Fungal infections after lung transplantation

https://doi.org/10.1016/j.trre.2007.12.007Get rights and content

Abstract

Lung transplantation (LT) is now considered to be the standard therapeutic intervention in some patients with end-stage pulmonary disease. Infectious complications after LT are relatively common due to the aggressive immunosuppression used in these receptors and local host factors derived from this type of transplant. The incidence of fungal infections after LT ranges up to 30%. However, the incidence of invasive mycoses has declined over the past decade. These mycoses are associated with high overall mortality rates despite increase of the antifungal armamentarium in the last years. Candida and Aspergillus spp produce most of these infections, but unusual moulds such as Scedosporium spp are increasingly recognized as opportunistic pathogens in LT. This review highlights the changing spectrum of invasive fungal infections, risk factors, antifungal prophylaxis, diagnosis, and treatment after LT.

Introduction

Infectious complications after lung transplantation (LT) are frequent as a direct consequence of the use of the aggressive immunosuppression employed in these receptors, as well as the presence of impaired mucociliary clearance, ischemic airway injury, altered alveolar macrophage phagocytic function, and direct communication of the transplanted organ with the enviroment. Moreover, pulmonary infections in LT recipients besides their direct impact on morbidity and mortality have an indirect effect with immunological consequences implicated in the genesis and clinical course of acute and chronic rejection.

Fungal infections (FIs) are associated with a high mortality rate in lung transplant recipients for several reasons: the difficulty of establishing an early diagnosis, the lack of effective treatment for infections by some filamentous fungi, the toxicity and interactions of some antifungal agents with immunosuppressive drugs, the scarce published experience about the use of prophylaxis with antifungal drugs in this setting, and finally, the loss of grafts as the result of reducing immunosupression to cure these infections.

Fungal infection occurs in 15% to 35% of patients after LT, and more than 80% are caused by Candida spp and Aspergillus spp, with an overall mortality rate of nearly 60% [1], [2], [3], [4], [5], [6]. Unusual moulds such as Scedosporium spp are increasingly recognized as important opportunistic pathogens in LT; other moulds such as Zygomycetes and species of Fusarium have less relevant role in LT, but in all cases, their infection is associated with a high rate of dissemination and poor outcome [7], [8]. However, the overall incidence of invasive mycoses in LT has declined over the past decade. This may be related to improved surgical techniques, decreases in the length of operations, units of blood transfused, more effective prophylactic strategies, and refinements in immunosuppressive regimens.

This review highlights changing spectrum of invasive FIs (IFIs), risk factors, antifungal prophylaxis, diagnosis, and treatment after LT.

Section snippets

Risk factors for IFIs

In general, risk factors for invasive mycoses in solid organ transplantation (SOT) are concentrated in specific subpopulations of transplant recipients. Risk factors for Candida infection are well known and usually are related with a complicated postoperative course in the intensive care unit during the early postoperative period (Candida colonization, central vascular lines, broad-spectrum antibiotics, total parenteral nutrition, and hospital length of stay), and they do not differ in LT

Aspergillus spp infection in recipients of LT

Aspergillus is a filamentous fungus with a wide environmental distribution [17]. Aspergillus infections remain among the most significant opportunistic infections after LT. Aspergillus fumigatus, the most pathogenic species, produces the most infections; however, Aspergillus flavus, Aspergillus terreus, and Aspergillus niger have been increasingly reported in IFI. Data from the compilation and synthesis of existing studies give a variable incidence of AI of 6% in the published series (range,

Diagnosis

The diagnosis of invasive mycoses in immunosuppressed patients poses significant clinical challenges. In fact neither radiological findings (patchy infiltrates or consolidation) nor respiratory samples have a high specificity. Symptoms of invasive mycoses are nonspecific, and initially, about 30% of cases are asymptomatic. Besides, Aspergillus is cultured from sputum in only 8% to 34%, and from bronchoalveolar lavage fluid (BAL) up to 62% of patients with invasive disease. Moreover, post LT

