacterial infections remain the most common cause of morbidity.

  • bacterial pneumonia
  • chronic graft versus host disease
  • allogeneic hematopoietic stem cell transplant

1. Introduction

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a lifesaving treatment for a multitude of benign and malignant diseases [1]. Annually, more than 50,000 alloHSCTs are performed worldwide [1][2]. Pulmonary complications remain a major contributor to morbidity and mortality following alloHSCT. Etiologies include non-infectious diseases, as well as lung infections caused by bacteria, fungi, and viruses [1].
Despite the utilization of antimicrobial prophylaxis and healthcare infection prevention measures, bacterial infections continue to cause significant morbidity and mortality in alloHSCT recipients [1][3]. Recent data report that up to 20–30% of alloHSCT recipients develop at least one episode of pneumonia, with bacteria being the predominant causative pathogen [3][4][5]. Increased susceptibility to bacterial organisms occurs due to alterations in the immune system, disruption of the microbial flora, lung architectural derangements, and malnutrition [3]. In addition, the frequent and prolonged exposures to healthcare systems increase the risk of acquiring nosocomial pathogens, including resistant bacteria [3].
The immunocompromised status following alloHSCT is multifactorial and affects multiple pathways of immune function. High-intensity cytotoxic conditioning chemotherapy is generally administered in the days prior to the infusion of allogeneic donor stem cells. This preparatory regimen functions both to eradicate any residual malignancy and to prevent native lymphocytes from attacking donor cells to optimize chances for successful engraftment. The preparative cytotoxic chemotherapy regimen targets rapidly dividing cells and, therefore, destroys hematopoietic cells and causes damage to mucosal barriers [6]. This disruption of oral, respiratory, and gut mucosa allow organisms to invade or relocate into underlying tissues. Recipients of alloHSCT are generally neutropenic for more than 10–14 days until engraftment of donor neutrophils, which places them at high risk for infections caused by bacteria and other pathogens. Furthermore, the recovery of lymphocyte cells and function can take months to years depending on cell source and iatrogenic immunosuppression post alloHSCT, causing prolonged deficiencies in cellular and humoral immunity [7]. Graft-versus-host-disease (GVHD) is a multisystem alloreactive inflammatory process by which donor lymphocytes recognize recipient tissue as “non-self” and can lead to significant multi-organ dysfunction. GVHD is a leading cause of morbidity and mortality in alloHSCT recipients and generally requires immunosuppression both prophylactically in the early months post alloHSCT, as well as for treatment of acute GVHD flares [8]. The depth and duration of this immunosuppression directly influences risk for opportunistic infections [9]. Risk for infection and GVHD post alloHSCT varies according to conditioning regimens, donor type (related versus unrelated), recipient traits (gender, age, and CMV serostatus), HLA match (matched, haploidentical, and mismatch), and cell source (peripheral blood, bone marrow, and umbilical cord), among other factors [10][11].

2. Chronic GVHD

Chronic graft versus host disease (cGVHD) is defined based on standard criteria defined by the National Institute of Health and is divided into a limited and extensive form [12]. The cGVHD population usually has dysfunctional cellular and humoral immunity, which is compounded by immunosuppressive agents used for its treatment [12][13]. The incidence of pneumonia declines by 100 days post alloHSCT with the exception of patients with cGVHD [1]. Nearly 28% of patients with cGVHD have three or more infections by 6 months post transplant [14]. Chronic GVHD causes inflammation, tissue injury, lymphoid organ dysfunction (including spleen, and thymus), dysregulated T and B cell responses, and abnormal tissue repair, often leading to fibrosis [14][15]. These complex processes result in cGVHD manifestations such as bronchiolitis or sclerodema and induce prolonged cellular and humoral immune deficits. Encapsulated bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae, have been dominantly seen in this population [1][12][16][17][18]. Pneumonia in the chronic GVHD patient carries a fivefold risk for mortality [12].

