In the absence of standardized diagnosis and the presence of unique clinical syndromes,
it is not surprising that considerable differences exist in the number of reported
incidences of disease and the outcomes of various infections in cardiothoracic transplant
(CTTX) recipients. Publications to date have employed variable and heterogeneous definitions
of CTTX-related infections, thereby limiting the comparison between the types and
incidence of infections and the generalizability of these data across transplant centers.
Currently, there are no standard international definitions for infections uniquely
related to CTTX, with the exception of Chagas disease and toxoplasmosis.
1
The purpose of the present working formulation is to provide consensus-derived expert
opinion of definitions for infections in CTTX for epidemiologic, research and registry
data use.
Scope
Standard definitions of infections specifically related to CTTX will allow for meaningful
comparison of the type and incidence of these infections between different types of
CTTXs, different regimens of immunosuppression and between different transplant centers,
thereby improving the reporting of infection-related morbidity and mortality after
cardiothoracic transplantation. The definitions proposed herein are suitable for epidemiologic
investigations and are intended to facilitate clinical decision-making.
The definitions described in what follows have been reviewed and approved by a multidisciplinary
working group of The International Society for Heart and Lung Transplantation (ISHLT).
Source
These definitions were adapted from surveillance definitions of healthcare-associated
sinusitis, tracheobronchitis and pneumonia, used in reporting to the National Healthcare
Safety Network (NHSN) and the Centers for Disease Control and Prevention's (CDC) surveillance
system for patient and healthcare personnel safety.
2
Definitions of invasive fungal infection (IFI) were based on those proposed by the
European Organization for Research and Treatment of Cancer and the Mycoses Study Group
of the National Institutes of Health (EORTC/MSG),
3
whereas definitions from the American Society of Transplantation and other source
documents represented the foundation for defining viral infections.1, 4
Bacterial infection overview
All bacterial infections
Bacterial infections are a major contributor of complications in the early post-transplant
period in heart- and lung-transplanted patients.5, 6 Some bacterial infections (e.g.,
pre-transplant colonization or donor-derived infections) have unique issues and implications
in CTTX recipients5, 7, 8, 9, 10, 11, 12; therefore, the definitions for these infections
for epidemiologic, research or ISHLT registry purposes are specifically addressed
herein. Many other bacterial infections (e.g., methicillin-resistant Staphylococcus
aureus or vancomysin-resistant enterococcus) are present similarly across hospitalized
patients and solid-organ transplant (SOT) recipients and are therefore not directly
addressed in what follows.
The existing literature in CTTX has largely classified bacterial infections as “early”
(e.g., post-operative) or “late” onset after transplantation, allowing transplant
clinicians to determine the source of these infections and focus prevention strategy
and early empirical antibiotic treatment regimens on the temporal onset of these infections.
A further timeline is used to classify all infections diagnosed in the hospital setting
as nosocomial, with onset 48 hours after the patient is admitted to the hospital,
and community-acquired infection, with onset at the time of admission or within 48
hours of admission. The latter definitions of infection may be artificial in the setting
of CTTX as some infections, although related to healthcare and immunosuppression,
may not occur within the established time-line of nosocomial infections. To fully
appreciate the impact of the potential source of infection, we propose using the categories
of nosocomial (after 48 hours of hospitalization) and community-acquired (prior to
48 hours of hospitalization) with the added category of community-acquired “transplant-related”
infections. This category would include infections by pathogens acquired by the CTTX
patient prior to time of transplantation and that are clearly related to the immunocompromised
state of the CTTX patient after transplantation that may increase the risk for specific
bacterial pathogens that are not common in the community. These pathogens may be related
to the donor or the recipient via pre-transplant colonization of the respiratory or
gastrointestinal (GI) tract and can be therefore regarded as “transplant-related”
in this setting.12, 13 It is also to be noted that community-acquired pneumonia may
be transplant-related if caused by organisms that are typically associated with transplants
(e.g., fungal, multidrug-resistant or atypical bacteria).
Respiratory bacterial infections
Respiratory bacterial infections occur frequently in lung transplant recipients. In
one study, 72 episodes per 100 lung transplants per year were reported.
14
The source of bacteria-causing pneumonia in lung transplant recipients may be the
donor, the recipient or the hospital environment. Nosocomial transmission from other
patients or healthcare workers can occur when hand hygiene or appropriate respiratory
isolation measures for other hospitalized infected patients are not routinely practiced.11,
15, 16, 17, 18, 19
The definitions of bacterial pneumonia present significant challenges in CTTX. Frequent
use of empirical anti-bacterial agents prior to specimen collection and the possibility
of concurrent allograft rejection make the use of standard guidelines, as presented
by the Centers for Disease Control and Prevention (CDC) for healthcare-associated
infections (HCAIs), difficult to apply.