Prophylaxis

Several prophylactic strategies with antifungal drugs have been reported to result in a decreased incidence and mortality of fungal disease in LT recipients [93], [94], [95]. However, there has not been a uniform approach, data are limited, and besides, there is a considerable variation in antifungal prophylaxis practices among lung transplant centers throughout the world. Most lung transplant programs are using universal antifungal prophylaxis in the postoperative period; about 30% use a

Antifungal therapy and management

AmBd has been the gold standard antifungal therapy for opportunistic FI for more than 4 decades. However, it is associated with undesirable toxicities and is commonly ineffective, predominantly in those patients with advanced immunosuppression. In addition, outcomes of salvage therapy after progression of infection or toxicity after initiation of AmB are extremely poor. For these reasons, antifungal agents with better tolerability and efficacy have been needed without delay. In the last decade,

Immune reconstitution syndrome

Although host immunity is crucial in the eradication of any infection, immunological recovery can also be detrimental and may contribute toward worsening disease expression [118]. The concept of immune reconstitution syndrome (IRS) and its precise diagnosis in the context of opportunistic mycoses remain poorly characterized. Immune reconstitution syndrome is best considered as a collection of localized and systemic inflammatory reactions of varying degrees that have both beneficial and noxious

Conclusion

This review highlights the risk factors and changing spectrum of IFI after LT. Despite the increasing impact of viral infections in LT, FIs still have a main role in LT. In fact, they remain a common cause of morbidity and mortality in the early and late post-transplant periods. Aspergillus spp and Candida spp account for most IFI, but recent epidemiological and clinical studies suggest the emergence of mycelial fungi other than Aspergillus as well as resistant strains of Candida in these

References (121)

  • J.R. Maurer et al.

    Infectious complications following isolated lung transplantation

    Chest

    (1992)
  • C. Chaparro et al.

    Infections in lung transplant recipients

    Clin Chest Med

    (1997)
  • R.D. Dowling et al.

    Disruption of the aortic anastomosis after heart-lung transplantation

    Ann Thorac Surg

    (1990)
  • R.V. Fleming et al.

    Emerging and less common fungal pathogens

    Infect Dis Clin North Am

    (2002)
  • G.W. Procop et al.

    Emerging fungal diseases: the importance of the host

    Clin Lab Med

    (2004)
  • E. Bouza et al.

    Mucormycoses: an emerging disease?

    Clin Microbiol Infect

    (2006)
  • D.P. Kontoyiannis et al.

    Invasive zygomycoses: update on pathogenesis, clinical manifestations, and management

    Infect Dis Clin North Am

    (2006)
  • F.R. McGuire et al.

    Mucormycoses of the bronchial anastomosis: a case of successful medical treatment and historic review

    J Heart Lung Transplant

    (2007)
  • M. Musk et al.

    Successful treatment of disseminated scedosporium infection in 2 lung transplant recipients: review of the literature and recommendations for management

    J Heart Lung Transplant

    (2006)
  • R. Raj et al.

    Scedosporium apiospermum fungemia in a lung transplant recipient

    Chest

    (2002)
  • H. Sahi et al.

    Scedosporium apiospermum (Pseudallescheria boydii) infection in lung transplant recipients

    J Heart Lung Transplant

    (2007)
  • F. Symoens et al.

    Disseminated Scedosporium apiospermum infection in a cystic fibrosis patient after double-lung transplantation

    Heart Lung Transplant

    (2006)
  • E.I. Boutati et al.

    Fusarium, a significant emerging pathogen in patients with hematologic malignancy: ten years' experience at a cancer center and implications for management

    Blood

    (1997)
  • K.L. Arney et al.

    Primary pulmonary involvement of Fusarium solani in a lung transplant recipient

    Chest

    (1997)
  • R. Herbrecht et al.

    Successful treatment of Fusarium proliferatum pneumonia with posaconazole in a lung transplant recipient

    J Heart Lung Transplant

    (2004)
  • D.H. Copp et al.

    Clinical and radiological factors associated with pulmonary nodule etiology in organ transplant recipients

    Am J Transplant

    (2006)
  • S. Husain et al.