3. Pathogenesis of Bacterial Pneumonia

Bacteria reach the lung through inhalation, aspiration, migration from the proximal airway, or hematogenous spread [3]. The majority of the pathogens are generally expelled via the mucociliary process along with other particulates trapped in the viscous and elastic fluid that lines the airways. Bacteria need to breach normal barrier defenses to reach the lung periphery [3].
Both structural and immunologic barriers protect the lungs from entry of invading pathogens. In an immunocompetent host, these barriers are often effective in eliminating most infections [3]. However, the resulting immune reaction in response to infection causes tissue injury and systemic inflammation [3]. Pneumonia, as a syndrome, is a culmination of these responses. It constitutes the radiographic findings that happen as a result of airspace filled by edema, debris, and white blood cells along with the systemic response fever and leukocyte elevation along with a productive cough [3].
Cancer, along with its treatments, leads to changes in both the innate and adaptive responses to a bacterial pathogen [3]. In addition, functional and anatomical defects may arise either directly related to the underlying neoplasm or its associated therapy. Complications related to therapy may result in a need for hospitalization and invasive procedures, which increases risk for acquiring nosocomial pathogens [3]. Furthermore, due to impaired immune function, the clinical presentation or radiographic findings of pneumonia may be blunted, sometimes leading to delayed diagnosis [3].

4. Mycobacterium Tuberculosis

The incidence of tuberculosis (TB) varies from 0.001% to more than 10% in highly endemic countries [19]. The incidence of active disease amongst alloHSCT recipients is nearly triple compared with autologous HSCT recipients, with the lungs being the most affected organ [1][19]. Patients with cGVHD are particularly susceptible given prolonged cellular immune dysfunction. Use of specific agents to treat GVHD, including corticosteroids, ruxolitinib, and anti-CD52 therapies augment the risk for active TB [20]. Mortality secondary to TB pneumonia can reach up to 50%; hence, early recognition and intervention is important [19]. Findings on imaging vary from infiltrates, miliary pattern, nodules, pleural effusions, or cavitary lesions [19]. While nucleic acid testing has a sensitivity of 84% and a specificity of 99%, false-negative results may occur in the setting of recent TB exposure and low burden of mycobacteria within a specimen [19]. Culture continues to be the gold standard for diagnosis [19]. In order to prevent reactivation of TB post alloHSCT, it is important to treat for latent TB in patients with abnormal interferon-gamma release assays or tuberculin skin test with ≥5 mm induration.

5. Nontuberculous Mycobacterial Infections

Nontuberculous mycobacterial (NTM) infections are more frequent in alloHSCT recipients compared with the general population, particularly among patients with pulmonary cGVHD [1][21] Recent data report that pulmonary NTM occurred in up to 2.9% of patients who received alloHSCT [22]. Treatment and clinical appearance are typical of the general population [1].
The use of macrolides in the treatment of post-alloHSCT patients who develop bronchiolitis obliterans syndrome (BOS) is controversial [21]. More recent data suggest an association with negative outcomes, especially worse airflow-free survival and stimulation of immune cells that increase the risk of relapse [23][24]. The chronic immunocompromised state following alloHSCT, including the use of numerous immunosuppressants, is linked to a significantly greater incidence rate of NTM infection in patients receiving alloHSCT than in the general population [21]. BOS appears to be a further risk factor for the development of NTM infection, presumably reflecting an immunological condition brought on by GVHD [21].

6. Legionnaires’ Disease

Legionella is an intracellular Gram-negative bacterium of environmental origin (particularly water sources) that most commonly presents as pneumonia in an entity termed Legionnaires’ disease (LD) [25][26]. It was first described in 1976 after a fatal outbreak of respiratory illness following a American Legion convention and was attributed to contamination within the hotel’s air conditioning system [27]. More than 50 species are recognized, and the most common to cause disease in humans is Legionella pneumophilia serogroup 1 [27]. Legionellosis is becoming more widely acknowledged as a cause of pneumonia due to the development of more accurate diagnostic testing techniques; in the US, its prevalence increased 217% from 2000 (n = 1110) to 2009 (n = 3522) [27]. While LD can affect immunocompetent hosts, immunocompromised patients with solid tumors or hematological malignancies; solid organ transplants; or immunosuppressive medications such as tumor necrosis factor (TNF) inhibitors, corticosteroids, or antirejection medications are at increased risk [26]. Most importantly, impaired cellular immunity increases risk for severe illness due to Legionella [25]. Legionella is often acquired via community exposure either by aerosolization or aspiration of freshwater reservoirs. In addition, Legionella has been associated with nosocomial outbreaks, including within transplant centers [28].