2
In addition, some microbiologic diagnostic procedures may not be routinely practiced
at many transplant centers and this may limit the employment of diagnostic criteria
for infections that require quantification of bacterial colony-forming units per milliliter
in the bronchoalveolar lavage (BAL) samples. This methodology has not been validated
in the immunocompromised host and is not standardized across institutions. Further,
the thresholds proposed may underestimate the episodes of bacterial pneumonia in the
CTTX population,
20
where early empirical intervention with anti-microbial agents prior to obtaining the
samples with suspected pneumonia is common practice. Presence of endobronchial stents
in lung transplant recipients further complicates the picture in defining various
clinical syndromes.
For these reasons, a specific classification of bacterial pneumoniae in CTTX recipients
is proposed based on radiographic findings, clinical symptoms, microbiology and histopathology
(including consideration of acute rejection in lung transplant patients).
In lung transplant recipients, the use of differential cytology in BAL may be helpful.21,
22, 23 The predominance of neutrophils with intracellular bacteria (hematoxylin–eosin
and gram stain) is more suggestive of the presence of a bacterial pneumonia than a
high proportion of lymphocytes or eosinophils in BAL. On the other hand, a lymphocytic
or eosinophilic BAL could indicate an acute graft reaction, although cytomegalovirus
(CMV), other viruses and atypical pathogens would need to be ruled out.
Acute rejection (AR) of the graft in lung transplant recipients presents a significant
consideration in the diagnosis of all pneumonias, including those due to bacteria.
There are frequent clinical scenarios where distinction between rejection and infection
is critically dependent upon histopathologic findings. In many cases, evidence for
infection and rejection coexist. Therefore, in the setting of lung transplantation,
the diagnosis of bacterial (or any) pneumonia is more precisely defined by the confirmation
or exclusion of AR when microbiologic criteria are not met.
24
The determination of AR requires histologic examination. If an AR is documented and
clinical and laboratory criteria for bacterial pneumonia are also fulfilled, the diagnosis
of AR and concomitant pneumonia is possible.
24
Accordingly, pneumonia should be indicated as pneumonia combined with an AR.
Respiratory bacterial infection diagnostic tools
•
Direct examination by light microscopy [gram stain, modified acid-fast bacilli (AFB)
stain for Nocardia spp, AFB stains for Mycobacteria].
•
Culture (including rapid culture methods for Legionella spp, Mycobacteria spp and
prolonged culture periods for detection of bacteria-causing infective endocarditis).
•
BAL cell analysis: rule-out contamination with <1% epithelial cells,
20
then quantitative, semi-quantitative or qualitative culture of BAL material or lung
biopsy, if available.
•
Quantitative, semi-quantitative or qualitative cytology of BAL.
•
Histopathology: special staining of lung tissue (if available) for bacteria (i.e.,
Brown and Brenn stain), Mycobacteria (AFB stain/auramine) and atypical bacteria (Fite
stain for Nocardia, etc.).
•
Nucleic acid amplification [including polymerase chain reaction (PCR) methods and
real-time PCR] methods for atypical respiratory bacteria (Legionella, Chlamydia and
Mycoplasma spp).
•
Enzyme immunoassays (EIA) antigen tests for pneumococcal and legionella antigens from
urine samples).
•
Serology (may be useful for research purposes only in select study designs).
Definitions of bacterial pneumonia and colonization in CTTX are given in Table 1a,
whereas the definitions of tracheobronchitis are given in Table 1b.
Table 1a
Bacterial Pneumonia and Colonization in CTTX
Infection
Signs/symptoms
Radiology
Microbiology/pathology
Histopathologic evidence of AR
Proven pneumonia, acute rejection (AR)- associated OR not AR associated
At least one of the following:
• Fever >38oC or hypothermia <36.5oC with no other recognized cause
• Leukopenia (<4,000 WBC/mm3) or leukocytosis (≥15,000 WBC/mm3)
And at least two of the following:
• New-onset of purulent sputum OR change in character/quantity of sputum OR increased
respiratory secretions suctioned
• New-onset or worsening cough, dyspnea, tachypnea, OR pleural rub, rales OR bronchial
breath sounds
• Worsening gas exchange (O2 desaturations, PaO2/FIO2 ≤240, increased O2 requirements,
increased ventilation demands)
• Pleural effusion
New/worsening radiographic changes on chest X-ray or CT scan
At least one of the following:
• Positive growth in blood culture unrelated to other source
• Positive growth in culture of pleural fluid
• Positive respiratory culture (sputum, bronchial secretions, BAL, bronchial protected
sterile brushing)
• ≥5% BAL-obtained cells containing intracellular bacteria on direct microscopic
exam
AR may be present or absent or not investigated
Probable pneumonia
As for proven
As for proven
Negative microbiology PLUS absence of AR by histopathology
AR must be excluded
Possible pneumonia
As for proven
As for proven
Microbiology negative or not performed PLUS concomitant clinical diagnosis of AR (without
histopathology)
No histopathology performed
No pneumonia, proven AR
As for proven
As for proven
Negative microbiology PLUS AR proven by histopathology
Histopathologic evidence of AR
Colonization
Asymptomatic OR no significant changes in symptoms; stable PFT; normal bronchoscopy
without:
• Endobronchial erythema AND
• Purulent secretions
Absent or unchanged
Recovery of pathogen in absence of clinical or radiographic changes
AR present or absent
Table 1b
Bacterial Tracheobronchitis and Bronchial Anastomotic Infections in Lung Transplant
Recipients
Infection
Signs/symptoms
Radiology
Microbiology
Histopathologic evidence
Proven tracheobronchitis
At least one of the following:
• New-onset purulent sputum OR change in character/quantity of sputum OR increased
respiratory secretions suctioned
• New-onset or worsening cough, dyspnea, tachypnea AND
• One or more endobronchial lesions (erythema, ulceration, necrosis and pseudomembrane
formation, including at the site endobronchial stent) without an alternative diagnosis
and without evidence of invasive parenchymal disease (Figure 1b)
Figure 1
Presentations of tracheobronchitis (TrB) and bronchial anastomatic infection (BAI)
in lung transplant recipients. (A) Normal bronchoscopy. (B) Bacterial tracheobronchitis.