    Prospective assessment of Platelia Aspergillus galactomannan antigen for the diagnosis of invasive aspergillosis in lung transplant recipients

    Am J Transplant

    (2004)
  • I. Gadea et al.

    Microbiological procedures for diagnosing mycoses and for antifungal susceptibility testing

    Enferm Infecc Microbiol Clin

    (2007)
  • H. Reichenspurner et al.

    Significant reduction in the number of fungal infections after lung-, heart-lung, and heart transplantation using aerosolized amphotericin B prophylaxis

    Transplant Proc

    (1997)
  • V. Calvo et al.

    Antifungal prophylaxis during the early postoperative period of lung transplantation. Valencia Lung Transplant Group

    Chest

    (1999)
  • R.M. Kotloff et al.

    Pulmonary complications of solid organ and hematopoietic stem cell transplantation

    Am J Respir Crit Care Med

    (2004)
  • B.H. Segal et al.

    Current approaches to diagnosis and treatment of invasive aspergillosis

    Am J Respir Crit Care Med

    (2006)
  • P.E. Marik

    Fungal infections in solid organ transplantation

    Expert Opin Pharmacother

    (2006)
  • B.D. Alexander et al.

    Infectious complications of lung transplantation

    Transpl Infect Dis

    (2001)
  • S. Husain et al.

    Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-Aspergillus mycelial fungi

    Clin Infect Dis

    (2003)
  • N. Singh et al.

    Aspergillus infections in transplant recipients

    Clin Microbiol Rev

    (2005)
  • J. Gavalda et al.

    Risk factors for invasive aspergillosis in solid-organ transplant recipients: a case control study

    Clin Infect Dis

    (2005)
  • S.M. Gordon et al.

    Aspergillosis in lung transplantation: incidence, risk factors, and prophylactic strategies

    Transpl Infect Dis

    (2001)
  • E.J. Anaissie et al.

    Pathogenic Aspergillus species recovered from a hospital water system: a 3-year prospective study

    Clin Infect Dis

    (2002)
  • F.P. Silveira et al.

    Cryptococcosis in liver and kidney transplant recipients receiving anti-thymocyte globulin or alemtuzumab

    Clin Infect Dis

    (2007)
  • S.I. Martin et al.

    Infectious complications associated with alemtuzumab use for lymphoproliferative disorders

    Clin Infect Dis

    (2006)
  • L.P. Nicod et al.

    Fungal infections in transplant recipients

    Eur Respir J

    (2001)
  • D.H. Hadjiliadis et al.

    Anastomotic infections in lung transplant recipients

    Ann Transplant

    (2000)
  • N. Singh et al.

    Late-onset invasive aspergillosis in organ transplant recipients in the current era

    Med Mycol

    (2006)
  • R. San Juan Garrido et al.

    Incidence, clinical characteristics and risk factor late infection in solid organ transplant recipients. Data from RESITRA study group

    Am J Transplant

    (2007)
  • N. Singh et al.

    Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective. Multicenter, observational study

    Transplantation

    (2006)
  • M.R. Kramer et al.

    Infectious complications in heart-lung transplantation. Analysis of 200 episodes

    Arch Intern Med

    (1993)
  • I.L. Paradis et al.

    Infection after lung transplantation

    Semin Respir Infect

    (1993)
  • E.P. Trulock

    Lung transplantation

    Am J Respir Crit Care Med

    (1997)
  • P.A. Flume et al.

    Infectious complications of lung transplantation. Impact of cystic fibrosis

    Am J Respir Crit Care Med

    (1994)
  • Cited by (72)

    • Fatal invasive aspergillosis caused by Aspergillus niger after bilateral lung transplantation

      2017, Medical Mycology Case Reports
      Citation Excerpt :

      Invasive aspergillosis is a common complication after lung transplantation (LT) and is associated with high morbidity and mortality rates [1,2].

    • Long-term outcomes and management of lung transplant recipients

      2017, Best Practice and Research: Clinical Anaesthesiology
    View all citing articles on Scopus
    View full text