7. Nocardia

Nocardia is an abundant Gram-positive, aerobic bacterium found worldwide in soil, water, and decaying vegetation [29]. Pulmonary infection, generally acquired via inhalation, can present as an acute, subacute, or chronic illness. Most common clinical symptoms are fever and cough but can also manifest as non-specific night sweats, fatigue, and malaise. Radiographically, it can present as pulmonary nodules, mass-like consolidations, infiltrates, or pleural effusion [29]. Infection of the central nervous system via hematogenous spread occurs in up to 20–50% of nocardiosis [29]. Nocardiosis is rare among alloHSCT recipients, with incidence being between 0.3 and 1.7% [29]. Trimethoprim-sulfamethoxazole is commonly used as a prophylaxis against Pneumocystis jiroveci pneumonia (PJP) in alloHSCT recipients and is often effective in preventing infection due to Nocardia sp. [29]. However, despite intermittent prophylactic TMP-SMX administration, some transplant recipients develop nocardiosis, demonstrating that infection risk likely depends on both the dosage of prophylactic TMP-SMX and other factors [29]. The use of atovaquone or other alternatives to PJP prophylaxis is associated with an increased risk of nocardiosis [29].

8. Pseudomonas Aeruginosa

Pseudomonas aeruginosa is a Gram-negative, aerobic, rod-shaped bacterium that can be isolated from environmental reservoirs including soil, plants, and animal tissue [30][31]. Using its potent binding components, including as flagella, pili, and biofilms, this bacteria can survive on water, various surfaces, and medical equipment [30]. P. aeruginosa is therefore prevalent in both natural and artificial settings, such as lakes, hospitals, and domestic sink drains [30]. A variety of diseases in humans are brought on by the opportunistic bacterium Pseudomonas aeruginosa [30]. It is now a significant contributor to antibiotic resistance and nosocomial infections [30]. Pseudomonas aeruginosa is a type of opportunistic bacteria that has been linked to a number of healthcare-associated infections, such as ventilator-associated pneumonia (VAP), bloodstream infections from central lines, surgical site infections, urinary tract infections, burn wound infections, keratitis, and otitis media [30]. It is a bacterium that can quickly acquire antibiotic resistance, adapt to environmental changes, and produce a wide range of virulence factors [30].

9. Preventative and Mitigation Measures

Multiple mitigation and preventative strategies can be utilized to help decrease the risk of infection [3]. Optimized hand hygiene, avoidance of sick contacts, and development of protected hospital environments have been shown to be effective [3][12]. Regular dental care is vital as well.
Vaccination has been studied extensively in this population [3][32]. The type of HSCT, the timing of immunization after transplantation, the age at transplantation, and the presence or absence of chronic GVHD all affect immune responses and development of long-term immunity [32]. Even after receiving vaccinations, patients may still have a compromised immune system, necessitating additional safety measures to reduce the risk of contracting infections [32]. Active GVHD, its treatment, and the use of rituximab within 6 months of immunization attenuate the immunological response to vaccines [32]. Recipients of alloHSCT are recommended to receive vaccine series for Streptococcus pneumoniae, Haemophilus influenzae type b, SARS-CoV-2, and seasonal influenza among other others [1][3]. IVIG can be considered in alloHSCT recipients in the first 200 days post-transplant if there was profound hypogammaglobulinemia, Ig levels <400 mg/dL [1].