(C) Fungal tracheobronchitis. (D) Bronchial anastomotic infection.
Negative chest X-ray OR one CT scan without the following:
• New/progressive and persistent infiltrate
• Consolidation
• Cavitation
May be positive if concurrent pneumonia is present
At least one of the following:
• Positive respiratory culture (sputum, bronchial secretions or tissue, BAL, bronchial
protected sterile brushing)
Histology showing inflammation with organisms or positive culture from the sterile
tissue ALONE
Probable tracheobronchitis
As for proven
As for proven
As for proven
Negative histology
Proven bronchial anastomotic infection
At least one of the following:
• New-onset purulent sputum OR change in character/quantity of sputum OR increased
respiratory secretions suctioned
• New-onset or worsening cough, dyspnea, tachypnea
AND endobronchial lesions (erythema, ulceration, necrosis and pseudomembrane formation)
restricted to the site of anastomosis without involvement of other parts of bronchial
tree or lung parenchyma
As for proven tracheobronchitis; may be positive if concurrent pneumonia is present
As for proven tracheobronchitis
As for proven tracheobronchitis
Probable bronchial anastomotic infection
As for proven
As for proven
As for proven tracheobronchitis
Negative histopathology
General comments regarding bacterial pneumonia/tracheobronchitis
1
Ventilator-associated pneumonia should be designated when reporting data. A distinction
should be made between non-invasive and invasive ventilation.
2
Aspiration pneumonia should be considered if the criteria are fulfilled for pneumonia
(Table 1a). The cause of this type of pneumonia should be noted.
3
Multiple or concurrent episodes of post-transplant pneumonia may occur. To determine
a new episode in a single patient, resolution of the initial infection must be determined
by clinical, laboratory or histologic evidence. The isolation of a new pathogen alone
is not indicative of a new episode of pneumonia. In contrast, a second pneumonia may
develop in a patient after single lung transplantation. Here, the contralateral lung
may develop an “independent” pneumonia by another organism.
4
Sputum samples are frequently contaminated with airway colonizers (e.g., coagulase-negative
Staphylococcus and Enterococcus spp), and therefore must be interpreted cautiously.
5
The interferon-gamma release assay (IGRA) serum test is not recommended for diagnosis
of acute tracheobronchitis disease, although a positive result is an indication of
latent disease or recent infection and a useful screening test if baseline IGRA testing
is performed prior to transplantation.
25
6
Episodes of airway colonization are not recorded as infections.
7
Histologic representation of chronic graft rejection may not impact the diagnosis
of bacterial pneumonia. Therefore, it is not included as criteria for pneumonia definition.
26
8
The definition of “possible pneumonia” category allows recording of pneumonia after
lung transplantation even if required diagnostic procedures were missed, which may
occur with prior anti-microbial treatment or delay in diagnostic testing, etc.
9
In lung transplant recipients, it is desirable to always give additional information
if evidence of acute graft rejection exists either by clinical or by histopathologic
diagnosis.
10
It is possible to have concurrent infections—pneumonia with sinusitis or anastomotic
tracheobronchitis.
11
Quantification of organisms in BAL is not considered essential for the diagnosis of
ventilator-associated pneumonia (VAP).
27
However, invasive diagnostics may help withdraw anti-bacterial therapy, which may
prevent further emergence of multi-resistant organisms in future.28, 29
12
The category of bacterial tracheobronchitis is classified into probable and proven
categories. They can only be diagnosed in the presence of bronchoscopic findings.
We have refrained from using the term microbiogically negative tracheobrochitis as
it requires more evidence.
13
Endobronchial stent–associated tracheobronchitis or bronchial anastomotic infections,
both fungal and bacterial, are categorized as probable (Table 2).
Table 2
Infections Associated With Ventilation or Endobronchial Stents
Infection
Signs/symptoms
Radiology
Microbiology
Histopathologic evidence
Ventilator-associated pneumonia (non-invasive or invasive ventilation); patient on
ventilator for at least 48 hours continuously
At least one of the following:
• Fever >38oC or hypothermia <36.5oC with no other recognized cause
• Leukopenia (<4,000 WBC/mm3) or leukocytosis (≥11,000 WBC/mm3)
And at least two of the following:
• New-onset purulent sputum OR change in character/quantity of sputum OR increased
respiratory secretions suctioned
• New-onset or worsening pleural rub, rales OR bronchial breath sounds
• Worsening gas exchange (O2 desaturations, PaO2/FIO2 ≤240, increased O2 requirements,
increased ventilation demands)
Two or more serial chest radiographs showing new/progressive infiltrate or consolidation
OR one CT scan with at least one of the following:
• New/progressive and persistent infiltrate
• Consolidation
• Cavitation
At least one of the following:
• Positive respiratory culture (sputum, bronchial secretions, BAL, bronchial protected
sterile brushing).
• ≥5% BAL-obtained cells containing intracellular bacteria on direct microscopic
exam.
Histology (biopsy showing histologic evidence of pneumonia OR positive culture from
the sterile tissue ALONE
Endobronchial stent associated:
• Tracheobronchitis
• Bronchial anastomotic infection
• Pneumonia
At least one of the following:
• New-onset purulent sputum OR change in character/quantity of sputum OR increased
respiratory secretions suctioned
• New-onset or worsening cough, dyspnea, tachypnea OR pleural rub, rales OR bronchial
breath sounds
AND endobronchial lesions restricted to the extent of endobrochial stent with or without
involvement of anastomosis or other parts of bronchial tree or lung parenchyma
Chest radiograph without:
• New or progressive and persistent infiltrate
• Consolidation
• Cavitation
• Nodules
OR CT scan without:
• New or progressive and persistent infiltrate
• Consolidation
• Cavitation
• Nodules
• Positive respiratory culture (sputum, bronchial secretions, BAL, bronchial protected
sterile brushing)
• ≥5% BAL-obtained cells containing intracellular bacteria on direct microscopic
exam
• Positive culture for mold/yeast
• OR positive PCR for mold /yeast
• OR positive GM in the BAL
OR at least TWO positive sputum cultures/PCRs of fungal organisms (including Candida
species)
Not applicable
14
No attempt is made to redefine atypical mycobacterial infections or pulmonary tracheobronchitis
in lung transplant recipients and the use of existing definitions from European and
North American societies are encouraged until further data emerge.30, 31, 32, 33
15
It is preferable to document the use of antibiotics in patients with pneumonia at
the time of culture data collection.
Viral infection overview
All viral infections
Cardiothoracic transplant recipients are at an increased risk for viral infections
with severe clinical sequelae. Some viral infections have unique considerations and
implications in CTTX recipients. The definitions for these viral infections are specifically
addressed herein and may be used for epidemiologic, research or registry purposes
in CTTX recipients.
Many other non-respiratory viral infections present similarly across SOT recipients.
Diagnosis and management of these viral infections have been addressed adequately
in other guidelines
1
and therefore will not be addressed herein.
Respiratory viral infections
Respiratory viral infections, including newly emerging viruses, occur frequently in
lung transplant recipients.
34
Some epidemiologic studies have suggested an association between respiratory viral
infection and the development of bronchiolitis obliterans syndrome (BOS).35, 36, 37,
38, 39, 40 These studies yielded mixed results and the association between respiratory
virus infection and BOS remains unclear.41, 42 The recent availability of molecular
diagnostics, including PCR and multiplex gene techniques for the recovery of many
viruses simultaneously from a single specimen, increased the recovery of pathogens
in respiratory infections that previously were considered to be of undetermined etiology.
42
Other viruses have been identified and are of uncertain pathogenicity. Further, with
the use of molecular diagnostic and deep gene sequencing techniques, novel respiratory
viral pathogens, such as human metapneumovirus, human coronaviruses and bocavirus,
have been identified.43, 44 These discoveries have led to the expansion of the repertoire
of respiratory viral pathogens and infections to be considered in any research of
the impact of respiratory viral infections after CTTX. Characteristic histopathologic
changes on lung biopsy specimens when these viruses are present have not been identified
by these methods, such as with CMV and herpes simplex virus (HSV), but efforts continue,
demonstrating the multidisciplinary approach to the accurate diagnosis of infection
in this population. The standardization of diagnosis and categorization of respiratory
viral infection is essential for the comprehensive evaluation and generalizability
of this growing area of study.
Lower respiratory viral infections (LVRIs) may occur with or without acute rejection.
Suspected acute rejection should be looked for if all criteria of LRVIs are fulfilled.
CMV in the lung
Definitions for CMV infection and disease, especially for use in research, have been
reported in the literature and used in other studies.1, 4 The methodology for CMV
recovery has shifted at many centers over the past decade from conventional viral
culture methods and antigenemia toward quantitative molecular diagnostics, including
PCR and hybrid capture assays.45, 46, 47 However, the issues related to the recovery
of CMV in BAL fluid in the absence of histopathologic evidence of CMV remain unresolved,
48
and investigations are ongoing to resolve this issue. Asymptomatic viral shedding
in the upper oropharynx by CMV is distinguished from active CMV disease in these definitions
and will assist in further assessing the role of CMV in CTTX. In early studies, the
recovery of CMV by viral culture in the absence of tissue diagnosis was considered
diagnostic of CMV pneumonitis.49, 50 However, further studies did not suggest that
CMV recovery from BAL was predictive of subsequent CMV pneumonitis.51, 52, 53, 54,
55 With the advent of sophisticated molecular diagnostics, the recovery of CMV from
BAL became more specific and reproducible compared with conventional or shell-vial
culture,
53
and additional studies suggested that CMV viral load in BAL fluid may be correlated
with invasive CMV pneumonia.2, 56, 57 However, the utility of CMV viral load in BAL
in predicting CMV pneumonitis remains uncertain in studies to date.
CMV diagnostic tools
•
Molecular diagnostics (from whole blood, plasma, BAL or tissue).
— Quantitative DNA PCR or hybrid capture assays.
— Qualitative PCR.
— Genotypic resistance testing.
•
Antigen pp65.
•
Viral culture (conventional or shell-vial centrifugation).
•
In situ immunohistochemistry.
•
Serology: not recommended for diagnosis.
Definitions for respiratory viral infections are given in Table 3a
and 3b.
Table 3a
Respiratory Viral Infection in CTTX
Infection
Signs/symptoms
Radiology
Virology
Respiratory viral infections (RVIs)
Asymptomatic RVI
None
No changes
Recovery of virus from nasopharynx or bronchoalveolar lavagea
Clinical RVI
Two or more of the following:
• Fever >38oC
• Rhinorrhea
• Nasal congestion
• Sore throat
• Sneezing
• Chills/rigors
• Myalgia
• Headache
AND exclusion of other etiology for symptoms including but not limited to recovery
of another pathogen or histopathology for acute rejection
Chest radiograph or CT scan not performed
Lack of confirmatory testing for respiratory viral pathogen (not performed or negative
assay)
Upper respiratory tract infection
As for clinical RVI
No evidence of lower respiratory tract Infection
Confirmation of a respiratory viral pathogen
Lower respiratory tract infection
Clinical symptoms (two or more of those listed above for URI) PLUSone or more of the
following symptoms of lower respiratory tract involvement:
• Cough
• Dyspnea
Physical findings (one or more of the following):
• Hypoxia (new onset or increasing)
• New or increased O2 requirement
• New crackles, rales or wheezing
Acute respiratory distress syndrome
New/worsening radiographic changes on chest X-ray or CT scan
Confirmation of a respiratory viral pathogen OR histopathologic evidence AND exclusion
of AR
a
Respiratory viral infection diagnostic tools: nucleic acid amplification (including
PCR methods); tissue (cell) culture, both conventional and rapid; culture (shell-vial/R-mix);
indirect and direct immunofluorescence antibody (IFA/DFA) tests; and enzyme immunoassays
(EIAs).
Table 3b
Cytomegalovirus (CMV) in CTTX
CMV infection
Without clinical symptoms
CMV detection in blood by viral culture, antigenemia or molecular diagnostics (DNA-based
assay)
CMV pneumonitis (proven)
Including but not limited to:
• Fever >38oC not attributable to extrapulmonary source
• Hypothermia( <36.5°C)
• Leucopenia (<4,000 WBC/mm3)
• Cough
• Dyspnea
• Hypoxia (new-onset or increasing)
• New or increased O2 requirement
New crackles, rales or wheezing
New/worsening radiographic changes on chest X-ray or CT scan
Detection of CMV in lung tissue by culture, immunohistochemistry or in situ molecular
diagnostics, with OR without CMV detection in blood or BAL by viral culture, antigenemia
or molecular diagnostics (DNA-based assay)
CMV pneumonitis (probable)
8
As in proven CMV pneumonitis
New/worsening radiographic changes on chest X-ray or CT scan
CMV detection in blood or BAL by viral culture, antigenemia or molecular diagnostics
(DNA-based assay)
CMV replication without clinical pneumonitis
Without clinical symptoms
No changes to chest X-ray or CT
CMV detection in BAL by viral culture, antigenemia or molecular diagnostics (DNA-based
assay)
Fungal infection overview
All fungal infections
CTTX recipients in general and lung transplant recipients in particular have the highest
risk of mold infection.
58
Recently published data suggest the cumulative incidence rate at 1 year to be 8%.58,
59 Among mold infections, the overwhelming majority of infections are due to Aspergillus
spp, followed by Scedopsorium spp and zygomycetes.
60
Despite the advancement in anti-fungal therapy, mortality remains at approximately
29% in Aspergillus infections.
60
Candida species was noted to be a major pathogen during the early CTTX period, although
it is rarely seen in lung transplant recipients in the current era.
61
Although the incidence of invasive candidiasis has remained low in lung transplant
recipients, this was the most common fungal infection noted in heart transplant recipients.
60
Respiratory fungal infections
Fungal infections in lung transplant recipients have certain characteristics that
make them unique compared with other SOT recipients as well as other immunocompromised
hosts. This includes the presence of certain risk factors, such as airway ischemia
and native lung or unique clinical syndromes, including tracheobronchitis, bronchial
anastomotic infection and colonization—syndromes observed only in lung transplant
recipients (Figure 2
).
62
Rejection syndromes in lung transplant recipients further complicate the clinical
presentation. Diagnosis of fungal infection based on histology alone may not be as
accurate due to the concomitant presence of acute or chronic rejection in these individuals.
24
Similarly, it is not only the unique clinical syndromes of fungal infection that set
them apart from the other immunocompromised hosts, but the diagnostic utility of non-invasive
testing also is different. Serum galactomannan has markedly lower sensitivity (30%)
in lung transplant recipients as compared with other immunocompromised hosts.63, 64
Similarly, the sensitivity of other serologic markers such as serum cryptococcal or
coccidiodal antigen, histoplasma urine antigen may be variable.65, 66, 67, 68 The
use of BAL for GM has resulted in sensitivities of >66% when a 0.58 or 0.66 optical
density (OD) index was used as a cutoff.69, 70 A higher cutoff (1.5 OD) yielded better
results in one study.
71
We suggest the use of BAL GM in the diagnosis of invasive aspergillosis (IA) in lung
transplant recipients. Similarly, fungal PCRs, especially from BAL specimens, are
more likely to be less sensitive for the diagnosis of disease than BAL specimens from
other immunocompromised hosts owing to colonization of the airways. Cell wall components
of fungi have also been used in the diagnosis of fungal infections. Currently available
β-glucan is non-specific and is negative in cases of cryptococcosis and zygomycosis.
72
In a recent study of lung transplant recipients, serum β-D-glucan sensitivity was
reported to be 93%, whereas specificity was merely 71%.
73
Figure 2
Common radiologic manifestations of proven invasive aspergillosis in lung transplant
recipients. (A) Fungal ball. (B) Solitary pulmonary nodule. (C) Cavitary lesion. (D)
Multiple consolidation.
The Mycoses Study Group (MSG) and the European Organization for Research and Treatment
(EORTC) recently updated the definitions of fungal infections in immunocompromised
hosts.
3
These definitions represent an excellent attempt to standardize the reporting of fungal
infections in studies. However, they fail to address the unique nature of clinical
syndromes in lung transplant recipients, particularly colonization, tracheobronchitis
and bronchial anastomotic infections.8, 74, 75 Also, the radiologic presentation of
invasive mycoses in cardiothoracic organ transplant recipients may not conform to
the classical “halo sign” presentation in neutropenic or stem cell transplant recipients
(Figure 2).
76
Moreover, the definitions do not account for the differences in the sensitivity of
serologic tests, particularly galactomannan in lung transplant recipients.69, 70,
77, 78 In addition, the category of possible fungal infection might not be applicable
in lung transplant recipients owing to a multitude of possible diagnoses in these
patients. The American Society of Transplantation (AST) also put forward a set of
definitions to be used in the study of these infections in SOT recipients.
1
The AST definitions do take into account some unique clinical syndromes in lung transplant
recipients but lack the detailed description of clinical syndromes. Reported studies
of fungal infections in lung transplant recipients used diverse definitions.14, 79,
80, 81, 82, 83 The following sets of definitions are proposed to standardize the reporting
of fungal infections, particularly mold and yeast (endemic mycoses, Candida spp and
Cryptococcus spp) infections in CTTX recipients, especially among general and lung
transplant recipients. The isolation of non-pathogenic molds or other non-pathogenic
fungi in BAL or sputum is not believed to satisfy the microbiologic criteria for the
diagnosis of probable invasive fungal infections in these patients without histologic
confirmation (Tables 4a
and 4b). However, these definitions of fungal infections do not address Pneumocystis
jiroveci infection, which has previously been adequately defined for use in CTTX.
1
Table 4a
Fungal Pneumonia in CTTX
Syndromea
Signs/symptoms
Radiology
Laboratory
Pneumonia
Proven:
Histology (biopsy showing histologic evidence of parenchymal invasion by fungal hyphae
or pseudohyphae) or positive culture from sterile tissue ALONE; OR with sign/symptoms
+ radiology + laboratory
Probable:
Sign/symptoms + radiology + laboratory + negative histology
At least one of the following:
• Fever >38°C OR hypothermia <36.5°C with no other recognized cause
• Leukopenia (<4,000 WBC/mm3) OR leukocytosis (≥12,000 WBC/mm3)
• New onset of purulent sputum OR
• Change in character OR quantity of sputum OR respiratory secretions suctioned
• New-onset or worsening cough, dyspnea, tachypnea, or pleural rub, rales or bronchial
breath sounds
• Worsening gas exchange (O2 desaturation, PaO2/FIO2 ≤240, increased oxygen requirements
or increased ventilation demand)
• Pleural effusion
Chest radiograph with:
• New or progressive and persistent infiltrate
• Consolidation
• Cavitation
• Nodules
OR CT scan with at least one of the followingb:
• New or progressive and persistent infiltrate
• Consolidation
• Cavitation
• Nodules
Single positive culture for mold BAL/bloodc
OR single positive PCR for mold BAL/blood OR positive galactomannan in the BAL; OR
at least TWO positive sputum cultures/PCRs of fungal organisms (excluding Candida
species)
a
In the absence of biopsy categorize as probable: In the presence of histologic findings
of both acute rejection and fungal invasion it should be classified as acute rejection
with proven fungal infection.
b
The presence of mosaic appearance and ground-glass opacity may represent development
of bronchiolitis obliterans syndrome or obliterative bronchiolitis.
c
Isolation of non-pathogenic molds in culture (e.g., Cladosporium spp, Phialemonium,
Chaetomium, Cunninghamella, Syncephalastrum, Curvularia, Dactylaria, Graphium or Phialophora)
or other non-pathogenic fungi [e.g., Penicillium (non-Marnefii), Paecilomyces or basidiomyctes]
do not qualify for the “probable” category. They should only be considered in the
“proven” category.
Table 4b
Fungal Tracheobronchitis in CTTX
Syndromea
Signs/symptoms
Radiology
Laboratory
Tracheobronchitis
Proven:
Histology (biopsy showing histologic evidence of invasion by fungal hyphae or pseudohyphae)
or positive culture from the sterile tissue ALONE; OR with sign/symptoms + radiology
+ laboratory
Probable:
Sign/symptoms + radiology + laboratory + negative histology
At least one of the following:
• New-onset of purulent sputum OR change In character OR quantity of sputum /respiratory
secretions suctioned
• New-onset or worsening cough, dyspnea, tachypnea or bronchial breath sounds
AND one or more endobronchial lesions (erythema, ulceration, necrosis and pseudomembrane
formation including at the site endobronchial stent) without an alternative diagnosis
and without evidence of invasive parenchymal disease (Figure 1c)
Chest radiograph without:
• New or progressive and persistent infiltrate
• Consolidation
• Cavitation
• Nodules
OR CT scan without:
• New or progressive and persistent infiltrate
• Consolidation
• Cavitation
• Nodules
Single positive culture for mold BALb
OR single positive PCR for mold BAL OR positive galactomannan in the BAL OR at least
TWO positive sputum cultures/PCRs of fungal organisms (excluding Candida species)
The presence of mosaic appearance and ground-glass opacity may represent development
of bronchiolitis obliterans syndrome or obliterative bronchiolitis.
a
In the absence of biopsy categorized as probable: In the presence of histologic findings
of both acute rejection and fungal invasion it should be classified as acute rejection
with proven fungal infection.
b
Isolation of non-pathogenic molds in culture (e.g., Cladosporium spp, Phialemonium,
Chaetomium, Cunninghamella, Syncephalastrum, Curvularia, Dactylaria, Graphium or Phialophora)
or other non-pathogenic fungi [e.g., Penicillium (non-Marnefii), Paecilomyces or basidiomyctes]
do not qualify for the “probable” category. They should only be considered in the
“proven” category.
Fungal infection diagnostic tools
•
Direct examination by light microscopy (gram, Giemsa and calcofluor stains).
•
Culture.
•
Histopathology: routine stains (hemotoxylin–eosin), special (Gomori methenamine silver,
mucicarmine, periodic acid–Schiff), direct immunofluorescence and in situ hybridization).
Histopathologic diagnosis is useful in establishing the diagnosis of endemic fungi
because of their distinctive morphology.
3
However, confusion may occur when attempting to differentiate the hyaline molds that
commonly cause invasive disease.
84
Fusarium spp and Scedosporium spp cannot be distinguished from Aspergillus spp in
tissue sections and even the zygomycetes, which are morphologically quite distinct
from Fusarium spp, Scedosporium spp and Aspergillus spp, have been confused with those
organisms. The two most commonly encountered yeasts in tissue section from cardiothoracic
transplant recipients, Cryptococcus spp and Candida spp, should be easily distinguished
in tissue because of the characteristic round shape of the former. Mucicarmine stain
of the capsular material of Cryptococus spp may further aid in its histopathologic
identification.
85
•
Nucleic acid amplification, including PCR methods and real-time-PCR (e.g., Myc assay
available for clinical specimens).
•
Enzyme immunoassay (EIA; cryptococcal antigen test, histoplasma antigen test and galactomannan).
•
Cell wall component (β-glucan test).
Definitions of fungal pneumonia, tracheobronchitis, bronchial anastomotic infection
and colonization in CTTX are given in Table 4a, Table 4b, Table 4c, Table 4d,
respectively.
Table 4c
Fungal Bronchial Anastomotic Infection in Lung Transplant Recipients
Syndromea
Signs/symptoms
Radiology
Laboratory
Bronchial anastomotic infection
Proven:
Histology (biopsy showing histologic evidence of invasion by fungal hyphae or pseudohyphae)
or positive culture from the sterile tissue ALONE; OR with sign/symptoms + radiology
+ laboratory
Probable:
Sign/symptoms + radiology + laboratory + negative histology
At least one of the following:
• New onset of purulent sputum OR change In character OR quantity of sputum OR respiratory
secretions suctioned
• New-onset or worsening cough, dyspnea, tachypnea, or bronchial breath sounds
AND endobronchial lesions restricted to the site of anastomosis without clinical or
histologic involvement of other parts of bronchial tree or lung parenchyma (Figure
1b)
Chest radiograph without:
• New or progressive and persistent infiltrate
• Consolidation
• Cavitation
• Nodules
OR CT scan without:
• New or progressive and persistent infiltrate
• Consolidation
• Cavitation
• Nodules
Single positive culture for mold in BAL OR single positive PCR for mold in BAL OR
positive galactomannan in the BAL OR at least TWO positive sputum cultures/PCRs of
fungal organisms (excluding Candida species)
a
In the absence of biopsy categorize as probable: In the presence of histologic findings
of both acute rejection and fungal invasion it should be classified as acute rejection
with proven fungal infection.
Table 4d
Fungal Colonization in CTTX
Syndrome
Signs/symptoms
Radiology
Laboratory
Colonization
ABSENCE of the following:
• Fever >38°C OR hypothermia <36.5°C with no other recognized cause
• New-onset of purulent sputum OR change In character OR quantity of sputum OR respiratory
secretions suctioned
• New-onset or worsening cough, dyspnea, tachypnea, or pleural rub, rales or bronchial
breath sounds
AND normal-appearing respiratory mucosa OR absence of endobronchial lesions including
the anastomotic site and without clinical or histologic evidence of invasive parenchymal
disease
Chest radiograph WITHOUT:
• New or progressive and persistent infiltrate
• Consolidation
• Cavitation
• Nodules
OR CT scan without:
• New or progressive and persistent infiltrate
• Consolidation
• Cavitation
• Nodules
Single positive culture for mold BAL/yeast OR single positive PCR for mold/yeast in
BAL OR positive galactomannan in the BAL OR at least TWO positive sputum cultures/PCRs
of fungal organisms (including Candida species)
Other infectious syndromes in cardiothoracic organ transplant recipients
Non–CTTX-specific infections, such as urinary tract infection (UTI), surgical site
infection (SSI), bloodstream infection (BSI), infective endocarditis (IE), Clostridium
difficile infection (CDI) and skin and soft tissue infections (SSTIs), are not included
herein.2, 86, 87, 88, 89, 90, 91, 92, 93, 94 The consensus opinion of the ISHLT ID
council encourages the use of previously published international definitions for these
infections, which have been well established outside of the CTTX population. The use
of these standard definitions will allow for intercenter comparisons of rates and
types of infections that should not be significantly impacted by the transplant.
Disclosure statement
Shahid Husain received grant from Pfizer, Astellas, Merck; Nina Singh received grant
from Pfizer; Michael Ison received grants, member of speaking bureau and advisory
board member for ADMA, Adamas, BioCryst, Chimerix, GlaxoSmithKlein, Roche, ViraCor,
Abbott, Abbott Molecular, Astellas, Biogen Idec; Atul Humar received grant, advisory
board member and consultant for Roche, Astellas; Andy Fisher received grant, advisory
board member and consultant for Medimmune, GSK, Chiesi, Boehringer Ingelheim; Kate
Gould member speaking bureau for Pfizer; Lianne G Singer received grants from Roche,
Pfizer, APT; Martha Mooney,Lara Danziger-Isakov, Frauke Mattner, Robin Avery, Robert
F. Padera, Leo Lawler, Richard Drew, Amparo Sole, Sean Studer, Patricia Munoz and
Margaret Hannan, nothing to disclose.