This entry is adapted from the peer-reviewed paper 10.3390/pathogens12050726

References

  1. Diab, M.; ZazaDitYafawi, J.; Soubani, A.O. Major pulmonary complications after hematopoietic stem cell transplant. Exp. Clin. Transplant. 2016, 14, 259–270.
  2. Aljurf, M.; Weisdorf, D.; Alfraih, F.; Szer, J.; Müller, C.; Confer, D.; Hashmi, S.; Kröger, N.; Shaw, B.E.; Greinix, H. Worldwide Network for Blood & Marrow Transplantation (WBMT) special article, challenges facing emerging alternate donor registries. Bone Marrow Transplant. 2019, 54, 1179–1188.
  3. Wong, J.L.; Evans, S.E. Bacterial Pneumonia in Patients with Cancer: Novel Risk Factors and Management. Clin. Chest Med. 2017, 38, 263–277.
  4. Schuster, M.G.; Cleveland, A.A.; Dubberke, E.R.; Kauffman, C.A.; Avery, R.K.; Husain, S.; Paterson, D.L.; Silveira, F.P.; Chiller, T.M.; Benedict, K. Infections in hematopoietic cell transplant recipients: Results from the organ transplant infection project, a multicenter, prospective, cohort study. In Open Forum Infectious Diseases; Oxford University Press: New York, NY, USA, 2017; p. ofx050.
  5. Aguilar-Guisado, M.; Jiménez-Jambrina, M.; Espigado, I.; Rovira, M.; Martino, R.; Oriol, A.; Borrell, N.; Ruiz, I.; Martín-Dávila, P.; de la Cámara, R. Pneumonia in allogeneic stem cell transplantation recipients: A multicenter prospective study. Clin. Transplant. 2011, 25, E629–E638.
  6. Zimmer, A.J.; Freifeld, A.G. Optimal management of neutropenic fever in patients with cancer. J. Oncol. Pract. 2019, 15, 19–24.
  7. Tomblyn, M.; Chiller, T.; Einsele, H.; Gress, R.; Sepkowitz, K.; Storek, J.; Wingard, J.R.; Young, J.; Boeckh, M.J. Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: A global perspective. Bone Marrow Transplant. 2009, 44, 453–455.
  8. Zeiser, R.; Blazar, B.R. Acute graft-versus-host disease—Biologic process, prevention, and therapy. N. Engl. J. Med. 2017, 377, 2167–2179.
  9. Robin, M.; Porcher, R.; Araujo, R.D.C.; De Latour, R.P.; Devergie, A.; Rocha, V.; Larghero, J.; Adès, L.; Ribaud, P.; Mary, J.-Y. Risk factors for late infections after allogeneic hematopoietic stem cell transplantation from a matched related donor. Biol. Blood Marrow Transplant. 2007, 13, 1304–1312.
  10. Bhatt, V.R.; Wang, T.; Chen, K.; Kitko, C.L.; MacMillan, M.L.; Pidala, J.A.; Al Malki, M.M.; Badawy, S.M.; Beitinjaneh, A.; Ganguly, S. Chronic graft-versus-host disease, nonrelapse mortality, and disease relapse in older versus younger adults undergoing matched allogeneic peripheral blood hematopoietic cell transplantation: A Center for International Blood and Marrow Transplant Research Analysis. Transplant. Cell. Ther. 2022, 28, 34–42.
  11. Rashidi, A.; Hamadani, M.; Zhang, M.-J.; Wang, H.-L.; Abdel-Azim, H.; Aljurf, M.; Assal, A.; Bajel, A.; Bashey, A.; Battiwalla, M. Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission. Blood Adv. 2019, 3, 1826–1836.
  12. Styczyński, J. Pneumonia in patients after hematopoietic stem cell transplantation. OnCOReview 2017, 7, A126–A138.
  13. Soiffer, R.J.; LeRademacher, J.; Ho, V.; Kan, F.; Artz, A.; Champlin, R.E.; Devine, S.; Isola, L.; Lazarus, H.M.; Marks, D.I. Impact of immune modulation with anti–T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood J. Am. Soc. Hematol. 2011, 117, 6963–6970.
  14. Soubani, A.O.; Miller, K.B.; Hassoun, P.M. Pulmonary complications of bone marrow transplantation. Chest 1996, 109, 1066–1077.
  15. Hamilton, B.K. Updates in chronic graft-versus-host disease. Hematology 2021, 2021, 648–654.
  16. Wollenberg, B.; Riera-Knorrenschild, J.; Neubauer, A.; Görg, C. Functional hyposplenia after allogenic bone marrow transplantation: A case report. Ultraschall Med. 2001, 22, 289–291.
  17. Youssef, S.; Rodriguez, G.; Rolston, K.V.; Champlin, R.E.; Raad, I.I.; Safdar, A. Streptococcus pneumoniae infections in 47 hematopoietic stem cell transplantation recipients: Clinical characteristics of infections and vaccine-breakthrough infections, 1989–2005. Medicine 2007, 86, 69–77.
  18. Rege, K.; Mehta, J.; Treleaven, J.; Jameson, B.; Meller, S.; Mitchell, P.; Milan, S.; Powles, R. Fatal pneumococcal infections following allogeneic bone marrow transplant. Bone Marrow Transplant. 1994, 14, 903–906.
  19. Saj, F.; Reddy, V.N.; Kayal, S.; Dubashi, B.; Singh, R.; Joseph, N.M.; Ganesan, P. Double Infection in a Patient with Chronic GVHD Post Allogeneic Transplant: Hickam’s Dictum Trumps Occam’s Razor!—A Case Report with Review of Literature. Indian J. Med. Paediatr. Oncol. 2022.
  20. Bergeron, A.; Mikulska, M.; De Greef, J.; Bondeelle, L.; Franquet, T.; Herrmann, J.-L.; Lange, C.; Spriet, I.; Akova, M.; Donnelly, J.P. Mycobacterial infections in adults with haematological malignancies and haematopoietic stem cell transplants: Guidelines from the 8th European Conference on Infections in Leukaemia. Lancet Infect. Dis. 2022, 22, e359–e369.
  21. Miyake, N.; Chong, Y.; Nishida, R.; Takenaka, K.; Kato, K.; Miyamoto, T.; Aono, A.; Takaki, A.; Mitarai, S.; Shimoda, S.; et al. Mycobacterium abscessus and massiliense lung infection during macrolide treatment for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation. J. Infect. Chemother. 2018, 24, 78–81.
  22. Peres, E.; Khaled, Y.; Krijanovski, O.I.; Mineishi, S.; Levine, J.E.; Kaul, D.R.; Riddell Iv, J. Mycobacterium chelonae necrotizing pneumonia after allogeneic hematopoietic stem cell transplant: Report of clinical response to treatment with tigecycline. Transpl. Infect. Dis. 2009, 11, 57–63.
  23. Bergeron, A.; Chevret, S.; Granata, A.; Chevallier, P.; Vincent, L.; Huynh, A.; Tabrizi, R.; Labussiere-Wallet, H.; Bernard, M.; Chantepie, S. Effect of azithromycin on airflow decline–free survival after allogeneic hematopoietic stem cell transplant: The allozithro randomized clinical trial. JAMA 2017, 318, 557–566.
  24. Vallet, N.; Le Grand, S.; Bondeelle, L.; Hoareau, B.; Corneau, A.; Bouteiller, D.; Tournier, S.; Derivry, L.; Bohineust, A.; Tourret, M. Azithromycin promotes relapse by disrupting immune and metabolic networks after allogeneic stem cell transplantation. Blood J. Am. Soc. Hematol. 2022, 140, 2500–2513.
  25. Sivagnanam, S.; Podczervinski, S.; Butler-Wu, S.M.; Hawkins, V.; Stednick, Z.; Helbert, L.A.; Glover, W.A.; Whimbey, E.; Duchin, J.; Cheng, G.S.; et al. Legionnaires’ disease in transplant recipients: A 15-year retrospective study in a tertiary referral center. Transpl. Infect. Dis. 2017, 19, e12745.
  26. Pouderoux, C.C.; Ginevra, C.; Descours, G.; Lle Ranc, A.G.; Beraud, L.; Boisset, S.; Magand, N.; Conrad, A.; Bergeron-Lafaurie, A.; Jarraud, S.; et al. Slowly or nonresolving legionnaires’ disease: Case series and literature review. Clin. Infect. Dis. 2020, 70, 1933–1940.
  27. Padrnos, L.J.; Blair, J.E.; Kusne, S.; Dicaudo, D.J.; Mikhael, J.R. Cutaneous legionellosis: Case report and review of the medical literature. Transpl. Infect. Dis. 2014, 16, 307–314.
  28. Sivagnanam, S.; Pergam, S.A. Legionellosis in transplantation. Curr. Infect. Dis. Rep. 2016, 18, 9.
  29. Molina, A.; Winston, D.J.; Pan, D.; Schiller, G.J. Increased Incidence of Nocardial Infections in an Era of Atovaquone Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant Recipients. Biol. Blood Marrow Transplant. 2018, 24, 1715–1720.
  30. Tuon, F.F.; Dantas, L.R.; Suss, P.H.; Tasca Ribeiro, V.S. Pathogenesis of the Pseudomonas aeruginosa biofilm: A review. Pathogens 2022, 11, 300.
  31. Sadikot, R.T.; Blackwell, T.S.; Christman, J.W.; Prince, A.S. Pathogen–host interactions in Pseudomonas aeruginosa pneumonia. Am. J. Respir. Crit. Care Med. 2005, 171, 1209–1223.
  32. Issa, N.C.; Baden, L.R. Current issues in vaccines for adult patients with hematologic malignancies. J. Natl. Compr. Cancer Netw. JNCCN 2012, 10, 1447–1454.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback